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Metabolic diseases

Introduction 1417
Production diseases 1418
Compton metabolic profile test 1418
Metabolic profiles for individual cows 1420
Parturient paresis (milk fever) 1420
Downer cow syndrome 1435
Acute hypokalemia in cattle 1440
Transit recumbency of ruminants 1441
Lactation tetany of mares (eclampsia, transit
tetany) 1441
Hypomagnesemic tetanies 1442
Hypomagnesemic tetany (lactation tetany,
grass tetany, grass staggers, Wheat pasture
poisoning) 1442
Hypomagnesemic tetany of calves 1450
Ketosis in ruminants (acetonemia in cattle,
pregnancy toxemia in sheep) 1452
Fatty liver in cattle (fat cow syndrome,
pregnancy toxemia in cattle) 1462
Equine hyperlipidemia 1466
Steatitis 1468
Neonatal hypoglycemia 1468
Postparturient hemoglobinuria in cattle 1471
Exertional rhabdomyolysis in horses (azoturia,
tying up, chronic intermittent
rhabdomyolysis)1472
Low milk fat syndrome 1474
Equine Cushing's disease (adenoma of the
pars intermedia of the pituitary) 1474
Introduction
Amongst domestic farm animals the metabolic diseases achieve their greatest importance in dairy cows
and pregnant ewes. In the other species these diseases occur only sporadically. The high-producing dairy
cow always verges on abnormal homeostasis,and the breeding and feeding of dairy cattle for high milk
yields is etiologically related to metabolic disease so common in these animals.
Periparturient period
In dairy cows,the incidence of metabolic diseases is highest in the period commencing at calving and
extending until the peak of lactation is reached, and their susceptibility appears to be related to the
extremely high turnover of fluids, salts and soluble organic materials during the early part of lactation.
With this rapid rate of exchange of water, sodium, calcium, magnesium, chlorides and phosphates, a
sudden variation in their excretion or secretion in the milk or by other routes, or a sudden variation in their
intake because of changes in ingestion, digestion or absorption, may cause abrupt, damaging changes in
the internal environment of the animal. It is the volume of the changes in intake and secretion and the
rapidity with which they can occur that affects the metabolic stability of the cow. In addition, if the
continued nutritional demands of pregnancy are exacerbated by an inadequate diet in the dry period, the
incidence of metabolic disease will increase. The effect of pregnancy is particularly important in ewes,
especially those carrying more than one lamb.
Disease of lactation
In the next phase of the production cycle, parturition is followed by the sudden onset of a profuse lactation
which, if the nutrient reserves have already been seriously depleted, may further reduce them to below
critical levels and clinical metabolic disease then occurs. The essential metabolite which is reduced below
the critical level determines the clinical syndrome which will occur. Most attention has been paid to
variations in balances of (1) calcium and inorganic phosphates relative to parturient paresis, (2)
magnesium relative to lactation tetany, (3) blood sugar and ketones and hepatic glycogen relative to
ketosis, and (4) potassium relative to hyperkalemia on cereal grazing, but it is probable that other
imbalances are important in the production of as yet unidentified syndromes.
During the succeeding period of lactation, particularly in cows on test schedules and under the strain of
producing large quantities of milk, there is often a variable food intake, especially when pasture is the sole
source of food, and instability of the internal environment inevitably follows. The period of early lactation
is an unstable one in all species. Hormonal stimulation at this stage is so strong that nutritional deficiency
often does not limit milk production and a serious drain on reserves of metabolites may occur.
Breed susceptibility
The fact that some dams are affected much more by these variations than others is probably explainable
on the basis of variations in internal metabolism and degree of milk production between species and
between individuals. Between groups of cows, variations in susceptibility appear to depend on either
genetic or management factors. Certainly Jersey cows are more susceptible to parturient paresis than cows
of other breeds, and Guernseys, in our experience, seem to be more susceptible to ketosis. Even within
breeds considerable variation is evident in susceptibility between families. Under these circumstances it
seems necessary to invoke genetic factors, at least as predisposing causes.
Management practices
Management practices of most importance are housing and nutrition. In those sections of North America
where cattle are housed during the winter, and in poor pasture areas,ketosis is prevalent. Inthe
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Channel Islands, local cattle are unaffected by lactation tetany whereas the disease is prevalent in the
United Kingdom. In New Zealand, metabolic diseases are complex and the incidence is high, both
probably related to the practice of having the cows calve in late winter when feed is poor, to the practice of
depending entirely on pasture for feed, and to the high proportion of Jerseys in the cattle population.
A knowledge of these various factors is essential before any reasonable scheme of prevention can be
undertaken. It should also indicate that although the more common disease entities are presented in this
chapter, there is high probability that a disturbance of more than one of the metabolites mentioned may
occur simultaneously in the one animal and give rise to complex syndromes which are not described here.
The disease entities dealt with must be considered as arbitrary points in a long scale of metabolic
disturbances.
Occurrence and incidence
Finally, only a knowledge of the etiological factors involved will help in understanding the incidence of
the various syndromes. Largely because of variations in climate, the occurrence of metabolic disease
varies from season to season and from year to year. In the same manner, variations in the types of disease
occur. For example in some seasons most cases of parturient paresis will be tetanic; in others, most cases
of ketosis will be complicated by hypocalcemia. Further, the incidence of metabolic disease and the
incidence of the different syndromes will vary from region to region. Ketosis may be common in areas of
low rainfall and on poor pasture. Lactation tetany may be common in colder areas and where natural
shelter is poor. Recognition of these factors can make it possible to devise a means whereby the incidence
of the diseases can be reduced.
The metabolic diseases, because of high prevalence and high mortality rate, are of major importance in
some countries, so much so that predictive systems are being set up. Rapid analysis of stored feed samples,
pasture and soil is commonly used in Europe and North America but the interesting development has been
the recognition of 'production diseases' and the consequent development of metabolic profile tests,
particularly in the United Kingdom and in Europe.
Production diseases
The term 'production disease' includes those diseases previously known as metabolic diseases', such as
parturient paresis (milk fever), hypomagnesemia, acetonemia and perhaps some other conditions, all of
which are attributable to an imbalance between the rates of 'input' of dietary nutrients and the 'output' of
production. When the imbalance is maintained, it may lead to a change in the amount of the body's
reserves of certain metabolites, or their 'throughput', and sufficiently large changes in throughput will give
rise to signs of production disease. The generalization applies principally to the hypoglycemias (ketosis)
and hypomagnesemias and partly to the hypocalcemias. In these diseases, output is greater than input
either because of the selection of cattle which produce so heavily that no naturally occurring diet can
maintain the cow in nutritional balance or because the diet is insufficient in nutrient density or unevenly
balanced. For example, a ration may contain sufficient protein for milk production but contains
insufficient precursors of glucose to replace the energy excreted in the milk. While agreeing with the
generalization on which the term 'production disease' is based, we propose to continue to use the
expression 'metabolic disease' because of common usage.
Because of the emphasis on health management beginning in the 1970s, it became popular to explore
methods of predicting the occurrence of metabolic disease in advance, so that control strategies could be
considered and put into place. It was thought possible to predict the occurrence of production disease in a
dairy7 herd by monitoring certain components of the blood on a regular basis. If the blood level fell below
'normal', it was assumed that intake needed to be increased to compensate for the negative balance created
by excessive output.
COMPTON METABOLIC PROFILE TEST
The Compton metabolic profile is based on the concept that the laboratory measurement of certain
components of the blood will reflect the nutritional status of the animal, with or without the presence of
clinical abnormalities. For example, a lower than normal mean blood glucose in a group of dairy cows in
early lactation may indicate an insufficient intake of energy which may or may not be detectable clinically.
On a theoretical basis, the ability of the laboratory to make an objective assessment of the input-output
(nutrient-productivity) relationships is an attractive tool for the veterinarian engaged in providing a
complete health management service to a herd. The test would theoretically be able to detect the
qualitative and quantitative adequacy of the diet of cows expected to produce a certain quantity of milk or
return to estrus within a desirable length of time following parturition. A reliable test for the early
diagnosis of nutritional deficiency or metabolic disease would be a major step forward in attempting to
optimize livestock production and obtain maximum yields at minimum costs. There was considerable
interest in the test following its earlier descriptions which stimulated considerable field research. The
results of the research have thus far indicated that the test may be useful only as an aid in the diagnosis of
nutritional imbalance and production diseases. The results of the test are usually difficult to interpret
without a careful conventional assessment of the nutritional status and reproductive performance of the
herd and it appears doubtful that the test would reveal significant abnormalities which could not be
detected using conventional clinical methods. There was considerable controversy about the practicality of
the test. The test must be carefully planned and is expensive. A regional diagnostic laboratory with
automated analytical equipment should be available and this is often a major limiting factor. The test
should not be undertaken unless normal values for each laboratory measurement are available from the
population within the area. The results from the groups within the herd are compared with local population
means. Metabolic profiles have also been suggested as an aid in the selection of superior individuals.
Test procedure
Blood samples are collected from three groups of seven cows each:
1.Dry cows
2.Medium-yield lactating cows
3.High-yield lactating cows.
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The samples are collected at least three times yearly: summer, autumn and winter or when nutritional
imbalance is suspected. The samples must be collected at the same time of day at each collection and
should be done with a minimum of excitement of the cows. An aliquot of 5 mL of blood is placed in vials
containing oxalate-fluoride for glucose and serum inorganic phosphorus, and 20-30 mL in heparinized
vials for the determination of the other components. The samples must be dispatched to the laboratory
within a few hours and must not be subjected to delays in delivery or to heat or cold. Ideally the samples
should be handled similarly each time. In some cases, urine samples are collected from each test lactating
cow and tested for the presence of urinary ketones, and the results correlated with the blood glucose levels
of each cow.
The following laboratory analyses have been carried out in the Compton metabolic profile test:
•Blood glucose
•Packed cell volume
•Hemoglobin
•Blood urea nitrogen
•Seruminorganicphosphate,magnesium, calcium, potassium and sodium
•Total serumprotein,albuminand globulins (calculated by difference)
•Other analytes
•Serum copper
•Serum iron
•Plasma non-esterified free fatty acids.
A miniprofile test which measures levels of blood glucose, serum urea nitrogen and albumin in cows
between 4 and 10 weeks after calving has been recommended as a sufficient test to assess the adequacy of
energy and protein intakes. The sampling is done at intervals of 4-6 weeks. The time of sampling can
affect the results. The values will change with the season and stage of lactation. In general, sampling
should be done when nutritional imbalance and/or the occurrence of metabolic diseases are anticipated,
which is usually during early lactation as cows approach their peak in the lactation curve. In regions or
situations where subclinical metabolic disease may be predictable based on previous experience (for
example, seasonal hypo-magnesemia in pregnant beef cattle), the sampling should be done before the
probable occurrence of the disease.
At the time of sampling, the following supplementary information should be collected:
1.Relating to the individual animals sampled:
•Age
•Exact milk yield and mastitis status
•Date of calving
•Weight of concentrate fed per day (on an average basis in the case of loose housing or the exact amount
fed in the milking parlor).
2.Relating to the whole herd:
•Estimates of the average daily for age intakes
•Analyses of forages and grains
•Total herd production and number of cows in milk
•Most recent bulk milk quality data
•Individual daily yield of six cows past their peak on three consecutive occasions (this is used to calculate
the rate of decline).
Interpretation of results and causes of variations
The interpretation of the results can be difficult. In dairy cattle the major objective is to demonstrate the
interrelationships between the components of the:
1.blood
2.nutrition
3.productivity
4.fertility.
The mean values for each lactational group of cows for each parameter are calculated and compared with
the population mean values which have been predetermined by survey. Most of the values of individual
cows and the mean values of the lactational groups will fall within the normal ranges for the population.
The difficulty has been in deciding when an individual value is abnormal, low normal or high normal
compared to the population mean and 'normal' ranges. Animals whose values are 2 SD (standard deviation)
or more different from the population means are considered abnormal. The percentage of abnormals
determines whether the herd or area is to be classified as an abnormal group. However, the threshold
percentage has not been determined.
The results should be presented in the form of histograms on graph paper indicating the individual cow
levels and for comparison the population means. It is important to present the results to the farmer in a
form in which the data can be easily recognized and compared. Scatter diagrams with values plotted from
all cows are also useful.
One of the major difficulties with the Compton metabolic profile test has been in identifying the
common causes of variation. The most consistent variation occurs between herds and next between
lactational groups within herds.
There are significant fluctuations in the blood composition of dairy cows associated with the interaction
between the effects of season, milk yield and stage of lactation. Urea and hemoglobin, together with
packed cell volume, have consistently been found to increase during the summer months in both lactating
and non-lactating cows. In addition, values for hemoglobin and packed cell volume have been found to be
inversely related to current milk yield in both summer and winter while magnesium concentrations show a
reverse trend: lower in non-lactating than in lactating cows, particularly in winter.
Protein intake and serum urea
There is a direct relationship between protein intake and the concentration of blood urea nitrogen. Low
concentrations of urea indicate that protein intake is minimal and an early warning that 'low protein status'
may develop in lactating cows later if protein intake is not increased. Low levels of albumin and
hemoglobin are indicative of a longstanding low-protein status. Mean values of packed cell volume (PCV),
hemoglobin and serum iron are consistently higher in non-lactating cows than in lactating cows. Individual
animals also possess different patterns of blood chemistry which may change with age. Globulin and total
protein concentrations increase with age, and concentration of inorganic phosphate, albumin, magnesium,
sodium and urea decrease with increasing age. These individual patterns exist even in the varied
environment of a dairy herd and in spite of changes in the concentrations with season, pregnancy and stage
of lactation, and tend to be more similar in related than unrelated animals.
Serum inorganic phosphorus
Serum inorganic phosphate levels tend to fall following long-term insufficient dietaryintake,and
hyperphosphatemia
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may occur in cattle grazing on highly fertilized pasture.
Serum calcium
Serum calcium levels vary only within narrow limits and are not sensitive indicators of input-output
balance. However, abnormally low levels in late pregnancy indicate a dangerous situation.
Serum magnesium
Serum magnesium levels are usually low during the winter months and subclinical hypomagnesemia exists
in many herds, especially pregnant beef cattle. This can be converted into clinical hypomagnesemia with a
sudden deprivation of feed or a sudden fall in environmental temperature. Supplementation of the diet with
magnesium salts is protective.
Serum sodium
Low levels of serum sodium occur in early lactation in cows grazing on summer pastures without
supplementation with salt. Levels down to 135 mmol/L may be associated with depraved appetite, and
polydipsia and polyuria.
Serum potassium
Serum potassium levels have been difficult to interpret because the levels of the electrolyte in serum are
not necessarily indicative of potassium deficiency. Its normal serum concentration is much more variable
than sodium and its average concentration in roughages of all kinds is nearly always in
excessofrequirements; any abnormalities are usually in the direction of excess.
Blood glucose
Blood glucose concentrations are usually lower m early lactation and during the winter months; in early
lactation there is a heavy demand for glucose and during the winter the energy intake is likely to be lower
than necessary to meet requirements. One major cause of variation in blood glucose may be the major
fluctuations in daily feed intake. Investigations of feed intake of dairy cows on commercial farms have
shown that concentrate dispensers are commonly incorrectly adjusted and errors of more than 50% in feed
intake are sometimes found. In situations of marginal energy imbalance, blood glucose concentration
levels may be unreliable as an index of the adequacy of energy intake.Severalfactors may cause short-term
changes in blood glucose. Blood glucose decreases at the time of milk secretion, which makes sampling
time critical. Blood glucose may also be influenced by the chemical nature of the carbohydrate and
physical form of the feed and the roughage content of the feed. In addition, elevation of blood glucose has
been associated with excitement and low environmental temperature.
There is some conflicting evidence about the relationship between mean values of blood glucose of a
lactational group and insufficient energy intake and reproductive inefficiency. In some work, there is an
expected relationship between low blood glucose and an increased incidence of ketosis. In others, the
relationship is not clear however there was a more consistent relationship between the actual energy intake
as a percentage of requirement and the plasma non-esteri-fied fatty acids, but this finding was not
sufficiently reliable to be useful. The mean plasma glucose concentrations within 3 days before or after
first service of cows which conceived on first service was higher than that of cows which returned, but the
difference was only approaching significance at the 5% level and it is doubtful whether this could be of
practical value. Although free fatty acids are more sensitive than blood glucose as an indicator of energy
status of the lactating cow, the excessive variability of this relationship during early lactation limits its
usefulness. Free fatty acids begin to increase several weeks prepartum, peak at parturition, and decrease
gradually to normal levels after several weeks of lactation. Blood glucose levels follow a similar pattern;
however, there may be a period in early lactation when blood metabolite levels, and particularly free tatty
acids, are not entirely responsive to energy intake, but arc perhaps under additional hormonal regulation.
Nutrition and reproductive performance
One excellent investigation of the relationship of selected blood components to nutrition and fertility of
dairy cows under commercial farm conditions concluded that within the nutritional ranges encountered,
the levels of selected blood components did not show a consistent relationship to nutrient balance or
potential fertility. The metabolic profile test is more appropriately regarded as an aid to the conventional
approach involving the examination of feeding systems and feedstuffs, herd records, management and
clinical condition. The test is probably useful for diagnosis and prognosis in extreme variations from
normalcy. Management procedures should not become unduly dependent on the metabolic profile concept
for the evaluation of energy status in early lactation.
METABOLIC PROFILES FOR INDIVIDUAL COWS
The prediction of whether an individual cow is metabolically within normal range to undergo a stressful
lactation at a high level of production would seem to be a useful undertaking. This could be particularly
important under management conditions of heavy concentrate feeding, lead feeding or zero grazing or
even indoor housing. There are no well-established protocols for conducting such profile tests. The
'parturition syndrome', dealt with later under the 'fat cow syndrome' is considered to be predictable by the
estimation of blood levels of total cholesterol and glutamic oxalate transaminase. In pastured cattle in New
Zealand the test has been found to be ineffective. Similar tests conducted on individual cows using many
serum enzymes and electrolytes as indicators have not proved to be useful if used on only one occasion.
REVIEW LITERATURE
Payne. J. M., Hibbitt, K. G. & Sansom, B. F. (1972) Production disease in farm animals. London: Bailliere
Tindall.
PARTURIENT PARESIS (MILK FEVER)
A disease of cattle, sheep and goats occurring around the time of parturition and caused by hypocalcemia
and characterized by weakness, recumbency and ultimately shock and death.
Synopsis
Etiology. Hypocalcemia just before or after parturition.
Epidemiology. Adult dairy cows in third parity and older; 4-9% with low case fatality. Most commonly
within 48 h after calving but also occurs several weeks before or after. Occurs in beef cattle in
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epidemics. Occurs in sheep and goats in epidemics usually following stressors. Prepartum diets high in
calcium.
Signs. Three progressively worse stages including the following signs
•Anorexia
•Ruminal atony
•Scant feces
•Inactivity
•General muscular weakness leading to sternal recumbency with lateral kink of neck
•Circulatory collapse with collapsed veins and weak pulse
•Dry muzzle
•Mental depression
•Hypothermia
•Weak heart sounds
•Dilated and sluggish pupils
•Ruminal stasis and bloat
•Lateral recumbency
•Tachycardia
•Death in few to several hours.
Clinical pathology. Hypocalcemia, hypophosphatemia, variable serum magnesium. Increased creatine
phosphokinase (CPK) and aminotransferase (AST) due to ischemic muscle necrosis.
Lesions. No specific lesions. Ischemic muscle necrosis of large muscles of pelvic limbs because of
prolonged recumbency.
Differential diagnosis list: Cattle: Metabolic and nutritional disease:
•Hypophosphatemia (p. 1537)
•Hypomagnesemia (pp. 1442, 1510)
•Downer cow syndrome (p. 1435)
•Fat cow syndrome (p. 1462)
•Carbohydrate engorgement (p. 284).
Toxemias:
•Peracute coliform mastitis (p. 639)
•Aspiration pneumonia (p. 450)
•Acute diffuse peritonitis (p. 251).
Injuries to pelvis and pelvic limbs:
•Maternal obstetrical paralysis (p. 1427)
•Dislocation of coxofemoral joint.
Sheep and goats:
•Pregnancy toxemia (p. 1452)
•Enterotoxemia (pp. 769, 770).
Diagnostic confirmation. Hypocalcemia and response to treatment with calcium borogluconate.
Treatment. Calcium borogluconate IV.
Calcium chloride in oral gel.
Control. Dietary management to reduce prepartum intake of calcium. Calcium gel oral dosing before
calving, at calving, and 12 and 24 h after calving. Parenteral vitamin D and analogs.
ETIOLOGY
A depression of the levels of ionized calcium in tissue fluids is the basic biochemical defect in milk fever.
A transient period of hypocalcemia occurs at the onset of lactation caused by an imbalance between
calcium output in the colostrum and influx of calcium to the extracellular pool from intestine and bone.
The onset of lactation results in a sudden large demand on the calcium homeostasis. A cow producing 10
kg of colostrum (2.3 g of Ca/kg) will lose 23 g of calcium in a single milking. This is about nine times as
much calcium as that present in the entire plasma calcium pool of the cow (1). Calcium lost from the
plasma pool must be replaced by increasing intestinal absorp¬tion and bone resorption of calcium. During
the dry period, calcium requirements are minimal at about 10-12 g/d. At parturition, the cow must
mobilize about 30 g or more of calcium into the calcium pool per day. Hypocalcemia occurs in spite of
apparently adequate function of the parathyroid and vitamin D endocrine system and most cows adapt
within 48 h after calving by increases in plasma concentrations of parathyroid hormone and 1,25-(OH)2 D
vitamin at the onset of the hypocalcemia and mobilize calcium by increasing intestinal absorption and
bone resorption.
About 5--20% of adult cows are unable to maintain plasma calcium and consequently develop severe
hypocalcemia or clinical milk fever which requires treatment (2).
EPIDEMIOLOGY
Occurrence
Cattle
The disease occurs most commonly in high-producing adult lactating dairy cattle. Lactating beef cows are
affected but less commonly.
AGE Mature dairy cows are most commonly affected in the 5-10-year age group, although rare cases have
been observed at the first and second calvings. The hypocalcemia at calving is also age related and most
marked in cows at their 3rd to 7th parturition; it is infrequent at the first parturition.
BREED There are differences in susceptibility between the breeds. Jerseys are most susceptible, an
incidence of 33% was observed in a sample compared with 9.6% incidence in other breeds. In a data set of
61-124 Finnish Ayrshire lactations, cows in higher producing herds were at increased risk of milk fever
and ketosis (3). The disease in beef cattle breeds occurs either in individual cows or in herd outbreaks (4).
INDIVIDUAL cows Individual cows, and to some extent families of cows, are more susceptible than
others; the disease tends to recur at successive parturitions. The hcritability of susceptibility to milk fever
and hypocalcemia has been assessed as insignificant; in several breeds examined it was of the order of
6-12%. Complete milking in the first 48 h after calving, as opposed to normal sucking by a calf, appears to
be a precipitating factor.
TIME OF OCCURRENCE in Cattle,milk fever occurs at three main stages in the lactation cycle. Most
prepartum cases occur in the last few days of pregnancy and during parturition but rare cases occur several
weeks before calving. Some cases will occur a few hours before parturition or at the time of parturition
when the attendant expects the cow to calve and the second stage of parturition does not occur because of
uterine inertia due to hypocalcemia. Most cases occur within the first 48 h after calving and the danger
period extends up to about the 10th post-partum day. Up to 20% of cases can occur subsequent to the 8th
day after calving. In such cases the declines in serum calcium and phosphorus levels are smaller and the
increases in serum magnesium levels are greater than in parturient cows. The clinical signs are also less
severe and there are fewer relapses after treatment. Occasional cases occur 6 8 weeks after parturition
(mid-lactation). Such cases are most often recurrences of the disease in highly susceptible cows which
were affected at calving. Undue fatigue and excitement may precipitate such attacks and there is a special
susceptibility at estrus. In the latter case, the depression of appetite by the elevation of blood estrogen
levels may be a significant factor.
STRESSORS Starvation for 48 h also causes severe depression of serum calcium levels and this may be of
importance in the production of hypocalcemic paresis in this species at times other than in the
postparturient period. Pregnant beef cattle may develop hypocalcemic paresis during the winter months
when they are
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fed on poor-quality roughage; within a group of such cows the less aggressive ones may suffer selective
malnutrition. The disease has also been recorded in beef cows affected with diarrhea of undetermined
etiology (5). As another explanation of the heightened susceptibility of cows at estrus, a possible
depression of the degree of ionization of calcium under the influence of increased serum estrogens is
suggested. However, there were no significant differences in total serum calcium or plasma ionized
calcium values in cows from 48 h before and after estrus.
Subclinical hypocalcemia occurs in dairy cattle during the first few weeks of lactation. Up to 50% of
aged cows may be unable to maintain plasma calcium above the lower normal limit (2.18 mmol/L) as
defined by the 99% confidence interval of plasma calcium concentrations in cows outside the first month
of lactation. The plasma levels of phosphorus also decrease and the plasma levels of magnesium increase
as occurs in cows at the time of parturition. Hypocalcemic episodes lasting 1-2 d may occur two or three
times with a periodicity of about 9 d. These cows are referred to as 'calcium cyclers' and the magnitude of
the cycling was increased by feeding cows 200 g/d of 1,25-dihydroxyvitamin D for 5 d around the time of
parturition. Fluctuations in the intestinal absorption of calcium during this period may be the cause of
calcium cycling. Subclinical hypocalcemia is of major significance because it inhibits reticulorumen
motility, which affects appetite and exacerbates the negative energy balance already existing in the cow in
first month of lactation.
Episodes of subclinical hypocalcemia occur in up to 50% of adult cows during the first few weeks of
lactation. It is suggested that these calcium cyclers are animals whose calcium homeostatic mechanisms
have not adapted well enough.
Hypocalcemic syndromes in ruminants are also observed at times other than related to parturition. Thus,
it can be part of an early or mild overeating of fermentable carbohydrate. The IV administration of certain
aminoglycosides, especially neoniycm, dihydrostrepto-mycin and gentamicin, may cause a reduction in
the degree of ionization of serum calcium and a syndrome similar to milk fever. Oral dosing with zinc
oxide (40 or 120 mg Zn/kg BW) as a prophylaxis against facial eczema in ewes causes a serious fall in
serum calcium levels 24 h later. Caution is recommended with the use of these drugs in parturient cows.
Sheep and goats
In sheep, the disease commonly occurs in outbreaks in groups of ewes exposed to forced exercise,
long-distance transport, sudden deprivation of food, and grazing on oxalate-containing plants or green
cereal crops. These circumstances commonly precipitate outbreaks of hypocalcemic paresis in sheep,
mature ewes are the most susceptible, particularly in the period from 6 weeks before to 10 weeks after
lambing. Up to 25% of the flock maybe affected at one time. The disease also occurs in young sheep up to
about 1 year old, especially when they graze green oats, but also when pasture is short in winter and spring,
as in southeast Australia. The disease is manifested by paresis but in the rest of the flock poor growth,
lameness and bone fragility can be detected. A sudden deprivation of feed or forced exercise of ewes can
cause marked depression of the serum calcium levels. However, ewes are in a susceptible state in early
lactation because they are in negative calcium balance. In late lactation a state of positive balance is due to
a low rate of bone resorption. There is an unexplained occurrence of hypocalcemia in sheep fed on hay
when they are supplemented with an energy-rich concentrate which increases their calcium intake. Some
of the concentrates fed to ewes in feedlots contain supplementary magnesium as a prevention against
hypomagnesemia, which may affect calcium absorption and precipitate hypocalcemia in susceptible ewes.
Another occurrence in ewes is at the end of a drought when the pasture growth is lush and very low in
calcium content. The incidence may be as high as 10% and the case-fatality rate 20% in ewe flocks in late
pregnancy or early lactation.
In goats, a depression in serum levels of calcium and phosphorus occurs similar to that in cows but in
ewes no such depression occurs at lambing and the intervention of a precipitating factor appears to be
necessary to further reduce the serum calcium level below a critical point.
Milking goats become affected mostly during the 4-6-year age group. Cases occur before and after
kidding, some later than 3 weeks after parturition. Clinical syndromes are identical to those in cows,
including the two stages of ataxia and recumbency. Serum calcium levels are reduced from normal levels
for partunent does of 9.4-3.6 mg/dL (2.35-0.9 mmol/L).
Morbidity and case fatality
Annual morbidity rates of 3.5 and 8.8% of susceptible adult cows have been recorded. The incidence has
increased in the last three decades coincident with an increase in milk production. In Australia, about 3.5%
of cows are at risk and in Finnish Ayrshires, the rate is 3.8% (6). Generally the disease is sporadic but on
individual farms the incidence may rarely reach 25-30% of high-risk cows. With early treatment relatively
few deaths occur in uncomplicated cases but incidental losses due to aspiration pneumonia, mastitis and
limb injuries may occur. From 75-85% of uncomplicated cases respond to calcium therapy alone. A
proportion of these animals require more than one treatment, either because complete recovery is delayed,
or because relapse occurs. The remaining 15-25% are either complicated by other conditions or incorrectly
diagnosed.
Risk factors
Major risk factors include:
1.Increasing age of cow
2.High-producing dairy cattle
3.Dry period nutrition
4.Housing.
Animal risk factors
Serum calcium levels decline in all adult cows at calving due to the onset of lactation. Serum calcium
levels decline to lower levels in some cows than in others and it is this difference which results in the
varying susceptibility of animals to parturient paresis. First-calf heifers rarely develop milk fever because
while some degree of hypocalcemia occurs during the first few days of lactation, they are able to adapt
rapidly to the high demands of calcium for lactation. With increasing age, this adaptation process is
decreased and results in moderate-to-severe hypocalcemia in most adult cows. The adaptation mechanism
is directly related to the efficiency of intestinal absorption of calcium, which decreases with increasing age.
CALCIUM HOMEOSTASIS
Three factors affect calcium homeostasis and variations
1423
in one or more of them may be important in causing the disease in any individual:
1.Excessive loss of calcium in the colostrum beyond the capacity of absorption from the intestines and
mobilization from the bones to replace.
Variations in susceptibility between cows could be due to variations in the concentration of calcium in the
milk and the volume of milk secreted
2.Impairment of absorption of calcium from the intestine at parturition
3.Mobilization of calcium from storage in the skeleton may not be sufficiently rapid to maintain normal
serum levels. The calcium mobilization rate and the immediately available calcium reserves are
sufficiently reduced incows in later pregnancy to render them incapable of withstanding theexpected loss
of calcium in the milk. In older cows, bone resorption makes only a minor contribution to the total rate of
calcium mobilization at parturition and is therefore of minor importance for the prevention of
periparturient hypocalcemia. Osteoblasts are the only type of bone cell to express the 1,25-(OH)2 D
receptor protein, and the decrease in the numbers of osteoblasts with increasing age could delay the ability
of bone to contribute calcium to the plasma calcium pool (1).
It was once postulated that failure to secrete sufficient levels of parathyroid hormone or
1,25-dihydroxyvitainin D was the primary defect in cows which developed milk fever. While it is accepted
that the calcium homeostatic mecha¬nisms, regulated by parathyroid hormone and 1,25-dihydroxyvitamin
D, fail to maintain normal blood calcium concentrations resulting in severe hypocalcemia, the nature of the
endocrine defect is not well understood. It was also once thought that calcitonin, a hormone which inhibits
bone calcium resorption was a cause of milk fever but this has not been demonstrated in cows with milk
fever (1). Recent studies have shown that the secretion of parathyroid hormone and the production of
1,25-dihydroxyvitamin D is similar in most cows with or without milk fever (1). However, about 20% of
cows treated for parturient paresis experience relapsing episodes of hypocalcemia which require further
treatment. These cows fail to produce adequate levels of 1,25-dihydroxyvitamin D at the onset of lactation
(7). Both relapsing and non-relapsing cows develop the same degree of hypocalcemia and secondary
hyper-parathyroidism, but production of 1,25-dihydroxyvitamin D is about two-fold greater in
non-relapsing cows than relapsing cows. Following treatment of parturient hypocalcemia with calcium
salts IV and restoration of rumenal and intestinal motility, non-relapsing cows establish calcium
homeostasis over the next 3-4 d by increasing intestinal absorption of calcium which is activated by a
sufficient level of 1,25-dihydroxyvitamin D. In relapsing cows, even when rumen and intestinal motility
are restored after treatment, hypocalcemia and paresis are likely to occur because of insufficient plasma
1,25-dihydroxyvitamin D. These cows may-remain in this stage of prolonged hypocalcemia for several
days, and only after a few days and several repeated treatments with calcium will the plasma levels of
1,25-dihydroxyvitamin D increase to an adequate level to maintain calcium homeostasis. It is also unlikely
that the parathyroid hormone-related protein in the colostrum of milk fever cows is involved in the disease
(8).
Tissue 1,25-dihydroxyvitamin D receptor concentrations decline with age, which renders older cows
less able to respond to 1,25-dihydroxyvitamin D (1). The intestinal 1,25-(OH)2 D receptor numbers decline
with age in the cow and thus the older cow is less able to respond to the hormone and will take longer to
adapt intestinal calcium absorption mechanisms to meet lactational demands for calcium (9).
A perplexing situation in dairy practice is the recently calved cow with peracute coliform mastitis which
may also be mildly hypocalcemic and have some of the clinical signs of milk fever. The Escherichia coli
endotoxin given IV depresses serum calcium and phosphate levels so that coliform mastitis may contribute
to a degree of hypocalcemia in individual cows. However, there is no evidence that cows with peracute
coliform mastitis require calcium therapy similar to that used in typical milk fever.
Dietary and environmental risk factors
Several dietary factors of the pregnant cow during the prepartum period (last 4 weeks) can influence the
incidence of milk fever in cattle.
DIETARY CALCIUM Feeding more than 100 g of calcium daily during the dry period is associated with
an increased incidence of milk fever (10). A 500 kg cow requires only about 31 g of calcium to meet daily
maintenance and fetal demands in late gestation. When a cow is fed a high calcium diet (>100 g Ca/d), its
daily requirement for calcium can be met almost entirely by passive absorption of dietary calcium. The
active transport of calcium from the diet and bone calcium resorption mechanisms are homeostati-cally
depressed and become quiescent. As a consequence, at calving, the cow is unable to use bone calcium
stores or intestinal calcium absorption mechanisms and is susceptible to severe hypocalcemia until these
mechanisms can be activated, which may take several days. In a survey of dairy herds in France, the
incidence of milk fever was higher in herds which had a higher dietary calcium in the mineral supplement
during the total dry period and by longer feeding of soybean meal to dry cows (11). Alkaline diets
containing an excessive concentration of sodium and potassium can result in an increased incidence of the
disease.
Feeding prepartum diets containing a low concentration of calcium prevents milk fever by activating
calcium transport mechanisms in the intestine and bone prior to parturition, thus allowing the animal to
adapt more rapidly to the lactational drain of calcium. Feeding diets high in calcium just before parturition
may also lower the incidence of milk fever by increasing the absorption of calcium. This will provide
sufficient calcium to overcome the relative lack of calcium from bone resorption which results from a high
calcium intake (12).
In sheep, hypocalcemia may occur in pregnant ewes fed a calcium-deficient diet over a prolonged period.
A high dietary level of magnesium in late pregnancy may also predispose to hypocalcemia in pregnant
ewes but this has not been documented. Ewes fed a diet with a fixed cation excess (82.3 mEq/100 g DM)
had higher urine pH and lower urine calcium concentrations, lower blood ionized calcium concentrations
after an overnight fast, and tended to develop hypocalcemia more rapidly after an ethylenediamine
tetra-acetatc (NaEDTA) infusion (13). This suggests that a dietary fixed cation-anion balance may be a
risk factor for hypocalcemia in pregnant ewes.
1424
DIETARY PHOSPHORUS Prepartum diets high in phosphorus (>80 g of P/d) also increases the
incidence of milk fever and the severity of hypocalcemia (1). High dietary levels of phosphorus increase
the serum level of phosphorus which is inhibitory to the renal enzymes that catalyze production of
1,25-(OH)2 D, which when decreased reduce the intestinal calcium absorption mechanisms prepartum.
ANION-CATION DIETARY BALANCE The anion-cation dietary balance exerts a strong, linear effect
on the incidence of milk fever. Recent studies indicate that the anion-ation balance (ACB) in the
prepartum diet may be more important than the level of dietary calcium as a risk factor for milk fever.
Prepartum diets high in cations such as sodium and potassium are associated with an increased incidence
of milk fever, while diets high in anions, especially chloride and sulfur, are associated with a decrease in
the incidence of the disease. Most forages such as legumes and grasses are high in potassium and are
alkaline. The high anion content of acidic diets tends to induce a metabolic acidosis which facilitates bone
resorption of calcium.
A meta-analysis of 75 feeding trials designed to study the nutritional risk factors for milk fever in dairy
cattle found that the prepartuni dietary concentrations of S and dietary anion-cation balance
[(Na+K)-(Cl+S)] were the two nutritional factors most strongly correlated to the incidence of milk fever
(12). Dietary S acts as a strong anion and reduces the risk of milk fever and increasing the dietary S
concentrations lowers the odds ratio of developing milk fever. Increasing dietary Na and crude protein
increased the odds ratios, but to lesser extent.
Because sodium is a strong cation, it increases the risk of milk fever. The incidence of milk fever has
been decreased by the addition of chloride and sulfur in excess relative to sodium and potassium in the
prepartum diet of Holstein cows. High anion diets increase the plasma levels of 1,25-(OH)2 D prior to
parturition, activating intestinal calcium absorption and possibly bone calcium resorption mechanisms
prior to onset of lactation (14).
The mechanism of the positive effect of crude protein on incidence of milk fever is uncertain. Crude
fiber was also significantly correlated to the incidence of milk fever. Other dietary electrolytes such as K
and Cl were not associated with milk fever.
ECONOMIC IMPORTANCE
Compared to many years ago, the economic losses from milk fever have decreased because calcium
borogluconate is an effective treatment which many owners can administer. Significant costs are
associated with veterinary intervention and losses due to complications. However, while veterinarians now
treat fewer cases of uncomplicated milk fever, there may be an increase in cases which are complicated by
factors other than hypocalcemia. There is a highly significant relationship between milk fever and dystocia,
retained fetal membranes, ketosis and mastitis. Cows which recover from milk fever are more likely to
develop ketosis and mastitis compared to those which do not have milk fever. Milk fever in dairy cattle is
a risk factor for several reproductive diseases such as dystocia, retained placenta, metritis and uterine
prolapse (15). Some studies have found that milk fever directly increased the likelihood of developing
hypomagnesemia, abomasal disease and ketosis (3). Dairy cows with hypocalcemia at parturtion had a
4.8-times greater risk of developing a left-sided displacement of the abomasum than cows with normal
levels of serum calcium (16). The overall net effect is that j an incident of milk fever potentially reduces
the mean productive life of a dairy cow by about 3 years.
PATHOGENESIS
Hypocalcemia
Hypocalcemia is the cause of the signs of typical'milk fever'.Atonyof skeletalmuscle and plain muscle are
well-knownphysiologicaleffects ofhypocalcemia. Hypophosphatemia and variations in levels of serum
magnesium also occur and have secondary roles.In experimental hypocalcemia in cattle, there is:
•A marked reduction in the stroke volume and cardiac output
•A50%reductioninarterialblood pressure
•A reduction in ruminal and abomasal tone and motility.
There is some conflicting evidence about the effects of hypocalcemia on abomasal motility (17). If these
changes occur in naturally occurring cases they would account for the muscle weakness, hypothermia and
depression of consciousness. In calves infused with NaEDTA, the systemic arterial pressure and amplitude
of ruminal contractions are severely decreased (18).
Experimental hypocalcemia
In experimental hypocalcemia in sheep, blood flow is reduced by about 60% to all tissues except kidney,
heart, lung and bladder in which the reduction is not as high (19). During periods of prolonged
hypocalcemia in cows and ewes, blood flow to skeletal muscles and the alimentary tract may be reduced to
60--70% of normal for a long period and predispose to the downer cow syndrome (20). In both cows and
sheep there is a significant increase in PO2 causing an impairment of oxygen uptake by the pulmonary
blood flow and an impairment of peripheral tissue uptake of oxygen during hypocalcemia in cows and
sheep. Serum calcium and serum phosphate levels are significantly lower in clinical cases than in normal,
comparable cows and there is some relationship between the severity of the signs and the degree of
biochemical change. The complete response to the parenteral administration of calcium salts in most cases,
and the occurrence of tetany coincident with hypocalcemia after the IV administration of NaEDTA is
further evidence of the importance of hypocalcemia. In addition, some signs indicative of
parathyroprivical tetany in other species are observed in the initial stages of milk fever:
•Early excitement
•Muscle twitching
•Tetany, particularly of the hindlimbs
•Hypersensitivity and convulsive movements of the head and limbs.
The IV infusion of EDTA into cows over a period of 4-8 h results in severe hypocalcemia and paresis
which is a reliable model for the reproduction of the disease. In the experimental disease, there are
additional signs such as excessive salivation, excessive lip and tongue actions and tail lifting (21). The
serum muscle enzyme levels of creatine phosphokinase (CPK) and aminotransferase (AST) increase due to
muscle injury associated with prolonged recumbency. Blood glucose
1425
levels increase, and serum phosphorus and potassium levels decrease. A prolongation of the ST interval of
the electrocardiogram (ECG) occurs, which may be useful as a diagnostic aid if suitable mini-ECG
recorders could be made available for field use.
The prolonged infusion of EDTA in sheep over 18 h at a rate to induce hypocalcemia and maintain
recumbency resulted in prolonged periods of recumbency ranging from 36 -64 h before the animals were
able to stand (10). There are also decreases in plasma sodium, plasma potassium and erythrocyte
potassium and prolonged increases in packed cell volumes, which suggests that fluid replacement therapy
may be indicated in cattle with prolonged recumbency associated with hypocalcemia (22). A 4-hour IV
infusion of EDTA in high erythrocyte potassium and low erythrocyte potassium dairy cows causes
decreases in plasma inorganic phosphorus and plasma potassium which are still below normal 24 h later
(23). The AST(SGOT), CPK, and packed cell volumes (PCVs) and white blood cell (WBC) counts are
also elevated 24 h later.Plasma magnesium and erythrocyte sodium and potassium were decreased but tins
action was delayed. The increase in PCV was most pronounced in the low erythrocyte potassium cows,
which may provide some clues about the pathogenesis of the downer cow syndrome. Some cows may have
a more precipitate increase in PCVs due to loss of plasma volume and an inability to mobilize calcium. A
200 mL solution of 10 g of sodium chloride and 0.5 g of potassium chloride can be given IV to sheep
safely over a period of 4-8 min to study the effects of administering such hypertonic solutions in downer
animals (23).
Peripartunent hypocalcemia may also result in some degree of impaired immune cell function but this
effect is not well understood (24). A decline m concentrations of plasma zinc is more severe in cows with
milk fever compared to parturient cows without milk fever but the significance is uncertain (25).
Hypocalcemia in late pregnant ewes could induce neonatal hyperthyroidism, hypomsuhne-mia and
metabolic alterations in their progeny (26).
Hypomagnesemia
When hypomagnesemia coexists with hypocalcemia the clinical signs continue but with normal or higher
than normal levels, relaxation, muscle weakness, depression and coma supervene. It is likely that the
hypocalcemic tetany is overcome by the relative hypermagnesemia (the ratio of Ca:Mg may change from
6:1 to 2:1) approximating the ratio at which magnesium narcosis develops. There is normally a rise in
serum magnesium levels at calving but in those cases of parturient paresis in which tetany is a feature
serum magnesium levels are low. These low levels are in many cases expressions of a seasonal
hypomagnesemia.
Hypophosphatemia
Low serum phosphorus levels occur in milk fever and contribute to the clinical signs. Some cases of milk
fever may not respond to calcium injections even though the serum calcium levels return to normal but
may appear to recover when the udder is inflated and serum phosphorus levels rise. Field observations
indicate sodium acid phosphate given orally or IV may result in recovery of cases not responding initially
to calcium salts. However, it is difficult to reconcile the biochemical and clinical findings with low serum
phosphorus levels because of the absence of recumbency in other animals with profound
hypophosphatemia for long periods. A possible explanation is that the hypophosphatemia which occurs in
milk fever is secondary to the hypocalcemia and recumbency rather than being a concurrent event. I here
is experimental evidence to support this and it also seems probable that the hypophosphatemia could
prolong the duration of recumbency.
CLINICAL FINDINGS
Cattle
Three stages of milk fever in cattle are commonly recognized and described.
Stage 1
In the first stage the cow is still standing. This is also the brief stage of excitement and tetany with
hypersensitivity and muscle tremor of the head and limbs. The animal is disinclined to move and does not
eat. There may be a slight shaking of the head, protrusion of the tongue and grinding of the teeth. The
rectal temperature is usually normal to slightly above normal. Stiffness of the hindlegs is apparent, the
animal is ataxic and falls easily and, on going down, the hindlegs are stuck out stiffly.
Careful observations by owners and veterinarians have revealed an even earlier stage than the first one. It
is characterized by anorexia, agalactia, rumen stasis, scant feces and a normal temperature, heart rate and
respirations. There are no obvious signs of excitement and hypersensitivity characteristic of the first stage.
Affected cows may remain in this prodromal stage for several hours; they are perplexing diagnostically
and respond quickly to calcium therapy. Cows with this form of hypocalcemia may be the 'calcium
cyclers' described earlier.
Stage 2
The second stage is prolonged sternal recumbency. Consciousness is usually depressed; the cow has a
drowsy appearance in sternal recumbency, usually with a lateral kink in the neck or the head turned into
the flank. When approached, some of these cows will open their mouths, extend their head and neck and
protrude their tongues, which may be an expression ot apprehension and fear in an animal unable to stand.
The tetany of the limbs present in the first stage is not present and the cow is unable to stand. The muzzle
is dry. the skin and extremities cool, and the rectal temperature subnormal (36-38℃, 97-101℉). There is a
marked decrease in the absolute intensity of the heart sounds and an increase in rate (about 80 bpm). The
arterial pulse is weak and the venous pressure is also low, making it difficult to raise the jugular veins. The
respirations are not markedly affected, although a mild forced expiratory grunt or groan is sometimes
audible.
The eyes are usually dry and staring. The pupillary light reflex is incomplete or absent and the diameter
of the pupil varies from normal to maximum dilatation. A detailed examination of the pupils of cows with
parturient paresis, non-paretic disorders and non-parturient paresis found that the mean sizes of the pupils
were not significantly different from one another (27). Rather, disparity of the size of the pupils was
common. Ruminal sta¬sis and secondary bloat are common and constipation is characteristic. There is also
relaxation of the anus and loss of the anal reflex.
In cows which develop hypocalcemia a few hours before or at the time of parturition,
1426
the second stage of parturition may be delayed, which is unexpected in a mature cow. Examination of the
reproductive tract usually reveals a fully dilated cervix and normal presentation of the fetus. The cow may
be in any stage of milk fever, and administration of calcium borogluconate IV will usually result in a rapid
beneficial response and normal parturition.
Prolapse of the uterus is a common complication of milk fever and often the calcium levels are lower
than in parturient cows without uterine prolapse. Thus it is standard practice to treat cases of uterine
prolapse with calcium salts IV.
Stage 3
The third stage is lateral recumbency. The cow is almost comatose and although the limbs may be stuck
out there is complete flaccidity on passive movement and the cow cannot assume sternal recumbency on
its own. In general, the depression of temperature and the cardiovascular system are more marked. The
heart sounds are almost inaudible and the rate increased to up to 120 bpm; the pulse is almost impalpable
and it may be impossible to raise the jugular veins. Bloat is usual because of lateral recumbency. Without
treatment, a few animals remain unchanged for several hours but most become progressively worse
during .a period of several hours and dye quietly from shock in a state of complete collapse.
CONCURRENT HYPOMAGNESEMIA. Mild to moderate tetany and hyperesthesia persisting beyond
the first stage suggests a concurrent hypomagnesemia. There is excitement and fibnllary twitching of the
eyelids, and tetanic convulsions are readily precipitated by sound or touch. Trismus may be present. The
heart and respiratory rates are increased and the he,in sounds are much louder than normal. Without
treatment death occurs during a convulsion.
CONCURRENT HYPOFHOSPHATEM1A.
With a concurrent hypophosphatemia, the clinical findings are typical of milk fever which responds to
calcium therapy in all respects except that the cow is unable to stand after treatment.
Sheep and goats
The disease in pastured ewes is similar to that in cattle. The early signs include a Stilty, proppygait
andtremorof the shoulder muscles. Recumbency follows, sometimes with tetany of the limbs but the
proportion of ewes with hypocalcemia which are recumbent in the early stages is much less than in cattle.
A similar generalization applies to female goats. The characteristic posture is sternal recumbency, with the
legs under the body or stretched out behind. Ruminal movements are absent, the head is rested on the
ground, there may be an accumulation of mucus exudate in the nostrils and the respiratory rate is increased.
The venous blood pressure is low and the pulse impalpable. Mental depression is evidenced by a drowsy
appearance and depression of the cornea reflex. Constipation is usual. Response to parenteral treatment
with calcium salts is rapid, the ewe is normal 30 min after a SC injection. Death often occurs within 6-12 h
if treatment is not administered. The syndrome is usually more severe in pregnant than in lactating ewes,
possibly because of the simultaneous occurrence of pregnancy toxemia or hypomagnesemia. Fat late
pregnant ewes on high grain diets indoors or in feedlots ; show a similar syndrome accompanied by
prolapses of the vagina and intestine.
Swine
As in cattle, signs develop within a few hours of farrowing. There is restlessness, a normal temperature
and anorexia followed by inability to rise and later lateral recumbency and coma. Milk How is decreased.
CLINICAL PATHOLOGY
Total serum calcium levels are reduced tobelow 8 mg/dL (2.0 mmol/L), usually to below 5 mg (1.2
mmol/L) and sometimes toas low as 2 mg (0.5 mmol/L).The reduction is usually, but not always,
proportional to theseverity of the clinical syndrome. Average figures for total serum calcium levels in
thethreespeciesare cows5.2+1.2 mg/dL(1.30+0.30 mmol/L), ewes 4.6+1.5 mg/dL (1.15+0.37
mmol/L),goatdoes 3.8+0.6mg/dL (0.94+0.15 mmol/L).
Total serum calcium levels are a basis for comparison between species. Blood levels of ionized calcium
are a better indicator of calcium status but their estimation has been too difficult until recently. Although
total serum calcium levels are used to express the animals' status with regard to calcium, it is possible that
differences between the ionized and non-ionized compartments of total calcium may be more important
than the total level. The development of a reliable calcium ion-selective electrode now makes it possible
quickly and directly to determine the biologically active portion of calcium in plasma or serum (28).
However, the correlation between ionized and total calcium is excellent (29). Equine, bovine, and ovine
blood may be stored for up to 48 h without any clinically relevant alteration of blood calcium ion
concentration (30).
Normal levels of ionized calcium (as CaF) in venous whole blood of cows are 4.3-5.1 mg/dL(1.06-1.26
mmol/L) serum, slight hypocalcemia 4.2-3.2 mg/dL (1.05-0.80 mmol/L), moderate 3.2-2.0 mg/dL
(0.79-0.50 mmol/L) and severe hypocalcemia <2.0 mg/dL (<0.50 mmol/L) serum. Total serum calcium
levels are reduced below normal in all cows at calving whether they have milk fever or not, but not in
ewes.
Serum magnesium levels are usually moderately elevated to 4-5 mg/dL (1.65 -2.06 mmol/L) but in
some areas low levels may be encountered, especially in cows at pasture.
Serum inorganic phosphorus levels are usually depressed to 1.5-3.0 mg/dL (0.48-0.97 mmol/L).
Blood glucose levels arc usually normal, although they may be depressed if ketosis occurs concurrently.
Higher than normal blood glucose levels are likely to occur in cases of long duration and arc therefore an
indication of a poorer than normal prognosis.
Serum muscle enzymes
Prolonged recumbency results in ischemic muscle necrosis and increases in the serum muscle enzymes
creatine phos-phokmase (CPK) and aspartate amino-transferase (AST) or SCOT. During prolonged
recumbency following treatment for milk fever, the levels of CPK will remain elevated if muscle necrosis
is progressive in animals which arc not rolled from side to side every few hours to reduce the effects of
compression on the large muscle groups of the pelvic limbs (see downer cow syndrome (p. 1435)).
Hemogram
Changes in the leukocyte count include an eosmopenia, a neutrophilia and a lymphopenia suggestive of
adrenal cortical hyperactivity, but similar changes occur at calving in cows which donot develop
1427
parturient paresis. High plasma cortisol levels (12) and packed cell volumes occur in cows with milk fever,
and are higher still in cows that do not respond to treatment. They are expressions of stress and
dehydration. Clinicopathological findings in the other species are not described in detail except with
regard to depression of total serum calcium levels.
NECROPSY FINDINGS
There are no gross or histological changes unless concurrent disease is present.
DIFFERENTIAL DIAGNOSIS
A diagnosis of milk fever is based on the occurrence of paresis and depression of consciousness in animals
following parturition. The diagnosis is supported by a favorable response to treatment with parenteral
injections of calcium solutions, and by biochemical examination of the blood. In ewes, the history usually
contains some reference to recent physical stress and the disease is more common in the period preceding
lambing.
In the immediate postpartum period, there are several diseases which cause recumbency in cows and
their differentiation is summarized in Table 28.1.
Several diseases which occur at the time of parturition must be differentiated from milk fever in cattle.
These are grouped here according to:
1.Other metabolic diseases
2.Diseases associated with toxemia and shock
3.Injuries to the pelvis and pelvic limbs
4.Degenerative myopathy
5.Downer cow syndrome.
Table 28.1 Differential diagnosis of common causes of recumbency in parturient adult cattle
Disease Epidemiology Clinical signs Clinical pathology Response to
treatment
Milk fever Mature cows, Early excitement Hypocakemia, less Rapid,
(parturient within 48 h of and tetany, then than 5 characteristic
paresis) calving, some depression, coma, mg/dl(1.25mmol/l) response
in mid-lactation hypothermia, calcium. High (muscle tremor,
flaccidity, pupil serum magnesium, sweating on
dilatation, weak over 3 mg/dL (1.25 muzzle,
heart sounds. No mmol/l), low defecation,
rumen movements. inorganic urination, pulse
Heart rate increases phosphate, less amplitude and
and worsens than 3 mg/dL (0.9 heart sound
mmol/l) intensity
improves first)
after IV
injection
soluble calcium
salt
Hypomagnesemia All classes of Excitement, Low serum Even after IV
(lactation, grass cattle, but most hypersensitivity, magnesium, less injection,
tetany) recently calved muscle tremor, than 1.2 mg/dL response in a
cows. Age no tetany. Recumbent (0.5 mmol/l) severe case may
barrier and with tetanic take 30 min,
cases occur up convulsions, loud much slower
to several heart sounds, rapid than response to
months after rate. Subacute calcium in milk
calving. May cases remain fever
occur in standing
pregnant beef
cattle
Severe toxemia Sporadic only. Recumbency, Profound Require
(acute diffuse Mastitis most depression to leukopenia. Serum supportive
peritonitis, common where coma, sleepy, dry calcium may be as response for
coliform mastitis) hygiene poor. nose, hypothermia, low as 7-8 mg/dL toxemia and
Peritonitis due gut stasis, HR over (1.75-2.0 mmol/l). shock.
to foreign body 100 bpm, may be Examine milk Response is
perforation of grunting. Examine (CMT) poor and
reticulum, mammary gland. temporary.
rupture of Examine abdomen Prognosis very
uterus or vagina for abdominal bad. May die if
disease treated IV with
calcium or
magnesium
salts

Maternal Prolonged Bright, alert, eat, Normal. CPK may Nil to clinical
obstetrical difficult drink, defecate, try become high if treatments.
paralysis (MOP) calving. Heifers to rise and cannot much muscle Need slinging
and young cows quite make it or do damage by hip sling or
or large calves splits. TRP and nursing on deep
delivered with rumen movements straw with
excessive normal frequent
traction movement. If
not recovered
by third day,
prognosis may
be unfavorable
Fat cow Fat dairy or Excessive body Evidence of Will recover if
syndrome beef cows in condition, hepatic disease cows begin to
late gestation or anorexia, apathy, eat. Treat with
at parturition. depression, fluids, glucose,
Some recumbency and insulin. Provide
predisposing looks like milk good quality
cause fever, scant soft palatable
precipitates feces, ketonuria roughage
illness in fat
animals
Downer cow Most common Moderately bright Variable. May be Variable
syndrome in situation active, eating. low inorganic response to
where milk Temperature phosphate, or calcium,
fever and slightly raised, HR potassium, or phosphorus and
lactation tetany 80-100 bpm. glucose. Ketonuria, potassium salts.
common and Unable to stand but usually proteinuria. Fluid therapy
intensity of tries -'creepers'. CPK and AST and provision
treatment is lax When dull and elevated of deep bedding
cows are left depressed, are and hourly
down too long 'non-alert downers'. rolling from
before Long course 1-2 side to side are
treatment weeks necessary

Physical injuries Ruptured As for MOP with Increased CPK and Supportive
gastrocnemius, ruptured SGOT therapy, deep
dislocation of gastrocnemius, bedding and
hip, etc. hock remains on frequent rolling
Sporadic ground when
sequelae to standing. Excessive
milk fever, may lateral mobility of
be contributed limb with hip
to by dislocation
osteoporosis,
slippery ground
surface,
stimulating to
rise too early
Acute Postpartum Recumbent, weak, Lower potassium, Potassium
hypokalemia cows treated faccid, unable to below 2.3m Eq Chloride IV and
with hold head off oral
soflupredone ground. Cardiac
arrhythmia
1428
Metabolic diseases
Hypomagnesemia may occur as the sole cause of recumbency or it may accompany a primary
hypocalcemia so that the case presented is one of parturient paresis complicated by lactation tetany.
Hyperesthesia, tetany, tachycardia and convulsions are common instead of the typical findings of
depression and paresis in milk fever.
Hypophosphatemia, which commonly accompanies milk fever, is suggested as a cause of continued
recumbency in cows after partial response to calcium therapy; serum inorganic phosphorus levels are low
and return to normal if the cow stands or following treatment with phosphate salts. A sudden onset of
recumbency in dairy cows associated with a marginal deficiency of phosphorus has been reported (31).
Hypokalemia in dairy cows is characterized by extreme weakness or recumbency, especially after
treatment for ketosis with isoflupredone (32). Hypokalemia is marked as ranging from 1.4 to 2.3 mEq/L.
The case-fatality rate is high in spite of therapy with potassium. Hypokalemic myopathy is present at
necropsy.
Ketosis may complicate milk fever, in which case the animal responds to calcium therapy by standing
but continues to manifest the clinical signs of ketosis, including in some cases the nervous signs of licking,
circling and abnormal voice.
Diseases associated with toxemia and shock
During the immediate postparturientperiod, several diseases occur commonly and are characterized by
toxemia.
Peracute coliform mastitis is characterized by:
•Fever initially followed by hypothermia
•Tachycardia
•Dehydration
•Weakness and recumbency
•Depression
•Ruminal stasis
•Diarrhea in some
•Enlarged mammary gland(s) with watery and serous-like secretions with
small particles barely visible.
Aspiration pneumonia secondary to regurgitation and aspiration of rumen contents may occur as a
complication of third-stage milk fever. Fever, dyspnea, expiratory grunt, severe depression and anxiety are
common. Auscultation of the lungs reveals the presence of abnormal lung sounds. Aspiration pneumonia
should be suspected if the animal has been lying on its side, especially if there is evidence of regurgitation
of ruminal contents from the nostrils, no matter how small the amount, or if there is a history of the animal
having been drenched. Abnormal auscultatory findings may not be detectable until the second day. Early
diagnosis is imperative if the animal is to be saved and the mortality rate is always high.
Acute diffuse peritonitis resulting from traumatic perforation of the reticulum or uterus is characterized
by:
•Severe depression
•Fever
•Weakness and recumbency
•Ruminal stasis
•Dehydration
•Grunting or groaning with each respiration
•Tachycardia
•Fluid splashing sounds on ballottement of the abdomen (paralytic ileus).
Carbohydrate engorgement results in:
•Depression
•Weakness
•Sternal recumbency
•Dehydration
•Tachycardia
•Ruminal stasis and moderate bloat
•Fluid-splashing sounds over rumen
•Low rumen juice pH
•Diarrhea
•Hypothermia
•Cool extremities
•Progressive worsening if not treated.
Many cases resemble second-stage milk fever.
Toxemic septic metritis occurs most commonly within a few days after parturition and is characterized
by:
•Depression
•Anorexia
•Fever
•Tachycardia (100-120 bpm)
•Ruminal stasis
•Presence of foul-smelling uterine discharge found on vaginal examination.
The fetal placenta may be retained. Some affected cows are weak and prefer recumbency, which
resembles milk fever. Prolapse and rupture of uterus causes varying degrees of:
•Shock with tachycardia
•Flypothermia and cool extremities
•Weakness and recumbency
•Rapid death.
A history of difficult parturition or assisted dystocia with fetotomy may be associated with rupture of
the uterus. The administration of calcium salts may cause ventricular fibrillation and sudden death.
Although some elevation of the temperature may be observed in these severe toxemic states, it is more
usual to find a subnormal temperature. The response to calcium therapy is usually a marked increase in
heart rate, and death during the injection is common. Every case of recumbency must be carefully
examined as these conditions may occur either independently or as complications of parturient paresis. In
our experience, about 25% of cases of postparturient recumbency in cows are due primarily to toxemia or
injury rather than to hypocalcemia.
Injuries to the pelvis and pelvic limbs
Injuries to the pelvis and pelvic limbs are common at parturition because of the marked relaxation of the
ligaments of the pelvic girdle. Seven types of leg abnormality have been described in this group at an
incidence level of 8.5% in 400 consecutive cases of parturient paresis (33). The abnormalities included
radial paralysis, dislocation of the hips and rupture of gastrocnennus muscle. In most instances the affected
animals are down and unable to stand but they eat, drink, urinate and defecate normally, have a normal
temperature and heart rate and make strong efforts to stand, particularly with the forelimbs.
Maternal obstetrical paralysis is the most common injury. Although this occurs most frequently in
heifers after a difficult parturition, it may also occur in adult animals following an easy birth, and
occasionally before parturition, especially in cows in poor body condition. The mildest form is evidenced
by a frequent kicking movement of a hindleg as though something was stuck between the claws. All
degrees of severity from this, through knuckling and weakness of one or both
1429
hindlegs, to complete inability to rise may occur, but sensation in the affected limb is usually normal.
There is traumatic injury to the pelvic nerves during passage of the calf. There are often gross
hemorrhages, both deep and superficial, and histopathological degeneration of the sciatic nerves. In
individual animals, injury to the obturator nerves is common and results in defective adduction of the
hindlimbs. The position ot the hindlimbs may be normal but in severe cases, especially those with
extensive hematoma along the sciatic nerve trunk, the leg may be held extended with the toe reaching the
elbow as in dislocation of the hip; however in the latter case there is exaggerated lateral mobility of the
limb. Additional injuries causing recumbency near parturition include those associated with degenerative
myopathy, dislocation of the hip and ventral hernia.
Dislocation ot the coxofemoral joint can cause recumbency and inability to stand in some cows, while
others can stand and move around (34). Recumbent cows are usually in sternal recumbency and the
affected limb is abducted excessively. In standing cows, the affected limb is usually extended, often
difficult to flex and often rotated about its long axis. The diagnostic criteria are:
1.Sudden onset of lameness with the affected limb extended and possibly rotated
2.Displacement of the greater trochanter of the femur from its normal position relative to the ischiatic
tuber and coxal tuber of the pelvis
3.Ability to abduct the limb manually beyond its normal range
4.CrepitUS in the hip on abduction and rotation of the limb
5.Ability to palpate the femoral head per rectum or per vaginum against the cra nial border of the ilium or
pubis in cases of cranioventral dislocation, or in the obturatorforamenincasesof caudoventral dislocation.
Manual replacement by closed reduction is successful in 80% of craniodorsal dislocation and 65% in
caudodorsal dislocation. The ability to stand before reduction is the most useful prognostic aid (35).
Degenerative myopathy (ischemic muscle necrosis)
Degenerative myopathy affecting primarily the large muscles of the thighs, occurs commonly in cattle
which have been recumbent for more than several hours. At necropsy, large masses of pale muscle are
present surrounded by muscle of normal color. Clinically it is indistinguishable from sciatic nerve
paralysis. Markedly increased serum levels of CPK occur in cows recumbent for several hours following
the initial episode of milk fever due to ischemic necrosis. Persistent elevation of CPK indicates
progressive ischemic muscle necrosis due to continued compression of large muscle masses of the pelvic
limbs. Rupture of the gastrocneniius muscle or separation of its tendon from either the muscle or the tuber
calcis may also cause myopathy.
Downer cow syndrome
Downer cow syndrome is a common sequel to milk fever in which the cow was in sternal recumbency for
several hours before being treated with calcium. Following treatment, most of the clinical findings
associated with milk fever resolved except the animal was unable to stand. Clinically the animal may be
normal except for recumbency and will commonly recover and stand normally within several hours or a
few days. Most downer cows eat and drink normally, their vital signs are within the normal range, and
their alimentary tract function is normal. However. some are anorexic, may not drink, exhibit bizzare
movements of lying in lateral recumbency and dorsally extend their head and neck frequently, moan and
groan frequently, assume a frog-legged posture with their pelvic limbs and crawl or creep around the stall,
and may die or are euthanized for humane reasons in a few days. The diagnostic dilemma with these cows
is that they resemble milk lever and whether or not to treat them with additional amounts of calcium salts
is questionable.
Non-parturient hypocalcemia
Paresis with mental depression and associated with low total scrum calcium levels can occur in cows at
times other than at parturition. The cause is largely unexplained but the syndrome occurs rarely in animals
other than ruminants. Hypocalcemia may occur after gorging on gram and may be a significant factor in
particular cases. Sudden rumen stasis due to traumatic reticulitis may rarely cause hypocalcemic paresis.
Diarrhea, particularly when cattle or sheep are placed onnew lush pasture, may also precipitate an attack.
Access to plants rich in oxalates may have a similar effect, particularly if the animals are unaccustomed to
the plants. Affected animals respond well to calcium therapy but relapse is likely unless the primary cause
is corrected. The differential diagnosis of diseases of non-parturient cows manifested principally by
recumbency is also summarized in Table 28.1.
Hypocalcemic paresis in sheep and goats
Hypocalcemia in sheep must be differentiated from pregnancy toxemia in which the course is much longer,
the signs indicate cerebral involvement and the disease is restricted to pregnant ewes. There is no response
to calcium therapy and a positive test for ketonuria is almost diagnostic of the disease. At parturition, goats
are susceptible to enterotoxemia and hypo-glycemia (rarely), both of which present clinical signs similar to
parturient paresis.
Hypocalcemia in sows
Hypocalcemia is rare in sows. The disease must be differentiated from the mastitis, metritis, and agalactia
complex, which is characterized by:
•lever
•Agalactia
•Anorexia
•Toxemia
•Enlarged mammary glands.
Treatment
Every effort should be made to treat affected cows as soon as possible after clinical signs are obvious.
Treatment during the first stage of the disease, before the cow is recumbent, is the ideal situation. The
longer the interval between the time the cow first becomes recumbent and treatment, the greater the
incidence of the downer cow syndrome due to ischemic muscle necrosis from prolonged recumbency.
Complications of milk fever occur when cows have been in sternal recumbency for more than 4 h. Farmers
must be educated to appreciate the importance of early treatment. Cows found in lateral recumbency (third
stage) should be placed in sternal recumbency until treatment is available. This will reduce the chances of
aspiration if the cow regurgitates. Cows that have difficulty
1430
finding solid, non-slip footing beneath them, for example, a slippery barn floor or slippery mud, will often
not try to stand and may develop ischemic myonecrosis. Avoidance of this complication necessitates the
placement of rubber or other mats under the cow or transportation of the cow to a piece of pasture with a
dense sward on it. A temperature of greater than 39℃(102℉) is an indication of a higher than average
mortality rate due to pre-existing complications.
Standard treatment
Calcium borogluconate at 100 -200 g is the treatment of choice. The solutions available vary from 18-40%
calcium borogluconate. Most cows with milk fever can be treated successfully with 8-10 g of calcium
(calcium borogluconate is 8.3% calcium). For cattle, 400-800 mlof a 25% solution is the usual dose. The
dose rate of calcium is frequently under discussion (25). There is a general tendency for veterinarians to
underdose with calcium salts, largely because of toxic effects which tend to occur when all of the calcium
is given intravenously. As an initial dose a large cow (540-590 kg) requires 800-1000 ml of a 25% solution
and a small cow (320-360 kg) 400-500 ml.. Underdosing increases the chances of incomplete response,
with inability of the cow to rise, or of relapse. In general, 12 g of calcium is superior to 8 g, whichin turn is
superior to 6 g.
In sheep and goats, the recommended amount is 15-20 g IV with an optional 5-10 g SC. Sows should
receive 100-150 mL of a similar solution IV or SC.
Routes of administration
IV and SC routes
The intravenous route is preferred because the response is rapid and obvious. The heart should be
auscultated throughout the intravenous administration for evidence of gross arrhythmia, bradycardia and
tachycardia. If any of these occurs, the intravenous administration should be interrupted and continued
only after the heart sounds return to normal. If the cardiac irregularity continues, the remainder of the
solution can be given subcutaneously. The best recommendation is to give as much of the solution as
possible intravenously and the remainder subcutaneously. The common practice of giving half the does
intravenously and half subcutaneously is a reasonable compromise because with this method there are
fewer relapses. If a cow has been previously treated subcutaneously by the farmer, additional calcium
given intravenously may cause toxicity if the improved circulation enhances the absorption of the
subcutaneous calcium.
SC route
The SC route is commonly used by farmers who treat affected cows at the first sign of hypocalcemia,
preferably during the first stage when the cow is still standing or as prophylaxis to all high-risk cows
immediately after calving. The SC route has also been used by veterinarians when the effects of IV
administration of calcium are uncertain or if an unusual response occurs during IV administration. There
are limitations to the effectiveness of SC calcium solutions given to cows with milk fever (36). Cows
given 300 mL of 33.3% or 40% calcium borogluconate SC had serum calcium levels of 1.4 mmol/L; those
receiving 600 mL had serum calcium levels of 2.1 mmol/L, at mean intervals of 4.8 and 12.0 h between
treatment by the herdman and veterinary attention (36). At the time of sampling, 48% of cows receiving
600 mL of calcium borogluconate had a serum calcium level below 2.0 mmol/L. If the veterinarian is
unable to treat the cow within 1 hour, a dose of 600 ml. of 40% calcium borogluconate should be given SC
in two sites and massaged well to promote absorption. Waiting for more than 1 hour to assess the effect of
one treatment SC is regarded as conducive to development of the downer cow syndrome. The cow should
then be placed in a dry area with her limbs positioned to minimize ischemic necrosis and covered with
straw and tarpaulins until the veterinarian arrives.
Toxemic cows are very susceptible to the IV administration of calcium borogluconate and death may
occur. In such cases the heart rate increases markedly (up to 160 bpm), there is respiratory distress,
trembling and collapse and the cow dies within a few minutes. SC or IP administration is preferred in cows
with severe toxemia due to aspiration pneumonia, metritis and mastitis.
Oral route
A further aid to parenteral therapy with solutions of calcium salts, especially for the purpose of increasing
recovery rates andpreventing relapses, is the oral administration of gels containing calcium chloride, which
are described under prevention.
Typical response to calcium borogluconate
Cows with milk fever exhibit a typical pattern of response to calcium borogconate IV if the response is
favorable, including:
•Belching
•Muscletremor,particularlyofthe flanksandoftenextending tothe whole body
•Slowingandimprovementin the amplitude and pressures of the pulse
•Increase in the intensity of the heart sounds
•Sweating of the muzzle
•Defecation.
The feces arc in the form of a firm fecal ball with a firm crust and covered with mucus, occasionally
with a few flecks of blood. Urination usually does not follow until the cow stands. A slight transitory
tetany of the limbs may also be observed. Many cows will eat and drink within minutes following
successful treatment if offered feed and water.
The rate of response to treatment is affected by many factors as set out below and it is unwise to quote
what might be expected as an acceptable rate of recovery after treatment. This is particularly true if cows
are treated by the farmer, and only difficult cases are presented to the veterinarian. In general, if all cases
are considered and there are no exceptional circumstances, recovery can be expected immediately after
treatment in about 60% of cases and in a further 15% after 2h -10% have recoveries complicated by one of
the diseases discussed earlier and 15% can be expected either to die or to require disposal. Of those which
recover after one treatment, 25-30% can be expected to relapse and require further treatment.
Unfavorable response to calcium borogluconate
An unfavorable response is characterized by a marked increase in heart rate in cows affected with toxemia
and acute heart block in apparently normal animals especially with overdosage, with too rapid injection
and in cases in which treatment has been unduly prolonged. In the latter,
1431
the maximum tolerated dose of calcium borogluconate by IV administration is about 250 mL of a 25%
solution. Overdosage may occur when farmers treat cases unsuccessfully by multiple SC injections and
these are followed by an IV dose. When the peripheral circulation is poor, it is probable that the calcium
administered SC is not absorbed until the circulation improves following the IV injection, and the large
doses of calcium then absorbed cause acute toxicity. In all cases of IV injection, the circulation must be
monitored closely. Some degree of arrhythmia occurs in most cases but if there is gross arrhythmia or a
sudden increase in heart rate, the injection should be stopped temporarily or continued with great caution.
In normal circumstances at least l0 min should be taken to administer the standard dose. The acute toxic
effect of calcium salts seems to be exerted specifically on heart muscle with a great variety of defects
occurring in cardiac action; the defect type depends on the specific calcium salt used and the speed of
injection. ECG changes after induced hypercalcemia show increased ventricular activity and reduced atrial
activity. Atropine is capable of abolishing the resulting arrhythmia.
Sudden death may also occur after calcium injections if the cow is excited or frightened, which may be
due to an increased sensitivity to epinephrine. When affected cows are exposed to the sun or a hot, humid
atmosphere, heat-stroke may be a complicating factor. In such cases an attempt should be made to reduce
the temperature to below 39.5℃ (103 ℉) before the calcium is administered. The incidence of cardiac
arrhythmia and other abnormalities as detected by ECG during treatment with calcium salts IV is so high
that there are doubts expressed about the suitability of this form of treatment.
Chronic toxicity may also occur. In laboratory animals, severe uremia due to extensive calcium deposits
in the kidney occur after the SC injection of calcium chloride and borogluconate, and similar deposits are
often seen at necropsy in cows dying after multiple injections of calcium salts administered at short
intervals.
Failure to respond to treatment
A failure to respond favorably to treatment may be due to an incorrect or incomplete diagnosis, or
inadequate treatment. A poor response to treatment includes (1) no observable changes in the clinical
findings immediately following the calcium administration or (2) the animal may respond to the calcium in
all respects with the exception of being unable to stand for varying periods of time following treatment.
An indequate response also includes relapses after successful recovery, which usually occur within 48 h of
the previous treatment. Relapses are more common in certain individual cows such as mature Jersey cows
which may experience as many as five or six episodes around one calving. Also, the incidence of relapses
is much higher in cases which occur just before calving than in those which occur afterwards. The needs of
individual animals for calcium replacement vary widely, depending on their body weight and the degree of
hypocalcemia. Incomplete responses may be more common in older cows and may be associated with
diminished skeletal reserves of calcium and inability of the normal mechanisms to maintain serum calcium
levels during the period of excessive demands of lactation. The duration of the illness and the posture of
the cow also affect the response. In an extensive field study, there were no downer cows or deaths in cows
still standing when first treated, 13% of downers and 2% of deaths occurred in cows in sternal recumbency,
and 37% of downers and 12% of deaths occurred in cows in lateral recumbency when first treated (37).
Therefore, in general, the longer the period from onset of milk fever to treatment, the longer the period of
post-treatment recumbency and the higher the case-fatality rate. In another study, 67% of cows recovered
after a single treatment, 90% after two treatments and 92-99% after three treatments. After routine
treatment, 37% of cases rose unassisted within 10 min 23% required some-assistance, 26% recovered after
longer periods of recumbency and 14% died or were destroyed or sold for slaughter. The best procedure to
follow if response does not occur is to revisit the animal at 12-hourly intervals and check the diagnosis. If
no other cause of the recumbency can be determined the initial treatment can be repeated on a maximum
of three occasions. Beyond this point further calcium therapy is seldom effective. A low body temperature,
due probably to exposure to low environmentaltemperature,and increased wind velocities, is positively
correlated with a high proportion of deaths and poor responses.
At the second visit, solutions containing either phosphorus, magnesium or dextrose may be administered,
depending upon the clinical signs presented and the results of available biochemical tests. Glucose is
usually administered as 500 mL of a 40% solution, sodium acid phosphate as 200 mL of a 15% solution,
and magnesium sulfate as 200-400 mL of a 15% solution. Composite solutions containing calcium,
magnesium, phosphorus and glucose are also in common use as initial treatments. There is controversy
about these so-called 'polypharmacy' preparations. They have no advantage, but are likely to remain
popular when milk fever cases are complicated by metabolic disorders other than hypocalcemia. They
have no effect on the relapse rate when compared with calcium salts alone.
Udder insufflation
Insufflation of the udder with air was an alternative treatment for cows which continued to relapse
following repeated calcium injections. With the availability and effectiveness of orally administered
calcium gels, udder insufflation cannot be recommended.
GENERAL MANAGEMENT AND CLINICAL CARE PROCEDURES
The care of the cow and the calf following milk fever is important. The calf should be removed from the
cow and for the first 48 h only sufficient milk drawn for the calfs maintenance. A gradual return to full
milking can then be permitted. If the cow is recumbent for any length of time, she must be kept propped
up in sternal recumbency and not left in lateral recumbency, which may result in regurgitation and
aspiration pneumonia. The cow should be rolled from side to side every few hours and provided with
adequate bedding or moved to a suitable non-slip ground surface. In extreme climatic conditions, erection
of a shelter over the cow is advisable if she cannot be moved to permanent shelter. It a cow is recumbent
for more than 48 h, assisted lifting using appropriate cow lifters several times daily should be considered.
However, heroic measures to get cows to stand should be avoided. Gentle nudging in the ribs or the use of
an electric prod are the maximum stimulants advised.The best
1432
assistance that can be given to a cow attempting to stand is a good heave at the base of the tail when she is
halfway up.
CONTROL
Various methods for the control of milk fever in ruminants, especially dairy cows, are available. They
include dietary management during the prepartum period, administration of calcium gels orally at the time
of parturition, and administration of vitamin D and its metabolites and analogs immediately before
parturition to enhance the mobilization of calcium. When the incidence of milk lexer increases to above
10% of high-risk cows (third or later lactations), a specific control program is necessary. When the
incidence is low, a specific control program may not be economical and the alternative is to monitor cows
carefully at the time of parturition and for 48 h after parturition and treat affected animals during the first
stage of the disease if possible.
Dietary management during prepartum period
Level of calcium in diet
Diets high in calcium during the prepartum period can result in a high incidence of milk fever, and diets
low in calcium will reduce the incidence of milk fever in dairy cows. Feeding more than 100 g of calcium
daily during the dry period is associated with an increased incidence of milk fever. A cow weighing 500
kg requires only about 30 g of calcium to meet maintenance and fetal calcium demands in late gestation.
Low calcium diets (20 g Ca/d) fed during the. last 2 weeks before parturition are highly reliable and
effective.
Level of phosphorus in diet
Increased levels of dietary phosphorus, greater than 80 g per head per day, can also increase the incidence
of milk fever. The increased intake increases the serum level of phosphorus which has an inhibitory effect
on renal enzymes. These enzymes catalyze the production of 1,25-(OH)2D, which when lowered will
reduce intestinal calcium absorption. If the reduction of calcium is impractical, the lowering of phosphorus
to below requirements may be beneficial.
Calcium and phosphorus ratio in diet
If the ration is low in calcium, the resultnig negative balance of calcium can be expected to stimulate
activity of the parathyroid gland. Early researchers made use of this physiological mechanism by feeding a
high phosphorus/low calcium ration to cows during the last month of pregnancy. With a Ca:P ratio of 6:1,
30% of cows developed parturient paresis; at a Ca:P ratio of 1:1, 15% developed the disease; and at a ratio
of 1:3.3, no cases occurred. Although there is no apparent effect on the subsequent lactation there is the
possibility, if the negative balance of calcium is prolonged or repeated frequently, that such a ration may
contribute to the development of oesteoporosis. Dietary phosphorus concentrations can have an influence
on calcium homeostasis.
Practicality of feeding diets low in calcium
There arc practical problems with the implementation of the recommendation to feed diets low in calcium.
It is difficult to reduce the amounts of calcium and phosphorus led to cows for several reasons:
1.Inability to grow sufficient quantities of feeds, such as corn silage, for the entire herd
2.Suitability of land for legume crops which are high in calcium
3.Inability to add sufficient phosphorus to lower the ratio of calcium to phosphorus to palatability when
quantities of phosphorus are added to the ration.
Most farms utilizing home-grown forages, especially alfalfa, find it difficult to obtain forages which are
low in calcium. In addition, while feeding diets low in calcium during the prepartum period is very
effective, the very low calcium intake required necessitates that the cow be in negative calcium balance
and in a state of withdrawal of calcium from bone.
Dietary cationanion difference
A more reliable method of controlling milk fever in dairy cows when the calcium intake exceeds NRC
requirements is to manipulate the dietary cation-anion difference (DCAD) (38). Diets high in cations,
especially sodium and potassium, tend to induce milk fever compared with those high in anions, primarily
chloride and sulfur, which can reduce the inci¬dence. Because most legumes and grasses are high in
potassium, many of the com¬monly used prepartum diets are alkaline. The feeding of diets which are high
in ratio of calcium to phosphorus and containing an excess of anions relative to cations will result in
increased concentrations of serum calcium due to an increase in the intestinal absorption of calcium.
In one study, the incidence of milk fever was 47% when prepartum cows were fed a ration with a
DCAD of +330.5 mEq/kg dietary DM and 0% incidence when the prepartum ration had a balance of-128.5
mEq/kg dietary DM (38). The incidence of milk fever was reduced by the addition of chloride and sulfur
in excess relative to sodium and potassium in the diet (38). Because anions are considered acidogeme and
cations alkalogenic, an excess of acid-forming elements in periods of calcium stress will increase the
concentration of calcium in the blood, either by intestinal absorption or bone mobilization (2. 39). Cows
fed prepartum diets containing alfalfa haylage with added chlorides of magnesium, ammonia and calcium
tended to have higher plasma calcium concentrations of calcium and a lower incidence of milk fever than
did cows fed cither of two cationic diets. Plasma hydroxyproline an index of bone resorption, also
increases prior to parturition in cows fed a high anion diet. The plasma levels of 1,25-(OH)2 D also
increase prior to parturition in cows fed a high anion diet, which increases calcium absorption and bone
resorption (39). Feeding rations with reduced mEq of dietary ([Na+ + K+]-[CI + SO4=]) to -4 mEq/kg
dietary DM to dry cows significantly affected some of the parameters of bone formation but did not
enhance the rate of bone resorption (40). Feeding acid diets to pregnant cows during the last 28 d of
pregnancy increased the mobilization of calcium by 13% 14 d before parturition and 28% by the time of
parturition, whereas it had declined by 14% at 14 d before parturition in alkali- fed cows (41). The
increased concentrations of 1,25-(OH)2 D were responsible for the stimulation of both intestinal calcium
absorption and bone resorption. which helped to prevent severe parturient hypocalcemia (41).
Ammonium chloride
The addition of ammonium chloride salts to prepartum diets offers considerable promise as a practical and
reliable method of control of milk fever. Experimentally, the addition of ammonium chloride and
ammonium sulfate, each at lOOg/head per day, to the prepartum diets 21 d prior
1433
to parturition, decreased the incidence of milk fever from 17% in the unsupplemented group to 4% in the
supplemented group. The advantages of ammonium salts are that they
1.Do not require the vise of diets low in calcium
2.Are relatively inexpensive
3.Are convenient to use
4.Are safe to feed.
The cation-anion balance of the diets, calculated as (Na+K)-(CI+S), was -75 mEq/kg dietary DM with
ammonium salts and +189 mEq/kg dietary DM without ammonium salts (42). Analyzing the feedstuffs for
sodium, potassium, chloride and sulfur, and adjusting the value (Na+K)-(C1 + S) to produce a
significantly negative total will effectively prevent parturient paresis. It has been suggested that the sum
(Na + K-CI) might be useful for prediction, and that if the total were less than 10 mEq per 100 g of dry
matter, parturient paresis would be prevented. Another suggestion is an 'ion balance' equation in which
calcium, phosphate, sodium and potassium are considered alkalogenic and sulfur and chloride are
acidogenic. Using this equation, a prepartal diet providing more than 8000 mEq of excess alkalogenic ions
is at considerable risk of inducing milk fever. To prevent the occurrence of milk fever when high calcium
diets are fed to dry cows, dietary cation-anion balance must be reduced below -3 mEq/100 g of diet dry
matter (33). In cows fed prepartum canonic diets, two processes under the control of parathyroid hormone,
the renal production of 1,25-(OH)2 D and osteo-clastic bone resorption. were temporarily refractory to
parathyroid stimulation (43).
Management practices
The following management practices are suggested:
• Avoid excessive calcium intake during the dry period
• Feed an adequate amount of phosphous to meet requirements and limit calcium intake to no more
than 100-125g/d. This appears to be a more practicalapproach to maintaining calcium homeostasis during
the period when cows are most pronetomilk fever than establishing a given Ca:P ratio. Since intestinal
absorption is a major inflow source of serum calcium during this period, keeping cows on feed is essential.
This may also reduce outflow of serum calcium
•Avoid overfattening by either reducing the energy concentration of the ration or restricting the intake
during the prepartum period.This also appears to stimulate appetite,thuskeeping cows on feed
•Avoid stresses at the time of parturition
•Provide a clean well-bedded box stall with conditions conducive to cow comfort and allow the animal to
exercise
•Make frequent observations of cows prone to milk fever from 48 h before to 48 h after parturition for
evidence of milk fever and immediate treatment will reduce the incidence of the downer cow syndrome
associated with milk fever
•At calving the cow should receive an oral dose of a calcium salt in a gel, as set out later, followed by a
diet with a high calcium content (over 1% of dry matter). The critical day is the day of calving, and a sharp
increase in calcium intake on this day can significantly reduce the occurrence of milk fever
•If hypomagnesemia is alikely concomitant, the diet should be supplemented with 60 g magnesium oxide
daily.
Calcium gel dosing
The oral administration of a gel containing 49% calcium chloride strategically before calving, at calving,
and at intervals within 1 day after calving is effective in preventing milk fever. One tube of gel (355 g)
containing 54 g of elemental calcium from a combination of calcium chloride (70%) and tricalcium
phosphate (30%) given approximately 12 h before calving, immediately after calving, 12 h after calving,
and 24 h after calving significantly increased serum calcium concentrations on the first and second day
after calving, especially in third-parity cows or older cows (44). The incidence of milk fever, parturient
hypocalcemia and displaced abomasum was also lower than in control cows. The oral administration of
two tubes within 1 h after parturition is also effective (45). Rectal administration is not recommended (46).
Calcium chloride is caustic and can cause oral lesions. Oropharyngeal abscesses secondary to
trauma and laceration caused by the administration of the boluses may occur (47). Field trials using
calcium propionate paste given orally at calving and repeated 12 h later reduced the incidence of milk
fever from 50% in control cows to 29% in treated cows (48).
Vitamin D and its metabolites or analogs
Vitamin D3 (cholecalciferol) administered parenterally was historically, a popular prophylactic against
milk fever. In an attempt to reverse the negative calcium balance of susceptible cows the administration of
vitamin D and its analogs have been used to increase intestinal absorption of calcium. Vitamin D3 is
hydroxylated in the liver and the resulting metabolite is 25-hydroxycholecalciferol. This is metabolized in
the kidney to 1,25-dihydroxycholecalciferol, which has an active hypercalcemic effect but is difficult to
synthesize. One of its analogs, 1-alphahydroxycholecalciferol is as active, is easy to prepare and is used
pharmacologically.
Oral dosing with vitamin D2 and the parenteral administration of vitamin D3 and dihydrotachysterol all
have their pro¬ponents. Oral dosing with 20 million units of vitamin D2, per day for 5 d to cows
immediately prior to calving can markedly reduce the expected incidence of milk fever. The exact date of
calving is often difficult to determine and if the administration is discontinued for up to 4 d before calving,
an unusually high incidence of the disease may follow, probably because of the depression of parathyroid
activity which follows the administration. The danger of causing metastatic calcifcation also exists as this
has been produced with smaller doses (10-20 million units daily for 10 d). Pregnant cows are more
susceptible to calcification than non-pregnant animals. Treatment with larger doses or for longer periods
than those recommended earlier should be avoided because of the danger of toxic effects. Smaller doses
reduce the risk of calcification but also reduce the degree of calcium retention.
A single dose of 10 million units of vitamin D3 IM given 2-8 d before parturition lias been considered as
optimal. A dose of 1 million units per 45 kg BW has given consistently better results. This may explain the
variable results and why results have been more favorable in Jersey cattle. If the cow fails to calve after
the 8th day,
1434
another 10 million units may be administered and repeated every 8 d until the cow calves. Subclinical
calcification may occur in vessel walls but this is unlikely if dietary calcium and phosphorus intake is
adequate. Single doses of 40 million units of vitamin D can be lethal. One of the disadvantages of this
method is the likelihood that cows which do not calve at the anticipated time can be more seriously
affected than if they receive no treatment. The hypercalcemic effect of cholecalciferol by injection is very
much longer when it is administered by IM injection (up to 25 d) than by IV injection (up to 3 d). for this
reason and because occasional cases of shock occur after the IV administration, especially if more than
one injection is given, the IM route is preferred. The injection of vitamin D is preferred to feeding it and a
protection rate of up to 80% can be anticipated. It is estimated that 95% of Jersey cattle are protected.
In spite of the very variable results obtained, the injection of vitamin D3 is still the most commonly used
method of prevention, principally because of its simplicity.But there are obvious differences in response
between breeds and between individual veterinarians
Other compounds with vitamin D activity but which avoid the possibility of causing hypervitaminosis D
and are therefore useful in the prevention of milk fever are:
1.25-Hydroxycholecalciferol injected IM at 8 mg 3-10 d before calving and repeated at weekly intervals.
Single doses of 4 mg are not effective in reducing the occurrence of parturient hypocalcemia or milk fever.
2.1,25-Dihydroxyvitamin D3 given at 200 µg daily, orally, to calving cows reduces the development of
hypocalcemia but does not completely revent milk fever (42). When 1,25-(OH)2 D is given IM between 1
and 4 d of calving, it is effective in pre venting milk fever. When adminis tered less than 24 h or more than
4 d before calving, parturient paresis is not effectively prevented (49). Repeated injections at 4-7-day
intervals until calving can be used, but toxicity can be a problem. A third problem with this metabolite is
that the IM injection can result in milk fever 1-2 weeks
after parturition because the exogenous metabolite may inhibit the endogenous production in some cows,
and when the exogenous product is cleared from the body, the cow is unable to produce sufficient
1,25-(OH)2 D to maintain enhanced intestinal absorption of calcium. 3.24-F-l,25-dihydroxyvitamin D3
given at 100-150 µg 5d before the expected date of parturition was effec tive (50). Cows which did not
calve within 7 d were given a second dose. The incidence of milk fever in untreated controls, those
receiving 100, and 150 µg, was 85%, 43% and 29%, respectively. The use of SC- released product
implanted 7 d before parturition and repeated at 7-day intervals until calving resulted in milk fever in 80%
of controls and 9% in treated cows (49). The SC pellet maintained levels of the vitamin D metabolite for
about l0d, compared with the IM injection, which results in very high concentrations in the plasma in the
first 48 h after injection. 4.1-Alpha hydroxyvitamin D3 at 350 µg IM is effective as a preventive to milk
fever if given 72 and 24 h before parturition. If calving has not occurred naturally within 72 h, a second
injec tion is given (51). Parturition is induced if calving has not occurred 2 d after the second injection.
The preferred site of injection is the serratus muscle of the neck, which results in a more effective response.
To avoid the problems created by cows not calving at the predicted time, a combined regimen including
induction of parturition by the administration of corticosteroid with the injection of
1-alpha-hydroxycholecalciferolis reported to be successful. Injection of cows with the same vitamin D
analog plus a prostaglandin (cloprostenol) was unsuccessful in preventing milk fever. A dose of 700 µg
given 6-8 d before calving is also recommended (52). Another recommendation suggests 500 µg at 2-5 d
prior to parturition. An evaluation of routine use of 1-alpha-hydroxyvitamin D3 indicated that cows which
developed retained placenta and metritis may be at greater risk of not conceiving within 150 d from
calving (53). There is some transfer of the metabolite from the maternal to fetal plasma. Injection within
24 h of the onset of milk fever is ineffective, but if it is given more than 24 h and less than 1 week before
the onset of the disease, the protection is excellent .
Miscellaneous prophylactic measures
There are a number of prophylactic measures currently in use, including:
.Incomplete milking after calving, which is unreliable
•Prophylactic injection of calcium solutions as soon after calving as possible, which is effective but may
be impractical
•Feeding of ammonium chloride to induce acidosis and enhance calcium
mobilization and ionization, has been recommended and there is some sup
port for its use. The ammonium chloride is fed with grain over the last few weeks of pregnancy,
commencing with 25 g and increasing to 100 g/d at calving.
The heritability of susceptibility to milk fever is thought to be high but there is a lack of good evidence
to support this view. When breeding plans and selection of bulls are being considered, attention should be
given to the use or deletion of susceptible cows as dams of bulls to be used in artificial insemination.
In species other than cattle the disease is commonly caused by errors in management and prevention
depends on their avoidance. High calcium intakes before parturition in ewes have also been thought to
contribute to the development of hypocalcemia. However, the maintenance of appetite and the avoidance
of alimentary tract stasis in late pregnancy appear to be important preventive measures which are likely to
insure an adequate calcium absorption. Pregnant and lactating ewes and cows should not be subjected to
unnecessary exercise or excitement. It is good practice to improve the plane of nutrition during late
pregnancy in ewes to avoid pregnancy toxemia but changes, particularly to lush pasture, should be made
gradually, and sheep moved from wooded pasture to open fields with little natural shelter should be
provided with some protection weather.
1435
DOWNER COW SYNDROME
Synopsis
Etiology. Ischemic necrosis of large muscles of pelvic limbs secondary to prolonged recumbency
associated with milk fever .Other causes of recumbency can also result in downer cow syndrome.
Epidemiology. Most common in dairy cows which have had milk fever but are unable to stand following
treatment with calcium Delay of more than 4 h in treatment for recumbent milk fever cows
Hypophosphatemia and/or hypokalemia may be risk factors.
Signs. Unable to stand following treatment for miIk fever. Sternal recumbency. Normal mental status, vital
signs and alimentary tract. Appetite and thirst normal. Most will stand in few days if provided good
c1inical care and secondary muscle necrosis minimized. Some cases have bizarre behavior of lateral
recumbency, abnormal position of legs, groaning, anorexia and die in several days.
Clinical pathology. Increased serum levels of creatine phosphokinase (CPK) and aminotransferase (AST);
serum phosphorus and potassium levels may be subnormal.
Lesions. Ischemic necrosis, edema and hemorrhage of large medial thigh muscles.
Diagnostic confirmation. Increased serum levels of CPK, AST, proteinuria; necropsy lesions in cow
unable to rise with no other lesions
Differential diagnosis list:
•See differential diagnosis of milk fever(p.1421)and Table 28.1
•Common causes of recumbency in dairy cows around time of parturition
include:
•Milk fever (p.1420)
•Hypomagnesemia (pp. 1442, 1510)
•Peracute coliform mastitis (p. 639)
•Maternal obstetrical paralysis (p. 1427)
•Fat cow syndrome (p. 1462)
•Physical injuries of pelvic lambs (dislocation of hip joints, rupture of gastrocnemius, femoral
fracture)
•Acute diffuse peritonitis(ruptured uterus, other causes).
Treatment. Provide feed and water and excellent bedding or ground surface like sand or dirt pack. Roll
animal from side to side every few hours. Fluid and electrolyte therapy as necessary
Control. All recently calved dairy cows which are at high risk for milk fever must be observed closely
12-24 h before and after calving for evidence of milk fever and while still standing; if recumbent do not
delay treatment for more than 1 hour. Can treat all high-risk cows with calcium chloride gel orally to
prevent clinical milk fever.
ETIOLOGY
Most commonly the downer cow is a.complication of milk fever (I). Ischemic necrosis of the large
muscles of the pelvic limbs and injuries to the tissues around
1436
the hip joint and of the obturator muscles are common in cows which do not fully recover and stand but
remain recumbent following treatment for milk fever. The injuries may also be the result of cows
'spread-eagling' their hindlimbs it they are unsteady during parturition or forced to stand or walk on a
slippery floor immediately before or following parturition. Dystocia due to an oversized calf may result in
extensive edema of the pelvic tissues and vulva, and failure of the cow to stand following parturition. If
these cows develop milk fever, it is unlikely they will be able stand following treatment with calcium.
EPIDEMIOLOGY
Occurrence
The disease occurs most commonly within the first 2 or 3 d after calving in high-producing dairy cows
immediately following milk fever. Cattle may also become persistently recumbent tor many reasons other
than complications of milk lever such as peracute coliform mastitis and carbohydrate engorgement.
Incidence
The incidence as a complication of milk lever is high because many affected animals are high producers
and of high economic value. Accurate data on the incidence are not available because of variations in the
nomenclature used and the accuracy of diagnoses. For example, some observations report that all cases are
caused by nerve injury (2). Cases included in this classification are classified by others as maternal
obstetric paralysis, obturator paralysis or hypophosphaterrua. Because it is a syndrome lacking in clinical
definition and includes all those 'other cases' which cannot be otherwise classified, the incidence varies
depending on the clinical acuity of the individual veterinarian, and on various environmental factors in
different areas. However, the incidence seems to be increasing, particularly in intensive dairy farming
areas, although this impression could arise from the increased necessity to effect a cure in valuable animals.
A mail survey of 723 dairy herds in Minnesota found an incidence of 21.4/1000 cow years at risk (2).
The overall outcome was that 33% recovered, 23% were slaughtered and 44% died. The owners perceived
that downer cows were high producers (48%) or average producers (46%), with only 6% being low
producers. Approximately 58% occurred within 1 d of parturition and 37% occurred during the first 100 d
of lactation. The incidence was highest (39%) during the three coldest months: December, January and
February. In New Zealand, the prevalence ranges from 3 5% of all dairy cows at calving time (3).
In a clinical and laboratory survey of 433 periparturient recumbent cows in New Zealand, 39%
recovered, 30% died and 52% were destroyed (3). The case-fatality rate was 11% higher in precalving
recumbent cows than postcalving cows.
Risk factors
Animal risk factors
COMPLICATION OF MILK FEVER Prolonged recumbency after a long delay in the treatment of milk
fever is a major risk factor. Prolonged recumbency before treatment for milk fever (more than 4-6 h)
results in ischemic necrosis due to obstruction of the blood supply, especially in a heavy cow if she lies on
one leg tor a long period (4). Cows which develop milk fever while in a standing tie-stall may slide
backwards into the gutter behind the stall, resulting in extreme pressure to their pelvic limbs and leading to
ischemic necrosis.
A case-control study to identity risk factors tor the development of downer cow syndrome within 30 d
postpartumin 12 dairy herds over 2705 lactations found that clinical hypocalcemia and stillbirth increased
the risk of the disease five-fold (5). Cows with retained placenta and dystocia were also more likely to
develop downer cow syndrome than cows without either problem.
A marked increase in the CPK levels in cows with milk fever and failure to stand after repeated
treatments is supporting evidence for ischemic necrosis associated with prolonged recumbency as a major
cause of downer cow syndrome (1). The CPK levels increase markedly between the first and second
treatments, which indicates that muscle damage has occurred and the levels are highest in cows which do
not recover.
Experimentally, enforced recumbency of cattle for 6, 9 or 12 h with one hindlimbpositionedunder
thebody results in downer cow syndrome. Affected cows are unable to stand and the affected limb is
swollen and held rigid similar to the injured limbs of human patients with compartmental/crush syndrome.
TRAUMATIC INJURIES TO PELVIS AND PELVIC LIMBS Traumatic injuries to the nerves of the
pelvis and hindlimbs are present in 25% or more of downer cows (1). The sciatic and obturator nerves are
vulnerable to injury by pressure from the calf moving through the pelvic canal during parturition. Pressure
injuries on the superficial nerves (radial and peroneal) of the extremities also occur in recumbent cows.
SERUM ELECTROLYTE IMBALANCES Serum electrolyte imbalances or deficits may be associated
with prolonged recumbency following treatment for parturient paresis.
HYPOCALCEMIA A persistent hypocalcemia following treatment for milk fever may exist in a downer
cow but is unlikely to be the principal cause because treatment with calcium salts does not resolve the
signs, even temporarily. However, the use of an insufficient amount of calcium for the initial treatment of
milk fever in large, heavy cows may result in an incomplete response and failure of the cow to stand. It
these cows are not retreated soon enough with an adequate amount ot calcium, ischemic necrosis of the
limb muscles occurs and leads to prolonged recumbency. In many cases, even after the cow is given a
sufficient amount of calcium, prolonged recumbency occurs due to the ischemic necrosis.
HYPOPHOSPHATEMIA The serum levels of inorganic phosphorus decline to below normal along with
a hypocalcemia in cases of milk fever. Following treatment ot milk fever with calcium borogluconate, the
levels of serum calcium and phosphorus return to normal if the animal responds favorably and stands
normally. Following treatment for milk fever, some cows do not or are unable to stand and their serum
phosphorous levels are subnormal. This persistent hypophosphatemia has been regarded as a cause of
downer cow syndrome associated with milk fever. Many veterinarians claim that these cows respond to
treatment with phosphorus. However, persistent recumbency
1437
is associated with subnormal levels of serum phosphorus which increase to normal if the cow stands
regardless of treatment with or without phosphorus. Mature dairy cows may become recumbent in early
lactation and subnormal levels of scrum phosphorus may be present (6). Other cows in the herd may be
lame due to demineralization of bones associated with a dietary deficiency of phosphorus.
HYPOMAGNESEMIA A long-term low-level hypoinagnesemia has been associated with the downer
cow, especially when it accompanies hypocalcemia. But it is usually manifested by a tetanic hyperesthetic
state which is not part of downer cow syndrome. Hypokalemia is, with hypophosphatemia, the most
commonly quote cause, especially in the so-called 'creeper' cows, which are bright and alert and crawl
about, but are unable to rise (7).
HYPOKALEMIA Ischemia due to prolonged recumbency associated with milk fever, may increase the
cell membrane permeability of muscle fibers and allow the loss of potassium from the cell; this in turn
causes the myotonia, which appears to be the basis of downer cow syndrome. This view is supported by
the low serum and muscle potassium levels in downer cows. Claims are made that potassium salts are
successful in treatment but these have been difficult to evaluate (3).
Hypokalemia occurs in dairy cows which have been treated with isopflupredone acetate for ketosis (8).
Affected animals are weak, recumbent and severely hypokalemic with serum potassium levels ranging
from 1.4-2.3 mEq/L.
Environmental and management risk factors
A slippery ground surface is a major risk factor. Cattle which must walk across slippery floors, especially
at the time of calving, may slip and fall and injure the large muscles of the pelvic limbs, resulting in an
inability to stand. Prolonged recumbency results in ischemic necrosis and downer cow syndrome.
Summary
Downer cow syndrome is a complication of the recumbency associated with milk fever. A delay of 4 h or
more in the treatment of cows with milk fever may result in ischemic necrosis of the muscles of the pelvic
limbs.Traumatic injury to leg muscles at the time of parturition or when the cow is unsteady and falls
during the first stage of milk fever will also result in the inability of the cow to stand following treatment
of milk fever.
PATHOGENESIS
Several different primary factors or diseases can result in recumbency.
Prolonged recumbency before treatment
A long delay in the treatment of milk fever can result in pressure damage and the subsequent inability to
stand after treatment for the primary disease. Prolonged recumbency results m pressure damage, which
occurs secondarily and is a factor common to all cases (2).
Regardless of the cause, the prolonged recumbency results in varying degrees of ischemic necrosis of
major muscles of the hindlimbs, particularly the semitendinous muscle and muscles caudal to the stifle.
Prolonged compression of the muscle leads to tissue anoxia, cell damage and inflammation which causes
swelling: the swelling causes a further increase in pressure which limits tissue perfusion and leads to a
detrimental cascade of events. The thick fascial boundaries of the semitendinous muscle prevents
expansion which results in pressure-induced compartmental syndrome. Sciatic nerve damage due to
pressure also occurs and may contribute to downer cow syndrome. Experimental external compression of
the pelvic limb of the goat, to simulate limb compression in recumbent cows, resulted in a marked
reduction in nerve condition velocity of the peroneal nerve which was associated with clinically evident
limb dysfunction. Damage to the peroneal nerve will result m hyperflexion of the fetlock if and when the
cow is able to stand.
Traumatic injury to limb muscles and nerves immediately prior to parturition or at the time of
parturition can also result in prolonged recumbency and subsequent pressure damage (1).
Experimental sternal recumbency
Experimentally induced sternal recumbency with one hindlimb positioned under the body to simulate
prolonged recumbency will result in a swollen rigid limb within 6-9 h (9). Following injury to the muscle
cells, the serum levels of CPK are markedly elevated at about 12 h after the onset of recumbency.
Proteinuria and in some severe cases myoglobinuna occur between 12 and 36 h after the onset of
prolonged recumbency, due to the release of myoglobin from damaged muscles. In cows which make
efforts to stand but cannot do so, continued struggling results in rupture of muscle fibers and hemorrhage
which increases the seventy.
Acute focal myocarditis may occur in about 10% of cases resulting in tachycardia, arrhythmia and the
unfavorable response to IV calcium salts observed in some cases. The cause of the myocardial lesion is
unknown but repeated administration of calcium salts has been suggested (1). Downer cows with a poor
prognosis also have greatly enhanced adrenocortical function (7).
The prolonged recumbency can result in additional complications such as acute mastitis, decubitus
ulcers and traumatic injuries of the limbs.
The pathogenesis of the non-alert downer cow is not understood (10). Most have had an initial episode of
milk fever but do not respond satisfactorily. Within 1 or 2 d, affected cows have a preference for lateral
recumbency anjd exhibit expiratory moaning and groaning. They represent about 2% of all cases of milk
fever.
Experimental prolonged hypocalcemia
Experimental prolonged hypocalcemia may provide some clues about the pathogenesis of downer cow
syndrome as a complication of milk fever. The prolonged infusion of ethylenediamine tetraacetic acid
(EDTA) in sheep over 18 h at a rate to induce hypocalcemia and maintain recumbency results in prolonged
periods of recumbency ranging from 36-64 h before the animals are able to stand (11). There are also
decreases in plasma sodium, plasma potassium and erythrocyte potassium and prolonged increases in
packed cell volumes, which suggests that fluid replacement therapy may be indicated in cattle with
prolonged recumbency associated with hypocalcemia (12). A 4-hour IV infusion of EDTA in high
erythrocyte potassium and low erythrocyte potassium dairy cows causes decreases in plasma inorganic
phosphorus and plasma potassium which are still below normal 24 h later (13). The AST, CPK, and PCVs
and WBC counts are also elevated 24 h later. Plasma magnesium
1438
and erythrocyte sodium and potassium were decreased but this was delayed. The increase in PCV was
most pronounced in the low erythrocyte potassium cows, which may provide some clues about the
pathogenesis of downer cow syndrome. Some cows may have a more precipitate increase in PCVs due to
loss of plasma volume and an inability to mobilize calcium. As a basis for studying the effects of
hypertonic solutions to correct these abnormalities in downer animals, a 200 mL solution of 10 g of
sodium chloride and 0.5 g of potassium chloride can be given IV to sheep safely over a period of 4-8 min
(14).
CLINICAL FINDINGS
Downer cow syndrome may occur independently, or follow apparent recovery after treatment for milk
fever, except for the prolonged recumbency. In the typical case, affected cows either make no effort or are
unable to stand following treatment for parturient paresis. About 30% of cows treated for milk fever will
not stand for up to 24 h following treatment. Those which are unable to stand after 24 h and after two
treatments are classified as downers. They are usually bright and alert and, although the appetite is reduced,
the cow eats and drinks moderately well. The temperature is normal and the heart rate may be normal or
elevated to 80-100 bpm. Tachycardia and arrhythmia occur in some cows, especially immediately
following the administration of calcium IV and sudden death has occurred. Respirations are usually
unaffected. Defecation and urination are normal but proteinuria is common and if marked may indicate
extensive muscle damage.
Some affected cows may make no effort to stand. Others will make frequent attempts to stand but are
unable to fully extend their pelvic limbs and lift their hindquarters more than 20-30 cm from the ground.
These frequent attempts to stand result in 'crawling' or 'creeping' along the ground with both hindlcgs in a
partially flexed position and displaced posteriorly the froglcg attitude. On a non-slippery surface (bare
ground, sand pack, or deep bedding) some cows are able to stand with some assistance by lifting on the tail
head or with the use of hip slings. Those cows which do not make an effort to stand usually cannot stand
even with assistance and if supported with hip slings will usually make no effort to bearweight with either
the hindlimbs or the forelimbs. Their limbs appear stiff, painful or numb and they are unable or reluctant
to bear weight. Damage to the peroneal nerve is usually present when there is hyperflexion of the fetlock
joints, which is evident if and when the cow is able to stand and bear weight on the hindlimbs.
In some cases, the hindlimbs are extended on each side of the cow and reach up to the elbows on each
side. In this position, the cow is bearing considerable weight on the medial thigh musculature and causing
ischeniic necrosis. This abnormal position of the legs may also be due to dislocation of one or both hip
joints or associated with traumatic injuries surrounding the hip joints with or without rupture of the
ligamentum teres. Regardless of the cause, the cow prefers this leg position and invariably will shift the
legs back to the abnormal position if they arc placed in their normal position.
In some cows the signs may be more marked and bizarre, including a tendency to lie in lateral
recumbency with the head drawn back. When placed and propped up in sternal recumbency, these cows
appear almost normal but. when they are left alone, within a short period of time they revert to the position
of lateral recumbency. Still more severe cases are . hyperesthestic .mil the limbs may be slightly stiff but
only when the cow is lying in Literal recumbency. I hese severe cases do not usually eat or drink, have
been described as 'non-alert downers', and are thought to have brain damage which has not been
documented (10).
Complications in the downer cow syndrome are common and often result in . death or the need for
euthanasia. Collform mastitis, decubitus ulceration, especially over the prominences of the hock and elbow
joint, and traumatic injuries around the tuber coxae caused by the hip slings arc common. When these
complications occur in the early stages of the disease, they commonly interfere with any progress being
made and become the focus of clinical attention.
The course of the disease is variable and dependent on the nature and extent of the lesions and the
quality of the care and comfort winch is provided for the cow during the first few clays. About 50% j of
downer cows will stand within 4 d or less if cared for properly. The prognosis is poor for those which are
still recumbent after 7 d, althoughsome affected cows have been down for 10-14 d and subsequently stood
up and recovered. Death may occur in 48-72 h following the onset and is usually associated with
myocarditis.
CLINICAL PATHOLOGY
The calcium, phosphorus, magnesium and glucose levels of the blood are within the normal range and the
results of hematological examinations are usually consistent with those found in normal cows which have
recently calved. The CPK and AST levels are usually markedly elevated by 18-24 h after the onset of
recumbency and continue to elevate within the next few days. Continued elevation of CPK levels indicates
continued muscle damage. In experimentally induced recumbency m cows, the CPK levels remained
within normal limits for the first 6 h. However, by 12 h there was a marked increase to mean values of 12
000 m/L rising to 40 000 iu/L by 24 h. There may be moderate ketonuria. A marked proteinuria is usually
evident by 18-24 h after the onset of recumbency. The proteinuria may persist for several days or be absent
within a few days. In severe cases, the urine may be brown and turbid because of severe myoglobinuria.
Low arterial blood pressures and abnormal electrocardiograms (ECGS) have been observed in some
animals.
Elevations of serum urea, muscle enzymes, and laboratory evidence of inflammation are considered the
best prognostic indicators of an unfavorable recovery (3). Cows with a serum urea level above 25 mmol/L
and serum creatinine levels above 130 mmol/L had a poor prognosis. The recovery rate was lower in cows
with a total protein: fibrinogen ratio less than 10:1. and evidence of neutropenia and/or left shift (3). The
CPK levels need to be interpreted in relation to the days of recumbency when the sample was taken.
Critical levels may be highest initially (up to 50 times the upper normal reference range) and reduce to 10
times normal range at 7 d of recumbency.
NECROPSY FINDINGS
Hemorrhages and edema of the skin of traumatic origin are common. The major pathological changes
consist of hemorrhages and degeneration of the medial thigh muscles. Hemorrhages around the hip joint
with or without rupture of the ligamentum teres are also common. Local areas of ischemic necrosis of the
musculature
1439
(gracilis, pectineus and adductor muscles) occur at the anterior edge of the pelvic symphysis (1).
Eosinophilic infiltration of ruptured necrotic thigh muscles of downer cows has been described (15).
Hemorrhages and edema of the nerves of the limbs (obturator, ischiatic, peroneal, radial) are also common
and usually associated with severe muscle damage. The heart is dilated and flabby and histologically there
is focal mycoarditis. There is fatty degeneration of the liver and the adrenal glands are enlarged.
Histologically there are also degenerative changes in the glomerular and tubular epithelium of the kidneys.
DIFFERENTIAL DIAGNOSIS
The diagnosis of downer cow syndrome is made after all other known causes of recumbency have been
eliminated in a cow which had milk fever and failed to stand within 24 h following two successive courses
of treatment. The other common causes of prolonged recumbency are described under the differential
diagnosis of milk fever (Table 28.1). It is difficult and time consuming to examine a downer cow
thoroughly to eliminate all other causes of recumbency. Only by repeated careful clinical examination will
the clinician avoid the embarrassment of failing to detect the presence of coliform mastitis, a fractured leg
or a dislocated hip.
TREATMENT
Fluid and electrolyte therapy
Many treatments including the injections of magnesium salts, phosphates, corticostcroids, stimulant tonics
and vitamin E and selenium have been used without consistent success. The use of parenteral solutions
containing potassium, calcium, magnesium and phosphorus has been recommended (7) but there is no
scientific evidence that these electrolytes,in addition to what was probably given to the cow already, are
indicated or are of any beneficial value. Large quantities of fluid and multiple electrolyte therapy by the
oral or parenteral route is indicated for cows which may not be drinking normal quantities of water.
Multiple electrolytes can be added to the drinking water if the cow is drinking normally.
Bedding and clinical care
The most important aspect of treatment is to provide the most comfortable bedding possible and to roll the
cow from side to side several times daily to minimize the extent of ischemic necrosis and para-analgesia
which results from prolonged recumbency. With conscientious care and the provision of good bedding,
palatable feed and liberal quantities of water, most cows will attempt to stand with some difficulty and
assistance within 24 h, and will stand unassisted and normally a day or two later. A sand or dirt pack is the
ideal ground surface which facilitates standing when downer cows attempt to stand (9). If affected cows
are left on a slippery ground surface, they will not make an effort to stand and will become progressively
worse. Cows should be milked normally and the udder kept clean by washing with germicide soap before
milking, and postmilking teat dips applied.
Assisted lifting to aid standing
The clinician and fanner are commonly faced with the questions of whether or not to lift a recumbent cow
which has not attempted to stand within a tew hours after treatment for milk fever. The guiding principle
should be the behavior of the cow. If the cow makes an effort to stand on her own or by some coaxing
such as a gentle lenudge m the ribs, she should be assisted to stand by insuring a good non-slip ground
surface, deep bedding are lifting up on the tail head when she attempts to stand. The cow should be rolled
from side to side every few hours and encouraged to stand a few times daily. With good clinical care, most
cows with the uncomplicated form of downer cow syndrome secondary to milk fever will stand in 12-24 h.
Lifting devices
Several different kinds of cow lifting devices have been used to assist downer cows to stand. Hip lifters,
which fit and tighten over the tuber coxae, and body slings like harnesses are designed to fit around the
abdomen and thorax of the animal. These devices can assist a downer cow to stand it she makes some
effort on her own and it appears that 'if she were given some help she could stand'. For those cows which
make some effort to stand, the hip lifters or slings can be applied and the animal lifted to the standing
position. If the animal bears weight on all four legs she should be allowed to stand with the
aidofthedevices for 20-30 min and then lowered down. This procedure should be repeated several times
daily. In most cases, such downer cows will stand on their own within a few days. While the cow is in the
standing position she can be milked and other clinical examinations can be carried out.
The hip lifters can result in traumatic injuries to the tissues surrounding the tuber coxae if not used
judiciously Animals which make no effort to stand and bear weight on their own must not be left
suspended in the lifter for more than a few minutes but lowered immediately. If the hip lifters are not
applied carefully, the animal may slip out of the device while she is being lifted, which commonly results
in tissue injury around the tuber coxae; fractures of the coxae have even occurred. These injuries are often
unnoticed clinically, contribute to persistent recumbency and the true extent of the lesions are evident at
necropsy. Lifting devices must be used carefully by experienced personnel.
Body slings which fit around the abdomen and thorax of the animal appear to be the ideal 'animal lifter'
because they distribute the weight over several sites in contrast to the hip lifters, which concentrate the
weight over the tuber coxae. However, the body slings are cumbersome to apply to a recumbent annual,
and require more time and experienced personnel to insure proper application. When the slings are applied
properly, they do appear to allow the lifted animal to stand comfortably for 30 min or more and promote
recovery.
Lifting cows which make no effort to stand on their own is usually unsuccessful. When lifted they
usually do not bear any significant weight.
A water flotation tank has been designed for the management of downer cows (16). A prototype
consists of a metal tub with inside dimensions of 92 in long, 43 in wide, and 51 in deep. The system is
affordable, portable, durable, effective and simple to use. The downer cow is pulled into the tub on a mat
and the ends of the tub closed to make a water-tight container with an open top like a bath tub. With the
cow's head held up by a halter, the tub is filled with water at 100-102℉ as quickly as possible. Cows in
lateral recumbency will roll into sternal recumbency when 12-24 inches of water are in the container and
will usually attempt to
1440
stand when the tub is one-half to two-thirds full. Cows are allowed to stand in the water for 6-8 h. If the
water temperature falls below 950F more hot water is added. When the decision is made to remove the cow,
the water is drained and the end of the tub opened, which allows the cow to walk out preferably onto a
ground or grass surface. A success rate of 46% has been reported (16). However, the success rate could be
higher if the selection of cases for flotation arc more rigorous. Cows with ruptured tendons, fractures,
luxated coxofemoral joints, septic polyarthritis and other physical injuries of the musculoskeletal system
are not good candidates lor flotation. The most suitable case for flotation would appear to be the downer
cow as a sequel to milk fever.
Animal welfare issue
The downer cow syndrome is an animal welfare issue and the veterinarian should be proactive about the
problem. Society is concerned about how downer animals are cared for and handled and the methods used
for their disposition (17). It recovery does not occur within a tew days the prognosis is uncertain and the
owner and veterinarian must decide whether to continue providing clinical care to the downer cow or if the
animal should be slaughtered for salvage or euthanized. Commercial slaughter ot recumbent cattle for
human consumption is esthetically undesirable and emotionally charged. However, recumbent cattle
represent an important source of income for cattle producers and others in the meat industry. In the United
States in 1990-1992, 117301 recumbent cattle were slaughtered at federally inspected abattoirs. Many
consumers believe that meat derived from any animal which cannot stand is unwholesome. However, most
recumbent cattle slaughtered for edible beef are not contaminated by bacteria but the viscera, especially
the liver, may present a food safety problem because of multifocal foci of hepatitis (18).
Government animal health regulatory agencies, livestock associations and veterinary associations are
now involved m drafting regulations on the care and handling ot non-ambulatory recumbent animals like
the downer cow (19). The principles of the humane movement of recumbent animals includes:
1.Not dragging the animal but placing it on some type of sled
2.Using ramps rather than dumping animals
3.Not mixing with other animals
4.Moving animals directly to slaughter and stunning them prior to unloading at the abattoir.
CONTROL
The early detection and treatment of milk fever will reduce the incidence and severity of downer cow
syndrome. Under ideal conditions, cows should be treated during the first stage ot milk fever before they
become recumbent. Once recumbent cows should be treated as soon as possible and not delayed for more
than 1 hour. Cows with milk fever should be well bedded with liberal quantities of straw or moved to a
soft-ground surface. Recumbent cows should be coaxed and assisted to stand if possible after treatment for
milk fever. If they are unable to stand, they should be rolled from one side to the other every few hours if
possible. It is usually difficult to get owners to comply with this recommendation but frequent rolling from
side to side is necessary to minimize the isehemic necrosis. Dairy cows should be placed in a comfortable
well-bedded box stall prior to calving and should be left in that box stall until at least 48 h after partition in
the event that milk fever develops.
ACUTE HYPOKALEMIA IN CATTLE
Hypokalemia in cattle may occur secondary to:
•Anorexia
•Diarrhea
•Upper gastrointestinal obstruction
•Right-sided displacement and torsion of the abomasum
•Impaction of the abomasum.
In most cases, the hypokalemia is not severe enough to cause weakness and recumbency. hypokalemia
resulting in severe weakness and recumbency has occurred in dairy cattle treated with isoflupredone
acetate for ketosis (I). Serum potassium levels were below 2.3 mEq. Cows ranged in age from 2-7 years,
all had a history of moderate to severe ketosis and had calved within the previous 30 d. Most had been also
treated with insulin, IV glucose, and oral propylene glycol. Affected cows were recumbent, profoundly
weak, appeared flaccid and lay in sternal or lateral recumbency. They were unable to support the weight of
their heads off the ground and they were commonly held in their flanks. Anorexia was common. Cardiac
arrhythmias were detectable on auscultation and atrial fibrillation was confirmed on electrocardiography.
Treatment included IV and oral administration of potassium chloride and fluid therapy but the response
was ineffective. Most affected cattle died or were euthanized. At necropsy, muscle necrosis was present in
the pelvic limbs and histological examination of non-weight bearing muscle revealed multifocal
myonecrosis with microphage infiltration and myofiber vacuolation, which is characteristic of
hypokalemic myopathy in man and dogs. It is important to note that myopathy was also present in muscles
1441
not subject to ischemia of recumbency.
Potassium excretion by the kidneys is via secretion by the distal tubular cells. Aldosterone or other steroids
with mineralocorticoid activity enhance distal tubular secretion of potassium by increasing permeability of
the tubular luminal membranes to potassium and increasing losses of potassium in the urine.
Glucocorticoids are often used to treat ketosis and the most commonly used are dexamethasone and
isoflupredone acetate. Dexamethasone has little niineralocorticoid activity compared to prednisone and
prednisolone, which arc related chemically to isoflupredone. Dexamethasone is recommended for the
treatment of ketosis in dairy cattle at a single dose of 10-20 mg IM, and repeated if necessary, 12-24h later.
Field observations indicate that repeated doses of isoflupredone acetate decrease plasma concentrations of
potassium by 70-80%, which suggests a strong niineralocorticoid activity. It is recommended that
isoflupredone be used judiciously and animals be monitored tor plasma potassium and any evidence of
weakness and recumbency. Treatment with oral potassium choride may be required but treatment may be
ineffective.
REFERENCE
(1) Sielman, P.. S. ei a). (1997)J Am. Vet. Med. Assoc, 210, 240.
TRANSIT RECUMBENCY OF RUMINANTS
Transit recumbency (tetany) occurs after prolonged transport, usually in cows and ewes in late pregnancy.
It is also recorded in lambs transported to teedlots (1), and in cows (2) and sheep (3) delivered to abattoirs.
It is characterized by recumbency, alimentary tract stasis and coma, and is highly fatal. It occurs in most
countries. Large losses are encountered when cows and ewes in late pregnancy are moved long distances
by rail, truck or on foot.
Although cows of any age in late pregnancy are most commonly affected, the disease has also been
recorded in cows recently calved, bullocks, steers, dry cows and lambs. Risk factors include:
• Heavy feeding before shipment
• Deprivation of teed and water for more than 24h during transit
•Unrestricted access to water
•Exercise immediately after unloading.
There is an increased incidence of the disease during hot weather. The cause is unknown although
physical stress is an obvious factor. In lambs there is:
1.Restlessness
2.Staggering
3.Partial paralysis of hindlegs
4.Early assumption of lateral recumbency.
Death may occur quickly, or after 2-3 d of recumbency. There is a mild hypocalcemia (7-7.5 mg/dL;
1.75-1.87 mmol/L). The recovery, rate even with treatment is only fair.
Clinical signs may occur while the cattle are still on the transportation vehicle or up to 48 h after
unloading. In the early stages, animals may exhibit excitement and restlessness, trismus and grinding of
the teeth. A staggering gait with paddling of the hindlegs and recumbency occur, and are accompanied by
stasis of the alimentary tract and complete anorexia. Animals that do not recover gradually become
comatose and die in 3-4 d. There may be a moderate hypocalcemia and hypophosphatemia in cattle. In
sheep of various ages, some are hypocalcennc and hypomagneserruc and some are hypoglycemic, but
some have no detectable biochemical abnormality (3). There are no lesions at necropsy other than those
related to prolonged recumbency. Ischemic muscle necrosis is the most obvious of these lesions. The
relationship of the disease to transport or forced exercise is diagnostic.
Some cases respond to treatment with combined calcium, magnesium and glucose injections. Repeated
parenteral injections of large volumes of electrolyte solutions are recommended. In lambs the SC injection
of a solution of calcium and magnesium salts is recommended but the response is usually only 50%, due
probably to an intercurrent myonecrosis (4).
If prolonged transport of cows or ewes in advanced pregnancy is unavoidable, they should be fed on a
moderately restricted diet for several days beforehand and provided with adequate food, water and rest
periods during the trip. The administration of an ataractic before loading is highly recommended,
especially for nervous animals (5). On unloading, they should be allowed only limited access to water for
24 h and should be allowed a minimum of exercise for 2-3 d.
REFERENCES
(1)Pierson, R. E. & Jensen, R. (1975) J. Am.Vet. Med. Assoc, 166, 260.
(2)Wamock,J. P. ct al. (1978) Jml. Vet.J., 54,566.
(3)Shorthose, W. R. & Shaw, F. D. (1977)Aust. Vet.J., 5.1, 330.
(4)Lucas, M.J. (1983) Mod. Vet. Pratt., 64, 213.
(5)van derWalt, K. (1961) J. S. Afi. Vet. Med.Assoc, 32, 283.
LACTATION TETANY OF MARES (ECLAMPSIA, TRANSIT TETANY)
Lactation tetany of mares is caused by hypocalcemia and is characterized by tetany, and incoordination
and recovery following treatment with calcium salts.
The disease was most common when draft horse breeding was widely practiced but is uncommon now.
The mortality rate is high in untreated animals.
Several risk factors are important. Most cases occur in lactating mares, cither at about the tenth day after
foaling or 1-2 d after weaning.
High-producing mares grazing on lush pasture are most susceptible and in many instances are engaged
in hard physical work. The housing of wild ponies, or prolonged transport may precipitate an episode. The
latter has been a particularly important factor in the etiology of the disease in Britain and has been credited
with precipitating it even in stallions and dry mares. Occasional cases occur without there being any
apparent cause (1).The disease has occurred in a 20-year-old gelding pony (2).
Many mild cases which recover spontaneously occur after transport but the mortality rate in some
shipments may be greater than 60%. Mares affected at the foal heat or at weaning are usually more
seriously affected and the mortality rate appears to be higher still.
Severely affected animals sweat profusely and have difficulty in moving because of tetany of the limbs
and incoordination. The gait is stiff and the tail is slightly raised. Rapid, labored respirations and wide
dilatation of the nostrils are accompanied by a distinct thumping sound from the thorax, thought to be due
to spasmodic contraction of the diaphragm. Muscular fibrillation, particularly of the masseter and shoulder
region,
1442
and trismus are evident but there is no prolapse of the membrana nictitans (3). Affected animals are not
hypersensitive to sound but handling may precipitate increased tetany. The temperature is normal or
slightly elevated, and although the pulse is normal in the early stages, it later becomes rapid and irregular.
The mare may make many attempts to eat and drink but appears to be unable to swallow and passage of a
stomach tube may be impossible. Urination and defecation are in abeyance, and peristalsis is reduced.
Within about 24 h the animal becomes recumbent, tetanic convulsions develop and become more or less
continuous: the mare dies about 48 h after the onset ot illness. The tetany and excitement in the early
stages may suggest tetanus but there is no prolapse of the third eyelid and there is the usual relationship to
recent toahng or weaning and physical exertion. The anxiety and muscle tremor of laminitis may also be
confused with those of lactation tetany, especially as it may occur in mares which have foaled and retained
the placenta. Pain in the feet is the diagnostic feature of this latter disease.
Hypocalcemia occurs with serum levels in the range ot 4-6 mg/dL (1-1.50 mmol/l.) and the degree of
hypocalcemia has been related to the clinical signs (4). When serum calcium levels are higher than 8
mg/dL (2 mmol/L) the only sign is increased excitability. At levels of 5-8 mg/dL (1.25-2 mmol/L) there
are tetanic spasms and slight incoordination. At levels of less than 5 mg/dL (1.25 mmol/L), there is
recumbency and stupor. Hypomagnesemia with serum magnesium levels of 0.9 mg/dL (0.37 mmol/L) has
been observed in some cases but only in association with recent transport. Hypermagnesemia has been
reported in other cases.
Treatment by IV administration of calcium borogluconate as recommended in tlie treatment ot
parturient paresis results in rapid, complete recovery. One of the earliest signs of recovery is the voiding of
a large volume of urine. Occasional cases which persist for some days are recorded.
HYPOMAGNESEMIC TETANIES
Tetany associated with depression of serum magnesium levels is a common occurrence in ruminants. The
syndrome associated with hypomagnesemia is relatively constant, irrespective of the cause, but the group
of diseases in which it occurs has been divided into hypomagnesemic tetany of calves, which appears to be
due specifically to a deficiency of magnesium in the diet, and a group of hypomagnesemias in ruminants
characterized by lactation tetany, in which there may be a partial dietary deficiency of magnesium but in
which nutritional or metabolic factors reduce the availability, or increase the body's loss, of the element so
that serum magnesium levels fall below a critical point. In general, the occurrence of hypomagnesemic
tetany is related to three sets of circumstances. Most common is the occurrence in lactating cows turned
out on to lush, grass-dominant pasture in the spring after wintering in closed housing the classic lactation
or grass tetany of Holland. Wheat pasture poisoning may occur when any type ot cattle or sheep is grazed
on young, green cereal crops. The third occurrence is in beet or dry dairy cattle running at pasture in the
winter, usually when nutrition is inadequate and where no shelter is provided in changeable weather rather
than in severe, prolonged cold. Less common forms occur in housed animals on poor teed.
Hypomagnesemia of sheep, although it is less common, occurs in the same general groups of
circumstances as the disease in cattle. A chronic hypomagnesemia, without manifestations ot tetany, can
be a cause of suboptimal production efficiency and may predispose to hypocalcemia.
HYPOMAGNESEMIC TETANY (LACTATION TETANY, GRASS TETANY, GRASS
STAGGERS, WHEAT PASTURE POISONING)
Synopsis
Etiology. The etiology is multifactorial, related to magnesium concentration in the diet and the presence of
competing cations such as potassium and sodium that affect either herbage magnesium status or
magnesium absorption.
Epidemiology. Disease of all classes of ruminants but reaches its highest incidence in older lactating cows
exposed to bad weather or grazing green cereal crops or lush grass-dominant pasture.
Clinical findings. Incoordination, hyperesthesia and tetany, tonic-clonic muscular spasms and convulsions.
High case fatality without treatment.
Clinical pathology. Serum, urine or cerebrospinal fluid (CSF) magnesium concentrations.
Hypomagnesemia, and in some circumstances hypocalcemia. Necropsy findings. None specific.
Diagnostic confirmation. Response to treatment, serum or urinary magnesium concentrations.
Treatment. Magnesium or combined calcium/magnesium solutions administered IV and/or SC.
Control. Magnesium supplementation but a palatable and practical delivery method is a problem.
Magnesium applied to pastures. Avoidance of movement and food deprivation at risk periods.
ETIOLOGY
Magnesium is the major intracellular divalent cation, and is an essential clement in a large number of
enzymic activities in the body. For this reason it might be expected that hypomagnesemia would be rare.
However, because, of the peculiarities of absorption of magnesium in the ruminant forestomachs, and the
use of animal and pasture management systems that can lead to marginal magnesium uptake, ruminants
are at risk of hypomagnesemia.
Magnesium homeostasis
There is no feedback regulatory mechanism to control concentrations of magnesium in the body of
ruminants. As a consequence, magnesium concentrations in blood and extracellular fluid are essentially
determined by the balance between dietary intake of magnesium, loss in feces and milk and the
modulating effect of magnesium homeostasis by the kidney.
Dietary intake
In normal circumstances, magnesium absorbed from the diet is sufficient to meet the requirements of the
body and excess amounts are excreted in the urine.
Renal excretion
The kidney is the major organ of homeostasis and can act to conserve magnesium. Magnesium is freely
filtered across the renal glomerulus and
1443
is reabsorbed within the renal tubules, the degree of reabsorption acting in homeostasis. When the dietary
intake of magnesium is decreased, blood and interstitial fluid magnesium concentrations fall; excretion of
magnesium in the urine will cease when serum concentrations fall below 1.8 mg/dL. The renal threshold
for magnesium excretion is partially under the control of parathyroid hormone and increased levels of
parathyroid hormone will act to conserve magnesium.
Magnesium reserves
There are large stores of magnesium in the body, especially in bone. These are available to the young calf
but mobilization decreases with age and in the adult ruminant there is little mobilization in response to
short-term deficits of magnesium (1). In ruminants, this control mechanism for magnesium can maintain
adequate concentrations of magnesium in bodily fluids in most production circumstances but it can fail
where there is a high requirement for magnesium coupled with a decreased intake. This combination leads
to hypomagnesemia and hypomagnesemic tetany is a possible outcome.
Lactation
Increased requirement for magnesium is almost always associated with the loss of magnesium in the milk
during lactation. Whereas the amount of magnesium in milk is not high (12mg/kg) the loss of magnesium
to milk represents a significant proportion of the dietary intake of magnesium. As a consequence of this
drain, most instances of hypomagnesemia occurin lactating animals around the period of peak milk
production, although in some circumstances the demands of late pregnancy are the cause of the increased
requirement. The decreased intake of magnesium can result from an absolute deficiency of magnesium in
the diet or because the availability or absorption of magnesium from the diet is impaired. These factors
determine the circumstances of occurrence of the disease and are the factors that can be manipulated for
control.
Factors influencing aborption of magnesium
In the adult ruminant, magnesium absorption occurs in the torestomach with little absorption in the
abomasum and small intestine. Some absorption occurs in the large intestine, particularly in sheep (2),
however it cannot compensate for malabsorption in the forestomach.
Na:K ratio in rumen
Magnesium is transported across the epithelium of the forestomachs by an active sodium-linked
ATPase-dependent transport system. Absorption, and the serum magnesium concentration, is influenced
by the Na:K ratio in the rumen, which is determined by the dietary and salivary concentrations of sodium
and potassium (3, 4). Absorption of magnesium increases with an increasing Na:K ratio to plateau at a
ratio of 5:1. Absorption is significantly impaired if the Na:K ratio is less than 3:1.
Young rapidly growing grass is low in sodium and high in potassium and can significantly depress the
Na:K ratio in the rumen fluid, causing impairment ot magnesium absorption. Depression is observed at
dietary potassium concentrations of greater than 22 g/kg dry matter.
Saliva normally has a high Na:K ratio but where there is a deficit of sodium in the diet, a proportion of
sodium in saliva may be replaced with potassium under the influence of aldosterone, which further
negatively influences the uptake of magnesium.
Approximately 40% of the total magnesium available in extracellular fluid is secreted daily in saliva and
20% of this is reabsorbed in the forestomach. When animals are on tetany-prone grass, this absorption is
impaired, which accounts for the susceptibility ot ruminants to hypomagnesemia compared to monogastric
animals (3).
Other factors influencing absorption
Young grass fertilized with nitrogenous fertilizers has an increased crude protein which is readily
fermentable and leads to increased ammonia concentrations. A sudden rise in ruminal concentrations of
ammonia impairs magnesium absorption in the rumen (5, 6). The uptake of magnesium is also influenced
by the carbohydrate content of the diet, magnesium absorption is improved with increasing amounts of
readily degradable carbohydrates (7). The mechanism of this action is not known but low concentrations
of readily degradable carbohydrate in tetany-prone pastures in combination with high concentrations of
protein maybe important to the occurrence of the syndrome (5). Volatile fatty acids provide the energy for
the active transport of magnesium across the rumen wall and increase magnesium absorption.
Other dietary substances have been proposed to influence the absorption of magnesium including
calcium and phosphorus, organic acids such as citric acid and transaconitate, fatty acids and aluminum, but
the significance of their role is controversial (5).
Magnesium in pastures and tetany hazard
The dietary intake of magnesium in grazing animals is directly related to the magnesiumconcentration
inpasturesbut other elements in pastures also influencemagnesium absorption by the ruminant as detailed
earlier.
Required magnesium concentrations
Hypomagnesemia can result from the ingestion of pastures that have insufficient magnesium to meet
dietary requirements. The estimated magnesium concentration in pasture required to meet the dietary
requirement tor pregnant or lactating cattle varies from 1.0-1.3 g/kg dry matter for pregnant cattle,
depending upon the stage of pregnancy, and 1.8-2.2 g/kg dry matter for lactating cattle with both estimates
assuming minimal interference of absorption by other elements in the pasture (8).
The recommended minimal 'safe' concentration of magnesium in pastures is 2g/kg dry matter for
lactating and pregnant cattle with a preference for a concentration of 2.5 g/kg dry matter.
Magnesium availability in pastures and hazard
Hypomagnesemia can also occur in animals grazing pastures with adequate concentrations of magnesium
but that contain high concentrations of potassium and nitrogen, which as detailed earlier, impair absorption
of magnesium in the rumen. Pastures with concentrations of potassium of greater than 30 g K/kg dry
matter ami nitrogen greater than 40 g N/kg dry matter are considered hazardous.
An alternate method for estimating the potential hazard of a pasture is to calculate the K/(Ca + Mg)
ratio using milliequi valentvalues for this estimate.
1444
Pastures with ratios above 2.2 are considered a risk (9).
Winter hypomagnesemia
The occurrence of hypomagnesemia is not restricted to cattle grazing lush pastures and it also occurs in the
winter periods. In housed lactating dairy cattle being fed conserved feeds, hypomagnesemia probably has
the same genesis as that in grazing cattle being associated with a high lactational dram of magnesium in
combination with the feeding of conserved feeds prepared from pastures with marginal magnesium
concentrations. It also occurs in cattle outwintered on poor quality teed.
Hypomagnesemia and hypocalcemia
In some outbreaks of hypomagnesemic tetany, there is also hypocalcemia and, although it is of less severe
degree than in parturient paresis, there is increasing evidence that the actual onset of clinical tetany may be
associated with a rapid fall in serum calcium levels superimposed on a pre-existing hypomagnesemia. This
is particularly true tor wheat pasture poisoning but can also apply to outbreaks with different predisposing
factors.
Chronic hypomagnesemia can have a profound effect on calcium homeostasis. Hypomagnesemia
reduces the production and secretion of parathyroid hormone, reduces hydroxylation ot vitamin D in the
liver, and also causes target organ insensitivity to the physiological effects of parathyroid hormone Mid
1,25-dihydr-oxyvitamin D3 (6, 10, 11). Chronic subclinical hypomagnesemia can increase susceptibility to
milk fever and can predispose to episodes of milk fever and downer cows in lactating dairy cows during
the period of peak lactation.
Summary of etiology
In summary, it appears that a number of factors are capable of causing hypomagnesemia in ruminants and
that under particular circumstances one or other of them may be of major importance.
In lactation tetany of cows and ewes turned onto lush pasture in the spring, a primary dietary
deficiency of magnesium or the presence of high relative concentrations of potassium and nitrogen in the
diet reduces the absorption of magnesium and possibly calcium.
In wheat (cereal) pasture poisoning, the ingestion of abnormally large amounts of potassium and low
levels of calcium in the diet leads to hypomagnesemia and also hypocalcemia.
Hypomagnesemic tetany in cattle wintered at pasture and exposed to inclement weather is associated
with low magnesium intake and inadequate caloric intake, and possibly to the resultant hyperactivity of the
thyroid gland.
Although the above suggestions as to the most important etiological factors in each set of circumstances
in which lactation tetany occurs may be valid, undoubtedly combinations of these and other factors have
etiological significance in individual outbreaks of the disease. The worst combination of causative factors,
and the most common circumstances in which the disease occurs, is inadequate energy intake with a low
dietary content of magnesium (grass pasture) in recently calved cows during a spell of cold, wet and
especially windy weather.
One other important factor is the variation between individual animals in susceptibility to
hypomagnesemia and to the clinical disease. These variations are quite marked in cattle and in intensively
managed, high-producing herds it is probably worthwhile to identify susceptible animals and give them
special treatment (12).
EPIDEMIOLOGY
Occurrence and risk factors for lactation tetany
Lactation tetany in dairy and beef cattle turned out to graze on lush, grass-dominant pasture after winter
housing is common in northern Europe, the United Kingdom and the northern parts of North America.
Grass tetany also occurs in Australia and New Zealand, where the cows are not housed in winter but have
access to a phenomenal flush of pasture growth in the spring (13). This also commonly occurs m beef
cattle in all countries.
With housed cattle, or cattle fed conserved feed during the winter, most cases occur during the first 2
weeks after the cattle are turned out to spring pasture. Pasture which has been heavily top-dressed with
fertilizers rich in nitrogen and potash is potentially the most dangerous. The disease may also occur on this
type of pasture even when the cattle have wintered on pasture in temperate regions. In regions where there
is an autumn flush of pasture, a high incidence ot hypomagnesemic tetany may occur in the autumn or
early winter.
Cattle in the first 2 months of lactation and 4-7 years of age are most susceptible, which probably
reflects an increased risk due to a higher loss of magnesium in milk. Friesian cows have lower magnesium
concentrations than Jerseys grazed under the same conditions (14).
In the northern parts of the United States, outbreaks commonly occur during periods of low barometric
pressure when the ambient temperature ranges between 7℃ (45℉) and 15.5℃ (60℉) and soil
temperatures are below 7℃ (45℉). Outbreaks may be precipitated by inclement weather. In beef cattle
there is commonly a history of poor nutrition and falling body condition in the past few-weeks due to
diminishing hay supplies.
Occurrence and risk factors for wheat (cereal) pasture poisoning
Wheat pasture poisoning is a misnomer as it can occur with grazing of any smallgram cereal pasture. It has
been recorded in many countries but is most prevalent where young cereal crops are utilized for 'winter
grazing’.The southwestern United States has experienced heavy losses of cattle caused by this disease.
This pasture can induce hypomagnesemia in pregnant and lactating cattle and sheep,the risk is with
young rapidly growing pasture, either in the spring, or in the autumn and winter with pastures planted in
late summer. The pasture is usually dangerous for only a few weeks but heavy losses may occur in all
classes ot sheep and cattle. Bos taunts breeds are more susceptible to the development of hypomagnesemia
than Bos indicia (15).
Occurrence and risk factors for winter hypomagnesemia
Hypomagnesemic tetany in cattle wintered in the open causes some losses in the United Kingdom, New
Zealand, southern Australia and the east-central states and Pacific slope of the United States. It occurs in
cattle grazed on pasture in the winter with minimal supplemental hay and in cattle grazed on aftermath
crops and corn stover. The disease occurs in regions with temperate climates, and risk is increased by
exposure to bad weather, which is exacerbated by absence of trees or other shelter in fields and by failure
to supply supplementary feed during these cold spells. The disease does not seem to occur in cattle kept
outside
1445
in prolonged winters where environmental temperature is consistently very low and there is adequate feed.
Hypomagnesenna is recorded in housed cattle in the winter in Europe.
Morbidity and mortality
In all of these forms of the disease, the morbidity rate is highly variable, reaching as high as 12% in
individual herds, and up to 2% in particular areas. The incidence varies from year to year depending
largely on climatic conditions and management practices, and the disease is often limited in its occurrence
to particular farms and even to individual fields.
Although an effective treatment is available, the case-fatality rate is high because of the short course.
Since animals die before they are observed to be ill, there are not accurate figures on case fatality, but it is
probably of the order of 30% in dairy cattle and considerably higher in beef cattle.
There have been few epidemiological studies specifically addressing the importance of the syndrome. In
Finland a lactational incidence rate varying between 0.1% and 0.3% is recorded, with an increase in
parity to at least 6 for lactation tetany occurring on pasture but not for indoor tetany (15). No association
with other diseases was found other than for milk fever. In Northern Ireland, approximately 10% of dairy
cows and 30% of beef cows have subnormal or deficient blood magnesium concentrations during the
grazing season and hypomagnesemia is considered the cause of 20% of the 'sudden death' mortality in beef
cattle (I6, 17). Surveys of beef cattle owners of the relative importance of different diseases invariably rate
hypomagnesemia high in importance.
Pasture risk factors
In most areas of the world there is a strong association between risk for hypomagnesemia and systems of
pasture improvement and pasture fertilization to increase forage yield. There are a number of influences on
the concentration of magnesium and other elements in pasture.
Pasture species
Hypomagnesemia is a problem on grassdominant pastures. Concentrations of calcium and magnesium are
higher in legumes and forbs than in grasses. Within the grasses, different genotypes of the same species
can differ markedly in calcium and magnesium concentrations and most cool season grasses have the
potential to produce hypomagnesemia. However, there are some differences and grasses with a high ratio
of potassium to calcium and magnesium (e.g. Dactylisglomerata, Loliumperenne, Phalaris arundinacea)
are more likely to cause grass tetany than those with low ratios (e.g. Bromus inermis, Poa pratensis,
Agrostis spp.) (9). On soil types where the disease is common, cool-season grass pastures top-dressed with
nitrogenous fertilizers are dangerous and their toxicity may be increased by the application of potash.
Warm-season grasses do not have the same risk and grass tetany is not a problem in cattle grazing
tropical grasses.
Cereal pastures
The greater tendency of cereal grazing to cause hypomagnesemia, is related to a high content of potassium
as well as a low content of magnesium. Tetany hazard, in order of decreasing hazard, is wheat, oats, barley,
rye (14).
Season
High concentrations of potassium and nitrogen and low concentrations of sodium and soluble
carbohydrates occur in pastures during the early growing season and during rapid growth following cold,
wet periods. Pasture magnesium concentrations may not be depressed but the K/(Ca+Mg) ratio is
increased (18).
Fertilization
Application of potash and nitrogenous fertilizers to pastures will decrease the concentration of calcium and
magnesium in plants and will also increase the concentration of potassium and nitrogen. There is some
evidence that nitrate sources of nitrogen depress magnesium less than ammonium sources of nitrogen.
Soil type
The availability of magnesium to the plant is influenced by soil type and some deficiencies in plant
magnesium can be corrected by soil fertilization with magnesium (19). There is no strong association with
any one soil type but high potassium concentrations are consistently associated with increased risk for
tetany.
Highly leached, acid, sandy soils are particularly magnesium deficient and the most likely to respond to
liming and magnesium fertilization (8). In very acidic soils, high aluminum concentrations may depress
magnesium uptake by plants.
A local knowledge of soil type and its influence on magnesium, potassium, calcium and nitrogen uptake
by pastures can allow the judicious selection or avoidance of the use of pastures for at-nsk groups during
periods of risk for hypomagnesemia (12).
Animal and management risk factors
Dry matter intake
The dry matter and energy intake of ruminants can influence susceptibility to hypomagnesemia (20). A
reduction in dry matter intake must reduce the magnesium intake and, in situations where
hypomagnesemia is already present, a further depression of serum magnesium levels can be anticipated
when complete or partial starvation occurs. An insufficient intake of fiber in the winter months can
precipitate hypomagnesemia in pastured cows and ewes and lipolysis is accompanied by a fall in serum
magnesium.
Period of food deprivation
Many outbreaks of hypomagnesemia are preceded by an episode of stress or temporary starvation.
Whether chronic hypomagnesemia pre-exists or not, a period of starvation in lactating cows and ewes is
sufficient to produce a marked hypomagnesemia and the fall may be sufficiently great to cause clinical
tetany. A period of bad weather, yarding, transport or movement to new pastures or the introduction to
unpalatable pastures may provide such a period of partial starvation.
Alimentary sojourn
Diarrhea is commonly associated with lactation tetany on spring pasture and by decreasing the alimentary
sojourn may also reduce magnesium absorption.
Climate
A close association between climatic conditions and serum magnesium levels has also been observed.
Reduced levels occur in adult cattle and sheep exposed to cold, wet, windy weather with little sunshine
and no access to shelter or supplementary feed. Supplementary feeding appears to reduce the effect of
inclement weather on serum magnesium levels and it is possible that failure to eat, or depression of
appetite, and a negative energy balance
1446
during bad weather may be a basic contributing cause to hypomagnesemia in these circumstances.
Animal movement
Epinephrine release will result in a precipitous tall in serum magnesium and tins may explain the common
observation that clinical cases are often precipitated by excitement or movement of the herd.
Intensive dairies
Intensive dairies that apply effluent on a limited land base can build soil potassium to high concentrations.
Silage from these grounds can have a high risk for inducing hypomagnesemia.
Hypomagnesemia in sheep
Hypomagnesemia occurs in sheep, particularly in Australia and the United Kingdom. The disease is not
common but appears to be increasingly associated with pasture improvement practices, and can cause
heavy losses in individual flocks. It is more common in ewes bred for milk and lamb production. In
outbreaks, ewcs with twins are more liable to develop clinical disease than those with singles and the
mam occurrence is in ewes 1-4 weeks after lambing with cases up to 8 weeks after lambing.
Disease is often precipitated by a management procedure involving movement and temporary food
deprivation and cases will occur within the first 24 h following this and for a few days afterwards. As in
cattle, disease occurs when ewes are placed on lush grass pastures but it is especially common where ewes
in early lactation are placed on young cereal pastures. Losses usually cease when the flock is moved onto
rough, unimproved pasture.
Cases also occur in sheep which are exposed to inclement weather when on a low nutritive intake.
Simultaneous hypomagnesemia and ketosis can occur in ewes after lambing it they are exposed to low
teed availability. Thesc cases do not respond well to treatment. Hypomagnesemia in ewes is predisposed
by prior pregnancy toxemia in the Hock.
PATHOCF.NESIS
Most evidence points to hypomagnesemia as the cause of the tetanic signs observed but the concurrent
hypocalcemia may have a contributory effect and m many instances may even be the dominant factor.
Most clinical cases of the disease have serum magnesium levels below 1 mg/dL (0.41 mmol/L) compared
with the normal levels in cattle of 1.7-3 mg/dL (0.70-1.23 mmol/L) and there is a striking relationship
between the incidence of the clinical disease and the occurrence of a seasonal hypomagnesemia.
The reduction in serum levels of magnesium is concurrent with a marked fall in the excretion of
magnesium in the urine. In affected herds and flocks, many clinically normal cows and sheep have low
serum magnesium levels. In some of these circumstances a concurrent hypocalcemia may be the
precipitating cause.
Magnesium has many influences on impulse transmission at the neuromuscular system, including
effects on the release of acerylcholine, on the sensitivity of the motor end plate, on the threshold of the
muscle membrane and on activation of the chohnesterase system. These offer an attractive hypothesis for
the muscular irritability seen with the disease. However, it has also been established that magnesium
concentrations in the cerebrospinal fluid are more predictive of clinical disease than those in serum, which
would indicate that alterations in CNS function are more important than alterations in peripheral nerve
function. It is also evident that CSF levels of magnesium in hypomagnesemic animals rise significantly
after treatment with a magnesium salt (21). The need for this to happen would explain the delay of about
30 mm after an IV injection before recovery occurs.
QLINICAL FINDINGS
For convenience, lactation tetany is described in acute, subacute and chronic forms.
Acute lactation tetany
The animal may be grazing at the time and suddenly cease to graze, adopt a posture of unusual alertness
and appear uncomfortable; twitching of the muscles and ears is also evident. There is severe
hyperesthesia and slight disturbances precipitate attacks of continuous bellowing and frenzied galloping.
The gait becomes staggering and the animal falls with obvious tetany of the limbs, which is rapidly
followed by clonic convulsions lasting for about a minute. During the convulsive episodes there is:
·Opisthotonos
·Nystagmus
·Champing of the jaws
·Frothing at the mouth
·Pricking of the ears
·Retraction of the eyelids.
Between episodes, the animal lies quietly but a sudden noise or touch may precipitate another attack.
The temperature rises to 40-40.5 ℃(104-105℉) after severe muscle exertion the pulse and respiratory
rates are also high. The absolute intensity of the heart sounds is increased so that they can be heard some
distance away from the cow. Death usually occurs within 5-1 h and the mortality rate is high because
many die before treatment can be provided. The response to treatment is generally good if the animal is
treated early.
Subacute lactation tetany
In this form of the disease, the onset is more gradual. Over a period of 3-4 d, there is slight mappctence,
wildness of the facial expression and exaggerated limb movements. The cow often resists being driven
and throws her head about as though expecting a blow. Spasmodic urination and frequent defecation are
characteristic. The appetite and milk yield are diminished and ruminal movements decrease. Muscle
tremor and mild tetany of the hindlegs and tail with an unsteady, straddling gait may be accompanied by
retraction of the head and trismus. Sudden movement, noise, the application of restraint or insertion of a
needle may precipitate a violent convulsion.
Animals with this form of the disease may recover spontaneously within a few days or progress to a
stage of recumbency with a similar but rather milder syndrome than in the acute form. Treatment is
usually effective but there is a marked tendency to relapse.
Chronic hypomagnesemia
Many animals m affected herds have low serum magnesium levels but do not show clinical signs. There
may be sudden death. A few animals do evidence a rather vague syndrome including dullness,
unthriftmess and indifferent appetite and may subsequently develop one of the more obvious syndromes.
In lactating cows, this may be the development of paresis and a milk fever-like syndrome that is poorly
responsive to calcium treatment. Depressed milk production has also been
1447
attributed to chronic hypomagnesemia in dairy herds in New Zealand (22, 23). The chronic type may also
occur in animals which recover from the subacute form of the disease.
Parturient paresis with hypomagnesemia
This syndrome is described under parturient paresis (p. 1425) and consists of paresis and circulatory
collapse in an adult cow which has calved within the preceding 48 h but in which dullness and flaccidity
are replaced by hyperesthesia and tetany.
CLINICAL PATHOLOGY
Serum or urinary magnesium concentrations can be used for clinical cases. Where an animal is dead and
hypomagnesemia is suspect, a presumptive diagnosis can be made from samples taken from other at-risk
animals in the group, or from the vitreous humor of the dead animal.
Serum magnesium concentrations
Normal serum magnesium concentrations are 1.7-3 mg/dL (0.70-1.23 mmol/L). These levels in cattle are
often reduced in seasonal subclinical hypomagnesemia to between 1 and 2 mg/dL (0.41 and 0.82 mmol/L)
but risk for tetany is not present until the level falls to below 1.2 mg/dL (0.49 mmol/L).
The average level at which signs occur is about 0.5 mg/dL (0.21 mmol/L) and in sheep it is suggested
that clinical tetany does not occur until the serum magnesium level is below 0.5 mg/dL (0.21 mmol/L).
Serum magnesium in some animals may fall to as low as 0.4 mg/dL (0.16 mmol/L) without clinical
illness. This may be due to individual animal variation in the degree of ionization of the serum magnesium
and in the difference between serum and CSF concentrations. It is also possible that a transitory elevation
of serum concentrations occurs after violent muscular exercise.
Total serum calcium levels are often reduced to 5-8 mg/dL (1.25-2.00 mmol/L) and this may have an
important bearing on the development of clinical signs. Serum inorganic phosphate levels may or may not
be low.
In wheat pasture poisoning of cattle there is hypocalcemia, hypomagnesemia and hyperkalemia. In acute
tetany, serum potassium levels are usually dangerously high and may contribute to the high death rate.
CSF magnesium concentrations
Magnesium concentrations in CSF can be used as a diagnostic procedure but CSF is not easily or safely
collected in tetany cases. Fluid collected up to 12 h after death can be used diagnostically.
Levels in CSF of 1.25 mg/dL (0.51 mmol/L) magnesium were round in tetanic cows with
hypomagnesemia (serum magnesium levels of 0.54 ± 0.41 mg/dL; 0.22 ±0.17 mmol/L). In clinically
normal cows with hypomagnesemia comparable levels in CSF were 1.84 mg/dL (0.74 mmol/L) and in
serum 0.4 mg/dL (0.16 mmol/L). In normal animals CSF levels are the same as in plasma, i.e. 2.0 mg/dL
(0.82 mmol/L) and up. The magnesium content of ventricular CSF may be quite different to that of lumbar
CSF. It is also more responsive to changes in magnesium levels of the blood and is preferred for diagnosis
at necropsy (24).
Urine magnesium concentrations
The occurrence of low urine magnesium levels is good presumptive evidence of hypomagnesemia (25).
Herd diagnosis
The kidney is the major organ of homeostasis and it has been argued that analysis of urine magnesium
status is a more accurate method of assessing herd magnesium status than serum magnesium
concentrations (26). The magnesium status of a herd, and the need to supplement the diet to prevent
lactation tetany, can be established from (1) serum magnesium levels, (2) urinary magnesium
fractional clearance ratios or (3) creatinine-cor-rected urinary magnesium concentrations.
Laboratory charges for urinary magnesium fractional clearance ratios are expensive. The determination
of the creatinine-corrected urinary magnesium concentration from 10 cows in a herd has been found to
be a more sensitive indicator of magnesium status of the herd than estimates from serum, and a better
predictor of response to supplementation. Values of less than 1.0 mmol/L indicate that a positive response
to supplementation is likely (26).
NECROPSY FINDINGS
There are no specific findings. Extravasations of blood may be observed in SC tissues and under the
pericardium, endocardium, pleura, peritoneum and intestinal mucosa. Agonal emphysema may also be
present. The magnesium content of the bovine vitreous humor is considered to be an accurate estimate of
magnesium status for 48 h after death, provided the environmental temperature does not exceed 23℃
(73℃) (24). Concentrations in the aqueous humor are not diagnostic (27).
DIFFERENTIAL DIAGNOSIS
Cattle
•Acute lead poisoning (p. 1578)
•Rabies (p. 1201)
•Nervous ketosis (p. 1453)
•Bovine spogiform encephalopathy (p.1233).
Sheep
•hypocalcemia (p. 1429)
•Phalaris poisoning (p. 1651)
•'Stagger'syndromes (pp. 1689, 1698,1703).
TREATMENT
IV administration of preparations containing magnesium or magnesium and calcium are used. The
efficiency of the various treatments appears to vary from area to area, and even within areas under
different conditions of management and climate. Response rates and recovery rates are much higher in
cases treated early in the clinical course. IV chloral hydrate may be administered to reduce the severity of
convulsions during treatment with magnesium. Case fatality, even with therapy, can be high, especially in
advanced cases.
Combined calcium/magnesium therapy
The safest general recommendation is to use a combined calcium-magnesium preparation (e.g. 500 mL of
a solution containing 25% calcium borogluconate and 5% magnesium hypophosphite for cattle, 50 mL for
sheep) IV followed by a SC injection of a concentrated solution of a magnesium salt. The details and risks
of administration of the type of solution is given in the section on parturient paresis (p. 1430). A
combination of 12% magnesium adipate and 5% calcium gluconate at a dose rate of 500 mL is also used.
Magnesium therapy
When magnesium solutions are used 200-300 mL of a 20% solution of magnesium sulfate may be injected
IV; this is followed by a rapid rise in serum magne-
1448
sium concentration which returns to preinjection levels within 3-6 h. A much slower rise and fall occurs
after SC injection and for optimum results the SC injection of 200 niL of a 50% solution of magnesium
sulfate has been recommended. A rise in serum magnesium of 0.5 mg/dL (0.21 mmol/L) occurs within a
few minutes and subsequent levels do not go above 5 mg/dL (2.06 mmol/L). In cases where serum
magnesium levels are low because of a seasonal hypomagne-semia, the injection of magnesium salts is
followed by a rise and then a return to the subnormal preinjection levels.
The IV injection of magnesium salts is not without danger. It may induce cardiac dysrhythmia, or
medullary depression may be severe enough to cause respiratory failure. If signs ot respiratory distress or
excessive slowing or increase in heart rate are noticed, the injection should be stopped immediately and, if
necessary, a calcium solution injected.
The substitution of magnesium lactate for magnesium sulfate has been recommended to provide a more
prolonged elevation of serum magnesium levels. A dilute solution (3.3%) causes minimal tissue injury and
cm be administered IV or SC. Magnesium gluconate has also been used as a 15% solution at dose rates of
200-400 mL. High serum magnesium levels are obtained more slowly and are maintained longer than with
magnesium sulfate.
The feeding ot magnesium-rich supplements, as described under control later, is recommended after
parenteral treatment.
Provision for further cases
The predisposing factors that lead to a case of hypomagnesemia apply to the herd as a whole and it is
probable that further clinical cases will occur before the effects of corrective strategies are in effect. In
extensive range situations, it is advisable to instruct the owner on how to treat cases as a delay in treatment
can markedly increase the rate of treatment failures. SC treatment is within the realm of most, but
successful therapy is also recorded by the rectal infusion of 30 g of magnesium chloride in a 100 mL
solution; serum concentrations of magnesium return to normal levels within 10 min of administration (28).
CONTROL
Where possible, animals at high risk should be moved to low-risk pastures
during the grass tetany season. High-risk pastures can be grazed by low-risk animals, steers or yearling
heifers for example, during this period.
The occurrence of hypomagnesemia can be corrected by the provision of adequate or increased amounts
of magnesium in the diet. The problem is in determining an adequate delivery system and this will vary
according to the management system. Thus blocked minerals containing magnesium or foliar dressing of
magnesium may be adequate delivery systems where there is a high stocking density of cattle, but they are
totally inadequate or economically unfeasible on range with one cow per 20 acres.
Magnesium oxide is commonly used for supplementation but other magnesium salts can be used and
they have an approximate equivalent availability (29). The biological availability of magnesium from
magnesium carbonate, magnesium oxide and magnesium sulfate for sheep has been determined as 43.8%,
50.9% and 57.6%, respectively.
Feeding of magnesium supplements
The preventive measure which is now universally adopted is the feeding of magnesium supplements to
cows during the danger period. The feeding of magnesite (containing not less than 87% magnesium
oxide), or other sources of magnesium oxide, prevents the seasonal fall in serum magnesium levels. Daily
administration by drenching, or in the feed, of at least 60 g of magnesium oxide per day is recommended
to prevent the disease. This is not always completely effective and m some circumstances large doses may
be necessary. Daily feeding of 120 g is safe and effective but 180 g daily may cause diarrhea. The dose for
sheep is 7 g daily or 14 g every second day. Magnesium phosphate (53 g/d) is also a safe and effective
way of insuring a good intake of magnesium. The protection afforded develops within several days of
commencing administration and terminates abruptly after administration ceases.
Problems with palatability
The problem with magnesium supplements is with getting the stock to eat the required amount as they are
unpalatable. This can be partially countered by mixing the supplement with molasses in equal parts and
allowing free access to the mixture, or feeding it in ball feeders,
but uniform intake by all animals does not occur and at-risk animals may still develop hypomagnesemic
tetany. Similarly, magnesium blocks may have limited efficacy in preventing hypomagnesemia (16, 17).
Spraying on hay
One method of attempting to insure an adequate intake of magnesium is to spray it on hay and to feed this
hay as a supplement during periods of grass tetany risk. The common practice is to:
1.Mix magnesite with molasses
2.Dilute mixture with water
3.Spray mixture onto hayin the windrows when it is being made
4.Inject mixture into the bales before
feeding or spray onto the hay at feeding
5.Determine the level of application by
the amount of hay intended to be fed.
Depending upon local circumstances, this method may or may not be effective, as cattle and sheep will
frequently not eat hay when on spring pasture unless they are confined for that purpose.
Pellets
Magnesium-rich pellets suggest themselves as a means of supplementation when the additional cost can be
borne. Palatability is again a problem and care needs to be taken to include palatable material in the pellets;
alternatively they may be mixed with other grain or molasses for feeding. Calves should be restricted from
access as magnesium oxide at high levels of intake (2% and 4% of the ration) is toxic to calves and causes
diarrhea with much mucus in the feces.
In some high-risk situations it may be advisable to provide magnesium in several forms to insure
adequate intake.
Routine daily drenching
A once-daily oral administration of magnesium oxide or magnesium chloride to lactating dairy cows (to
provide 10 g magnesium per cow), administered with a drenching gun just before the cows leave the
milking parlor, is used in New Zealand to insure adequate supplemental magnesium during periods of high
risk. The cows become used to the procedure (and the farmers adept at carrying it out) and it causes
minimal disruption of management.
1449
Heavy magnesium 'bullets'
The use of heavy 'bullets' of magnesium to prevent hypomagnesemia has been effective in laboratory trials
and they are available commercially in some countries. The objective is to place a heavy 'bullet' of
magnesium in the reticulum from which site it constantly liberates small amounts of magnesium - about 1
g/d. This objective is achieved and the occurrence of the clinical disease is usually greatly reduced but not
eliminated. In dangerous situations, it is customary to administer up to four bullets at a time. As with all
bullets, there is a proportion lost by regurgitation and by passage through the gut. A special sheep-sized
'bullet' is used in ewes with similar results.
Top dressing of pasture
This, together with magnesium-rich fertilizers, raises the level of magnesium in the pasture and decreases
the susceptibility of cattle to hypomagnesemia. For top dressing, calcined magnesite (1125 kg/ha) or
magnesic limestone (5600 kg/ha) are satisfactory, the former resulting in a greater increase in pasture
magnesium.
Other magnesium-containing fertilizers can be used depending on cost. The duration of the improved
magnesium status varies with the type of soil: greatest on light sandy loams on which a dressing of 560
kg/ha of calcined magnesium can provide protection for 3 years. On heavy soils protection for only 1 year
is to be expected. To avoid unnecessary expense, it may be possible to top dress one field with the
magnesium fertilizer and keep this field in reserve for spring grazing. Fertilization with magnesium is
expensive and the response of pastures varies markedly with the soil type. It is advisable to seek
agronomic advice.
Foliar dusting and spraying
The magnesium content of pastures can be raised much more quickly by spraying with a 2% solution of
magnesium sulfate at fortnightly intervals or by application of very finely ground magnesium oxide to the
pasture (30 kg/ha) before grazing commences. The technique is referred to as 'foliar dusting or spraying'
and has the advantage over feed supplementation that the intake is standard. It is very effective in cattle in
maintaining serum magnesium levels and preventing the occurrence of the clinical disease.
Dusting is with 20-50 kg MgO/ha can provide protection for up to 3 weeks but the duration is adversely
influenced by wind and rain. A MgO-bentonite-water slurry sprayed onto pastures (26 kg MgO and 2.6 kg
bentonite/ha) is effective in providing protection in high rainfall periods.
Provision in drinking water
The problem with water medication is that the water intake of the group to be treated is not known but
may be minimal on rapidly growing pastures. However, water medication may provide a delivery system
for magnesium on management systems such as extensive range pastures where other methods may have
limited success. Water sources other than the medicated supply need to be fenced off or otherwise
restricted. The addition of magnesium sulfate (500 g/100 L) or mag¬nesium chloride hexahydrate (420 g/
100 L) to the water supply during the risk period for hypomagnesemia has proved effective.
Management of pasture fields
The economics of daily farming make it necessary to produce maximum pasture growth, and the
development of tetanyprone pastures is unavoidable in many circumstances. In some areas it may be
possible to reduce the danger of such pastures by encouraging the development of legumes. In other areas
the period of legume growth does not coincide with the period of maximum risk for grass tetany.
Restricting the amount of potash added to pastures, especially in the period immediately preceding the
risk period for tetany, or using potash fertilizers m the autumn or late spring after the period of risk, can
reduce risk of the disease. The grazing of low-risk animals on high-risk pastures is another strategy.
Insuring that ample salt is available during the danger period to counteract the high intake of potassium
can also reduce risk of the disease.
Plant geneticists are developing cultivars of cool-season grasses with high magnesium content that
could be used for grazing during the tetany season. Lactating sheep grazing a high magnesium cultivar of
perennial rye grass (Lolium perenne cv Radmore) in the spring have shown higher blood magnesium
concentrations than sheep grazing control cultivar (30).
Provision of shelter
In areas where winter pasturing is practiced, the observation that serum magnesium levels fall during the
winter and in association with inclement weather suggests that cattle and sheep should be provided with
shelter at such times. If complete housing is impractical, it may be advisable to erect open access shelters
in those fields that have no tree cover or protection from prevailing winds. Fields in which lactating cows
are kept should receive special attention in this regard. Unfortunately, the disease is most common on
highly improved farms, where most natural shelter has been removed and it is desired to keep the cows on
the highly improved pasture to maintain milk production or fatten calves rapidly.
Time of calving
In areas where the incidence of the disease is high, it may be advisable to avoid having the cows calve
during the cold winter months when seasonal hypomagnesemia is most likely to develop. Unfortunately it
is often important to have cows calve in late winter to take advantage of the flush of spring growth when
the cows are at the peak of their lactation.
Feeding on hay and unimproved pasture
Because of the probable importance of lush, improved, grass pasture in producing the disease, the
provision of some gram, hay or rough grazing may reduce its incidence. It is most important that the
periods of fasting, such as occur when cattle or sheep are yarded or moved or during bad weather, should
be avoided, especially in lactating animals and when seasonal hypomagnesemia is likely to be present.
REVIEW LITERATURE
Rendig, V. V. &; Grimes, I). L. (1979) Grass tetany. Special Publication No., 35, American Society of
Agronomy, Wisconsin, USA.
Rohcrson, D. L., Koppel, L. C. & BolingJ. A. (1989) Management practices to overcome the incidence
of grass tetany. J. Anim. Sd., 67, 3470-3484.
Rogers, P. A. M. (1979) Hypomagnesemia and its clinical syndromes in cattle: a review. Irish Vet. J., 35,
115.
Littledike, E. T , Young, J. W. & Beitz, D. C. (1981) Common metabolic diseases of cattle: ketosis,
milk fever, grass tetany, and the downer cow complex.J. Dairy Sci., 64, 1465-1482.
1450
Fontenot,J. P., Allen, V. G., Bence, G. E. & Goff, J. P. (1989) Factors influencing magnesium
absorption and metabolism in ruminants. J. Anim. Sci., 67, 3445 3455.
Hoffsis, G. E., Saint-Jean. G. & Rings, D. M. (1989) Hypomagnesemia in ruminants. Comp. Com.
F.iluc. Pract. Vet., 11(4), 519-526.
McCaughan, C.J. (1992) Treatment of mineral disorders in cattle. Vet. Clitt. North Am.: Food Anim.
Pract., 8(1), 107-145.
Dua, K. & Care, A. D.(1995) Impaired absorption of magnesium in the aetiology of grass tetany. Br.
Vet.J., 151, 413-426.
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(21)Meyer. 11. (1977) Vet. Sci. Commum., I. 43.
(22)Anonymous (1984) Surveillance,11(1), 5.
(23)Caple, I. W. & 1 lalpin, C. G. (1985) Sydney Pert Grai. Course Dairy Production,76, 307.
(24)Lincoln, S. D. & Lane, V. M. (1985) Am.J Vet. Res , 46. 160.
(25)Allsop, T. F. & I'.iuh, J. V. (1985) Res. Vet Sd . 38, 61.
(26)Sutherland. R.J. et al. (1986) NZ vet.J,54. 133.
(27)Whitaker, D. A. et al. (1986) Vet. Rec.118, 570.
(28)Bacon, J. A. et al. (1990)J. Dairy Sci.. 75,470.
(29)Davenport. G. M. et al. (1990) J. Anim.Sd., 68, 3765.
(30) Binnie, R. C. ct al. (1996) Crass Forage Sci., 51, 456.
HYPOMAGNESEMIC TETANY OF CALVES
Synopsis
Etiology. Hypomagnesemia, resulting from inadequate magnesium in the diet. Epidemiology. Most
commonly calves 2-4 months of age, on whole milk or milk replacer diets and poor or no roughage.
Diarrhea and chewing bedding or other coarse fiber may exacerbate the deficiency.
Clinical findings. Apprehension, agitation, hypersensitivity to all external stimuli, fine muscle tremors
progressing to spasticity and violent convulsions. Rapid course and high case-fatality rate.
Clinical pathology. Serum magnesium levels below 0.8 mg/dl, bone calcium:magnesium ratio above
90:1.
Necropsy findings. Calcification of the spleen, diaphragm and endothelium of the aorta and endocardium.
Enzootic muscular dystrophy is often concurrent.
Diagnostic confirmation. Blood magnesium and response to treatment. Bone calcium:magnesium ratios.
Treatment and control. Magnesium injection and dietary supplementation with magnesium compounds.
ETIOLOGY
The disease results when the dietary intake ot magnesium is inadequate for the requirements of the calf.
Affected animals may have concurrent hypocalcemia.
Magnesium homeostasis in the calf
Milk has low concentrations ot magnesium. A milk diet provides adequate magnesium for the
requirements of a growing calf up to a body weight of approximately 50 kg, but if milk is the sole diet, the
intake of magnesium will be inadequate for requirements once Ins body weight is reached (1). The deficit
will perpetuate if the other feeds that are fed are also low in magnesium.
In the young calf, magnesium is absorbed in the intestine; however, the efficiency of magnesium
absorption decreases markedly up to about 3 months of age, when maximum susceptibility to the disease
occurs. The efficiency of absorption is decreased by a reduction in transit time in the intestine caused by
diarrhea.
In contrast to adult cattle,young calves can mobilize body stores of magnesium, which are principally
located in the skeleton. Approximately 40% of the magnesium stored in the skeleton can be mobilized,
which will protect against a short-term deficit (1).
Hypomagnesemic tetany in calves is often complicated in field cases by the coexistence of other
diseases, especially enzootic muscular dystrophy.
EPIDEMIOLOGY
Occurrence
The disease is not common. Cases may occur sporadically or a number of deaths may occur on the one
farm within a short period of time.
Risk factors
The disease can occur under a number of different circumstances.
Most commonly, hypomagnesemic tetany occurs in calves 2-4 months of age or older which are fed
solely on a diet of whole milk, and calves receiving the greatest quantity of milk and growing most
rapidly are more likely to be affected because of their greater need for magnesium tor incorporation into
developing soft tissues. It is most likely to occur in calves being fattened for veal. Those cases winch
occur on milk replacer appear to be related to chronic scours and low magnesium content of the replacer.
This problem is less common than it once was because most modern commercial milk replacers have
added adequate magnesium.
A significant loss of magnesium in the feces also occurs in calves allowed to chew fibrous material
such as bedding; the chewing stimulates profuse salivation and creates greater loss of endogenous
magnesium. Peat and wood shavings are bedding materials known to have this effect.
Cases have also been reported in calves fed milk-replacer diets or milk, concentrates and hay, and in
calves running at pasture with their clams. Deaths due to hypomagnesemic tetany have also occurred in
3-4-months-old calves whose hay and silage rations were low in magnesium content (2).
Hypomagnesemia also occursin young cattle, about 6 months of age, which are being fattened
intensively indoors for the baby beef market. The phosphorus content of their diet is high and a lack of
vitamin D is probable. The
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situation is exacerbated by a shortage of roughage. The hypomagnesemia is accompanied by a
hypocalcemia.
Experimental reproduction
A condition closely resembling the field syndrome has been produced experimentally by feeding an
artificial diet with a very low content of magnesium; a high calcium content and biochemical
hypomagnesemia is readily produced in calves with a diet based on skim milk and barley straw (3).
Hypomagnesemia hasas also been produced experimentally in very young foals by feeding a diet with a
very low magnesium content. The clinical signs are similar to those in calves, and the calcification found
in the walls of vessels of calves also occurs in foals.
PATHOGENESIS
On affected farms, calves are born with normal serum magnesium levels of 2-2.5 mg/dL (0.82-1.03
mmol/L) but the levels fall gradually in the succeeding 2-3 months, often to below 0.8 mg/dL (0.33
mmol/L). Tetany does not occur until the serum magnesium falls below this concentration and is most
severe at concentrations below 0.6 mg/dL (0.25 mmol/L), although some calves in a group may have
concentrations even lower than this and show few clinical signs.
Magnesium deficiency inhibits the release and action of parathyroid hormone and this is believed to
be the genesis of the concurrent hypocalcemia (4). It is probable that depression of the serum calcium
level precipitates tetany in animals rendered tetany prone by low serum magnesium levels. Tetanic
convulsions can occur in hypocalcemic calves in the absence of hypomagnesemia.
Hypomagnesemic tetany is not related in any way to enzootic muscular dystrophy, although the diseases
may occur concurrently.
CLINICAL FINDINGS
The first sign in the experimental disease is constant movement of the ears. The temperature is normal and
the pulse rate accelerated. Hyperesthcsia to touch, and grossly exaggerated tendon reflexes with clonus,
are present. Shaking of the head, opisthotonos, ataxia without circling, and a droopy, backward carriage of
the ears are constant. There is difficulty in drinking due to the animal's inability to get to the bucket.
Initially, the calves arc apprehensive, show agitation and retraction of the eyelids when approached,
and are hypersensitive to all external stimuli but show no tetany. Later, fine muscle tremors appear,
followed by kicking at the belly, frothing at the mouth and spasticity of the limbs. Convulsions follow,
beginning with stamping of the feet, head retraction, champing of the jaws and falling.
During the convulsions the following signs are present:
•Jaws are clenched
•Respiratory movements cease
•There are tonic and clonic movements of the limbs
•There is involuntary passage of urine and feces
•There are cycles of protrusion and retraction of the eyeballs.
The pulse rate rises to 200-250/min and the convulsions disappear terminally. The pulse becomes
impalpable and cyanosis appears before death.
In field cases the signs are almost identical but are rarely observed until the terminal tetanic stage. Older
calves usually die within 20-30 min of the onset of convulsions but young calves may recover temporarily
only to succumb to subsequent attacks. Cases which occur in young calves with scours, usually at about
2-4 weeks of age, show ataxia. hyperesthesia, opisthotonos and convulsions as the presenting signs (5).
The convulsion is usually continuous and the calves die within 1 h.
CLINICAL PATHOLOGY
Serum magnesium levels below 0.8 mg/dL (0.33 mmol/L) indicate severe hypomagnesemia and clinical
signs occur with levels of 0.3-0.7 mg/dL (0.12-0.20 mmol/L). Normal values are 2.2-2.7 mg/dL (0.9-1.1 1
mmol/L). Erythrocyte magnesium concentrations are also low. indicating a chronic deficiency. Serum
calcium levels tend to fall when serum magnesium levels become very low and are below normalin most
clinical cases.
The estimation of the magnesium in bone (particularly ribs and vertebrae) is a reliable confirmatory
test at necropsy. Values below a ratio of 70:1 for calcium: magnesium may be regarded as normal and
above 90:1 are indicative of severe magnesium depletion. In the normal calf the ratio is about 55:1.
Absolute bone calcium values are not decreased and ar often slightly elevated. An incident; change is the
marked increase in serur creatinme phosphokinase levels observe in calves after an acute attack of
hypomagnesemic tetany.
NECROPSY FINDINGS
There is a marked difference between th necropsy lesions of some natural cases and those m the
experimental disease. In field cases, there is often calcification of the spleen and diaphragm, and calcifiei
plaques are present in the aorta and endo cardium, together with hyaline degeneration and musculature. In
other case necropsy lesions similar to those ii enzootic muscular dystrophy occur.
In experimentally produced case these lesions are not evident but there extensive congestion in all
organs, and hemorrhages in unsupported organs including the:
•Gallbladder
•Ventricular epicardium
•Pencardiium fat
•Aorta
•Mesentery wall
•Intestinal wall.
The lesions are obviously terminal and are associated with a terminal venous necrosis. Some field cases
present a picture identical to this.
DIFFERENTIAL DIAGNOSIS
•Acute lead poisoning
•Enterotoxemia caused by Closthdium perfringens Type D
•Polioencephalomalacia
•Tetanus
•Vitamin A deficiency
•Meningitis.
TREATMENT
Response to magnesium injections (100 mL of a 10% solution of magnesium sulfate) is only transitory
because of the severe depletion of bone reserves of magnesium. This dose provides only a single day's
requirements. Follow-up supplementation of the diet with magnesium oxide or carbonate as described
later is advisable. Chloral narcosis or tranquilization with an ataractic drug may be essential to avoid death
due to respiratory paralysis during convulsions.
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CONTROL
The provision of a hay that is high in magnesium, such as alfalfa, helps to prevent the disease as will
well-formulated concentrates.
Supplementary feeding of magnesium
If begun during the first 10 days of life, supplementary magnesium feeding will prevent excessive falls of
serum magnesium, but if begun after the calf is 7 weeks old, may not prevent further depression of the
levels. Supplementation should continue until at least 10 weeks of age. Daily feeding of the magnesium
compound and fairly accurate dosing are necessary to avoid scouring or inefficient protection. For calves
of average growth rate appropriate close rates are 1 g/d for calves to 5 weeks of age, 2 g/d for calves 5 10
weeks of age and 3 g/d for calves 10 15 weeks of age of magnesium oxide or twice this dose of carbonate.
Supplementation of the diet with magnesium restores serum calcium levels to normal as well as correcting
the hypomagnesemia.
Magnesium alloy bullets
Two bullets of the sheep size (together releasing approximately 1 g/d of magnesium) per calf, have shown
high efficiency in preventing the clinical disease and also the hypomagnesemia which precedes it. Calves
kept indoors and fed largely on milk should get adequate mineral supplement and vitamin D (70 000 in
vitamin D3/d). Magnesium utilization will not be affected but calcium absorption, which is often
sufficiently reduced to cause a concurrent hypocalcemia, will be improved.
REFERENCES
(1)Sansom, B. F. (1981) Vet. Ann., 21, 74.
(2)Rayssiguier, P.J. et al. (1977) Vet. Sii. Commun., 1, 235.
(3)Mulci, C. M & Daniels, R. C. W. (1989)J Vet. Med., 36, 783.
(4)Schnieder, K. M. et al. (1985) Ami. Vet.J., 62, 82.
(5)Mills, J. (1992) Vet. Rec, 131,60.
KETOSIS IN RUMINANTS (ACETONEMIA IN CATTLE, PREGNANCY TOXEMIA IN SHEEP)
Synopsis
Etiology. A multifactorial disorder of energy metabolism. Negative energy to hypoglycemia and
ketonemia (the accumulation in blood of acetoacetate, beta-hydroxybutyrate and their decarboxylation
products acetone and isopropanol). The diseases in cattle and sheep occur in different parts of the
pregnancy-lactation cycle.
Epidemiology. Primary ketosis occurs in well-conditioned cows with high lactation potential, principally
in the first month of lactation with a higher prevalence in cows with a higher lactation number. Secondary
ketosis occurs where other disease reduces feed intake.
The disease in sheep is associated with a falling plane of nutrition, principally in the last month of
pregnancy, in ewes bearing twins and triplets but can be induced by other stress at this time.
Clinical findings. Cattle show wasting with decrease in appetite, fall in body condition and milk
production. Some have short periods of bizarre neurological and behavioral abnormality. Response to
treatment is good. Sheep have encephalopathy with blindness, muscle tremor, convulsions, metabolic
acidosis and a clinical course of 2-8 d, usually terminating fatally unless treated early.
Clinical pathology. Hypoglycemia, ketonemia, ketonuria or elevated ketones in milk.
Necropsy findings. None specific. Twin lambs and fatty liver.
Diagnostic confirmation. Ketonemia, ketonuria or elevated ketones in milk. Elevated
beta-hydroxybutyrate (BHBA) in aqueous humor of dead sheep.
Treatment. In cattle, parenteral glucose with corticosteroid and oral glucose precursors such as propylene
glycol, occasionally insulin. Similar treatment in sheep, or oral glucose and electrolyte therapy. Cesarian
section or induction of parturition in sheep. In cattle, the disease responds readily to treatment and is
self-limiting, but in sheep the disease is highly fatal.
Control. Correction of energy imbalance. Herd and flock biochemical monitoring coupled with condition
scoring.
ETIOLOGY
Glucose metabolism in ruminants
The maintenance of adequate concentrations of glucose in the blood is critical to the regulation of energy
metabolism. The ruminant absorbs very little dietary carbohydrate as hexose sugar because dietary
carbohydrates are fermented in the rumen to short chain fatty acids, principally acetate (70%), propionate
(20%) and butyrate(10%).Consequentlyglucose needs in ruminants must largely be met by
gluconeogenesis. Propionate and ainino acids are the major precursors for gluconeogenesis with
glycerol and lactate of lesser importance (1).
PROPIONATE is produced in the rumen from starch, fiber and proteins. It enters the portal circulation
and is efficiently removed by the liver, which is the primary glucose-producing organ. Propionate is the
most important glucose precursor; an increased availability can spare the hepatic utilization of other
glucose precursors (2), and production of propionate is favored by a high grain inclusion in the diet (3).
AMINO ACIDS The majority of amino acids are glucogenic and are also important precursors for
gluconeogenesis. Dietary protein is the most important quantitative source but the labile pool of body
protein is also an important source; together they contribute to energy synthesis and milk lactose synthesis
as well as milk protein synthesis (1).
DIETARY ACETATE is transported to peripheral tissues and to the mammary gland and metabolized to
long chain fatty acids for storage as lipids or secretion as milk fat.
Ketone formation
Ketones arise from two major sources: butyrate in the rumen and mobilization of fat. A large proportion of
butyrate produced by rumen fermentation of the diet is converted to beta-hydroxybutyrate (BHBA) in the
rumen epithelium and is absorbed as such. Free fatty acids produced from the mobilization of fat are
transported to the liver and oxidized to produce acetyl-CoA and NADH.
Acetyl-CoA may be oxidized via the TCA cycle or metabolized to acetoacetyl-CoA. Its oxidation via
the TCA cycle depends upon adequate supply of oxaloac-etate from the precursor propionate. If
propionate, and consequently oxaloacetate, is deficient, oxidation of acetyl-CoA via the TCA cycle is
limited and it is metabolized to acetoacetyl CoA and subsequently to acetoacetate and BHBA (1).
The ketones BHBA and acetoacetate can be utilized as an energy source. They are normally present in
blood and their concentration is a result of the balance between production in the liver and utilization by
the peripheral tissues.
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Hepatic insufficiency in ketosis
The uptake of fatty acids by the liver leads to a fatty liver. Hepatic insufficiency has been shown to occur
in bovine (4) and ovine ketosis but it does not occur in all bovine cases (5).
It has been suggested that hepatic insufficiency occurs in those cows predisposed to ketosis by
overfeeding in the dry period (6).
Since one of the reactions to hypoglycemia is mobilization of fat reserves and uptake of fat by the liver,
some degree of hepatic insufficiency is to be expected as a secondary development of the disease.
Role of insulin and glucagon
The regulation of energy metabolism in ruminants is primarily governed by insulin and glucagon. Their
counteracting effects play a central role in the homeostatic control of glucose. A low insulin: glucagon
ratio stimulates lipolysis in adipose tissue and ketogenesis in the liver. Cows in early lactation have low
insulin:glucagon ratios because of low blood insulin and are in a catabolic state (6). Elevated ketones may
stimulate insulin production and may act as a negative feedback (7). Regulation is also indirectly governed
by somatotropin, which is the most important determinant of milk yieldin cattle and is also lipolytic.
Factors that decrease the energy supply to ruminants, that increase the demand for glucose, or that increase
the utilization of body fat as an energy source are likely to increase ketone production and ketonemia.
There is however considerable cow-to-cow and ewe-to-ewe variation in susceptibility to clinical ketosis.
Energy balance
In high-producing dairy cows there is often a negative energy balance in the first few weeks of lactation.
The highest dry matter intake does not occur until 8-10 weeks after calving but peak milk production is at
4-6 weeks and energy intake may not keep up with demand. In response to a negative energy balance and
low serum concentrations of glucose and insulin, cows will mobilize adipose tissue with consequent
increases in serum concentrations of non-esterified fatty acids and BHBA. The hepatic mitochondrial
metabolism ot fatty acids promotes both gluconeogenesis and ketogenesis.Cowspartition nutrients during
pregnancy and lactation and are in a lipolytic stage in early lactation (8); cows arc at risk for ketosis during
this period. Similarly the energy requirements in late pregnant twin-bearing ewes may place them in a
lipolytic status.
ETIOLOGY OF BOVINE KETOSIS
It is not unreasonable to view clinical ketosis as the top end of a spectrum of a metabolic state that is
common in heavily producing cows in the postcalving period. This is because high yielding cows in
early lactation are in negative energy balance and are subclini-cally ketotic as a result.
Ruminants are particularly vulnerable to ketosis because,although very little carbohydrate is absorbed as
such, a direct supply of glucose is essential to tissue metabolism, particularly the formation of lactose. The
utilization of volatile fatty-acids for energy purposes is also dependent upon a supply of available glucose.
This vulnerability is further exacerbated, particularly in the cow, by the tremendous rate of turnover of
glucose.
In the period between calving and peak lactation the demand for glucose is increased and cannot be
completely restrained. Cows will reduce milk production in response to a reduction of energy intake, but
this does not follow automatically nor proportionately in early lactation because hormonal stimuli for milk
production overcome the effects of reduced food intake. Under these circumstances lowered blood glucose
levels result in a lowered blood insulin. Long chain fatty acids are released from fat stores under the
influence of both a low blood insulin:glucagon ratio and the influence of high somatotropin concentration,
and this leads to increased ketogenesis.
Subclinical ketosis
Elevated concentrations of blood ketones without clinical disease, subclinical ketosis, occur more
commonly than clinical ketosis and have significant economic importance. Various studies have shown
that subclinical ketosis is common in high-producing cows 2-7 weeks post-partum, with recorded
prevalence ranging from 7-34% (2,9-11). It takes only a small additional nutritional or metabolic insult for
these to develop clinical ketosis.
Individual cow variation
The rate of occurrence of negative energy status, and therefore the frequency of clinical cases, has
undoubtedly increased sharply in the recent past because of the steep increase in the lactation potential of
the modern dairy cow. Because of the mammary gland’s metabolic precedence in the partitioning of
nutrients, especially glucose, milk production continues at a high rate, causing an energy drain. In many
individual cows the need for energy is beyond their capacity for dry matter intake.
Clinical ketosis has been produced in recently calved dairy cows by reducing the daily feed intake by
15-20% ad libitum and supplementing it with 1,3-butanediol, a ketogenic substrate. The biochemical
characteristics of ketosis including depletion of hepatic glycogen and major increases in hepatic stores of
triglycerides and ketone bodies were produced but ketosis was only produced in those cows that had a
predisposition to the disease (12,13).
Types of bovine ketosis
There arc many theories on the cause, biochemical and hormonal pathogenesis of ketosis, and the
importance of predisposing factors. Reviews of these studies are cited at the end of this disease section. In
general, it can be stated that clinical ketosis occurs in ruminants when they are subjected to demands on
their resources of glucose and glycogen that cannot be met by their digestive and metabolic activity.
Recently Lean (1) has presented a classification of the disease based on its natural presentation in dairy
herds, and one that accounts for the early lactational demand for glucose, a limited supply of propionate
precursors and preformed ketones or mobilized lipids in the pathogenesis. Such a classification includes
the following geneses of ketosis, which will be discussed in turn:
1.Primary ketosis (production ketosis)
2.Secondary ketosis
3.Alimentary ketosis
4.Starvation ketosis
5.Ketosis due to specific nutritional deficiency.
Primary ketosis (production ketosis)
This is the ketosis of most herds, the socalled estate acetonemia. It occurs in cows in good to excessive
body condition that have high lactation potential and are being fed good-quality rations. There
1454
is a tendency for the disease to recur in individual animals, winchis probably areflection of variation
between cows in digestive capacity or metabolic efficiency. Thesecharacteristics appear not tobeinherited
(14) and it is more probable thatthe rationsfed cause abnormalinternalmetabolism or ruminal function and
leadto the development of ketosis.
Secondary ketosis
This occurs where other disease results in a decreased food intake. The cause of the reduction in food
intake is commonly the result of abomasal displacement, traumatic reticulitis, metritis, mastitis or other
diseases common to the postparturient period. A high incidence of ketosis has also been observed in herds
affected with fluorosis. An unusual occurrence reported w as an outbreak of acetonemia in a dairy herd fed
on a ration contaminated by a low level (9.5 ppm) of lincomycin, which caused ruminal microbial
dysfunction (15). The proportion of cases of acetonemia which are secondary, and their diagnosis as such,
are both matters of great interest as a significant proportion of cases of ketosis are secondary to other
disease.
Alimentary ketosis
This form is due to excessive amounts of butyrate in silage and possibly also due
to decreased food intake resulting from poor palatability of high butyrate silage. Silage made from
succulent material may be more highly ketogenic than other types of ensilage because of its higher content
of preformed butyric acid (16). Spoiled silage is also a cause and toxic bio-genic amines in silage, such
as putresin, may also contribute (17). This type of ketosis is commonly subclinical but it may predispose to
the development of production or primary ketosis.
Starvation ketosis
This occurs in cattle that are in poor body condition and that are fed poor-quality feedstuffs. There is a
deficiency of propionate and protein from the diet and a limited capacity of gluconeogenesis from body
reserves. Affected cattle recover with correct feeding.
Ketosis due to specific nutritional deficiency
Specific dietary deficiencies of cobalt and possibly phosphorus may also lead to a high incidence of
ketosis. This may be due in part to a reduction in the intake of total digestible nutrients (TUN), but in
cobalt deficiency the essential defect is a failure to metabolize propionic acid into the tricarboxylic acid
(TCA) cycle. The problem is restricted to the cobalt deficient areas of the world, although the occurrence
of cobalt deficiency in high-producing dairy cows in non-deficient areas has been described (18).
ETIOLOGY OF OVINE KETOSIS
Hypoglycemia and hyperketonemia are the primary metabolic disturbances in ovine ketosis as they are in
the bovine disease. In sheep, the precipitating causes are the energy demands of the conceptus in the latter
part of pregnancy. there are some biochemical differences between the two diseases, e.g. an elevation of
plasma cortisol levels and significant hepatic dysfunction in pregnancy toxemia. Furthermore, in the
terminal stages, the biochemical pathogenesis of the two diseases appears to be quite dissimilar.
The most important etiological factor in pregnancy toxemia is a decline in the plane of nutrition during
the last 2 months of pregnancy, particularly in ewes that are carrying twins or triplets, and in ewes that
have been well fed in early and mid-pregnancy. There is a great deal of variation between sheep in the
ease with which the disease can be produced experimentally, and in the variation in incidence of the
naturally occurring disease in conditions which appear to be conducive to its development.
It is probable that the difference between sheep depends upon the metabolic efficiency of the liver.
Ewes that are predisposed to the disease have an ineffective gluconeogenic response to the continued,
preferential demands for glucose by well-grown twin fetuses, resulting in hypoglycemia and the
accumulation of ketone bodies and cortisol.
The elevation of plasma cortisol levels, which is commonly encountered in ewes with pregnancy
toxemia, has attracted attention because of its possible indication of adrenocortical involvement in causing
the disease. It seems more likely that the observed increase is in response to environmental and nutritional
stresses (19), and possibly to failure by the liver to metabolize the cortisol.
According to the broad circumstances of occurrence, the disease in sheep can be divided as to cause as
either 1. primary pregnancy toxemia, 2. Fat ewe pregnancy toxemia, 3. starvation pregnancy toxemia, or 4.
secondary pregnancy toxemia.
Primary pregnancy toxemia
This is the most common manifestation and results in most flocks from a combination of a fall in the
plane of nutrition during the latter half of pregnancy coupled with a short period of fast in conjunction
with a management procedure in late pregnancy such as crutching, shearing and drenching. In some
outbreaks the ewes have been moved on to better pasture during late pregnancy to prevent the occurrence
of ketosis but it occurs because the ewes are unaccustomed to the type of feed and do not eat well, or
because they are more exposed to bad weather and seek shelter rather than graze. Cold, inclement
weather and an absence of shelter also appear to markedly increase the incidence. Another common
occurrence is when ewes are bred too early and the pasture is not sufficiently advanced to provide a rising
plane of nutrition m late pregnancy. Occasionally a stress alone will induce the condition such as: (1)
transport in late pregnancy, (2) change in environment, or (3) the housing of late pregnant sheep not used
to being housed.
Fat ewe pregnancy toxemia
This occurs without a stress induction in ewes that are very well fed and are in an overfat condition in
late pregnancy. Fat ewes will experience a voluntary fall in food intake in late pregnancy due to the
reduction of the rumen volume by the pressure of intra-abdominal fat and the developing fetus. Commonly
there is concurrent hypocalcemia.
Starvation pregnancy toxemia
This occurs in ewes that are excessively thin. It is relatively uncommon but occurs in extensive grazing
systems where there is prolonged drought and no alternative feed supply and can be seen in any production
system where there is mismanagement.
Secondary pregnancy toxemia
This usually occurs as a sporadic disease as the result of the effect of an intercurrent disease such as foot
rot, which affects food
1455
intake. Heavy worm infestation, e.g. with Haemonchus contortus, would add a similar drain on glucose
metabolism and increase the chances of development of the disease.
The disease occurs in goats during late pregnancy, where it is identical to ovine pregnancy toxemia and
also in lactating does, where it resembles bovine ketosis. Goats exhibit greater dominant/submissive
characteristics than sheep and this can result in lower food intake in submissive goats in groups that are
hand fed.
EPIDEMIOLOGY
Ketosis in cattle
Occurrence
Ketosis is a disease of dairy cattle and is prevalent in most countries where intensive farming is practiced.
It occurs mainly in animals housed during the winter and spring months and is rare in cows that calve on
pasture.
The occurrence of the disease is very much dependent upon management and nutrition and varies
between herds. As might be expected, lactational incidence rates differ between studies but rates of 3.3%
and 7.4% are reported from two Canadian studies (20, 21) and 6% from a Finnish study (22). Rates of
sub-clinical ketosis are much higher, especially m undernourished herds, and can approach 34% (2,4,
9-11).
Animal and management risk factors
The disease occurs in the immediate post-parturient period with 90% of cases occurring in the first 60 days
of lactation (9-11, 23). Regardless of specific etiology it occurs most commonly during the first month of
lactation, less commonly in the second month, and only occasionally in late pregnancy. In different studies
the median time to onset following calving has varied from 10-28 d (20, 23). Cows of any age may be
affected but the disease increases from a low prevalence at the first calving to a peak at the fourth. Clinical
ketosis can also recur in the same lactation. There is little evidence for an heritable predisposition
(11,19,23-25).
In addition to those diseases that can produce secondary ketosis, there is a greater risk for the
development of ketosis in cows that have an extended dry period, have a long dry period, are excessively
fat at calving, and that develop milk fever, retained placenta, lameness or hypomagnesemia (20, 24, 25,
26-29). Overfeeding in late lactation predisposes ketosis in the next lactation. Cows with twins are also at
risk for ketosis in the terminal stages of pregnancy (30, 31). Cows that have received bovine
somatotrophin may be at less risk for ketosis in the subsequent lactation (29).
Economic significance
Clinical and subclinical ketosis is one of the major causes of loss to the dairy-farmer (32). In rare instances
the disease is irreversible and the affected animal dies but the main economic loss is due to the loss of
production while the disease is present and failure to return to full production after recovery (1). Both
clinical and subclinical ketosis are accompanied by decreased milk yields and lower milk protein and
milk lactose (1, 10, 29, 33) and increased risk for delayed estrus and lower first service conception rates,
increased intercalving intervals (10, 34) and increased risk of cystic ovarian disease and mastitis (11, 35,
36).
Sheep
Occurrence
Pregnancy toxemia occurs wherever sheep are raised but it is primarily a disease of intensive farming
systems and is relatively rare in extensive grazing units unless there is drought or poor management.
Animal and management risk factors
The disease occurs only in ewes in the last 6 weeks of pregnancy, usually during the last month, and in
ewes carrying triplet or twin lambs, although ewes bearing a single, large lamb may also be affected. The
disease is uncommon in maiden ewes because of their low fecun¬dity and increases in prevalence up to
parity three. In a study of sheep diseases in Canada, 19% of flocks were reported to have the disease (37).
There is probably no breed difference in susceptibility and breed differences probably reflect differences
in fecundity and differences in management systems. The British hill breeds arc possibly more resistant to
the development of pregnancy toxemia in the face of nutritional deprivation of the ewe but resistance is
achieved at the expense of lamb birth weight and has the penalty of higher neonatal mortality. There are
however differences in the susceptibility of individual sheep that appear to be related to differences in
rates of hepatic gluconeogenesis (38).
The attack rate in a flock varies with the nature and severity of the nutritional deprivation and the
proportion of the flock at risk. It can be very high in starvation pregnancy toxemia, whereas fat ewe
pregnancy toxemia is generally of sporadic occurrence. In outbreaks that follow management procedures
or other stressors, clinical disease is not manifest until 48 h afterwards and new cases will develop over
several days. Intercurrent disease in late pregnant ewes, such as foot rot or foot abscess, may predispose
pregnancy toxemia.
Economic significance
The economic effect of the disease is considerable. Without treatment, the case-fatality rate approaches
100% and in individual flocks the disease can reach a level of incidence sufficient to be classed as an
outbreak. Flocks that experience pregnancy toxemia will also have a higher than normal mortality in
neonatal lambs and usually a decrease in wool quality. Pregnancy toxemia predisposes to
hypomagnesemia in sheep.
PATHOGENESIS
Bovine ketosis
The principal metabolic disturbances observed,hypoglycemia and ketonemia, may both exert an effect on
the clinical syndrome. However, in the experimental disease in cattle, it is not always clear what
determines the development of the clinical signs in cases that convert from sub-clinical to clinical ketosis
(39). In many cases, the severity of the clinical syndrome is proportional to the degree of hypoglycemia
and this, together with the rapid response to parenterally administered glucose in cattle, suggests
hypoglycemia as the predominant factor. This hypothesis is supported by the development of prolonged
hypoglycemia and a similar clinical syndrome to that of ketosis, after the experimental, IV or SC injection
of insulin (2 units/kg BW).
However, in most field cases the severity of the clinical syndrome is also roughly proportional to the
degree of ketonemia. This is an understandable relationship as ketone bodies are produced in larger
quantities as the deficiency
1456
of glucose increases. However, the ketone bodies may exert an additional influence on the signs observed.
Acetoacetic acid is known to be toxic and probably contributes to the terminal coma in diabetes mellitus in
man.
The nervous signs which occur in some cases of bovine ketosis are thought to be caused by the production
of isopropyl alcohol, a breakdown product of acetoacetic acid in the rumen, although the requirement of
nervous tissue for glucose to maintain normal function may also be a factor in these cases.
Spontaneous ketosis in cattle is usually readily reversible by treatment;incomplete or temporary
response is usually due to the existence of a primary disease with ketosis present only as a secondary
development, although fatty degeneration of the liver in protracted cases may prolong the recovery period.
Changes in ruminal flora after a long period of anorexia may also cause continued impairment of digestion.
The higher susceptibility of postpartum cows to local and systemic infections may be related to
impairment of the respiratory burst of neutrophils which occurs with elevated levels of BHBA (40).
Pregnancy toxemia in sheep
The disease in sheep is manifest with encephalopathy and is frequently not reversible unless treated in the
early stages. The onset of clinical signs is always preceded by hypoglycemia and hyperketonemia.
although the onset of signs is not related to minimum glucose or maximum ketone levels.
The cause of the encephalopathy is not certain but it is probable that it is a hypoglycemic
encephalopathy resulting from hypoglycemia in the early stages of the disease (41-43). In affected ewes,
there is an abnormally high level of cortisol in plasma and both early and recent research has suggested
that adrenal steroid diabetes contributes to the pathogenesis (44).
Renal dysfunction is also apparent in the terminal stages of ovine ketosis, and may also contribute to the
development of clinical signs and the fatal outcome. Those ewes which are carrying only one lamb and
have been well fed prior to a short period of undernutrition may develop a subacute syndrome both
clinically and biochemically.
CLINICAL FINDINGS
Bovine ketosis
Two major forms of bovine ketosis arc described - wasting and nervous - but these are the two extremes of
a range of syndromes in which wasting and nervous signs are present in varying degrees of prominence.
THE WASTING FORM is the most common of the two and is manifest with a gradual but moderate
decrease in appetite and milk yield over 2-4 d. In herds that feed components separately, the pattern of
appetite loss is often unusual in that the cow first refuses to eat grain, then ensilage but may continue to eat
hay. The appetite may also be depraved.
Body weight is lost rapidly, usually at a greater rate than one would expect from the decrease in appetite.
Farmers usually describe affected cows as having a “woody” appearance due to the apparent wasting and
loss of cutaneous elasticity due presumably to disappearance of SC fat. The feces are firm and dry but
serious constipation does not occur. The cow is moderately depressed and the hangdog appearance and
disinclination to move and to eat may suggest the presence of mild abdominal pain.
The temperature and the pulse and respiratory rates are normal and although the ruminal movements
may be decreased in amplitude and number, they are within the normal range unless the course is of long
duration when they may virtually disappear. A characteristic odor of ketones is detectable on the breath
and often in the milk.
Very few affected animals die, but without treatment the milk yield falls and although spontaneous
recovery usually occurs over about a month, as equilibrium between the drain of lactation and food intake
is established, the milk yield is never fully regained. The fall in milk yield may be as much as 25% and
there is an accompanying sharp drop in the solids-not-fat content of the milk. In the wasting form, nervous
signs may occur in a few cases but rarely comprise more than transient bouts of staggering and partial
blindness.
THE NERVOUS FORM Signs are usually bizarre and begin quite suddenly. The syndrome is suggestive
of delirium rather than of frenzy and the characteristic signs include:
• Walking in circles
• Straddling or crossing of the legs
• Head pushing or leaning into the stanchion
• Apparent blindness
• Aimless movements and wandering
• Vigorous licking of the skin and inanimate objects
• Depraved appetite
• Chewing movements with salivation.
Hyperesthesia may be evident, the animal bellowing on being pinched or stroked. Moderate tremor and
tetany may be present and there is usually an incoordinate gait. The nervous signs usually occur in short
episodes which last for 1 or 2 h and may recur at intervals of about 8-12 h. Affected cows may injure
themselves during the nervous episodes.
Subclinical bovine ketosis
Many cows that are in negative energy balance in early pregnancy will have ketonuria without showing
clinical signs, but will have diminished productivity including depression of milk yield and a reduction in
fertility. Potential milk production is reduced by 1-9% (11,33). Surveys of large populations show a
declining prevalence of ketosis-positive cows after a peak in the period immediately after calving, and a
positive relationship between hyperketonemia and high milk yield (9,35). Infertility may appear as an
ovarian abnormality, delayed onset of estrus or as endometritis resulting in an increase in calving to
conception interval and reduced conception rate at first insemination. In Europe, endometritis itself is
thought to be a sequel to a nutritional stress at this time, but much of the stress there is due to overfeeding
in early lactation which increases the risk for both endometritis and acetonemia (45,46).
Ovine ketosis
The earliest signs of ovine ketosis are separation from the group, failure to come up for feeding, and
apparent blindness which is manifested by an alert bearing but a disinclination to move. The ewe will
stand still when approached by attendants or dogs and will turn and face them but make no attempt to
escape. If it is forced to move, it blunders into objects and when an obstacle is encountered, presses against
it with its head. Many affected ewes stand in water troughs all day and lap the water. Constipation is
1457
usual, the feces are dry and scanty and there is grinding of the teeth.
In later stages, marked drowsiness develops and episodes of more severe nervous signs occur but they may
be infrequent and are easily missed. In these episodes, tremors of the muscles of the head cause twitching
of the lips, champing of the jaws and salivation, and these are accompanied by a cog-wheel type of clonic
contraction of the cervical muscles causing dorsiflexion or lateral deviation of the head, followed by
circling. The muscle tremor usually spreads to involve the whole body and the ewe falls with toniclonic
convulsions. The ewe lies quietly after each convulsion and rises normally afterwards but is still blind.
In the periods between convulsions there is marked drowsiness which may be accompanied by head
pressing, the assumption of abnormal postures including unusual positions of the limbs and elevation of
the chin - the“stargazing”posture - and incoordination and falling when attempting to walk. A smell of
ketones may be detectable on the breath of the ewe.
Affected ewes usually become recumbent in 3-4 d and remain in a state of profound depression or coma
for a further 3-4 d, although the clinical course is shorter in fat ewes with pregnancy toxemia. Fetal death
occurs commonly and is followed by transient recovery of the ewe, but the toxemia caused by the
decomposing fetus soon causes a relapse.
Affected ewes commonly have difficulty in lambing. Recovery may ensue if the ewe lambs or the lambs
are removed by cesarean section in the early stages of the disease. In an affected flock the disease usually
takes the form of a prolonged outbreak; a few ewes become affected each day over a period of several
weeks. Recovered ewes may subsequently show a wool break.
CLINICAL PATHOLOGY
Hypoglycemia, ketonemia and ketonuria are characteristic of the disease
Cattle
BLOOD GLUCOSE levels are reduced from the normal of approximately 50 mg/dL to 20-40 mg/dL in
cattle and sheep. Ketosis secondary to other diseases is usually accompanied by blood glucose levels
above 40 mg/dL and often above normal.
Ketones
BLOOD KETONE levels are elevated from a normal of up to 10 mg/dL to 10-100 mg/dL. The levels are
high also in secondary ketosis but are rarely above 50 mg/dL. In Europe, serum beta-hydroxybutyrate
measured in SI units is used for analysis of ketonemia. Normal cows have concentrations of less than 1.0
mmol/L and cows with ketosis have levels greater than 1.5 mmol/L and often in excess of 2.5 mmol/L.
URINE KETONES Quantitative estimation of urinary ketones may be unsatisfactory because of the wide
variations that occur depending upon the concentration of the urine. In clinically normal cattle, urinary
ketones may be as high as 70 mg/dL, although they are usually lower than 10 mg/dL. Levels of 80-1300
mg/dL indicate the presence of ketosis which may be primary or secondary.
MilK KETONE levels are rather less variable, ranging from a normal of 3 mg/dL up to an average level
of 40 mg/dL in cows with ketosis.
COWSIDE TESTS are based on color reaction of ketone bodies and may be conducted on milk or urine.
Milk is usually tested with sodium nitroprusside in the well of a porcelain plate. Commercial tablets or dip
sticks are available for testing urine. The color change should be compared with a set of standard color
references. There is some difference of opinion as to whether primary and secondary ketosis can be
differentiated on the basis of the degree of color change in the reagent, but primary cases always give a
strong reaction, whereas a moderate reaction is more common in secondary cases. Rough quantitative
estimations of blood ketones can also be quickly made with some commercial reagents.
Cowside tests have the advantage of being inexpensive, giving immediate results, and they can be used
as frequently as necessary. A minor source of error is that the concentration of ketone bodies in these
fluids will depend not only on the ketone level of the blood but also on the amount of urine excreted or on
the milk yield. Milk is less variable, easier to collect and may give fewer false negatives with subclinical
ketosis. A recent study reported that when subclinical ketosis was defined as a blood beta-hydroxybutyric
acid concentration of 1.4 mmol/L or greater, the sensitivity of the milk test was 90% and the specificity
96%. The sensitivity of the urine test was 100% but specificity was low (10). A dip stick test for
semiquantitative measurement of beta-hydroxybutyric acid in milk is recently available in some countries
and has good sensitivity (47).
CLINICAL CHEMISTRY AND HEMATOLOGY
White and differential cell counts are variable and not of diagnostic value for ketosis.
There are usually elevations of liver enzymes but liver function tests are within the normal range. Liver
biopsy is the only accurate method to determine the degree of liver damage (48).
Liver glycogen levels are low and the glucose tolerance curve may be normal. Volatile fatty acid levels
in blood and rumen are much higher in ketotic than in normal cows and the ruminal levels of butyric acid
are markedly increased relative to acetic and propionic acids. There is a small but significant fall in serum
calcium levels (down to about 9 mg/dL (2.25 mmol/L), due probably to increased loss of base in the urine
to compensate for the acidosis.
Sheep
In sheep, the initial changes are similar to those found in cattle but the sequel is not. Hypoglycemia can be
used as a diagnostic aid in the early stages of the disease but is of limited value later in the course as by the
time that sheep become recumbent, blood glucose levels may be normal or grossly elevated. This may be
the result of fetal death which has been shown to remove the suppressing effect of the fetus on hepatic
neoglucogenesis (38).
Ketonemia and ketonuria are constant and serum beta-hydroxybutyrate concentrations are in excess of
3.0 mmol/L (42).
Sheep develop a severe metabolic acidosis, renal failure with a terminal uremia, and become
dehydrated. In contrast to cattle, liver function tests are abnormal (49). Elevation of plasma cortisol occurs
in pregnancy toxemia and concentrations above10 ng/ml are indicative of pregnancy toxemia (50), but
pregnancy toxemia and clinical hypocalcemia can both cause sufficient stress to promote such an elevation.
NECROPSY FINDINGS
The disease is not usually fatal in cattle but fatty degeneration of the liver and
1458
secondary changes in the anterior pituitary gland and adrenal cortex may be present.
Pregnancy toxemia in ewes is almost always fatal without treatment intervention. At necropsy there is
severe fatty degeneration of the liver and there are usually twin lambs and evidence of constipation.
Histopathologically there is also a poorly defined renal lesion and there may be evidence of neuronal
necrosis (41). The lambs may be dead and in varying stages of decomposition. Hepatic glycogen levels are
usually very low in both sheep and cattle.
Concentrations of beta-hydroxybutyrate in the aqueous humor or the CSF greater than 2.5 or 0.5 mmol/L,
respectively, are supportive of a diagnosis of pregnancy toxemia (42).
DIFFERENTIAL DIAGNOSIS
Cattle
The clinical picture is usually too indefinite, especially in cattle, to enable a diagnosis to be made solely on
clinical grounds. General consideration of the history, with particular reference to the time of calving, the
duration of pregnancy in ewes and the feeding program, and biochemical examination to detect the
presence of hypoglycemia, ketonemia and ketonuria are necessary to establish a diagnosis.
Wasting form
• Abomasal displacement (pp.321,326)
• Traumatic reticulitis (p.303)
• Primary indigestion (p.280)
• Cystitis and pyelonephritis (pp.491,492)
• Diabetes mellitus (rare) (p.360).
Nervous form
• Rabies (p.1201)
• Hypomagnesemia (pp.1442,1510)
• Bovine spongiform encephalopathy (p.1233).
Sheep
Pregnancy toxemia is usually suspected in late pregnant ewes which show nervous signs and die within
2-7 d and there may be a history of exertion or sudden deprivation of food. Hypocalcemia can occur under
similar circumstances but:
1. The onset is within 12 h of the stress
2. A considerable proportion of the flock will be affected at the same time
3. The disease is manifest with myasthenia
4. It has a much shorter course of 12-24 h
5. Affected animals respond well to treatment with solutions of calcium salts.
• Listeriosis
• Cerebral abscess (p.533)
• Rabies.
TREATMENT
In cattle, a number of effective treatments are available but in some affected animals the response is only
transient; in rare cases the disease may persist and cause death or necessitate slaughter of the animals.
Most of these cases are secondary and failure to respond satisfactorily to treatment is due to the primary
disease.
The rational treatment in ketosis is to relieve the need for glucose formation from tissues and allow
ketone body utilization to continue normally. Theoretically the simplest means of doing this is by the
administration of glucose replacement therapy. The effect of the administration of glucose is complex but
it allows the reversal of ketogenesis and the establishment of normal patterns of energy metabolism (7).
Replacement therapy
Glucose (dextrose)
The IV injection of 500 mL of a 50% solution of glucose results in transient hyperglycemia, increased
insulin and decreased glucagon secretion, and reduced plasma concentration of non-esterified fatty acids.
It effects a marked improvement in most cows but relapses occur commonly unless repeated treatments are
used. This is probably due to the transience of the hyperglycemia or insufficient dosing - the dose required
varies directly with the amount of lactose being lost in the milk. A significant proportion of the
administered glucose is lost to urinary excretion. SC injections prolong the response but are not
recommended as they cause discomfort, and large unsightly swellings, which often become infected may
result. IP injections of 20% solution of dextrose may be used alternatively but are also accompanied by
risk of infection.
Other sugars
Other sugars, especially fructose, either alone or as a mixture of glucose and fructose (invert sugar), and
xylitol have been used in an effort to prolong the response but idiosyncrasies to some preparations, in the
form of polypnea, muscle tremor,weakness and collapse, can occur while the injection is being given.
Propylene glycol and glycerine
To overcome the necessity for repeated injections, propylene glycol or glycerine (225 g twice daily for 2 d
followed by 110 g daily for 2 d to cattle) can be administered as a drench. These solutions, or salts of
propionic acid, can be administered in the feed and give excellent results. Administration in feed is
preferred by some because this method avoids dangers of aspiration with drenching; however, cows not
used to its inclusion in the feed may show feed refusal. It is recommended that for best results, dosing with
these preparations be preceded by an IV injection of glucose.
Parenteral infusions of glucose solutions and the feeding of glycerol depress the fat content of milk, and
the net saving in energy may favorably influence response to these drugs. Glycerol and propylene glycol
are not as efficient as glucose because conversion to glucose does utilize oxaloacetate. Propylene glycol is
absorbed directly from the rumen and acts to reduce ketogenesis by increasing mitochondrial citrate
concentrations; its metabolism to glucose occurs via conversion to pyruvate with subsequent production of
oxaloacetate via pyruvate carboxylase (7).
Other glucose precursors
Because of its glucogenic effect, sodium propionatc is theoretically a suitable treatment but when
administered in 110-225 g doses daily, the response in cattle is often very slow. Lactates are also highly
glucogenic but both calcium and sodium lactate (1 kg initially, followed by 0.5 kg for 7 d) and sodium
acetate (110-500 g/d) have given less satisfactory results than those obtained with sodium propionate.
Ammonium lactate (200 g for 5 d) has however, been used extensively with reported good results. Sodium
ethyl oxaloacetate given IV is effective in natural and experimental cases in ewes but is unlikely to be a
practical form of treatment because of cost.
Hormonal therapy
GLUCOCORTICOIDS The efficiency of glucocorticoids in the treatment of bovine ketosis has been
amply demonstrated in both experimental and field cases. Hyperglycemia occurs within 24 h of
1459
administration and appears to result from a repartitioning of glucose in the body rather than from
gluconeogenesis (7). Historically, many preparations have been used successfully but current drugs are
more potent, require lower dosage, and have fewer side-effects. A hyperglycemic state is produced for 4-6
d in ketotic cows given 10 mg of dexamethasone 21-isoni-cotinate and other preparations such as
dexamethasone sodium phosphate (40 mg) and flumethasone (5 mg) are also used. Label regulations vary
between countries and in general the recommendations of the manufacturer with regard to use and dosage
should be followed. Profound hypokalemia with high case fatality is a potential sequel to prolonged
repeated therapy of ketosis with isofluprednone acetate (51). Response of cows with primary ketosis to
treatment with corticosteroids and IV glucose is superior, with fewer relapses, than therapy with
corticosteroids or glucose alone (52).
INSULIN facilitates cellular uptake of glucose, suppresses fatty acid metabolism and stimulates hepatic
gluconeogenesis. It is administered in conjunction with either glucose or a glucocorticoid and may be of
particular value in early-onset cases of ketosis that are unresponsive to glucose or corticosteroid therapy
(7). The dose of protamine zinc insulin is 200-300 iu per animal administered SC every 24-48 h as
required.
ANABOLIC STEROIDS have also been used for treatment of lactational ketosis and ketosis in late
pregnant cows that are overfat, stressed or have twin fetuses. Experimentally, 60 mg and 120 mg of
trenbolone acetate are effective as single injections but no extensive field trials are recorded and the drug
is banned for use in food animals in most countries.
MISCELLANEOUS TREATMENTS VitaminB12 and cobalt are indicated in regions where cobalt
deficiency is a risk factor for ketosis. They are sometimes administered to cattle with ketosis in regions
where cobalt deficiency does not occur but their therapeutic value is not proven. Cysteamine (a biological
precursor of coenzyme A) and also sodium fumarate have been used to treat cases of the disease. Reported
results were initially good but the treatment has not been generally adopted. The recommended dose rate
of cysteamine is 750 mg IV for three doses at 1-3-day intervals.
There is some limited evidence that niacin given in the feed has a beneficial effect on the disease in cattle
(1, 23) and on the glucogenic potential of diets in sheep. Niacin is antilipolytic and induces increases in
blood glucose and insulin. It has been suggested that it should be supplemented from 2 weeks prior to
parturition to 12 weeks postpartum (53).
Treatment in sheep
Sheep treated very early in the course of the disease generally respond favorably but response to therapy is
poor once sheep have become recumbent and the IV administration of 50% dextrose at this time may
hasten death. Therapy requires the correction of fluid, electrolyte and acid-base disturbances in addition to
replacement therapy with glucose.
PARENTERAL THERAPY Ideally, individual sheep should be examined biochemically and the
corrective therapy based accordingly, with fluids, electrolytes and glucose given over a prolonged period
of time. One recommendation for replacement therapy is the administration of 5-7 g of glucose IV 6-8
times a day in conjunction with 20-40 units of zinc protamine insulin given IM every other day for 3 d
(54).
In many sheep-raising areas intensive monitoring and therapy is not possible because of access, expense,
or the number of sheep involved in an outbreak. In the absence of biochemical monitoring, therapy with
glucose should be accompanied by the IV injection of isotonic sodium bicarbonate or lactated Ringer's
solution and the administration of further fluids by a stomach tube. Less intensive therapy includes the use
of propyiene glycol or glycerine (ll0g/d by mouth), which have given excellent results for some workers
but poor results for others.
Standard doses of corticosteroids have little therapeutic effect in sheep and therefore treatment with
these drugs is not recommended. Very large doses are effective in ewes still able to stand but the success
probably rests in the removal of the glucose drain by the induction of premature parturition.
ORAL THERAPY Success in therapy is reported with the oral drenching, every 4-8 h, of 160 mL of a
solution containing 45 g glucose, 8.5g sodium chloride.6.17g glycine and electrolytes, which is available
commercially as a concentrated oral rehydration solution for calves with diarrhea. This therapy is now
commonly used in the United Kingdom. Drenching of non-pregnant sheep with this solution is followed
by higher blood concentrations of glucose than those achieved following drenching with glycerol or
propylene glycol. Reported recovery rates in pregnancy toxemia are 90% in early cases and 55% in
advanced cases (55). Vasopressin has been used to induce closure of the esophageal groove in conunction
with the oral administration of glucose.
Treatment with recombinant bovine somatotrophin in conjunction with dextrose and electrolytes may
improve ewe survival and result in a greater viability of lambs born (56).
REMOVAL OF FETUS Cesarian section
can be used as an alternate to replacement therapy. Provided ewes are in the early stages of the disease,
removal of the lambs by cesarean section is probably the therapy that has the greatest success rate.
Induction of parturition is another option. Either should only be attempted in the early stage of the
disease as in the later stages the ewe’s condition is irreversible and the fetuses are often dead and
decomposed. Induction with corticosteroids has been effected with dexamethasone 21-isonicotinate or the
sodium phosphate at a dose rate of 16-25 mg per ewe but dexamethasone trimethylacetate appears to be
ineffective. Lambs will be born 48-72 h after injection.
When clinical cases occur, the rest of the flock should be examined daily for any evidence of ketosis
and affected animals treated immediately with propylene glycol or glycerol. Supplementary feeding of the
flock should be commenced immediately, with particular attention given to an increase in carbohydrate
intake. With timid sheep, especially Merinos, the simple provision of feed may not be enough. It may be
necessary to improve the palatability of the ration, and to get the sheep started by force feeding.
CONTROL
It is difficult to make general recommendations for the control of the disease because of the many
conditions under which it occurs, its probable multiple etiology
1460
and feeding systems that vary from those that feed components separately to those that feed total mixed
rations.
Cattle
Cows should neither have been starved nor be overfat at calving. One recommendation is that there should
be a target of less than 10% of late lactation and dry cows with condition scores of 4 on a 1-5 scale (57).
An adequate caloric intake should be insured in the early part of lactation. In heavy-producing, heavily fed
herds the big problem is to provide enough feed to avoid a deficient caloric intake, relative to utilization,
but at the same time to avoid imbalance, ruminal acidosis on a too-high carbohydrate diet and acetonemia
on a diet too high in protein. Too low a feeding frequency can lead to an increase in rates of ketosis (46).
Careful estimation of diets by reference to feed value tables is recommended and detailed
recommendations on diet and management have been provided (58,59).
Points of general advice for herds in which feeding systems are not highly sophisticated are that cows
should not be too fat nor too thin at the end of lactation, and that feeding in preparation for the next
lactation should not begin until about 4 weeks prior to calving. At that time, the silage, or hay. or pasture
being used as a maintenance ration should be supplemented with 1kg/d concentrate and this amount
gradually increased to 5 kg daily at calving time. After calving the concentrate ration should be increased
gradually as production increases, and be of the order of 3 kg/100 kg BW hay for maintenance (3 kg
ensilage is equivalent to 1kg hay) and 1kg grain for each 3kg milk produced. In general, feeding should be
at a slightly higher level than production actually warrants - lead feeding. The protein in the total ration
should not exceed 16%, certainly not more than 18%, the carbohydrate should be readily digestible, and it
oats or maize are used they should be crushed, and the hay or ensilage must be of good quality.
In high-producing cows being fed stored feeds, poor quality roughage commonly leads to acetonemia.
Wet ensilage containing much butyrate, and moldy or old and dusty hay, are the main offenders. In
concentrates it is the change of source which creates off-feed effects and precipitates attacks of
acetonemia.
Cows that are housed should get some exercise each day and in herds where the disease is a particular
problem during the stabling period, the cattle should be turned out to pasture as soon as possible in the
spring.
The ration should contain adequate amounts of cobalt, phosphorus, and iodine.
If there is a high incidence in a herd receiving large quantities of ensilage, reduction of the amount fed
for a trial period is indicated.
The prophylactic feeding of sodium propionate may be considered in problem herds: 110 g/d for 6
weeks, commencing at calving, has given good results in reducing the incidence of clinical bovine ketosis
and improving production. Propylene glycol (350 mL/d for 10 d after calving, or as 6% of a concentrate
ration for 8 weeks) has been similarly used with moderately good results.
Theoretically, any procedure which increases the ratio of propionate to acetate production in the rumen
would be of assistance in preventing ketosis. Monensin is a growth stimulant which acts in this way and
the effective use of the compound in the prevention of ketosis in dairy cows has been reported (1, 23, 60)
but it will also result in milk fat depression. The dose rate used was 25 mg/d monensin in a grain feed mix.
Dose rates need to be monitored carefully because of the risks of toxicity which are described separately,
Ionophores are not labelled for inclusion in lactating cow rations in some countries. Somatotropin also has
considerable promise for the control of bovine ketosis (1).
The control of clinical ketosis is integrally related to the adequate nutrition of the cow in the dry and
lactating period. This encompasses details such as:
•Dry matter intake
•Fiber digestibility
•Particle size distribution
•Energy density
•Fat incorporation in early lactation rations
•Protein content
•Feeding systems
•Rumen size
•Other factors better covered in texts on nutrition.
These subjects have been visited from the point of view of clinical veterinary nutrition in a recent
review series of articles (59). Experimental observations have tended to reduce the importance of heavy
feeding of ensilage, failure to provide an adequate mineral mixture and failure to provide grain to stall-fed
cows in late pregnancy. However, in view of the known multiple-factor etiology of this disease, these
experiments do not prove that under particular sets of circumstances one or other of these factors may not
be the precipitating cause.
Sheep
The same general recommendations apply in the prevention of ovine ketosis as in the prevention of ketosis
in cattle. Insure that the plane of nutrition is rising in the second half of pregnancy, even if it means
restricting the diet in the early stages.
Ewes that are in condition score 2.5-3.0 on a 1.0-5.0 scale at 90 d of gestation and are in an ideal
situation to respond to increased feeding in the latter part of gestation (19). If necessary, ewes with higher
condition scores at the end of the first month of pregnancy can be fed to lose 0.5 condition score during the
period to the third month of pregnancy without any significant effect on the ewe or lamb size or viability.
Many small farm sheep producers have sheep in too great a condition score early in pregnancy.
The last 2 months are particularly important in the prevention of pregnancy toxemia as 70% of the
lamb's birth weight is gamed during the last 6 weeks of pregnancy. During this period, the provision of a
concentrate containing 10% protein at the rate of 0.25 kg/d, increasing to 1 kg/d in the last 2 weeks, has
provided good protection. During this period the ewe should gain an increase of body weight of 10% for
ewes with single lambs and 18% in ewes carrying twins. For the flock this represents a flock body
condition score that maintains or gains to 3.0 3.5 during this period. Higher body condition scores can
result in higher birth weight of lambs but other than in stud flocks these are not economic and the standard
commercial flock runs the risk of fat ewe pregnancy toxemia with higher targeted body condition scores.
An exception is the maiden ewe group which needs to be fed separately in order to provide for the
requirement for growth in addition to the requirement for pregnancy, in fat ewes the only nutritional
method of improving energy
1461
intake is to increase the energy density of the diet.
There are managemental difficulties in any nutritional program for sheep because of the way they are
husbanded. If there were a satisfactory way of easily determining the stage of pregnancy and whether there
are one, two or three or no fetuses present, and if the sheep could then be divided into a number of
subflocks so that the appropriate feeding regimen could be provided, it would be economical if separate
paddocks and labor were available, to arrange a preventive feeding program. The use of ultrasound offers
this selection and allows feeding to specific group requirements.
Some account needs to be taken also of those ewes (and does) which are timid and for this and other
reasons slow feeders. If supplementary feeding is practiced in a confined space, with insufficient trough
space for all the flock to eat at one time, and if the feed fed is in small amounts and highly edible, a large
proportion of ewes will get little or no feed. These difficulties add up to a formidable barrier in large flocks
with minimum labor. It is necessary before embarking on a nutritional support program to estimate cost
effectiveness. At the low level of prevalence that pregnancy toxemia usually achieves in well-managed
flocks, it is often more profitable to do nothing and to let the disease occur in the very occasional sheep
and treat it accordingly.
Sudden changes in type of feed should be avoided and extra feed provided during bad weather. Shelter
sheds should be available, and in purely pastoral areas lambing should not occur before the pasture is well
grown. A high incidence is often encountered in small, well-fed flocks where the ewes get insufficient
exercise. In such circumstances the ewes should be driven about for half-an-hour twice daily and, if
pasture is available, only concentrate should be fed so that they will be encouraged to forage for
themselves.
General control
HKRD MONITORING Biochemical monitoring of herds for subclinical ketosis and adequacy of
periparturient feeding can be conducted using blood glucose estimations on a sample of cows in their 2nd
week of lactation (53). Blood glucose levels of below 35 mg/dL (1.9mmol/L) suggest subclinical ketosis.
For individual cows, blood glucose estimations should be done at about 14 d after calving. Regular tests
for ketones in urine in the 2nd week after parturition has also been recommended for early detection of
ketosis.
Blood or milk BHBA levels or milk acetone levels are probably more accurate. Cut point levels vary
with investigators but cow serum BHBA concentrations greater than 1.2-1.7 mmol/L (7-10mg/dL), milk
BHBA concentrations greater than 100 mmol/L, or milk acetone concentrations greater than 0.70 mmol/L
are indicative of subclinical ketosis (9,47). It has been suggested that milk acetone concentration should
not exceed 0.05 mmol/L for maximal potential milk production (36).
FLOCK MONITORING for latent pregnancy toxemia during the last 6 weeks of pregnancy can be
conducted using blood BHBA as an indicator with concentrations of 0.8 mmol/L indicating adequate
energy intake, 0.8-1.6 mmol/L inadequate energy intake and levels greater than 1.6 mmol/L indicating
severe undernourishment.
REVIEW LITERATURE
Brockman, R.I.(1979) Roles for insulin and glucagon in the development of ruminant ketosis.
Can.Vet.J.,20,121.
Littledike,E. T.,Young.J.W.& Beitz,D.C.(1981) Common metabolic diseases of cattle: ketosis. milk
fever, grass tetany and downer cow complex.J.Dairy Sci.,64,1465-1482.
Kronfield.D.S.(1982) Major metabolic determinants of milk volume, mammary efficiency, and
spontaneous ketosis m dairy cows.J.Dairy Sci.,65. 2204-2212.
Baird, G. D. (1982) Primary ketosis in the high-producing dairy cow: clinical and subclinical
disorders,treatment,prevention and outlook.J.Dairy Sci.,65,1-10.
Kelly, J. M. & Whitakcr. D. A. (1984) Subclinical ketosis and dairy cows. Vet.Ann., 24, 83-93.
Brockman. R.P.& Loorveld, B(1986) Hormonal regulation of metabolism in ruminants; a review.
Livestock Prod. Sci.,14.313-334.
Marteniuk. J. W. & Herdt, T.H.(1988)Pregnancy toxemia and ketosis of ewes and does. Vet. din. North
Am.: Food Anim. Pract., 4(2), 307-315.
Lean. I.J., Brass. M L.,Baldwin, R. L. & Trout, H. F. (1991) Bovine ketosis: a review. I. Epidemiology
and pathogenesis. Vet. Bull., 61, 1209-1218.
Herdt,T.H.& Emery,R. S. (1991) Therapy of diseases of ruminant intermediary metabolism.Vet.
Clin.North Am.: Food AnimPract.,8(1).91-106.
Lean,I.J.,Bruss,M.L.,Baldwin, R.L. & Trout, H. F.(1992) Bovine ketosis:a review II. Biochemistry and
prevention.Vet. Hull., 62,1-13.
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FATTY LIVER IN CATTLE (FAT COW SYNDROME, PREGNANCY TOXEMIA IN CATTLE)
Synopsis
Etiology. Mobilization of excessive body fat to liver during periods of negative energy balance at time of
parturition or in early lactation of dairy cows and late pregnancy of beef cows.
Epidemiology. High-producing dairy cows overfed during dry period may develop fatty liver syndrome
just before or after calving precipitated by any factor or disease which interferes with feed intake. Occurs
in well-conditioned beef cattle in late pregnancy when energy intake suddenly decreased. Moderate and
subclinical degrees of fatty infiltration may adversely affect reproductive performance of dairy cows.
Signs. Inappetence to anorexia, ruminal atony, lethargic, inactive, ketonuria, fat body condition, weakness
and recumbency if worsens. Recover if continue to eat and appetite improves.
Clinical pathology. Increase in serum hepatic enzyme levels, increase in ketone bodies; increased fat in
liver biopsy.
Lesions. Fatty infiltration of liver.
Diagnostic confirmation. Liver biopsy.
Differential diagnosis list:
•Left-sided displacement of abomasum
(p. 321)
•Right-sided displacement of abomasum (p. 326)
•Milk fever (p. 1420)
•Parturition syndrome
•Abomasal impaction (p. 314)
•Vagus indigestion (p. 311)
•Peritonitis (p. 250).
Treatment. Fluid and electrolyte therapy including glucose IV. Propylene glycol orally. Provision of
palatable feed.
Control. Avoid overfeeding during late lactation and dry period. Avoid situations which reduce feed
intake at time of parturition.
ETIOLOGY
Fatty liver is caused by the mobilization of excessive quantities of fat from body depots to the liver. It
occurs either because of a deprivation of feed in fat beef cattle, more severe in those bearing twins, or
because of a sudden demand of energy in the immediate postpartum period in well-conditioned lactating
dairy cows. The disease is an exaggeration of what is a common occurrence in high-producing dairy cows
which are in a state of negative energy balance in early lactation (1). Body fat, especially SC fat, is
mobilized and deposited primarily in liver but also muscle and kidney. Whether or not the cow is truly fat
at parturition may not be important in determining the degree of fat mobilization, but the degree of
negative energy balance in early lactation is critical.
EPIDEMIOLOGY
Fatty infiltration of the liver is common in high-producing dairy cattle from a few weeks before and after
parturition and is associated with several periparturient diseases, and an increase in the
calving-to-conception interval. A severe form of fatty infiltration of the liver immediately before or after
parturition is known as the fatty liver or fat cow syndrome or pregnancy toxemia of cattle which can be
highly fatal. In beef cattle, the disease occurs most commonly in late pregnancy when the nutrient intake is
decreased in cattle which were previously well fed and in good body condition.
Fatty infiltration of the liver is part of a generalized fat mobilization syndrome which occurs in early
lactation, particularly in high-yielding dairy cows, as milk production outstrips appetite and body reserves
are used to meet the energy deficit (2). The deficit occurs because dietary intake cannot meet the energy
requirements for the high yield. Peak yields of milk are reached 4-7 weeks after calving, but the highest
levels of volun¬tary feed intake are not reached until 8-10 weeks after calving. As a result of the energy
deficit, the cow mobilizes body reserves for milk production and may lose a large amount of body weight.
In about 30% of high-producing cows the infiltration is severe and is associated with reversible but
significant effects on liver structure and function. In some populations of cows, the incidence of fatty liver
is much lower and insignificant (3).
In North America, the introduction of the system of challenge feeding of dairy cows was associated
with an increased incidence of the disease. The overall effect of the system is to provide excess energy in
the diet during late pregnancy or during the dry period generally. The diets fed may contain a high
percentage of the cereal grains, corn ensilage, or brewer's grams. In this system, high-energy rations are
fed beginning a few weeks before parturition. The total daily amount of feed is increased by regular
increments to reach a high level at parturition and peak levels to coincide with the peak in the lactation
curve several weeks after parturition. This resulted in some excessively fat cows at the time of parturition,
when energy demands are high. The disease has also occurred in dairy cows which were fed excessive
amounts of high-energy rations throughout the dry period. In dairy herds, the fatty liver syndrome has also
been associated with an increase in the incidence of milk fever, ketosis and left-sided displacement of the
abomasum, all of which are much more difficult to treat successfully because of the fatty liver.
The body condition score at calving can have a direct effect on the health, milk yield and fertility of
cows (4). It represents
1463
the cumulative effects of the dry period, the body condition score at drying off and the loss of body
condition during the dry period. The risk of retained placenta may be greater for cows underconditioned at
drying, whereas cows that lost more body condition during the dry period may be more affected by both
retained placenta and metritis; the two effects are independent of each other. The risk of ketosis is
increased in cows overconditioned at calving, which may be due to a long dry period. Cows calving in a
higher body condition score produced more milk, fat and protein in the first 90 d of lactation and the effect
was most pronounced on milk fat content (4). Cows with a higher body condition score at calving were
less prone to anestrus but did not conceive more successfully to first service. A reduction of six open days
in primiparous cows was estimated for each additional unit of body condition score at calving.
Multiparous cows which lost more body condition during the dry period are more prone to inactive ovaries
and are more likely to be open 150 d after calving in the next lactation.
In a field study the percentage of cattle dying or being culled because of disease was affected by the
amount of hepatic triglyceride -15%, 31% and 42% for cattle with mild, moderate and severe hepatic
lipidosis, respectively (1).
Cattle have been classified into three groups on the basis of liver fat content determined histologically 1
week after parturition (5). Less than 20% lipid corresponds to less than 50 mg/g liver by weight, 20-40%
lipid, 50-100 mg/g liver, and greater than 40% represents more than 100 mg/g liver (5). These
concentrations correspond to mild, moderate and severe cases of fatty infiltration. Cows with less than
20% lipid in the liver at 1 week after calving are considered normal, and those with more than 20%, are
considered to have a fatty liver. About 30% of high-yielding dairy cows m the United Kingdom are
considered to have a fatty liver 1 week after calving. Clinical evidence of hepatic disease may not occur
consistently until liver lipid concentrations are in the range of 35-45% or more.
Outbreaks of the disease have occurred in dairy herds in which up to 25% of all cows were affected
with a case-fatality rate of 90%. Dairy cows with abnormally long, dry periods also have a tendency to
become obese and develop the fatty liver syndrome of parturition. The feeding of dairy cows in large
groups as in loose housing systems has been associated with an increase in the incidence of the disease.
In dairy cattle, there is a relationship between the occurrence of a subclinical fatty liver within the first
few weeks after parturition and inferior reproductive performance due to a delay in the onset of normal
estrus cycles and a reduction in the conception rate which results in an increase in the average days
between calving and conception (6). There may be differences in reproductive performance between cows
with mild and moderate fatty livers early after calving (7). However, an examination of the postpartum
hormone profiles of cows with fatty liver did not reveal the pathogenetic mechanism of the reduced
fertility (8). The fat cow syndrome may also be associated with an increased incidence of parturient paresis
and unresponsive treatment for ketosis in early lactation.
The disease can occur in non-lactating dairy cows by the imposition of a partial starvation diet in late
pregnancy m an attempt to reduce the body weight of cows which are considered to be too fat (9).
Changing the diet of pregnant beef cows from silage to straw in an attempt to reduce their body weight and
the incidence of dystocia has resulted in outbreaks of the disease.
In beef cattle in North America, the severe form of the disease, pregnancy toxemia, is seen most
commonly in the last 6 weeks of pregnancy in cows which are fat and pregnant with twins. The affected
cows are usually well fed until late pregnancy when an unexpected shortage of feed occurs, or the cows
are too fat and cannot consume sufficient low-energy feed to meet the demands of pregnancy. Under usual
circumstances the disease in beef cattle occurs sporadically: the morbidity is about 1% but the mortality is
usually 100%.
Pregnancy toxemia of cattle has occurred in pregnant beef cattle in Australia (10) and the United
Kingdom. First-calf heifers were more commonly affected than older cows and most were in late
pregnancy (7-9 months) or had just recently calved. Cows pregnant with twins are particularly susceptible.
Cows exposed to toxic lupins may also develop the disease. In Australia, only beef cattle have been
involved in pregnancy toxemia; the fat and the obese arc most commonly affected. The disease occurred
most notably when there was a shift to autumn calving (February to April) when feed supplies were low
because of low, late summer rainfall. The cows were in good to fat body condition because of lush pastures
in the spring and early summer, but by autumn when the calving season approached, the feed supplies
were low and the nutritive value of the pasture inadequate. The lack of feed combined with the expensive
nature of supplementary feeding resulted in an inadequate level of nutrition during late pregnancy.
Similarly the control of internal parasitism, especially ostertagiasis, is not intensively practiced. The
morbidity is usually from 1-3% but may be as high as 10% and the disease is usually fatal.
PATHOGENESIS
Under normal physiological conditions, the total amount of fat increases in the liver beginning a few
weeks before calving, rises to an average of about 20% (of wet weight basis) 1 week after calving and
declines slowly to the normal level of less than 5% by 26 weeks after calving. However, the levels vary
from almost none to 70% among cows 1 week after calving. Fat mobilization begins about 2-3 weeks
before calving and is probably induced by a changing hormonal environment prior to calving rather than
an energy deficit. After calving there is a larger increase in fat accumulation. The changes in the liver in
dairy cows are functional and reversible and related to the metabolic demands of late pregnancy and early
lactation (11). The gradual increase in plasma non-ester-ified fatty1 acids (NE.FAs) during the final
prepartum days may explain the gradual depression in dry matter intake and a contributing factor to
triglyceride accumulation in the liver (12). During this period there is also an elevated level of plasma
glucose and a lowered plasma betahydroxybutyrate (BHBA) concentration. The serum levels of lecithin:
cholesterol acyltransferase activity in spontaneous cases of fatty liver in cows are also decreased, which
may be associated with reproductive performance because cholesteryl esters are utilized for the synthesis
of steroid hormones (13).
The heavy demands for energy in the high-producing dairy cow immediately after parturition, or in the
pregnant beef cow which may be bearing twins, result
1464
in an increased rate of mobilization of fat from body reserves, usually SC tat, to the blood which transports
it to body tissues, particularly liver but also muscle and kidney. Any decrease in energy intake caused by a
shortage of feed or an inability of the cow to consume an adequate amount of feed during the critical
periods of late pregnancy or early lactation would result in the mobilization of an excessive amount of free
fatty acids. This results in increased hepatic lipogenesis with accumulation of lipid in enlarged hepatocytes,
depletion of liver glycogen and inadequate transport of lipoprotein from the liver (11). Most of the lipid
infiltration of the liver in dairy cows after calving is in the form of triacylglycerols because of the
increased uptake of NEFAs and a simultaneous increase in diacylglycerol acyltransferase; the activity of
this enzyme is activated by fatty acids (6).
Ruminants may be prone to fatty liver because their hepatic tissue has limited capacity to export very
low density lipoprotein (8). Also, a prepartum surge of estrogen may contribute to the development of tatty
liver in ruminants by increased tatty acid esterification along with limited export of triglyceride (14). The
serum concentrations of triacylgly-cerol-rich lipoproteins are reduced m cattle with naturally occurring
hepatic lipidosis.
During fat mobilization, there is a concurrent loss of body condition and SC adipose tissue. The degree
of mobilization will be dependent on the fatness of the cow and extent of the energy deficit. Fat and thin
cows respond differently to the metabolic demands of early lactation (11). Fat cows appear less able to
utilize mobilized tatty acids and as a result accumulate esterified tat in tissues. This can adversely
influence susceptibility to disease and the response of the cow to that disease imposes further metabolic
demands, particularly on muscle and protein metabolism.
Both SC fat and skeletal muscle mass .are decreased after calving and fat cows lose 2.5 times more
muscle fiber area than thin cows. Thus the loss of body condition is due to total tissue mobilization
(protein and fat) rather than fat alone. There appears to be a higher rate of protein mobilization m tat cows
than in thin cows.
The severity of fatty liver has been arbitrarily classified into severe, moderate and mild, based on the
amount of triglyceride present in the hepatocytes (5). Fatty infiltration of muscle also occurs and appears
to be correlated with the degree of hepatic lipidosis (15); this condition may also be related to the
weakness and recumbency seen in severe cases of cows with fatty liver syndrome. In severe hepatic
lipidosis, the accumulation of triglyceride in the cytoplasm is accompanied by disturbances in hepatic
structure and function which may result in hypoglycemia and ketonemia; these signs are manifested as
anorexia and depression and there may be clinical evidence of nervous signs. Some severe cases appear to
develop hepatic failure, do not respond to therapy, and become weak and recumbent and die. Terminally
there is a marked hyperglycmia. A leukopenia has been observed in dairy cows with more than 20% liver
fat in the 2nd week after calving (16). This may be related to the increased incidence of postparturient
diseases such as mastitis and endometritis observed in cows with subclinical fatty liver. However, this is
not necessarily a cause-and-effect relationship. The case-fatality rate in severe cases may reach 50% or
more.
Cows which are not fat initially do not develop fatty liver syndrome. Pregnant beef cows in thin body
condition on pasture can become extremely emaciated and eventually recumbent and die of starvation, but
they do not develop pregnancy toxemia.
The pathogenesis of the relationship between reduced reproductive performance and mild or moderately
severe fatty liver in dairy cows within the first 2 weeks after calving is unclear.
CLINICAL FINDINGS
In dairy cattle, fat cow syndrome occurs usually within the first few days following parturition and is
commonly precipitated by any condition which interferes with the animal's appetite temporarily, such as:
•Parturient hypocalcemia
•Left-sided displacement of the abomasum
•Indigestion
•Retained fetal membranes
•Dystocia.
Affected cows are usually excessively fat with body condition scores of 5/5 or higher. Excessive
quantities of SC fat arc-palpable over the flanks, the shoulder areas and around the tail head. The affected
cow usually does not respond to treatment for some of these diseases and becomes anorexic. The
temperature, heart rate and respirations are within normal ranges. Rumen contractions are weak or absent
and the feces are usually scant. Periods of prolonged recumbency are common and affected cows may
have difficulty in standing when they arc coaxed to stand. A severe ketosis which does not respond to the
usual treatment may occur. There is marked ketonuria. Affected cows will not eat and gradually become
weaker, totally recumbent and die in 7-10 d. Some cattle exhibit nervous signs consisting of a staring gaze,
holding the head high, and muscular tremors of the head and neck. Terminally there is coma and
tachycardia.
In cattle with moderately severe fatty liver, the clinical findings are much less severe and most will
recover within several days if they continue to eat even small amounts of hay.
In fat beef cattle shortly before calving, affected cows are aggressive, restless, excited and
uncoordinated with a stumbling gait, and sometimes have difficulty m rising and they fall easily. The feces
are scant and firm and there is tachycardia. When the disease occurs 2 months before calving, the cows are
depressed for 1- 14 d and do not eat. Eventually they become sternally recumbent. The respirations are
rapid, there may be an expiratory grunt, and the nasal discharge is clear but there may be flaking of the
epithelium of the muzzle. The feces are usually scant but terminally, there is often a fetid yellow diarrhea.
The disease is highly fatal; the course is 10-14 d and terminally there may be coma with cows dying
quietly.
Clinical pathology
The changes will depend on the severity of the fatty liver, severe cases with hypoglycemia, ketonemia and
ketonuria similar to a severe case of ketosis.
Serum biochemistry
The concentration of serum NEFAs is increased, there is an increase in DHBA, serum bilirubin and
increases in the serum levels of liver enzymes which are released following liver cell injury (17). In
addition there are decreases in cholesterol, albumin, magnesium and insulin.
1465
The biochemical changes associated with fatty liver syndrome in cows have been described based on
blood and liver samples taken from cows at the abattoir immediately after slaughter (18).
Serum liver enzymes
Significant increases occur in the serum activities of isocitric dehydrogenase (ICDH), glucose-6-phosphate
dehydrogenase (G6PDH), glutamic dehydrogenase (GLDH), lactic dehydrogenase (LDH), malic
dehydrogenase (MDH), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and acid
phosphatase (ACP). Increased serum levels of AST are weakly associated with increased total liver lipid.
AST is not exclusively a liver enzyme but is also present in muscle, kidney and small intestine and any
increase may reflect injury to other tissues. The bromsulphalein (BSP) clearance test, γ-glutamyl
transpeptidase (GGT) and sorbitol dehydrogenase (SDH) have also been used as liver function tests in
cattle with hepatic lipidosis associated with displaced abomasa but are not considered diagnostic.
Blood ketones
In fatty infiltration of the liver in severely ketotic cows there is a positive correlation between blood ketone
body concentrations and the degree of fatty liver (1). However, diurnal variations in the concentrations of
plasma BHBA make their diagnostic interpretations difficult and unreliable as a diagnostic aid for fatty
liver.
Liver biopsy and analysis
A liver biopsy can be used to determine the severity of the fatty liver and the concentration of triglyceride
and is the most reliable method of accurately estimating the degree of fatty infiltration of the liver.
The triglyceride concentration of liver in normal cows ranges from 10-15% on a wet weight (WW) basis
(19). Estimation of the lipid content of bovine liver samples obtained by biopsy may be made by
biochemical or histological methods (19). Both methods provide reasonable estimates of liver fat content
over a wide range of values. The lipid content of bovine liver is highly correlated with its specific gravity
and the submersion of needle biopsy specimens into water, and copper sulfate solutions with specific
gravities of 1.025 and 1.055 can be used as a test to estimate lipid content (20). For routine clinical
diagnosis, three solutions of specific gravities of 1, 1.025 and 1.055 can be used. Liver samples which
float in all three solutions contain greater than 34% lipid, those that sink in water but float in 1.025 and
1.055 specific gravity solutions contain less than 34% but greater than 25% lipid, whereas those that float
only in 1.055 specific gravity solutions contain less than 25% but greater than 13% lipid. Samples which
sink in all three solutions contain less than 13% lipid. Some limited evidence indicates that cows with liver
lipid concentrations above 34% are severely affected and can be expected to have clinical manifestations
of hepatic insufficiency. Those with liver lipid levels between 34% and 25% are moderately affected and
might have-some clinical evidence of hepatic insufficiency. Those between 25% and 13% are mildly
affected, which is the range of most postpartum dairy cows without any evidence of disease. Liver lipid
concen¬trations below 13% are inconsequential (20).
Ultrasonography of liver
Digital analysis of hepatic ultrasonograms have been used to evaluate fatty infiltration in dairy cattle (21)
and has the highest sensitivity, specificity, accuracy, and positive and negative predictive values, followed
by ultrasonography compared to bipod and serum analysis (22).
Hemogram
In cattle with subclinical fatty liver there may be a leukopenia, neutropenia and lymphopenia (16).
NECROPSY FINDINGS
In severe fatal cases the liver is grossly enlarged, pale yellow, friable and greasy. Mild and moderate cases
are usually not fatal unless accompanied by another fatal disease such as peracute mastitis. The degree of
fatty infiltration in these is much less obvious. The histological changes include the occurrence of fatty
cysts or lipogranulomas, enlarged hepatocytes, compression of hepatic sinusoids, a decreased volume of
rough endoplasmic reticulum and evidence of mitochondria! damage (11). The latter two changes are
reflected in reduced albumin levels and increased activities of liver enzymes m the blood.
DIFFERENTIAL DIAGNOSIS
In dairy cows, fatty liver must be differentiated from those diseases which occur commonly immediately
following parturition. Left-sided displacement of the abomasum results in a secondary ketosis,
inappetence, and pings over the left abdomen.
Retained placenta and metritis may be accompanied by fever, inappetence to anorexia, rumina atony,
and a foulsmelling vaginal discharge. A degree of fatty liver may occur in these cows, making it
indistinguishable from the effects of the retained placenta and metritis.
Primary ketosis may occur immediately after parturition or within several days rather than at the most
common time, at 6-8 weeks of lactation. Inappetence. ruminal hypotonicity, marked ketonuria, and a good
response to glucose and propylene glycol are characteristic.
In beef cattle, pregnancy toxemia before parturition must be differentiated from abomasal impaction
(p. 314), vagus indigestion (p. 311) and chronic peritonitis (p. 256).
TREATMENT
The prognosis for severe fatty liver is unfavorable and there is no specific therapy. In general, cows with
fat cow syndrome which are totally anorexic for 3 d or more usually die m spite of intensive therapy.
Those which continue to eat in increasing daily amounts will recover with supportive therapy and
palatable feeds. Several different therapeutic approaches have been tried based on empirical experience.
Intensive therapy directed at correcting the effects of the ketosis and the fatty liver is required. The
recommended treatment includes continuous IV infusion of glucose and multiple electrolyte solutions,
and the intraruminal administration of rumen juice (5-10 L) from normal cows in an attempt to stimulate
the appetite of affected cows. Corticosteroids such as dexamethasone at a dose of 20 mg every second day
until recovery have also been used (23). Recombinant bovine somatotrophin at a dose of 640 mg SC has
been used and clinical impressions indicated that it was beneficial for the treatment of fat cow syndrome
(24). There were no significant differences between the treated and untreated groups in the plasma
concentrations
1466
of glucose, BHBA, albumin, total protein or calcium. However, plasma urea concentration was decreased
in the precalving cows 7 and 10 d after treatment with somatotrophin, and in postcalving cows with fat
cow syndrome (24). Propylene glycol given orally promotes gluconeogenesis and insulin (zinc protamine)
at 200-300 SC twice daily promotes the peripheral utilization of glucose. Liberal quantities of highly
palatable good quality hay and an ample supply of water should be provided. Water and multiple
electrolytes (10 30 L) can be administered intraruminally. The use of choline chloride at a dose rate of 25 g
every 4 h, SC or orally has been recommended for the treatment of severe cases. The use of anabolic
steroids (Vebonol 300 mg or trenbolone acetate is recommended) provides some improvement but all
treatments are less effective the longer their commencement is delayed. In mild and moderate cases
therapy is usually not required.
When outbreaks of fat cow syndrome occur in pregnant beet cattle, all remaining cows should be sorted
into groups according to body conditions and fed accordingly. Excessively tat cows should be fed the best
quality hay which is available with a supplement. Fat cows should be exercised by feeding them on the
ground and forcing them to walk.
CONTROL
Because of the large economic losses associated with pregnancy toxemia in cattle, even, economic effort
must be made to prevent the disease. The principal method of control is to prevent pregnant cattle from
becoming fat during the last trimester of pregnancy, particularly during the dry period in dairy cattle.
During pregnancy, mature cattle should receive sufficient feed to meet the needs for maintenance and
pregnancy and the total daily nutrient intake must increase throughout the last trimester to meet the needs
of the fetus. However, this increase is usually difficult to control without some cows getting fat and others
losing weight. Sorting cows into groups on the basis of size and condition and feeding accordingly is
recommended. Metabolic profiles may be used as a means of assessing energy status and correspondingly
the likelihood of occurrence or otherwise of acetonemia or pregnancy toxemia. Both blood glucose and
HHBA levels can be used.
In dairy cattle, all of the common diseases which occur immediately after parturition must be treated
promptly and every effort made to maintain a high energy intake in high-producing cows, particularly
those which calve in a fat condition. Every effort must be made to maintain the appetite of these cows. The
use of propylene glycol will promote gluconeogenesis and minimize the mobilization of depot fat. The
daily oral administration of 1 L of propylene glycol beginning 10 d prepartum reduces the triglyceride
accumulation by 32% and 42% at 1 d and 21 d postpartum, respectively, and the NEFA and the BHBA
concentrations are also reduced (25).
Body condition scoring of dairy cows at strategic times can be used to monitor the nutritional status of
the herd and minimize the incidence and severity of fatty liver syndrome (26). The scoring should be done
throughout the production cycle as part of a herd health program. Scoring done at calving, at 21-40 d, and
90-110 d postpartum can be used to monitor the nutritional status of the herd. Scoring done at 100-60 d
before drying off provides an opportunity for management to make appropriate adjustments in the feeding
program so that optimal body condition goals are achieved. The optimum body condition score of a cow at
calving which will result m the most economical amount of milk has not yet been determined. On a scale
of 5, the suggested optimum score at calving has ranged from 3-4 (27). The optimum score will probably
depend on the characteristics of the individual herd which include type of cow, type of feedstuffs available,
season of the year, environmental temperature and the people doing the actual body condition scoring.
REFERENCES
(1)Gerloti, B.J. et al. (1986)J. Am. Vet. Med.Assoc., 188, 845.
(2)Reid, I. M. & Roberts, C.J. (1983) Irish Vet.J, 37, 104.
(3)Grohn, Y. et al. (1987) Ada Vet. Scant.,28, 143.
(4) Markusfeld, O. et al. (1997) Vet. Rec, 141, 67.
(5)Gaal, T. et al. (1983) Res. Vet. Sci., 34, 245.
(6)Van Den Top, A. M. et al. (1995) J. DairySci., 78, 2208.
(7)Heinonen, K. et al. (1987) Ada Vet.Scand., 28, 151.
(8)Watson, E. D. & Williams, L. A. (1987)Amm. Prod., 45, 9.
(9)Gcrloff, B.J. & Herdt, T.J. (1984) J. Am.Vet. Med. Assoc., 185, 223.
(10)Caple, I. W. ct al. (1977) Aust. Vet.J, 53,289.
(11)Reid, I. M. rt al. (1986) Amm. Prod., 43,7.
(12)Vazquez-Anon, M. et al. (1994)}. DairySci., 77, 1521.
(13)Nakagawa, H. et al. (1997) Vet. Res.Commun., 21. 1.
(14)Grummen, R. R. et al. (1990)J Dairy Sci.,75, 1537.
(15)Roberts, C.J. et al. (1983) Vet. Pathol, 20,23.
(16)Reid, I. M. et al. (1984) Res. Vet. Sci., 57,63.
(17)Avidar, Y. et al. (1986) IsraelJ. Vet. Med.,42, 318.
(18)Bogin, E. et al. (1988)}. Comp. Pathol., 98,387.
(19)Collins, R. A. et al. (1985)J. Comp.Pathol, 95, 437,
(20)Herdt, T. H. et al. (1983)J. Am. Vet. Med.Assoc., 182, 953.
(21)Acorda, J. A. et al. (1994) Vet. Radiol., 55,120.
(22)Acorda.J. A. et al. (1995) Vet. Q., 17, 12.
(23)Andrews, A. H. et al. (1991) Vet. Rec, 29,216.
(24)Maisey, I. et al. (1993) Vet. Res., 155, 293.
(25)Studer, V. A. et al. (1993)7. Dairy Sci., 76,2931.
(26)Hady, P. J. ct al. (1994) J. Dairy Sci., 77,1543.
(27)Braun, R. K. et al. (1987) Comp. ComEduc. Pract. Vet., 9, F62.
EQUINE HYPERLIPIDEMIA
Synopsis
Etiology. Deranged fat metabolism.
Epidemiology. Pregnant or lactating middle-aged, overweight ponies, donkeys and American Miniature
horses. Worldwide. Sporadic.
Clinical signs. Depression, anorexia, weight loss, ventral edema, muscle fasciculation, mania,
recumbency.
Clinical pathology. Hyperlipidemia (triglyceride > 500 mg/dL, 5 mmol/L). Lesions. Widespread lipidosis,
swollen liver, hepatic rupture.
Treatment. Enteral or parenteral feeding, insulin, heparin, Treat underlying disease. Control. Maintain
optimal body condition. Prevent disease and nutritional stress.
ETIOLOGY
The disease is due to insulin resistance and a derangement in fat metabolism (1).
EPIDEMIOLOGY
Occurrence
The disease occurs worldwide in Shetland and other ponies, donkeys and miniature
1467
donkeys, and American Miniature horses (2, 3, 4).
The disease is sporadic, although multiple cases may occur on a farm. The annual incidence of the
disease in ponies in southeastern Australia is 5% (5), but less than 2% in donkeys in the United Kingdom
(6). The case-fatality rate is 40-80% (5). Incidence varies with season and locality, the disease in ponies in
Europe occurs most commonly during late gestation (January to March), while in Australia the disease is
more common in ponies during early lactation (November to January).
Animal risk factors
The disease is most common in females (90% of cases), uncommon in stallions and geldings, and rare in
foals (1, 3, 5). Most affected ponies are more than 4 years old and the peak incidence occurs in 9-year-olds
(5, 7). In donkeys, the incidence of disease increases with age (6).
Pregnancy and lactation increase the risk of the disease in ponies (1,5) but not in donkeys (6). The
disease in Miniature Horses is always associated with underlying disease (2, 3). Underlying disease is
identified in 50% of cases in ponies, however many cases occur in pregnant or lactating mares without
evidence of other disease (5, 7). Overweight ponies and donkeys are at increased risk, and the onset of
disease is often preceded by some sort of stress, typically transport or food deprivation (5, 6).
Characteristically the disease occurs in fat, middleaged, pregnant or lactating ponies that experience a
decrease in feed intake.
PATHOGENESIS
The combination of the innate insulin resistance of ponies and a nutritional stressor, such as disease,
pregnancy, lactation or food deprivation, results in unchecked mobilization of fatty acids from adipose
tissue at a rate that exceeds the gluconeogenic and ketogenic capacity of the liver. The effect of the insulin
resistance may be exacerbated by an increase in serum cortisol concentrations associated with stress or
disease (8). Excess fatty acids are reesterified in the liver to triglycerides and released into the circulation
as very low-density lipoproteins.
The fundamental defect is in the control of hormone-sensitive lipase.
the enzyme responsible for hydrolysis of triglycerides to free fatty acids and glycerol in adipose tissue.
Unchecked activity of this enzyme results in mobilization of fatty acids in hyperlipemic ponies that is 40
times the rate in normal ponies. There is no dysfunction of lipoprotein lipase, the enzyme mediating
uptake of plasma free fatty acids by tissue (1).
Hyperlipidemia causes widespread Lipidosis and organ dysfunction (1). Hepatic lipidosis
compromises liver function resulting in accumulation of toxic metabolites and derangement in coagulation.
CLINICAL FINDINGS
The clinical course vanes between 3 and 22 d but is generally 6-8 d. Depression, weight loss and
inappetence are the initial signs in 90% of cases (5). Approximately 50% of cases have fasciculation of
muscles of the limb, trunk or neck. Ventral edema unrelated to parturition occurs in approximately 50% of
cases. Inappetence progresses to anorexia and the depression progresses to somnolence and hepatic coma.
Compulsive walking or mania develop in 30% of cases. Signs of mild colic, including flank watching,
stretching and rolling, are evident in 60% of cases. The incidence of jaundice is variable. Many animals
show a willingness to drink but are unable to draw water into the mouth and swallow. Others continually
lap at water. The temperature is normal or moderately elevated and heart rate and respiratory rates are
increased above the normal. Diarrhea is constant in the terminal stages.
Visual examination of the plasma or serum phase of a blood sample collected from an affected animal
will reveal cloudy, milky, mildly opalescent plasma.
CLINICAL PATHOLOGY
There is usually leukocytosis with neutroplnlia. Hyperlipidemia is a consistent feature of the disease.
Serum triglyceride concentrations will be at least 5 mmol/L (500 mg/dL), and may be 20 times that of
normal. Serum cholesterol and free fatty acid concentrations are also increased, although less so than
triglycerides. The plasma triglyceride concentration is of minimal prognostic use in ponies, but most
American Miniature horses with triglyceride concentrations above 1200 mg/dL die (3, 7).
Plasma glucose concentration is usually low. Ketonemia and ketonuria do not occur. Biochemical
evidence of liver disease is characteristic of the advanced disease. Serum activity of GGT may be
elevated before clinical signs of disease are apparent. Serum creatinine and urea nitrogen concentrations
increase as renal function declines. Blood clotting time increases. Metabolic acidosis develops terminally.
Hematological and biochemical variables may also be affected by any underlying disease.
Diagnostic confirmation of hyperlipemia is achieved by demonstration of hyperlipidemia plasma
triglyceride concentrations above 5 mmol/L (500 mg/dL) in a horse with appropriate clinical signs.
NECROPSY FINDINGS
Extensive fatty change is present in most internal organs, but especially in the liver, which is yellow to
orange, swollen and friable. Liver rupture with intra-abdominal hemorrhage may be present. Tissue pallor
due to lipid accumulation is also prominent in the kidney, heart, skeletal muscle and adrenal cortex.
Serosal hemorrhages of the viscera reflect disseminated intravascular coagulation. The necropsy should
also include an examination for lesions which might predispose the animal to hyperlipidemia, such as
pancreatic damage or laminitis. Histologically, widespread microvascular thrombosis as well as
intracellular lipid in various tissues are evident.
Samples for postmortem confirmation of diagnosis
Formalin-fixed liver, kidney, heart, adrenal, skeletal muscle and pancreas for light microscopic
examination.
DIFFERENTIAL DIAGNOSIS
•Parasitism
•Anemia (p. 414)
•Liver disease including pyrrolizidine toxicosis (pp. 347, 1661)
•Serum hepatitis (p. 355)
•Aflatoxicosis (p. 1685).
Hyperlipemia should be considered in anypony with a history of weight loss,inappetence and progressive
somnolence,especially in late pregnancy or early lactation.
TREATMENT
The principles of treatment are:
1468
•Treatment of the underlying or inciting disease
•Restoration and maintenance of a positive energy balance
•Correction of any defects in hydration, acid-base and electrolyte status
•Reduction of the hyperlipidemia.
Every effort should be made to determine if there is an underlying disease, and it should be treated
aggressively. Parasitism is a common inciting disease, as are equine Cushing's disease (p. 1474) and
neoplasia (lymphosarcoma, gastric squamous cell carcinoma) in older ponies.
The negative energy balance must be corrected. A mature, non-pregnant and non-lactating 200 kg (440 1b)
pony has energy requirements of 9.3 Mcal/d (38 mJ/d) whereas a lactating pony has energy requirements
of 13.7 Mcal/d (57.2 mJ/d) and every effort should be made to meet these requirements (9). Affected
animals should be encouraged to eat and should be offered a range of palatable feeds. However, most
affected horses will not voluntarily consume sufficient feed, and must be supplemented either orally or
intravenously.
Oral supplementation using a commercial equine enteral nutrition preparation or human preparation
has been successful in American Miniature horses and donkeys (2). If these are not available, a homemade
gniel can be used (2). These preparations are administered every 6 h through a nasogastric tube.
Alternatively, glucose can be given orally (1 g/kg, as 5% solution every 6 h, about 5 L to a 250 kg pony) or
intravenously (5% solution, 100 mL/kg/d as a continuous drip).
Mares in late pregnancy should be aborted and lactating mares should have the foal removed.
Dehydration and abnormalities in electrolyte and acid-base status should be corrected by oral or IV
administration of isotonic fluids (lactated Ringer's solution) and, if necessary, sodium bicarbonate.
Liver failure should be treated with oral neomycin (20 mg/kg, every 6 h) or lactulose (1 mL/kg, every 6
h).
Hyperlipidemia should be reduced by minimizing free fatty acid production by adipose tissue and
enhancing triglyceride removal from plasma. Free fatty acid production is minimized by insuring adequate
energy intake and normal plasma glucose concentrations and by the administration of insulin (protamine
zinc insulin, 0.1 to 0.3 iu/kg SC every 12-24 h). Blood glucose concentrations should be monitored and the
insulin dose may need to be adjusted.
Heparin (40 to 100 iu/kg SC every 6-12 h) can be given to increase lipoprotein lipase activity and
promote the clearance of triglycerides from plasma. Severely affected ponies may have an increase in
clotting time that could be exacerbated by heparin.
Corticosteroids and adrenocorticotropic hormone are contraindicated in treatment of this disease.
CONTROL
Ponies should be maintained in optimal body condition, and nutritional stress avoided. A parasite and
disease control program should be instituted. Transport of pregnant and lactating ponies should be avoided.
REVIEW LITERATURE
Watson. T. D. G. (1991) Hyperlipaemia m ponies. In Practice, 16, 267-272.
REFERENCES
(1)Watson, T. D. G. & Love, S. (1994) Comp.Com. Educ. Pract. Vet.. 16. 89.
(2)Moore, B. R. et al. (1994) J. Vet. Int. Med.,8. 376.
(3)Mogg, T. D. & Palmer.J. E. (1995)J Am.Vet Med. Assoc., 207. 604.
(4)Schotman, A.J. H. & Wagenaar, G. (1969) Zenlralbl. Veterinarmed., A16, 1.
(5)Jeffcott, L. B. & field,J. R. (1984) AMI Vet. J., 62, 140.
(6)Reid, S. W. & Mohammed, H. O. (1996)J.Am. Vet. Med. Assoc., 209, 1449.
(7) Watson, T. D. G. et al. (1992) Vet. Rec, 131, 48.
(8)Jeffcott, L B. & Field,J. R. (1985) Vet. Rec,116. 461.
(9)On, E. A. (1989) Nutrieni requirements of horese hington DC: National Research Council, 5.
STEATITIS
Generalized fat necrosis and steatitis occur rarely in foals (1, 2). The cause is unknown. There are
widespread inflammatory changes in adipose tissue which are characterized clinically by firm plaque-like
swellings under the skin. Panniculitis, an unusual form of steatitis limited to the subcutaneous tissues has
been reported in an aged pony mare (1). Generalized steatitis has also been reported in an adult pony mare
(2). The affected animal had lost weight in spite of having a normal appetite. Soft swellings 2 4 cm in
diameter may be present under the skin of the abdominal wall and over the back. Hard plaque-like
swellings may also be present over the upper cervical area. Polypnea and dyspnea may be present and
ventral abdominal edema and fever may be present. Biopsy of some of the SC swelling reveals
histopathological evidence of fat necrosis with mineralization. At necropsy, the SC fat is hard, dry and
yellow-white with areas of necrosis forming abscess-like lesions up to 3 cm deep and 10 cm in diameter.
The fat lining the abdominal wall may contain firm yellow-white and red tissue nodules up to 3 cm in
diameter. Generalized steatitis with fat necrosis ('yellow fat disease') has been recognized in many species
at various ages and is thought to be related to a dietary deficiency of vitamin E and selenium along with an
intake of polyunsaturated fatty acids.
REFERENCES
(1)Dyson, S. & Platt, H. (1985) Equine Vet.J..17. 145.
(2)Taylor, F. G. R. et al. (1988) Vet. liec. 122,349.
NEONATAL HYPOGLYCEMIA
Synopsis
Etiology. Insufficient milk ingestion by newborn piglets in first few days of life or piglets affected with
any disease which interferes with milk intake or that have enteropathy and are unable to digest milk.
Epidemiology. Most common in piglets under 3 days of age. Sows have insufficient milk. Morbidity
30-70%, mortality 100%.
Occurs in twin or triplet lambs exposed to hypothermia. Occurs rarely in calves with diarrhea. Occurs
premature foals.
Signs. Incoordination, shivering, dull, plaintive squeal, cold periphery, pale skin, weak, recumbent,
terminal convulsions and death.
Clinical pathology. Hypoglycemia.
Lesions. No gross lesions. Stomach may be empty.
Diagnostic confirmation. Response to treatment with glucose.
Differential diagnosis list:
Piglets
•Coliform septicemia
•Transmissible gastroenteritis (p. 1106)
•Viral encephalomyelitis (pp. 1114, 1219)
•Other septicemias.
1469
Lambs
•Watery mouth disease (p. 1766)
•Hypothermia (pp. 52, 129).
Calves
•Coliform septicemia (pp. 63, 789)
•Bacterial meningitis (p. 538)
•Dehydration and acidosis associatedwith enterotoxigenic colibacillosis(pp. 789, 791).
Treatment. IV or IP glucose solutions.
Control. Insure adequate colostrum and milk intake for newborn piglets, lambs and calves.
ETIOLOGY
An inadequate intake of milk is the primary cause of hypoglycemia in piglets. This may be due to failure
of the sow's milk supply or to failure of the piglets to suck. Failure to suck may be due to such diseases as
coliform septicemia, TGE, streptococcal infections, myoclonia congenita and hemolytic disease of the
newborn (1). Piglets under 4 d of age rapidly develop hypoglycemia under fasting conditions; older pigs
do not (2).
In piglets affected with transmissible gastroenteritis (TGE), there is decreased digestion of lactose,
reduced absorption of glucose following the severe and diffuse intestinal villous atrophy and, combined
with the low-energy reserves of the newborn piglet, severe hypoglycemia can occur (3). Hypoglycemia
may occur in newborn calves with acute severe diarrhea and when they are deprived of milk or a source of
carbohydrates for more than a few days.
Hypoglycemia occurs in twin or triplet lambs which become hypothermic after 12 h of age (4).
EPIDEMIOLOGY
Newborn pigs encounter several challenges to their survival during the initial hours of life. One is the
inherent problem of glucose homeostasis with the first day of life being the most critical period. Liver
glycogen is rapidly depleted postanatally (12-24 h) for the maintenance of blood glucose. Little insulation
against heat loss is provided by the sparse hair coat and the 1-2% total body fat at birth. There is only a
small amount of carcass fat and no brown fat, and consequently the piglet is dependent almost exclusively
on carbohydrate metabolism for subsistence. Therefore, maintenance of the physiologically critical energy
metabolite, glucose, depends on the ability of the neonatal pig to compete with its littermates for regular
nourishment from its dam.
Neonatal hypoglycemia in piglets occurs primarily during the first 3 d after birth. The disease has been
recorded mainly from North America and the United Kingdom. Most affected piglets die if left untreated;
the morbidity is usually 30-70% and may be as high as 100% in individual litters. Apart from deaths due to
hypoglycemia, many piglets are too weak to avoid the sow and are killed by overlaying. Piglets which fail
to ingest sufficient colostrum or milk because of a failure of the sow's milk supply or because of an
inability of the piglet to suck normally are the most common primary circumstances. A secondary
determinant occurs when piglets affected with an enteritis such as transmissible gastroenteritis are unable
to properly digest the lactose in milk and absorb sufficient glucose.
Hypoglycemia occurs in twin and triplet lambs which may be immature or undersized and are subjected
to cold exposure and hypothermia (4). About 50% of the total lipid present in the newborn lambs is in the
adipose tissue in the form of brown fat which is used by the lambs for non-shivering thermogenesis during
the first 24 h following birth (5). However, the lipid content of newborn lambs can vary from 1.5-4.5% of
birth weight and small lambs have low levels. Neonatal viability of lambs decreases as birth weight
decreases, which may be related to their low lipid content in relation to body size (5). Additional factors
include mismothering and complete absence of the ewe in lambs only a few days of age.
Hypoglycemia in calves has been recorded as a concurrent disease with diarrhea (6, 7). The
hypoglycemia may be secondary to the interference with absorption and digestion caused by the diarrhea.
The signs are characteristic but the hypoglycemia docs not respond to glucose therapy as quickly, if at all,
as in other species (6). However, hypoglycemia in diarrheic calves is not considered to be a significant
problem if affected calves receive a supply of milk or milk replacer during the convalescent period.
Hypoglycemia occurs in foals which are born premature and unable to suck the mare, those with
septicemias, and those exposed to hypothermia.
PATHOGENESIS
The piglet is born with liver glycogen levels which may be as high as 200 mg/g WW, while muscle
glycogen may reach 120 mg/g WW. The blood glucose level at birth is low at 30-60 mg/dL (1.66-3.33
mmol/L) and increases rapidly after feeding on colostrum to 95 mg/dL (5.25 mmol/L) (8). Satisfactory
gluconeogenesis does not develop in piglets until the 7th day after birth, and during this period glycogen
stores are likely to be rapidly exhausted if the intake of milk is restricted. The blood glucose level is then
extremely unstable and dependent entirely upon dietary sources. The first week of life is thus the danger
period (1). Deprivation of food after this produces only loss of weight and has no effect on blood glucose
levels. This particular susceptibility to hypoglycemia in the early postnatal period seems to be
characteristic of the pig and may play a major role in causing losses in piglets by contributing to the effects
of various infectious and non-infectious agents.
Signs appear first when blood glucose levels fall to about 50 mg/dL (2.775 mmol/L), although further
depression to levels as low as 7 mg/dL (0.388 mmol/L) has been observed. Even in such extreme cases,
complete recovery is possible after the administration of glucose (1). The hypoglycemic comatose state
induced in piglets by fasting occurs as blood glucose values fall below 40 mg/dL (2.2 mmol/L) (3).
Experimental hypoglycemia produced by the injection of insulin causes a clinical syndrome similar to that
of the naturally occurring disease.
In piglets with TGE, the blood glu¬cose levels decreased from a normal of 119 mg/dL (6.6 mmol/L) to
36 mg/dL (2.0 mmol/L) (9). This hypoglycemia coincides with the onset of lethargy followed by a
comatose state in a few hours.
CLINICAL FINDINGS
The disease is most characteristic in piglets under a few days of age. Incoordination is apparent first and
the piglet has progressive difficulty in maintaining balance until recumbency becomes permanent. There is
shivering, dullness and anorexia, and often a typical weak squeal. A characteristic feature is the subnormal
rectal temperature and the cold, clammy skin which also evidences marked pallor and ruffling of the hair.
The pallor is
1470
related to the failing circulation. The heart rate becomes increasingly feeble and slow and may fall as low
as 80/min. In many cases there are few additional signs but convulsions are recorded as a common
occurrence by some observers (1). These vary from aimless movements of the head and forelimbs to
severe tetanic convulsions. In the latter there are violent galloping movements, particularly with the
hindlegs, opisthotonos and champing of the jaws. Tortuous movements and rigidity of the neck and trunk
also occur. Terminally, coma develops and death follows 24-36 h after the onset of signs. The clinical
findings are similar in other species with weakness, incoordination, hypothermia, eventual recumbency
and coma being characteristic. The nervous signs are most common in the piglet and not seen in the other
species.
CLINICAL PATHOLOGY
Blood glucose levels of less than 50 mg/dL (2.8 mmol/L) in piglets are considered to indicate clinical
hypoglycemia. The hypoglycemic comatose state induced in piglets by fasting occurs is blood glucose
values below 40 mg/dL (2.2 mmol/L) (3). Significant rises in blood non-protein nitrogen and urea nitrogen
are often observed but appear to be related to catabolism rather than to renal dysfunction (10).
In calves with acute severe diarrhea, the blood glucose may tall to below 40 mg/dL (2.2 mmol/L) in
30-50% of cases (7).
NECROPSY FINDINGS
There are no visible lesions. Absence of curd in the stomach is good contributory evidence of lack of
intake of milk but in many cases it will be obvious that some milk was consumed. Hepatic glycogen levels
are usually negligible.
DIFFERENTIAL DIAGNOSIS
Unless blood glucose levels are estimated, the predominantly nervous signs may lead to an error in
diagnosis. However, hypoglycemia and a good response to treatment with glucose may occur when the
hypoglycemia is secondary to another disease. A definite diagnosis of neonatal hypoglycemia must depend
on elimination of other diseases as primary causes.
Piglets
Coliform septicemia and enterotoxigenic
colibacillosis are characterized by weakness, recumbency, collapse and dehydration.
Viral encephalomyelitis and pseudorabies cause an almost identical clinical picture but are not restricted
in occurrence to pigs less than 1 week old.
Bacterial meningoencephalitis, including streptococcal septicemia and listeriosis, may also affect pigs
of this age. Necropsy examination should make definition of viral and bacterial infections a relatively easy
task.
Lambs
Watery mouth disease is characterized by weakness, drooling from the mouth,
hypothermia, distended fluid abdomen and hypoglycemia.
Foals
Premature foals born several days before term, are weak and unable to stand and suck, and are
hypoglycemic.
Septicemias occur in foals born at term and are characterized by depression, failure to suck, inactivity,
fever, dehydration, petechiation and death in several hours if not treated intensively.
TREATMENT
Piglets with primary hypoglycemia should be given glucose (15mL of 20% solution) IP, repeated even 4-6
h until the animal will suck a foster dam or drink an artificial diet. Protection from cold is important and an
environmental temperature of 27-32℃(80-90℉) will improve the survival rate of piglets (10). The
combined use of oral fluid therapy and the IP administration of 5% dextrose at a rate of 25 mL/kg BW to
piglets affected with hypoglycemia associated with TGE did not correct the hypoglycemia (9). A newborn
piglet weighing 1250 g requires 170 kcal (711 kj) per day when maintained at 30 ℃(88℉); 30 ml. of a 5%
dextrose solution would provide approximately 1.5 g of glucose, which would yield only 5.6 kcal (23 kJ)
per dose. It would be difficult to provide the energy requirements by parenteral administration of 5%
dextrose because the amount of fluid injected per day should not exceed 8% of their body weight (9).
Hypoglycemia and hypothermic lambs can be resuscitated by an IP injection of a 20% solution of glucose
at a rate of 10 mL/kg BW followed by rewarming the air at 40(104) (11).
CONTROL
Avoidance of the causative factors described earlier constitutes prevention. Piglets should be carefully
observed during the first week of life for early signs of any disease and treatment instituted promptly.
Maintenance of a stable environmental temperature at 32 (90) may delay the onset of the disease, or in
marginal circumstances prevent its occurrence.
Lambs require between 180 and 210 ml. colostrum/kg BW during the first 18 h after birth in order to
provide sufficient energy for heat production (12). The administration of colostrum at a rate of 30 mL/kg
BW within a few minutes after birth, directly into the stomach using a catheter and syringe, is
recommended to boost the energy supply of the small lamb (5). Ewes which are well fed during late
pregnancy produce more colostrum than their lambs need, those with singletons have enough for a second
lamb, but in most underfed ewes the lamb requirements for colostrum exceed the ewe's production.
Colostrum can be readily obtained by milking those ewes with excess production. The effects of feeding
ewe colostrum, cow colostrum, or ewe milk replacer, on plasma glucose in newborn lambs have been
compared (13). Both ewe and cow colostrum resulted in a two-fold increase m plasma glucose within 1-3
h; the milk replacer caused marked hyperglycemia.
REFERENCES
(1)Goodwin, R F. W. (1955) lir. Vel.J.,Ill, 301.
(2)Goodwin, R. F. W. (1957) Vet. Rec, 69,1290.
(3)Drolet, R. et al. (1984) Can.J. Comp.Med., 48, 282.
(4)Eales, F. A. ct al. (1982) Vet. Rec, I10,118.
(5)Robinson, J. J. (1981) Livestock Prod. Sci.,8, 273.
(6)Tennant, B. et al. (1968) Cornell Vet., 58,136.
(7)Lewis, L, D. et al. (1975) Am.J. Vet. Rec,36, 413.
(8)Mersmann, H.J. (1974) J. Aram. So., 38,1022.
(9)Drolet, R. ct al. (1985) Can.), Comp.Med, 49, 357.
(10)Momll, C. C. (1952) Am.J. Vet. Res., 13,164, 171, 322,325, 327.
(11)Eales, F. A. et il. (1982) Vet. Rec, 110,121.
(12)Mellow. D.J. & Murray, L. (1986) Vet.Rec, 118, 351.
(13)Bales, F. A. et al. (1982) Vet. Rec, 111,451.
1471
POSTPARTURIENT HEMOGLOBINURIA IN CATTLE
Synopsis
Etiology. Dietary phosphorus deficiency. Feeding cruciferous plants. May occur in copper deficiency
area. Ingestion of cold water.
Epidemiology. High-producing dairy cows, 2-4 weeks after calving. Feeding cruciferous crops. Copper
deficient area.
Signs. Hemoglobinuria, inappetence, reduced milk production, pallor of mucous membranes, tachycardia,
dyspnea, icterus late stages. Death may occur. Recovery takes several days.
Clinical pathology. Low serum inorganic phosphorus, low packed cell volume (PCV), dark red urine.
Lesions. Icterus, hepatomegaly, red urine in bladder.
Diagnostic confirmation. Low serum phosphorus, low PCV, hemoglobinuria.
Differential diagnosis. (See Table 20.3)
Treatment. Whole blood transfusion. Sodium acid phosphate IV. Dicalcium phosphate orally.
Control. Insure adequate intake of dietary phosphorus and copper.
ETIOLOGY
In North America, diets low in phosphorus or unsupplemented with phosphorus are usually associated
with the disease in dairy cattle. In New Zealand, one form of the disease may be related to copper and
selenium nutrition.
The feeding of cruciferous plants has been associated with the disease (1) but many cases occur
unassociated with such diets and their role as a cause is uncertain. The current hypothesis is that ingested
hemolytic agents, some of them identified, for example in rape, some of them not, cause erythrocyte lysis
in some circumstances.
EPIDEMIOLOGY
Only adult cows develop the typical hemolytic syndrome, usually in the period 2-4 weeks after calving.
Highproducing dairy cows in their third to sixth lactations are most commonly affected. The disease does
not occur commonly m beef cattle. Phosphorus-deficient soils and drought conditions are considered
predisposing causes, and the disease is often a problem on particular farms. In areas of severe phosphorus
deficiency the disease may occur at pasture. but in Europe and North America it is more common during
prolonged periods of housing.
Although this disease has been observed in many countries its relatively low incidence makes it a minor
disease. The case-fatality rate may be as high as 50% but only one or two animals in a herd arc affected at
a time.
Experimental production of the disease in one cow has been reported after feeding a low phosphorus
diet for three successive pregnancies (2). However, other signs of phosphorus deficiency occurred 18
months before hemoglobinuria developed, and the case responded well to supplementary feeding with
bone meal. A prolonged hypophosphatemia is thus considered to be a predisposing cause. For example, in
a group of animals in which the disease occurs, the dry cows and yearlings may have normal serum
inorganic phosphorus levels, milking cows are in the low-normal range, and cows which have calved
within the preceding 2 months have low levels.
In New Zealand, two distinct forms have been observed (1). In one situation, young cattle at about 2
years of age are affected with subclinical anemia of the Heinz body type and hypophosphatemia is not a
feature. In the other, the North American type of the disease is also seen in which older mature
high-producing cows are affected and hypophosphatemia is common in the affected animals and in healthy
herd mates (1). In New Zealand, copper deficiency is considered an important etiological factor because
copper supplementation reduces the incidence of the disease in herds in marginally copper-deficient areas
(3). The particular circumstances in which the erythrocytes of a cow become more sensitive than normal to
these hemolysms include hypophosphatemia and hypocupremia, and in NewZealand possibly in selenium
deficiency (1). However, no abnormality in copper status is present in most cases of postparturient
hemoglobinuria in other countries. Low levels of copper in the blood and liver of cows with the
Heinz-body anemia and in the pasture grazed are also observed. The low copper status appears to be
related to the application of molybdenum and lime.
The ingestion of cold water or exposure to extremely cold weather may precipitate an episode of
hemoglobinuria (4). A similar condition accompanied by hypophosphatemia has been observed in late
pregnancy in Egyptian buffalo (5) and in the postparturient period in Indian buffalo (6).
Cases may also occur when cows graze rape, turnips or other cruciferous plants or when large quantities
of beet pulp are fed. These diets are normally low in phosphorus, beet pulp (0.10% dry matter) and turnips
(0.22% dry matter).
PATHOGENESIS
There is an association with hypophosphatemia and a low dietary intake of phosphorus, and it is presumed
that the drain of lactation causes further depletion of phosphorus reserves. The dependence of mammalian
red blood cells on glucose metabolism for the main source of energy for viable function and structure
makes them highly vulnerable to factors inhibitory to the glycolytic pathways. Hypophosphatemia results
in a decrease in red blood cell glycolysis and adenosine triphosphate (ATP) synthesis. Subnormal
concentrations of ATP predispose red blood cells to altered function and structure, a loss of normal
deformability, and an increase in fragility and hemolysis with resultant hemoglobmemia and
hemoglobinuria (7, 8). The changes in the red blood cells are irreversible and the lifespan of the cells is
probably diminished because they are unable to regain their previous structure and function. Copper and
selenium may be important because they are commonly deficient in feedstuffs. Both copper and selenium
may also provide some protection against the effects of orally acquired hemolytic agents in cruciferous
plants (2, 9). The clinical findings are those of acute hemolytic anemia and in fatal cases death is due to
anemic
CLINICAL FINDINGS
Hemoglobinuria, inappetence and weakness develop suddenly and there is a severe depression of the milk
yield, although in some less acute cases, the cow continues to eat and milk normally for 24 h after
discoloration of the urine is evident. Dehydration develops quickly, the mucous membranes are pallid, and
the cardiac impulse and jugular pulse are much augmented. A moderate temperature rise (40℃; 103.5℉)
often occurs. The feces are usually dry and firm. Dyspnea may be obvious and tachycardia is common.
jaundice may be apparent in the late stages.
1472
Pica may be observed in the other animals in the group. The course of the acute disease extends from 3-5 d;
the cow becomes weak and staggery and finally recumbent. Gangrene and sloughing of the tip of the tail
or the digits has been observed occasionally. Death may occur within a few days. In non-fatal cases,
convalescence requires about 3 weeks and recovering animals often show pica. Ketosis commonly occurs
coincidentaly.
In a herd where the disease occurs, there may be additional signs of phosphorus deficiency, although
when the deficiency is marginal the general condition of the herd may be excellent. A similar acute
syndrome to that described earlier, and less severe cases of anemia, may occur sporadically in animals on
lush spring pasture.
CLINICAL PATHOLOGY
In marginal phosphorus-deficient areas, normal non-lactating animals in an affected herd may have serum
inorganic phosphorus levels within the normal range. Lactating cows in an affected herd may have
moderately low levels of 2 3 mg/dl. (0.65-0.97 mmol/L) and affected animals extremely low levels of
0.4-1.5 mg/dL (0.13-0.48 mmol/L). Erythrocyte counts and hemoglobin levels are also greatly reduced.
Heinz bodies may be present in erythrocytes in the New Zealand disease (10). The urine is dark red-brown
to black in color and usually moderately turbid. No red cells are present in the urine. A low copper status
of the blood and liver of affected cows and the pasture grazed is also recorded (11).
NECROPSY FINDINGS
The blood is thin and icterus is widespread throughout the body. The liver is swollen, and fatty infiltration
and degeneration are evident. Discolored urine is present in the bladder.
DIFFERENTIAL DIAGNOSIS
Postparturient hemoglobinuria is characterized by an acute hemolytic anemia in cows calved within the
preceding 4 weeks. Other causes of acute hemolytic anemia are not confined to the postcalving period.
Laboratory examination is usually necessary to confirm the diagnosis and to eliminate hematuria as a
cause of the discoloration of the urine. The differential diagnosis of red urine in cattle is summarized
in Table 20.3.
TREATMENT
A transfusion of whole blood is indicated in severe cases. A delay of 12 h often seems to lead to an
irreversible state. A minimum of 5 L of blood to a 450 kg cow is recommended. This will usually suffice
for up to 48 h by which time an additional transfusion may be necessary if the cow is weak and the
mucous membranes pale. Following successful blood transfusions, fluid therapy is recommended as both
sup¬portive therapy and to minimize the danger of hemoglobinuric nephrosis. The administration of
phosphorus to acutely ill animals should include the IV administration of 60 g of sodium acid phosphate in
300 ml. of distilled water and a similar dose SC, followed by further SC injections at 12-hourly intervals
on three occasions and similar daily doses by mouth. Oral dosing with bone meal (120 g twice daily) or
dicalcium phosphate or a suitable source of calcium and phosphorus daily for 5 d is recommended
followed by inclusion in the ration. Hematinics during convalescence are recommended. Ketosis is a
common complication of the disease and additional treatment for it may be required.
CONTROL
An adequate intake of phosphorus according to the requirements for maintenance and milk production
should be insured, particularly in early lactation. A decrease in the incidence of the disease is reported
after copper supplementation of cattle in a copper-deficient area (3).
RHVUiW LITERATURE
Ma. Williams, P. S. et al. (1982) Postparturient
hemoglobinuria: a review of the literature.Can. Vet.J., 23, 309-312.
(1)F.Uison, R. S. et al. (1986) NZ Vet.J., 34, 7.
(2)Mac Williams, P. S. et al. (1982) Can. Vet.J, 23, 309.
(3)Smith, B. et al. (1975) NZ Vet.J., 23, 73,109.
(4)Penny, R. H. C. (1956) Vet. Rec, 68, 238.
(5)Awad, F. I. & El-Latif, K. A. (1963) Vet.Rec, 75, 11, 298.
(6)Kurundkar, V. D. et al. (1981) ind.J.Amm. Sa., 51, 35.
(7)Ogawa, E. ct al. (1987) Am.J. Vet. Res.,48, 1300.
(8)Wang, X. L. et al. (1985) Res. Vet. Sci.,39. 333.
(9)Wang, X. L. et al. (1985) Res. Vet. Sci.,39, 373.
(10)Martmovich, D. Ik Woodhouse,D. A.(1971) NZ Vet.J., 19, 259.
(11)Gardner, D. F.. etal. (1976) NZ Vet.J.,24, 107.
EXERTIONAL RHABDOMYOLYSIS IN HORSES (AZOTURIA, TYING UP, CHRONIC
INTERMITTENT RHABDOMYOLYSIS)
Synopsis
Etiology. Multiple causes including inherited anomalies of muscle metabolism. Most cases are idiopathic.
Epidemiology. Sporadic disease of working horses worldwide. Often associated with exercise after a
period of several days of unaccustomed rest.
Clinical signs. Poor athletic performance, muscle stiffness and cramping, stilted gait, unwillingness to
walk, firm and painful muscles, recumbency and death.
Clinical pathology. Increased serum creatine kinase, aspartate aminotransferase and lactate
dehydrogenase activity, and myoglobin concentration.
Lesions. Myonecrosis with secondary myoglobinuric-nephropathy. Diagnostic confirmation. Clinical
signs and serum creatine kinase and aspartate aminotransferase activity.
Treatment. Rest, IV fluids, analgesics, antiinflammatory drugs.
Control. Consistent exercise and diet. Phenytoin.
ETIOLOGY
The cause of most cases of exertional rhabdomyolysis is not determined. Anomalies of muscle
metabolism including polysaccharide storage myopathy of Quarter horses (p. 1748) and draft breeds (1),
mitochondria! myopathy (2), and defects in sarcolemmal function (3) are identified in a small proportion
of cases. Other putative causes include:
•Hypothyroidisni
•Hormonal imbalance
•Vitamin E and selenium deficiency
•Electrolyte abnormalities including sodium or potassium deficiency
•High carbohydrate diets
•Exercise at irregular intervals
•Viral infections.
Conclusive evidence that any of these factors are an important cause of the disease is lacking.
EPIDEMIOLOGY
Exertional rhabdomyolysis ot athletic horses occurs as a sporadic disease worldwide. Estimates of its
incidence and case-fatality rate are not available, however it is recognized to be an important disorder of
Standardbred and Thoroughbred
1473
racehorses, 3-day event horses and endurance horses. Outbreaks of rhabdomyolysis not associated with
exercise in horses at pasture in the United Kingdom and Canada are reported (4). There was an incidence
of 20% of at-risk animals and a case-fatality rate of 66%.
The disease is almost always associated with exercise; more than 50% of cases in Thoroughbred
racehorses become evident during or immediately after exercise, and most of the remaining cases are
evident after a short period of rest (hours) after exercise (5). Occurrence of the disease is unpredictable - a
horse working strenuously for weeks without a problem can develop the disease after a routine exercise
bout.
Exertional rhabdomyolysis is thought to occur more commonly in young female horses, although
epidemiological evidence of this is lacking. A genetic linkage with susceptibility to the disease is present
in Standardbred trotters in Sweden (6) and there is a familial incidence of the disease in Thoroughbred
racehorses (7).
PATHOGENESIS
The underlying cause is usually not known, but the inciting cause is almost always exercise. However,
exertional rhabdomyolysis is not, contrary to earlier suggestions, associated with excessive lactate
accumulation in muscle or systemic lactic acidosis (8). Whatever the inciting cause, the end result is loss
of integrity of the cell membrane of muscle cells, with subsequent muscle dysfunction and death. Cell
contents, including myoglobin and enzymes, are released into surrounding tissues and enter the blood.
Myoglobinuria results in myoglobinuric nephropathy and renal failure in severe cases.
CLINICAL FINDINGS
The clinical findings are variable and range from poor performance to recumbency and death. Signs may
be mild and resolve spontaneously within 24 h or severe and progressive.
The usual presentation is a young (2-5-year-old) female racehorse with recurrent episodes of stiff gait
after exercise. The horse does not perform to expectation and displays a short stepping gait that may be
mistaken for lower leg lameness. The horse may be reluctant to move when placedin its stall, be
apprehensive and anorexic, and frequently shift their weight. More severely affected horses may be unable
to continue to exercise, have hard and painful muscles (usually gluteal muscles), sweat excessively, be
apprehensive, refuse to walk, and be tachycardic and tachypneic. Affected horses may be hyperthermic.
Signs consistent with abdominal pain are present in many severely affected horses. Deep red urine
(myoglobinuria) occurs but is not a consistent finding. Severely affected horses may be recumbent.
CLINICAL PATHOLOGY
Mildly or inapparently affected horses will have moderate increases in serum creatine kinase (CK)
(20000-50000 iu/L), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activity.
Severely affected horses have large increases in CK(> 100 000 iu/L) and other muscle-derived enzymes.
Serum CK and AST activities peak approximately 5 and 24 h after exercise, respectively (9) and in the
absence of further muscle damage may not return to normal levels for 7-10 d. The persistence of increased
AST activity, compared to CK, is useful in identifying affected horses days or weeks after the episode (9).
Serum myoglobin concentrations increase markedly during exercise in affected horses, and decline within
24-48 h (9). Serum carbonic anhydrase III activity is increased in horses with exertional rhabdomyolysis
(10).
Severely affected horses are often hyponatremic (< 130 mEq/L), hyperkalemic (> 5.5 mEq/L),
hypochloremic (< 90 mEq/L), azotemic (increased serum urea nitrogen and creatinine concentrations) and
acidotic or alkalotic. Hemoconcentration (hematocrit > 50%, 0.5 L/L) and increased serum total protein
concentration (> 80 g/L) indicative of dehydration are common. Myoglobinuria is detectable either
grossly or on chemical analysis and should be differentiated from hemoglobinuria or hematuria.
Muscle biopsy during the acute or convalescent stages reveals myonecrosis of Type II (fast twitch,
oxidative) fibers, mild myositis and fibrosis.
NECROPSY FINDINGS
Horses dying of exertional rhabdomyolysis have widespread degeneration of striated muscle, principally
the muscles of exertion, but often involving the diaphragm and heart. Affected muscles tend to be dark and
swollen, but may have a pale, streaked appearance. The kidneys are swollen and have dark brown
medullary streaks. Dark brown urine is present in the bladder. Histologic examination reveals widespread
necrosis and hyaline degeneration of predominantly Type II (fast twitch, oxidative) fibers. In horses with
recurrent disease there may be evidence of myofiber regeneration. Myoglobinuric nephrosis is present in
severely affected horses.
Samples for postmortem confirmation of diagnosis
Formalin-fixed kidney and affected muscle for light microscopic examination.
DIAGNOSTIC CONFIRMATION
Biochemical confirmation of muscle damage by demonstration of increased serum CK or AST activity, in
conjunction with appropriate clinical signs, provides the diagnosis.
DIFFERENTIAL DIAGNOSIS
•Ear tick (Otobius megnini) induced muscle cramping
•Polysaccharide storage myopathy of Quarter horses
•Cassia occidentalis toxicosis (p. 1670)
•Hyperkalemic periodic paralysis (p. 1749)
•Laminitis (p. 1805)
•Colic (p. 197)
•Pleuritis (p. 456)
•Aorto-iliac thrombosis (p. 395).
TREATMENT
The treatment chosen depends on the severity of the disease. The general principles are rest, correction of
dehydration and electrolyte abnormalities, prevention of complications including nephrosis and laminitis,
and provision of analgesia (12).
Mildly affected horses (heart rate < 60 bpm, normal rectal temperature and respiratory rate, no
dehydration) may be treated with rest and phenylbutazone (2.2 mg/kg, orally or IV every 12 h for 2-4 d).
Horses should be given mild exercise with incremental increases in workload as soon as they no longer
have signs of muscle pain. Access to water should be unrestricted.
Severely affected horses (heart rate > 60 bpm, rectal temperature > 39℃ (102℉), 8-10% dehydrated,
reluctant or unable to walk) should not be exercised, including
1474
walking back to their stable, unless it is unavoidable. Isotonic, polyionic fluids, such as lactated Ringer's
solution, should be administered IV to severely affected horses to correct any dehydration and to insure a
mild diuresis to prevent myoglobinuric nephropathy (see pp. 92, 150 for details of fluid therapy). Less
severely affected horses can be treated by administration of fluids by nasogastric intubation (4-6 L every
2-3 h). Urine should be alkalimzed by administration of sodium bicarbonate (1.3% solution IV, or 50-100
g of sodium bicarbonate orally every 1 2 h) to minimize the nephrotoxicity of myoglobin. Affected horses
should not be given diuretics.
Phenylbutazone (2.2-4.4 mg/kg, IV or orally, every 12-24 h), flunixin meglumine (1 mg/kg IV every 8
h) or ketoprofen (2.2 mg/kg IV every 12 h) should be given to provide analgesia. Mild sedation
(acetylpromazine 0.02-0.04 mg/kg IM, or xylazine, 0.1 mg/kg IM, both with butorphanol, 0.01 to 0.02
mg/kg) may decrease muscle pain and anxiety. Tranquillizers with vasodilatory activity, such as
acetylpromazine. should only be given to horses that are well hydrated. Muscle relaxants. such as
melhocarbamol, are often used but have no demonstrated efficacy.
Recumbent horses should be deeply bedded and repositioned by rolling every 2 1 h. Severely affected
horses should not be forced to stand.
CONTROL
Prevention centers on insuring that horses are fed a balanced ration with adequate levels of vitamin E,
selenium and electrolytes, and have a regular and consistent program of exercise. Despite lack of clear
evidence for a widespread role for vitamin E or selenium deficiency in exertional rhabdomyolysis, horses
are often supplemented with 1 iu/kg of vitamin E and 2.5 µg/kg of selenium daily in the feed. Care should
be taken not to induce selenium toxicosis. Sodium bicarbonate and other electrolytes are often added to
the feed of affected horses, but their efficacy is not documented. Phenytoin has proven useful in the
treatment of recurrent rhabdomyolysis. It is administered at a dose rate of 6 -8 mg/kg, orally, every 12 h,
and the dose adjusted depending on the degree of sedation produced (a reduced dose should be used if the
horse becomes sedated) or lack of effect on serum CK or AST activity. Phenytoin can be administered to
horses for months. Dimethylglycine, dantrolene altrenogest and progesterone are all used on occasion
in horses with recurrent rhabdomyolysis, but again without demonstrated efficacy.
REVIEW LITERATURE
Beech, J. (1997) Chronic exertional rhabdomyolysis. Vet. Clin. North Am.: Equine Pract., 13, 145-168.
REFERENCES
(1)Valentine, B. A. et al. (1997) Equine Vet.J.29, 220.
(2)Valberg, S.J. et al. (1994) Muscle Nave, 17,305.
(3)Beech, J. et al. (1993) Res. Vet. So., 54, 110.
(4)llosie, B. IX etal. (1986) Vet. Rec, 119,144.
(5)Hams. P. A. (1991) Br. Vet,J., 147,273.
(6)Collinder, E. et al. (1997) Equine Vet.J ,29, 117.
(7)MacLeay.J. M. et al. (1995) J. Vet. Int.Meet., 9, 224.
(8)Valberg, S. et al. (1993) Equme Vet.J., 25,17.
(9)Valberg, S. et al. (1993) F.quwe Vet.J., 25,11.
(10)Nishita, T. et al. (1995) Am.J. Vet. Rei..56, 162.
(11)MadiganJ. E. et al. (1995)J. Am. Vet. Med. Assoc, 207, 75.
(12)Andrews, F. M. (1994) Vet. Clin. North Am.: Equine Pract., 10, 567.
LOW MILK FAT SYNDROME
The secretion of a normal volume of milk but with its milk fat reduced, often to less than 50% of normal,
is a significant cause of wastage in high-producing cows. It occurs most commonly in cows on low-fiber
diets, for example, lush, irrigated pasture or grain rations that are ground very finely or fed as pellets (1). It
is assumed that a decreased formation of acetate in the rumen is the cause of a depletion of fatty acid
precursors and the fall in butterfat.
RElERENCE
(1) van Beukelen, P. et al. (1982) Bovine Pract.,17, 150.
EQUINE CUSHING'S DISEASE (ADENOMA OF THE PARS INTERMEDIA OF THE
PITUITARY)
A disease of older horses caused by non-malignant hypertrophy and hyperplasia of melanotropes of the
pars intermedia of the pituitary gland and characterized by polyuria, polydipsia, hirsutism and laminitis.
ETIOLOGY
A non-malignant functional tumor comprised of melanotropes of the pars intermedia of the pituitary gland.
The cause of the tumor is unknown.
EPIDEMIOLOGY
The disease occurs worldwide in all breeds of horses and ponies. It is sporadic, non-infectious and
non-contagious. The prevalence of the disease is approximately 0.1% (1). The case-fatality rate is high
(approaching 100%) because of the advanced age of most affected horses, the severity of the disease, and
the cost of palliative treatment.
There is no apparent sex or breed predisposition, although the disease may be more common in ponies.
Affected animals are usually at least 7 years old, and the average age at presentation is 20 years.
PATHOGENESIS
Hypertrophy and hyperplasia of melanotropes of the pars intermedia of the pituitary gland results in
unchecked secretion of pro-opiomelanocortin and compression of the neurohypophysis, hypothalamus
and optic chiasma. Production of pro-opiomelanocortin by melanotropes is not under the negative
feedback control of glucocorticoids and as a result affected horses produce large quantities of
pro-opiomelanocortin, melanocyte-stimulating hormone, β-endorphin and smaller but still excessive
quantities of adrenocorticotropic hormone (ACTH) (2, 3). Production of ACTH results in loss of the
normal circadian rhythm in serum cortisol concentration and hyperadrenocorticism, and secondary
diabetes mellitus. The space-occupying effects of the tumor may cause blindness because of compression
of the optic chiasma, and diabetes insipidus, because of neurohypophyseal dysfunction.
CLINICAL FINDINGS
Affected horses exhibit one or more of hirsutism, hyperhidrosis, polyuria, polydipsia, polyphagia and a
docile demeanor. There is often central obesity, characterized by excessive fat deposition in the crest of
the neck and in the supraorbital fossae. Rarely, affected horses are blind or have seizures. Hirsutism, the
presence of a long, often curly hair coat that is not shed during the warmer
1475
months, is a relatively consistent and specific finding in affected horses. Affected horses are often infertile,
have laminitis, and heal poorly.
CLINICAL PATHOLOGY
There is often mild neutrophilia and lymphopenia. Serum biochemical analysis may demonstrate
hyperglycemia and an increase in alkaline phosphatase activity. Resting serum cortisol concentrations of
affected and normal horses are similar and not useful in diagnosis. Glucosuria may be present.
Diagnostic confirmation is achieved by the overnight dexamethasone suppression test (2). After
collection of a serum sample for measurement of cortisol, dexamethasone (40 (µg/kg 1M) is administered
at about 5 p.m. A second blood sample is collected 15 h later, with the option to collect a third sample 19 h
after dexamethasone administration. Normal horses will have a serum cortisol concentration of less than 1
µg/dL (28 nmol/L) in the second and third blood samples, whereas affected horses will not show a
significant reduction in serum cortisol concentration from that of the initial sample. The sensitivity and
specificity of this test both are approximately 100%. Other tests have been suggested, but either their
sensitivity and specificity have not been determined, or they involve measurement of multiple variables or
of hormones for which assays are not readily commercially available (4, 5). The test of choice is the
overnight dexamethasone suppression test.
NECROPSY FINDINGS
The pituitary gland is usually enlarged due to the increased numbers of melanocorte cells comprising an
adenoma of the pars intermedia. The adrenal cortices are usually of normal width but may be thickened in
some cases. With the appropriate clinical history, the observation of a well-defined nodule within the
pituitary gland is usually sufficient for confirmation of the diagnosis, but histology and
immunohistochemical testing of the mass can be performed.
DIFFERENTIAL DIAGNOSIS
Diabetes mellitus (p. 360)
Diabetes insipidus Both of these diseases are exceedingly rare in horses
Obesity
Psychogenic polydipsia or salt eating.
TRHATMENT
Treatment is palliative. There is no effective treatment of the pars intermedia adenoma and the aim of
treatment is to reduce secretion of the products of the melanocortes through the use of dopamine agonists
or serotonin antagonists. Treatment must be continued for the life of the horse.
Cyproheptadine, a serotonin antagonist, is often used as the initial treatment and is administered at 0.25
mg/kg orally every 24 h for 1 month. If an acceptable response is achieved then this dose is continued, if
not, then the dose is increased to 0.25 mg/kg every 12 h. If the response to cyproheptadine is inadequate,
the dopamine agonists pergolide mesylate (0.014 mg/kg orally every 24 h) or bromocriptine (0.03-0.09
mg/kg orally even,12 hours) may be effective.
Symptomatic treatment should include clipping of the hair coat in spring, treatment of laminitis and
wounds, and prevention of injuries and infection.
CONTROL
None.
REVIEW LITERATURE
van der Kolk.J. H. (1997) Equine Cushing's disease. Equine Vet. Educ, 9, 209-214.REFERENCES
(1)Evans, D. R. (1972) Proc. Am. Assoc. Equine.Pract., 18, 4I7.
(2)Dybdal, N. O. et al. (1994) J. Am. Vet. Med.Assoc, 204, 627.
(3)Orth, 1). N et al. (1982) Endocrinol. 110.1430.
(4)van derKolk.J. H. et al. (1995) Domest.Atiim. Endocrinol., 12, 35.
(5)Eiler, H. et al. (1997) J. Am. Vet. Med.Assoc. 211, 79.