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Pediatric Anesthesia ISSN 1155-5645

REVIEW ARTICLE

Fluid homeostasis in the neonate


Frances OBrien1 & Isabeau A. Walker2,3
1 Department of Paediatrics, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Headington, Oxford, UK
2 UCL Institute of Child Health, London, UK
3 Department of Anaesthesia, Great Ormond Street Hospital NHS Foundation Trust, London, UK

Keywords
neonate; fluids; salt solutions; colloids;
blood transfusion; NICU
Correspondence
Isabeau A. Walker, Department of
Anaesthesia, Great Ormond Street Hospital
NHS Foundation Trust, Great Ormond
Street, London WC1N 3JH, UK
Email: isabeau.walker@gosh.nhs.uk
Section Editor: Andy Wolf
Accepted 12 November 2013
doi:10.1111/pan.12326

Summary
The physiology of the neonate is ideally suited to the transition to extrauterine life followed by a period of rapid growth and development. Intravenous
fluids and electrolytes should be prescribed with care in the neonate. Sodium
and water requirements in the first few days of life are low and should be
increased after the postnatal diuresis. Expansion of the extracellular fluid volume prior to the postnatal diuresis is associated with poor outcomes, particularly in preterm infants. Newborn infants are prone to hypoglycemia and
require a source of intravenous glucose if enteral feeds are withheld. Anemia
is common, and untreated is associated with poor outcomes. Liberal versus
restrictive transfusion practices are controversial, but liberal transfusion
practices (accompanied by measures to minimize donor exposure) may be
associated with improved long-term outcomes. Intravenous crystalloids are
as effective as albumin to treat hypotension, and semi-synthetic colloids cannot be recommended at this time. Inotropes should be used to treat hypotension unresponsive to intravenous fluid, ideally guided by assessment of
perfusion rather than blood pressure alone. Noninvasive methods of assessing cardiac output have been validated in neonates. More studies are required
to guide fluid management in neonates, particularly in those with sepsis or
undergoing surgery. A balanced salt solution such as Hartmanns or Plasmalyte should be used to replace losses during surgery (and blood or coagulation
factors as indicated). Excessive fluid administration during surgery should be
avoided.

Introduction
In the neonate, fluid homeostasis is determined by the
physiological demands of transition to extrauterine life
and the period of rapid growth and development in the
first few weeks and months after birth. Prematurity
imposes additional challenges due to incomplete organ
development. For the anesthetist, administration of
intravenous fluids to maintain cardiovascular stability is
one of the most basic interventions in pediatric anesthesia, yet practical evidence-based guidelines concerning
intravenous fluid management are surprisingly difficult
to find. Much of the literature regarding fluid homeostasis in neonates relates to neonatal intensive care (in particular management of preterm neonates), where it has
been shown that excessive intravenous fluid is harmful,
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particularly in the first few days of life. Intravenous fluid


management can be particularly challenging in neonates
with sepsis or in those undergoing a major surgical intervention. In adult perioperative practice, it is now established that fluid management strategies have an
important effect on long-term outcomes, and it is likely
that this is also the case in children, particularly in
neonates (1,2).
This article revises some of the basic physiological
principles underlying fluid management in neonates, the
particular considerations of preterm infants, and the
changes that occur around the time of birth. We describe
a practical approach to intravenous fluid management in
the neonatal intensive care unit and during the perioperative period, including the principles underlying the use
of crystalloids, colloids, and blood transfusion.
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Fluid homeostasis in the neonate

Fluid compartments and the capillary endothelial


glycocalyx model
Fluid homeostasis in adults has been reviewed recently
(3,4). Water comprises 60% of lean body mass; twothirds of body water is intracellular and about one-third
is in the extracellular fluid (ECF) compartment. Sodium
is the principle extracellular cation and chloride the
principle anion; potassium and phosphate are the principle intracellular cations and anions respectively, and
there is a high intracellular protein content. Transmembrane ion channels and electrochemical gradients maintain the distribution of ions, and movement of water
across semipermeable cell membranes maintains osmotic
equilibrium. Water and sodium homeostasis is maintained by the balance between intake and losses
(measured and insensible), thirst, and the activity of
the renin-angiotensin-aldosterone system, naturetic
peptides, and antidiuretic hormone.
The ECF is divided into intravascular fluid (containing plasma and cellular constituents of blood) and the
interstitial fluid compartments. Movement of fluid
(including proteins) between the intravascular and the
interstitial fluid compartment is crucially dependent on
the capillary endothelium and the overlying capillary
endothelial glycocalyx, which together form the
endothelial glycocalyx layer (EGL). The endothelial
glycocalyx consists of glycoproteins and proteoglycans
containing glycosaminoglycans attached to the endoluminal surface of the capillary endothelium. Albumin is
contained within the glycocalyx layer, and the endothelial glycocalyx layer requires a normal level of plasma
albumin to function.
The vascular endothelium/glycocalyx barrier is freely
permeable to water, semipermeable to albumin, but
impermeable to large protein molecules (>70 kDa) in
plasma. Sodium and chloride ions pass freely into the
interstitial fluid via ion channels in the capillary endothelium. The colloid osmotic pressure and hydrostatic
pressure in the interstitial fluid are low, and under normal circumstances, outward hydrostatic pressure from
the lumen of the capillary and the (smaller) inward pull
of the colloid osmotic pressure from the capillary results
in a continuous net outward leak of protein and fluid
throughout the length of the capillary into the interstitial fluid; this is cleared from the interstitial space as
lymph so as to avoid the accumulation of interstitial
edema.
The EGL has an important role in inflammation,
hemostasis, and regulation of vasomotor tone. The
endothelial glycocalyx (EGC) is fragile and is damaged
by rapid infusion of intravenous fluids, surgery,

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F. OBrien and I.A. Walker

ischemia, hypoxia, inflammatory cytokines, and acute


hyperglycemia; the net result is an increase in vascular
permeability and increased loss of plasma protein,
including albumin into the interstitial space, which
results in interstitial edema. This transcapillary leak of
albumin may be greatly increased in shock. Various substances have been shown to protect the EGC (sevoflurane, hydrocortisone, and antithrombin III) and may
confer therapeutic benefit.
When capillary hydrostatic pressure is low, the transcapillary leak ceases. When intravenous fluid is given
(crystalloid or colloid), it is retained in the intravascular
volume initially until hydrostatic pressure increases and
filtration into the interstitial space is resumed; thus,
crystalloids should theoretically be as effective as colloids in hypovolemic fluid resuscitation, rather than the
traditional 3 : 1 volume ratio, and this is born out in
clinical studies (see below). However, if colloid is given
in the euvolemic state, it is retained in the plasma volume causing hemodilution and a fall in hematocrit,
increases transcapillary filtration, and potentially causes
displacement of albumin into the interstitium. A crystalloid solution also increases hydrostatic pressure and
transcapillary filtration, but reduces colloid osmotic
pressure so that fluid filtration is increased to a greater
extent than with a colloid infusion, and there is less
marked hemodilution.
Fluid compartments in the neonate
In utero, the fetus exists in a fluid filled environment
the major determinant of fluid balance is placental
blood flow and later in development, absorption of
amniotic fluid through the gastrointestinal tract. Early
in fetal life, 90% of the body weight is water, and the
ECF fluid volume is expanded, representing 60% of
body weight. As the fetus develops, naturesis and diuresis result in contraction of the interstitial fluid volume
so that by term, water comprises 75% of body weight
and the ECF fluid volume comprises 40% of body
weight (5,6). Contraction of the interstitial fluid volume
continues through infancy and early childhood such
that the adult distribution of total body water is
obtained by 10 years of age (6). Preterm birth has a
major effect on body water composition; water represents 90% of the body weight of a baby born at
23 weeks gestational age (GA), and 8085% of the body
weight of a baby born at 2530 weeks (7) (see Table 1).
The normal blood volume in the neonate is approximately 80 mlkg1 (depending on the time the cord is
clamped), approximately 100 mlkg1 in preterm
infants.

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Fluid homeostasis in the neonate

Table 1 Variation in total body water composition and extracellular


fluid (ECF) volume at birth in relation to gestational age and body
weight
Gestational age
(weeks)

Body
weight (BW) (g)

Total body
water (%BW)

ECF volume
(%BW)

2327
2832
3640

5001000
10002000
>2500

8590
8285
7176

6070
5060
~40

Neonatal physiology and cardiorespiratory


adaptation after birth
Cardiorespiratory adaptation
Birth represents a time of profound physiological
change as placental blood flow ceases and the baby transitions to independent life. The fetal lungs are filled with
fluid, and production of fetal lung water ceases during
labor; liquid is squeezed out of the lungs during the second stage of delivery, but most of the fetal lung water is
absorbed into the pulmonary capillaries and lymphatics
as the first breaths are taken. Oxygen tension rises and
pulmonary vascular resistance falls. This period of cardiorespiratory adaptation also involves closure of the
fetal shunts (foramen ovale, ductus venosus, and ductus
arteriosus). The ductus arteriosus constricts as oxygen
tension rises and, in most term babies and well preterm
babies, is closed functionally by 2 days of life, with anatomical closure by 23 weeks. The ductus arteriosus
may remain patent if oxygen tensions are low, or in the
presence of sepsis, acidosis, or high circulating prostaglandin levels. Patent ductus arteriosus (PDA) is common in preterm infants for these reasons and is seen in
50% of preterm neonates with birth weight <800 g.
PDA results in left to right shunt, increased pulmonary
blood flow and increased risk of chronic lung disease,
necrotizing enterocolitis (NEC), and poorer long-term
outcomes (8). The incidence of PDA is affected by intravenous fluid management during this vulnerable period,
as will be described below.
The postnatal diuresis
Fluid requirements are low in the first few days of life in
the term neonate. Breast-feeding is becoming established
and urine output is low due to the high levels of circulating vasopressin around the time of birth. In the first few
days after birth pulmonary vascular resistance continues
to fall and pulmonary venous return increases, this
causes release of atrial naturetic peptide, which in turn
results in a brisk diuresis (9). The postnatal diuresis is
associated with contraction of the ECF due to the loss
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Pediatric Anesthesia 24 (2014) 4959

of isotonic fluid from the interstitial fluid compartment


and a reduction in body weight of 510% in healthy
term babies. Weight is usually at a nadir around day 5,
but most babies regain their birth weight between 7 and
10 days. Weight loss of 1015% may occur in the first
week of life during postnatal adaptation in preterm
infants (<27 weeks GA), and they may take longer to
regain their birth weight.
Expansion of the ECF by excessive administration of
sodium and water, particularly before the postnatal
diuresis has occurred, has an adverse effect on outcomes, particularly in extremely low birth weight infants
(1014). A Cochrane review of randomized controlled
studies comparing liberal to restricted water (and
sodium) intake in preterm neonates demonstrated a significant increase in postnatal weight gain, and increased
risk of PDA and NEC, with a trend to increased risk of
bronchopulmonary dysplasia, intracranial hemorrhage,
and death (11). A retrospective chart review of 204 neonates <32 weeks GA from a single institution suggested
restricted water intake in the first 3 days of life (constant
calorie intake) was protective for the development of
PDA, with the difference remaining after controlling for
gestational age and severity of illness (14). A randomized controlled trial in neonates <30 weeks GA showed
that early sodium supplementation (4 mmolkg1
day1) was associated with delayed postnatal diuresis,
delayed reduction in ECF, and increased oxygen
requirement at 1 month (12,13).
Renal function in the neonate
After the postnatal diuresis, the neonate grows rapidly.
Renal function is ideally adapted to cope with a liquid
(milk) diet with relatively low sodium content. Sodium
is required for growth and is retained avidly in the distal
tubules under the influence of the renin-angiotensinaldosterone system (RAAS). Although the kidney has a
full complement of nephrons from around 35 weeks gestation, the renal tubules are short and there is limited
ability to concentrate the urine (6). High volumes of
dilute urine are therefore produced (urinary osmolality
300 mOsmolkg1) at a rate of around 23 mlkg1h1
(4550 mlkg1day1). Neonates are also able to produce more dilute urine in the face of a high water load
(provided ADH levels are not elevated), but they have
limited ability to concentrate the urine, so become dehydrated easily (11). Growth of the kidney is associated
with increasing complexity and length of the renal
tubules, and increasing ability to concentrate the urine,
so that by a year of age, infants are able to vary the concentration of urine between 50 and 1400 mOsmolkg1,
as in adults (6).
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Fluid homeostasis in the neonate

Neonates are susceptible to disorders of sodium balance, and both sodium and water content in intravenous
fluids need to be considered carefully. Aldosterone secretion is slow to be reduced in the face of a sodium load,
for instance from isotonic fluid boluses, intravenous
flushes, and drugs, and may result in hypernatremia or
sodium retention with edema formation. It is recommended that neonates are given sodium-free fluids until
after the postnatal diuresis to allow for contraction of
the ECF volume (12,13), but inadequate sodium intake
thereafter will result in hyponatremia. This is particularly important in preterm neonates as the RAAS is
less active, and they have a limited ability to retain
sodium in the distal renal tubule. Inadequate sodium
intake is associated with severe hyponatremia and poor
long-term neurological outcomes in preterm neonates
(16).
Insensible water loss in neonates
In adults, insensible water loss (IWL) consists mostly
of water lost via evaporation through the skin (twothirds) or respiratory tract (one-third). In neonates,
IWL from the skin varies with gestational age; the
more preterm the infant, the greater the transepidermal
water loss as there is a higher body surface area to
weight ratio, and the skin in the most preterm neonates
is thin and fragile and poorly keratinized. Use of a
radiant warmer or phototherapy significantly increases
IWL and can have a significant affect on fluid balance.
In extreme preterm infants, IWL losses may exceed
renal water losses (15). Evaporation of water from the
skin is associated with cooling due to the effect of the
latent heat of evaporation. Difficulty in keeping a baby
warm may be an indication of excessive IWL. IWL
may be reduced by nursing preterm infants <2 weeks of
age in a heated humidified incubator (>80% humidity),
but if the baby is taken out of the incubator (for
instance for surgery) or if the incubator is left open for
procedures, this protection will be lost. Insensible water
loss decreases as preterm neonates mature, and ambient
humidity may be gradually decreased with time. The
incidence of hypernatremic dehydration and temperature instability in preterm infants are good indicators
of the quality of nursing care in a neonatal intensive
care unit.
Humidification reduces IWL from the lungs in ventilated babies, and humidification is also required for
babies receiving nasal CPAP or nasal high flow
therapy. Postextubation, respiratory IWL may be high
if a neonate receives unhumidified oxygen via nasal
cannulae.

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F. OBrien and I.A. Walker

Nutritional requirements
Fluid requirements cannot be considered in isolation
from nutritional requirements, particularly the requirements for glucose, although a detailed consideration is
beyond the remit of this article. Blood glucose falls
immediately after birth, but rises in the first few hours in
response to endogenous glucose production or feeding.
Neonates metabolize ketones as well as glucose as an
important energy substrate in the brain, so are relatively
protected from damage due to hypoglycemia. However,
prolonged hypoglycemia below 2.6 mmoll1 is associated with abnormal neurological outcomes. Preterm
neonates are at risk of hypoglycemia if enteral feeding is
delayed (for example, to reduce the risk of NEC), and
they have limited glycogen stores. Intravenous glucose
should be provided to babies at risk of hypoglycemia at
a starting rate of 57 mgkg1min1 (10% dextrose
70100 mlkg1day1), and blood glucose should be
monitored (15).
Blood transfusion
Anemia is common in neonates in the NICU, partly due
to the transition from synthesis of fetal hemoglobin to
adult hemoglobin A that starts at birth, limited responsiveness to erythropoietin in the neonate, and rapid
growth. Anemia is also related to timing of clamping of
the umbilical cord at birth, iatrogenic anemia from
repeated blood samples in the NICU, sepsis, and surgical interventions (17,18).
Untreated anemia is associated with apnea, poor
weight gain, and poor neurodevelopmental outcomes.
It has also been suggested that prior blood transfusion
may be a risk factor for NEC, particularly in extreme
preterm neonates, although the precise mechanism is
not clear. Suggestions include alterations in gut perfusion associated with feeding in neonates with hemodynamically significant PDA, the severity of preexisting
anemia, or immunological mechanisms associated with
the transfusion of red cells without leukocyte depletion (19,20). Interestingly, neonates are also disproportionately represented in the UK Serious Hazards of
Blood Transfusion reporting system, primarily related
to misidentification (lack of wrist bands), and over
transfusion (18). As neonates are such frequent recipients of blood transfusions, questions arise as to what
trigger for transfusion should be used, what should be
the target hemoglobin, and how to minimize donor
exposure. Hemostasis in neonates is discussed elsewhere in this journal and will not be considered here
(21).

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Fluid homeostasis in the neonate

Measures suggested to reduce exposure of neonates to


blood transfusion include delayed clamping of the
umbilical cord at birth (also associated with greater
cardiovascular stability in preterm infants, reduced
incidence of NEC and intraventricular hemorrhage);
limiting blood sampling to a minimum, according to
protocol; optimizing nutrition; and selection of lower
threshold hemoglobin values for transfusion, depending
on the level of respiratory support required (22,23). A
single-center randomized controlled study of restrictive
versus liberal transfusion in preterm neonates did not
affect donor exposure (there was a single-donor program to split adult donor units into smaller pediatric
packs) and suggested that a more liberal transfusion policy was associated with a lower incidence of parenchymal hemorrhage, periventricular leukomalacia, apnea,
and improved long-term neurodevelopmental outcomes
(24,25). Reduction in apnea and brain injury was not
confirmed in a large multicentre study (Preterm Infants
in Need of Transfusion, PINT study) (26). A Cochrane
review concluded that a restrictive transfusion policy
was associated with moderate reduction in transfusion
with no increased short-term risk, but further trials were
required to look at long-term impact (27). A large randomized controlled study is currently under way to look
at the effect of transfusion thresholds on long-term neurocognitive outcome in extremely low birth weight
infants (the ETTNO study) (28). In the meantime, some
practical guidelines have been suggested (see Table 2)
(29).
Ideally, adult packs should be split into smaller pedipacks (3666 ml) to minimize donor exposure, and in
addition to routine screening, all neonatal transfusions
in the UK are leucodepleted, from CMV negative,
low antibody titer repeat donors. Irradiated blood
is required for those with immune deficiency (e.g.,

Table 2 A practical guide for transfusion in the neonate (modified


from Venkatesh V, Khan R, Curley A et al. How do we decide when a
neonate needs a transfusion. Brit J Haematol 2013 160: 421433)

Indication for transfusion


Blood loss or anemia immediately
after birth
Ventilated
Age <1 week
Age >1 week
Oxygen therapy/CPAP
Age <1 week
Age >1 week
No respiratory support, stable
Age >1 week

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Pediatric Anesthesia 24 (2014) 4959

Suggested
hemoglobin (gl1)
120

<120
<110
<100
>90
75

suspected 22q11 deficiency) to avoid graft versus host


disease. For the anesthetist, the following formula to
calculate the volume of blood required to raise the
hemoglobin a given level has been evaluated in critically
ill children and neonates (30):
Volume of packed red cells (ml)
required rise in Hb g  dl1  weightkg  4:8 1
In the randomized controlled study by Bell and
colleagues, blood transfusion reduced cardiac output in
neonates who were anemic (Hb 91 gl1) (presumably
due to improved oxygen delivery), but this effect is not
seen in infants with a higher starting hemoglobin (Hb
136 gl1) (31); hemoglobin of 120140 gl1 serves as a
useful target for transfusion in the intraoperative period.
Excessively high hematocrit (>65%) should be avoided
as this will increase blood viscosity, reduce tissue oxygen
delivery, and is associated with worse long-term outcomes (32).
Management of hypotension
A major concern in the neonatal intensive care unit is
the management of hypotension, particularly in preterm
infants in the first few days of life. Low cardiac output
and hypotension are associated with increased risk of
intracranial hemorrhage, NEC, worse long-term neurodevelopmental outcomes, and increased mortality. Traditionally, the definition of hypotension in a preterm
infant is taken as MAP <30 mmHg (or equivalent to the
gestational age in mmHg). Approaches to the treatment
of hypotension include volume expansion with boluses
of crystalloid or colloid, or the use of inotropes. Interventions to improve long-term outcomes are hampered
by lack of evidence, and challenges associated with measurement of cardiac output rather than simple measurement of blood pressure (33).
Volume expansion crystalloid versus colloid
Hypovolemia due to acute blood loss is logically treated
with blood, as described above, and other abnormal
losses (such as nasogastric tube losses), with isotonic
fluid replacement. A survey of specialist pediatric anesthetists in 2001 suggested that the choice of fluids for
plasma volume expansion in infants and children varied
by geographical location, with semi-synthetic colloids
commonly used, and albumin mainly used for neonates
(34). Recent publications have challenged the use of
semi-synthetic colloids and suggested caution regarding
the use of albumin and excessive volumes of intravenous crystalloid in perioperative or critically ill patient
(35).
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Fluid homeostasis in the neonate

A Cochrane review of eight randomized controlled


studies did not show any benefit of routine volume
expansion to improve outcomes in preterm infants,
using normal saline or colloid (albumin, fresh frozen
plasma, or gelatin) (36). The largest study considered
volume expansion within 2 h of birth with fresh frozen
plasma or gelatin compared with maintenance infusion
of 10% dextrose to prevent cerebral hemorrhage, but
found no difference in outcome at discharge or after
2-year follow-up (37,38). One small study compared the
effect of saline 10 mlkg1 compared with 5% albumin
10 mlkg1 for treatment of hypotension in preterm
infants. Hypotension was defined as mean arterial pressure <25 mmHg for infants with birth weight 1 kg,
<30 mmHg for infants birth weight 11.49 kg, and
<35 mmHg for infants with birth weight 1.51.99 kg.
Saline was as effective as albumin in treating hypotension, but albumin was associated with more fluid
retention in the first 48 h. There were no differences in
long-term outcome (inotropic support, death, chronic
lung disease) (39), and the authors recommended that
saline should be used in preference to colloid for treatment of hypotension in this situation. Studies in very
low birth weight preterm neonates randomized to two
fluid regimens in the perinatal period showed that
colloid infusion (as albumin or fresh frozen plasma if
coagulation was abnormal) was an independent predictor of worse long-term outcomes and suggested that
colloids should be used with caution in the perinatal
period (40,41).
Randomized controlled studies in adult practice and
older children have helped throw further light on fluid
choices for intravenous volume resuscitation, and readers are referred to a recent comprehensive review on this
topic (35). The saline versus albumin fluid evaluation
study (SAFE) for fluid resuscitation in adult intensive
care suggested no difference in overall mortality at
28 days, although subsequent analysis suggested there
may have been a potential benefit in patients with severe
sepsis (42). The Fluid Expansion as Supportive Therapy
(FEAST) study suggested no difference in outcome
between saline versus albumin boluses for children presenting with febrile illness suggestive of severe sepsis,
although this study excluded neonates and patients
undergoing surgery (43). The SAFE and FEAST studies
also demonstrated the same clinical effectiveness for
similar volumes of saline or albumin, as predicted from
theoretical considerations (3,4,35). However, it was
notable in the FEAST study that both albumin and
saline groups were associated with worse outcome at
48 h than the no-fluid bolus control group, which has
challenged the concept of acute volume resuscitation in
children with compensated shock (44). The recently
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F. OBrien and I.A. Walker

updated Cochrane review of albumin for resuscitation


and volume expansion in critically ill patients again confirmed no overall benefit of albumin versus crystalloids
such as saline (45).
Two recent large randomized controlled studies comparing 6% hydroxyethyl starch (HES) (130/0.42) to
Ringers lactate or saline for volume resuscitation in
adult patients in ICU suggested increased mortality
and/or need for renal replacement therapy at 90 days in
patients receiving HES (46,47). Safety information on
long-term outcomes after use of starch solutions in
neonates is extremely limited (48), and on the basis of
the adult data, these solutions cannot be recommended.
The information on outcomes after use of gelatin solutions in neonates is also limited. A prospective sequential comparison study in adults suggested increased
incidence of acute kidney injury where HES or gelatin
was used compared crystalloids (49), and it would also
seem prudent to avoid large volumes of gelatins in
neonates.
Which crystalloid solution?
For many years, many clinicians have preferred balanced salt solutions such as Hartmanns or Ringers
Lactate in anesthetic practice. Normal saline contains a
higher than physiological concentration of sodium and
chloride ions, which may result in hyperchloremic acidosis and adverse effects on renal or immune function (35).
An observational study of patients in an adult ICU
where there was a change from high chloride containing
solutions (0.9% saline, gelatin, albumin in saline) to
restricted chloride containing solutions (Plasma-lyte,
Hartmanns, chloride-poor 20% albumin) suggested the
low chloride containing solutions were associated with
less acute kidney injury and need for renal replacement
therapy (50). Similarly, review of a large database of
adults undergoing open abdominal surgery showed
fewer major complications (blood transfusion, acid-base
disturbance, postoperative infection, renal impairment)
and improved mortality in those who received a balanced salt solution (Plasma-lyte) compared with 0.9%
saline (51). The balanced salt solutions do not contain
the same ion content as plasma, and theoretically, high
volumes of balanced salt solutions may be associated
with hyponatremia or high lactate concentration (Hartmanns, Ringers), or cardiotoxicity due to high acetate
concentration (Plasma-lyte) (35).
Use of inotropes
Clinical signs of low perfusion include delayed capillary
refill, low BP, and metabolic acidosis, but there is a
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Pediatric Anesthesia 24 (2014) 4959

F. OBrien and I.A. Walker

Fluid homeostasis in the neonate

poor correlation between low systemic arterial blood


pressure and systemic perfusion as some babies may
have normal blood pressure but low perfusion, or low
blood pressure, but normal perfusion. In the first 24 h
after birth, critically low perfusion in a preterm infant
may be associated with relatively high afterload, exacerbated by left to right flow through a patent duct and
positive pressure ventilation; after 24 h, systemic vascular resistance usually falls, so perfusion may be normal
but associated with a low blood pressure. Care needs to
be individualized and inotropes associated with systemic
vasodilatation (dobutamine, milrinone), or pressor
agents (dopamine, epinephrine) should be chosen
according to the clinical situation (33). Swings in blood
pressure, particularly in preterm infants, should be
avoided as this is thought to be associated with intraventricular hemorrhage. Ideally, inotropes should only
be used if there are signs of poor perfusion, rather than
based on an arbitrary value of blood pressure, and decisions about fluid loading versus use of inotropes should
ideally be made using some form of assessment of
cardiac output.

contour analysis, echocardiography, and transesophageal Doppler (TED) (52). The National Institute for
Health and Care Excellence medical technologies guidance supported the use of the CardioQ-ODM esophageal Doppler monitor in adults undergoing major or
high-risk surgery, or where invasive monitoring would
be considered. Use of the TED was associated with
reduction in postoperative complications, the need for
central venous access, and the length of stay compared
with conventional clinical assessment (53). TED has
been shown to provide an accurate assessment of cardiac output in children of all ages when compared with
thermodilution and can track changes in cardiac output
in response to fluid loading or changes in inotropes (54).
TED has also been used in neonates and infants 2.5
5 kg undergoing surgery and to identify fluid responsiveness more reliably than clinician assessment; the
authors suggested that the use of the TED may guide
appropriate fluid management during surgery and
would help avoid excessive fluid boluses in neonates
where there is no increase in cardiac output in response
to a fluid challenge (55).

Hemodynamic monitoring in neonates

Laboratory assessment

Cardiac output and perfusion are traditionally inferred


from clinical signs such as blood pressure, central
venous pressure (CVP), heart rate, oxygen saturation,
capillary refill time, urine output, core-peripheral temperature difference, supplemented by laboratory measurements of base excess, mixed venous oxygen
saturation, and lactate. Clinical signs are notoriously
inaccurate, and some, such as signs, used to identify
dehydration older babies and children (e.g., altered skin
turgor, sunken anterior fontanel, dry mucous membranes) are not generally useful in the newborn, particularly preterm infants. Clinical signs such as
tachycardia may imply dehydration, reduced intravascular volume, decreased stroke volume, or low cardiac
output associated with myocardial dysfunction or sepsis. However, increased heart rate may also be a reflection of pain, discomfort, environmental stress (noise,
light), pyrexia, or a side effect of caffeine therapy used
to prevent chronic lung disease. Similarly, delayed capillary refill occurs in low cardiac output states, but it
can also be seen in infants with peripheral vasoconstriction from cold stress, acidosis, and drugs that cause
vasoconstriction.
Noninvasive methods of assessing cardiac output
have been validated in children and are being used
increasingly in clinical practice. Examples include nearinfrared spectroscopy (NIRS) for measuring regional
perfusion in the brain and splanchnic circulation, pulse

Term neonates who are sick and preterm babies will


require daily measurement of serum electrolytes, urea,
and creatinine in the early days following delivery. In
the first 24 h, these results may reflect maternal values;
for instance, hyponatremia is commonly seen in babies
whose mothers received oxytocin; serum creatinine normally declines postnatally, but these changes may be
delayed in extremely preterm babies. Extremely preterm
babies will need more frequent measurement of electrolytes (e.g., 8 hourly) as they can rapidly become dehydrated due to IWL; the presence of hypernatremia may
indicate the need for a more generous fluid intake. Routine blood gas analysis and lactate measurement are
undertaken to assess ventilation and adequacy of perfusion. Urinary electrolytes and specific gravity can be
measured either routinely or depending on clinical
circumstances; diuretics such as furosemide may make
interpretation of results difficult.

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Intravenous fluid and electrolyte prescription in


the NICU
Intravenous fluid prescriptions in the NICU need to be
individualized according to the gestational age, postnatal age, and comorbidities. Prescriptions should take
account of the maintenance requirement for water and
electrolytes, transfusion and volume requirements to
maintain cardiac output and tissue oxygen delivery, and
55

Fluid homeostasis in the neonate

nutritional requirements, particularly to maintain blood


glucose. Sodium and water intake should usually be
restricted until the postnatal diuresis has taken place,
but it is also important to maintain intravascular volume and to keep physiological variables such as heart
rate, blood pressure, and urine output stable. Errors in
fluid management may result in serious morbidity, and
intravenous fluids need to be prescribed carefully, on an
individual basis, as for any other drug.
Fluid balance
An accurate record of fluid balance is essential, supplemented by regular clinical assessments as described
above. Fluid intake calculations should take all sources
of fluid into account, including intravenous crystalloid,
parenteral nutrition, drug infusions, fluid boluses, and
milk. Urine output is measured by weighing nappies
or by measuring urine collected in urinary bags or
by catheter. Drain losses should also be taken into
consideration.
Regular measurement of weight is important to assess
overall fluid balance. Sudden or large increases in weight
generally reflect fluid retention with abnormal distribution of fluid due to increase in interstitial, bowel, or pulmonary fluid, depending on gestational age and
associated medical problems, for instance in sepsis,
NEC, or respiratory distress syndrome. Babies with
severe respiratory distress receiving muscle relaxants to
facilitate ventilation may become very edematous due to
accumulation of interstitial fluid. Quantifying and managing reduced cardiac output due to intravascular fluid
volume depletion in the presence of tissue edema is a
particular challenge, especially in the preterm neonate.
Maintenance fluid and electrolyte requirement in the
first few days of life
Total fluid requirement includes the maintenance
requirement to replace measured losses (urine, stool)
and insensible water loss (IWL), and the fluid requirement for growth.
Insensible water loss is high in the first few days of life
and is further increased by prematurity, radiant warmers, increased body temperature, and some types of
phototherapy. Urine output may be low or absent in the
first 24 h after birth, but thereafter should be at least
1 mlkg1h1. As the baby grows, a urine output of
approximately 6080 mlkg1day1 is required to
excrete the urinary renal solute load. Stool water is usually 510 mlkg1day1. Depending on gestation,
weight gain for normal growth is 1015 gkg1day1, of
which 7080% is water.
56

F. OBrien and I.A. Walker

Insensible water loss cannot be measured but should


be estimated to allow for appropriate fluid prescription.
IWL can be estimated using the following formula:
IWL fluid intake urine output
weight loss (or weight gain)

The fluid requirements for well term and preterm


babies are shown in Table 3. Extremely preterm infants,
especially if under radiant warmers, may occasionally
require more than 200 mlkg1day1 during the first
23 days of life. Greater weight loss than expected, low
urine output, rising urine specific gravity, and/or rising
serum sodium concentration suggests inadequate fluid
administration, so intravenous fluid should be increased.
Conversely, intravenous fluid should be reduced if
serum sodium is falling, or weight did not decrease
appropriately or actually increased following delivery.
Electrolyte requirements
Sodium (or potassium) is rarely required in the first
24 h of life. After the first 24 h, a newborn baby
requires 23 mmolkg1day1 of sodium and 12
mmolkg1day1 of potassium. Supplementation will
need to be fine-tuned according to measurement of electrolytes and urine output (and consideration of disease
status). Extremely preterm infants (who are well) require
additional sodium supplements. They are unable to
effectively retain bicarbonate and are unable to adequately acidify their urine. This may lead to the development of a metabolic acidosis. Excessive administration
of sodium chloride (given as flushes for IV cannulae, to
carry drugs, as fluid boluses etc.) may result in hyperchloremic acidosis. For these reasons, sodium is often
given in the form of sodium acetate in total parenteral
nutrition (TPN) and additional sodium bicarbonate
may be given to replace renal losses of bicarbonate.
After the first week of life, during active growth,
the requirement for sodium and potassium increases;

Table 3 Volume of fluid required according to gestational age, birth


weight, and postnatal age
Fluid requirement (mlkg1 day1)
Postnatal day

Term/LBW

VLBW/ELBW

Day 01
Day 2
Day 3
Day 4
Day 5

5060
7080
100120
120150
150180

8090
120
150
180
180

LBW, low birth weight <2.5 kg; VLBW, very low birth weight
<1.5 kg; ELBW, extremely low birth weight <1 kg.
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F. OBrien and I.A. Walker

35 mmolkg1day1 of sodium and 23 mmolkg1


day1 of potassium being the usual amounts required.
Many preterm infants may require 68 mmolkg1
day1 of sodium, and there are those who need even
more (sometimes up to 12 mmolkg1day1). This is
partly due to inability to retain sodium, but may also be
secondary to the use of diuretics.
Fluid and electrolyte requirements during surgery
The aim of perioperative fluid management is to maintain oxygen delivery to the tissues, to maintain blood
volume, organ perfusion, and fluid homeostasis, and to
avoid hypoglycemia. Intravenous fluid is given to provide maintenance requirements and replace fluid losses,
and to support the blood pressure if required; in the
past, an arbitrary allowance has also been made for
unquantifiable third space losses, but this concept is no
longer valid (3,4).
Inadequate or excessive fluid administration during
surgery may be associated with poor outcomes. Metaanalysis of randomized controlled trials of fluid therapy
in major elective open abdominal surgery in adults suggests that the goal should be enough but not too
much (1). The authors defined fluid regimens as balanced if the volume of perioperative fluid was based
on the daily maintenance requirement for fluid, restrictive if fluid was given at less than maintenance requirement, or liberal if the regimen was associated with
fluid loading. There was a 59% reduction in complications, and reduction in length of stay of 3 days in
patients managed in a state of fluid balance rather
than fluid imbalance. There was a doseresponse relationship between fluid given, weight gain, and complications in patients receiving liberal fluids in one study
(56). There are very few studies describing perioperative fluid management in neonates, and this should be
an area for future research. The Canadian Pediatric
Surgery Network (CAPSNet) published an analysis of
the CAPSNet database describing preclosure fluid
resuscitation in 407 live-born neonates with gastroschisis, a condition typically associated fluid loss from
exposed bowel (2). Resuscitation fluids were defined
as fluid boluses (in mlkg1) in excess of the standard
maintenance dextrose infusion of 6080 mlkg1day1.
Multivariate outcomes analysis demonstrated that for
every 17 mlkg1 resuscitation fluid, there was one
additional day of ventilation, TPN and length of hospital stay, and an increase risk of bacteremia. The
authors concluded that, as for standard neonatal care,
routine fluid boluses in euvolemic infants should be
avoided and should only be given in response to
hypovolemia.
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Pediatric Anesthesia 24 (2014) 4959

Fluid homeostasis in the neonate

There are very few studies regarding intraoperative


fluid losses in neonates, so it is difficult to give precise
guidance. Most neonates presenting for surgery in the
first few days of life will be managed in the neonatal unit
and should be well-hydrated, fully resuscitated, and
receiving intravenous maintenance fluids with glucose.
In practice, intraoperative fluid management is usually
based on the maintenance requirement for intravenous
fluid with replacement of measured losses, and continuous clinical assessment to determine adequacy of perfusion, with frequent analysis of hematocrit, base excess,
lactate, and blood glucose. On a practical note, great
care should be taken with intravenous lines in neonates,
and all central lines should be accessed with an aseptic
nontouch technique. Many neonates, particularly preterm neonates with NEC, may be dependent on TPN
for many weeks, and line-related sepsis is a major concern. Peripherally inserted long lines are easily blocked,
and infusions through these lines should not be stopped
in theater; similarly, care should be taken not to bolus
glucose containing fluids, and separate intravenous lines
are required for maintenance glucose and isotonic
replacement fluids.
Glucose requirements during surgery
The glucose requirement during surgery is less than
maintenance due to the stress response to surgery, but
interruption of glucose infusion during surgery is associated with an increased risk of hypoglycemia. Blood
glucose should be monitored carefully, or a low-dose
glucose infusion continued (57). In practical terms,
blood glucose can be maintained in the normal range by
continuing maintenance 10% infusion at a reduced rate
or by the use of 12% glucose in isotonic solution as
maintenance fluid (58).
Water requirement during surgery
Maintenance requirement for water during surgery is
low as vasopressin levels are raised and urine output is
low. Insensible losses should be minimized by appropriate care (warmed humidified gases, warming blankets).
In preterm infants, surgery is often undertaken in the
neonatal intensive care unit, which has the advantage of
minimizing insensible fluid losses.
Replacement fluids during surgery
Replacement fluid should be provided in the form of an
isotonic balanced salt solution such as Hartmanns or
Plasmalyte (or blood or fresh frozen plasma/platelets as
indicated). Our practice is to continue the maintenance
57

Fluid homeostasis in the neonate

F. OBrien and I.A. Walker

infusion of dextrose, and using a separate line, to give


boluses of 10 mlkg1 Hartmanns and monitor fluid
losses and clinical parameters such as heart rate, blood
pressure, filling pressure, and capillary refill. Near
patient testing of hemoglobin, base excess, lactate, electrolytes, blood glucose, and coagulation is routine.
Excessive fluid administration should be avoided, particularly in the first few days of life. It is important to
constantly reassess fluid administered compared with
fluid losses and useful to consider volume delivered relative to total blood volume. Inotropic support should
be started if the neonate is hypotensive with signs of
poor perfusion, but is not fluid responsive. Ideally,
noninvasive assessment of cardiac output should be
measured, although this is not yet routine. Noninvasive

measurement of cardiac output is becoming the norm


in high-risk surgery in adult practice, and ideally, we
should be able to offer the same individualized goal
directed therapy to our most vulnerable patients in
future.
Acknowledgments
No ethical approval needed. This research was carriedout without funding.
Conflict of interest
No conflicts of interest declared.

References
1 Varadhan KK, Lobo DN. A meta-analysis
of randomised controlled trials of intravenous fluid therapy in major elective open
abdominal surgery: getting the balance right.
Proc Nutr Soc 2010; 69: 488498.
2 Jansen LA, Safavi A, Lin Y et al. Preclosure
fluid resuscitation influences outcome in gastroschisis. Am J Perinatol 2012; 29: 307312.
3 Doherty M, Buggy DJ. Intraoperative fluids:
how much is too much? Br J Anaesth 2012;
109: 6979.
4 Woodcock TE, Woodcock TM. Revised
Starling equation and the glycocalyx model
of transvascular fluid exchange: an improved
paradigm for prescribing intravenous fluid
therapy. Br J Anaesth 2012; 108: 384394.
5 Friis-Hansen B. Body water compartments
in children: changes during growth and
related changes in body composition. Pediatrics 1961; 28: 169181.
6 Haycock G. Disorders of the kidney and urinary tract. In: Rennie J, ed. Robertons Textbook of Neonatology, 4th edn. Edinburgh:
Elsevier Churchill Livingstone, 2005:
929944.
7 Hartnoll G, Betremieux P, Modi N. Body
water content of extremely preterm infants
at birth. Arch Dis Child Fetal Neonatal Ed
2000; 83: F56F59.
8 Archer N. Cardiovascular disease. In: Rennie J, ed. Robertons Textbook of Neonatology, 4th edn. Edinburgh: Elsevier Churchill
Livingstone, 2005: 619660
9 Modi N, Betremieux P, Midgely J et al.
Postnatal weight loss and contraction of the
extracellular compartment is triggered by
atrial naturetic peptide. Early Hum Dev
2000; 59: 201208.
10 Bell EF, Warburton D, Stonestreet BS et al.
Effect of fluid administration on the development of symptomatic patent ductus arterio-

58

11

12

13

14

15

16

17

18
19

20

sus and congestive heart failure in premature


infants. N Engl J Med 1980; 302: 598604.
Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity
and mortality in preterm infants. Cochrane
Database Syst Rev 2008; 1: CD000503.
Hartnoll G, Betremieux P, Modi N. Randomised controlled trail of postnatal sodium
supplementation on body composition in
25-30 week gestational age infants. Arch Dis
Child Fetal Neonatal Ed 2000; 82: F24F28.
Hartnoll G, Betremieux P, Modi N. Randomised controlled trail of postnatal sodium
supplementation on oxygen dependency and
body weight in 25-30 week gestational age
infants. Arch Dis Child Fetal Neonatal Ed
2000; 82: F19F23.
Stephens BE, Gargus RA, Walden RV et al.
Fluid regimens in the first week of life may
increase risk of patent ductus arteriosus in
extremely low birth weight infants. J Perinatol 2008; 28: 123128.
Modi N. Fluid and electrolyte balance In:
Rennie J, ed. Robertons Textbook of
Neonatology, 4th edn. Edinburgh: Churchill
Livingstone; 2005: 335354.
Baraton L, Ancel PY, Flamant C et al.
Impact of changes in serum sodium levels on
2-year neurologic outcomes for very preterm
neonates. Pediatrics 2009; 124: e655e661.
Bell EF. When to transfuse preterm babies.
Arch Dis Child Fetal Neonatal Ed 2008; 93:
F469F473.
Kelly AM, Williamson LM. Neonatal transfusion. Early Hum Dev 2013; 89: 855860.
Amin SC, Remon JI, Subbarao GC et al.
Association between red cell transfusions and
necrotizing enterocolitis. J Mat Fetal Neonatal Med 2012; 25(S5): 8589.
Stritze A, Smyth J, Synnes A et al. Transfusion-associated nectrotising enterocolitis in

21
22

23

24

25

26

27

28

neonates. Arch Dis Child Fetal Neonatal Ed


2013; 98: F10F14.
Arnold P. Coagulation and the surgical
neonate. Pediatr Anesth 2014; 24: 8997
Rabe H, Diaz-Rossello JL, Duley L et al.
Effect of timing of umbilical cord clamping
and other strategies to influence placental
transfusion at preterm birth on maternal and
infant outcomes. Cochrane Database Syst
Rev 2012; 8: CD003248.
Carroll PD, Widness JA. Non-pharmacological, blood conservation techniques for
preventing neonatal anemia effective and
promising strategies for reducing transfusion.
Semin Perinatol 2012; 36: 232243.
Bell EF, Strauss RG, Widness JA et al.
Randomized trial of liberal versus restrictive
guidelines for red blood cell transfusion in
preterm infants. Pediatrics 2005; 115:
16851691.
McCoy T, Conrad AL, Richman L et al.
Neurocognitive profiles of preterm infants
randomly assigned to lower or higher
hematocrit thresholds for transfusion. Child
Neuropsychol 2011; 17: 347367.
Kirpalani H, Whyte RK, Andersen C
et al. The premature infants in need of
transfusion (PINT) study: a randomized,
controlled trial of a restrictive (low) versus
liberal (high) transfusion threshold or
extremely low birth weight infants.
J Pediatr 2006; 149: 301307.
Whyte R, Kirpalani H. Low versus high haemoglobin concentration threshold for blood
transfusion for preventing morbidity and
mortality for very low birth we7ight infants.
Cochrane Database Syst Rev 2011; 9:
CD000512.
ETTNO investigators. The effects of transfusion thresholds on neurocognitive outcome
of extremely low birth-weight infants (ETT-

2013 John Wiley & Sons Ltd


Pediatric Anesthesia 24 (2014) 4959

F. OBrien and I.A. Walker

29

30

31

32

33

34

35
36

37

38

39

NO) study: background, aims, and study


protocol. Neonatology 2012; 101: 301305.
Venkatesh V, Khan R, Curley A et al. How
do we decide when a neonate needs a transfusion. Brit J Haematol 2013; 160: 421433.
Morris KP, Naqvi N, Davies P et al. A new
formula for blood transfusion volume in the
critically ill. Arch Dis Child 2005; 90:
724728.
Fredrickson LK, Bell EF, Cress GA et al.
Acute physiological effects of packed red
blood cell transfusion in preterm infants with
different degrees of anaemia. Arch Dis Child
Fetal Neonatal Ed 2011; 96: F249F253.
Sarkar S, Rosenkrantz TS. Neonatal
polycythemia and hyperviscosity. Semin
Fetal Neonatal Med 2008; 13: 248255.
Evans N. Assessment and support of the
preterm circulation. Early Hum Dev 2006; 82:
803810.
S
oderlind M, Salvignol G, Izard P et al. Use
of albumin, blood transfusion and intraoperative glucose by APA and ADARPEF members: a postal survey. Paediatr Anaesth 2001;
11: 685689.
Myburgh JA, Mythen MG. Resuscitation
fluids. N Engl J Med 2013; 369: 12431251.
Osborn DA, Evans NJ. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane
Database Sys Rev 2004; 2: CD002055
Northern Neonatal Nursing Initiative
(NNNI) Trial Group. A randomized trial
comparing the effect of prophylactic intravenous fresh frozen plasma, gelatin, or glucose
on early mortality and morbidity in preterm
babies. Eur J Pediatr 1996; 155: 580588.
Northern Neonatal Nursing Initiative
(NNNI) Trial Group. Randomized trial of
prophylactic early fresh frozen plasma or gelatin or glucose in preterm babies: outcome at
2 years. Lancet 1996; 348: 229232.
So KW, Fok TF, Ng PC et al. Randomised
controlled trial of colloid or crystalloid in
hypotensive preterm infants. Arch Dis Child
1997; 76: F43F46.

2013 John Wiley & Sons Ltd


Pediatric Anesthesia 24 (2014) 4959

Fluid homeostasis in the neonate

40 Kavvadia V, Greenough A, Dimitriou G


et al. Randomized trial of fluid restriction in
ventilated very low birthweight infants. Arch
Dis Child 2000; 83: F91F96.
41 Greenough A, Cheeseman P, Kavvadia V
et al. Colloid infusion in the perinatal period
and abnormal neurodevelopmental outcome
in very low birth weight infants. Eur J Pediatr 2002; 161: 319323.
42 The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med
2004; 350: 22472256.
43 Maitland K, Kiguli S, Opoka R et al.
Mortality after fluid bolus in African
children with shock. N Engl J Med 2011; 364:
24832495.
44 Maitland K, George E, Evans J et al.
Exploring mechanisms of excess mortality
with early fluid resuscitation: insights
from the FEAST trial. BMC Med 2013; 11:
68.
45 Roberts I, Blackhall K, Alderson P et al.
Human albumin solution for resuscitation
and volume expansion in critically ill
patients. Cochrane Database Syst Rev 2011;
11: CD001208.
46 Perner A, Haase N, Guttormsen AB et al.
Hydroxyethyl starch 130/0.42 versus Ringers
acetate in severe sepsis. N Engl J Med 2012;
367: 124134. [Erratum, N Engl J Med 2012;
367: 481]
47 Myburgh JA, Finfer S, Bellomo R et al.
Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;
367: 19011911.
48 S
umpelmann R, Kretz FJ, Luntzer R et al.
Hydroxyethyl starch 130/0.42/6:1 for perioperative plasma volume replacement in 1130
children: results of an European prospective
multicenter observational postauthorization
safety study (PASS). Pediatr Anesth 2012; 22:
371378.
49 Bayer O, Reinhert K, Sakr Y et al. Renal
effect of synthetic colloids and crystalloids in
patients with severe sepsis: a prospective

50

51

52

53

54

55

56

57

58

sequential comparison. Crit Care Med 2011;


39: 13351342.
Yunos NM, Bellomo R, Hegarty C et al.
Association between a chloride-liberal vs
chloride-restrictive intravenous fluid administration strategy and kidney injury in critically
ill adults. JAMA 2012; 308: 15661572.
Shaw AD, Bagshaw SM, Goldstein SL et al.
Major complications, mortality, and resource
utilization after open abdominal surgery:
0.9% saline compared to Plasma-Lyte. Ann
Surg 2012; 255: 821829.
Skwono JJ, Broadhead M. Cardiac output
measurement in pediatric anesthesia. Pediatr
Anesth 2008; 18: 10191028.
National Institute for Health and Clinical
Excellence. CardioQ-ODM oesophageal
doppler monitor. NICE medical technology
guidance 3. 2011. http://www.nice.org.uk/
nicemedia/live/13312/52624/52624.pdf.
Accessed 6 November, 2013.
Tibby SM, Hatherill M, Murdoch IA. Use of
transesophageal Doppler ultrasonography in
ventilated pediatric patients: derivation of
cardiac output. Crit Care Med 2000; 28:
20452050.
Raux O, Spencer A, Fesseau R et al. Intraoperative use of transoesophageal doppler to
predict fluid response to volume expansion in
infants and neonates. Br J Anaesth 2012; 108:
100107.
Brandstrup B, Tonnesen H, Beier-Holgersen
R et al. Effects of intravenous fluid restriction on post-operative complications: comparison of two peri-operative fluid regimens:
a randomized assessor-blinded multicenter
trial. Ann Surg 2003; 238: 641648.
Larsson LE, Nilsson K, Niklasson A et al.
Influence of fluid regimens on perioperative
blood glucose concentrations in neonates. Br
J Anaesth 1990; 64: 419424.
Berleur MP, Dahan A, Murat I et al. Perioperative infusions in paediatric patients: rationale for using Ringer lactate solution with
low dextrose concentration. J Clin Pharm
Ther 2003; 28: 31e40.

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