Hypovolemic Shock and Edema Due to Increased Capillary Permeability

Melvin Horwith, MD, Jack W. C.

A

Hagstrom, MD, Robert

C. K.

Riggins, MD, and E. Hugh Luckey, MD

patient had fatal hypovolemic shock and edema. As in previously reported cases, the mechanism of shock appears to be loss of protein and fluid from the vascular bed. Extensive studies of all patients have revealed no cause for this extraordinary vascular permeability. Analysis of the reported cases suggests that subsequent patients with this syndrome should have analyses per-

formed to determine the presence of vascular reactants such as kinins. A study of these cases suggests a method of treatment of similar episodes of hypovolemic shock. Observations from this case and the one previously reported from this center suggest that vasopressor agents such as catecholamines probably are contraindicated.

plasma, blood, and isotonic saline, the blood and plasma volumes returned to predicted levels and remained stable. Further laboratory studies excluded the presence of occult hemorrhage, Addison's disease, myocardial infarction, dia betes insipidus, salt-losing nephritis, or abnormal renal function as contributory causes of hypovolemic shock. Three months following this episode, he was readmitted to the hospital with "mild" serum hepatitis which resolved without specific therapy. In May 1960, the patient had a third attack of hypotension and shock that was similar to that of July 1958, and it also subsided spontaneously. In November 1961, again after an upper-respiratory tract infection, he noted the recurrence of diaphoresis, nausea, vomiting, faintness, and syncope, and was read mitted to a local hospital. His temperature was normal, but the pulse rate and blood pressure were unobtainable; in addition, physical examination revealed firm, nonpitting

The

rarity of hypovolemic shock accompanying massive edema is emphasized by the absence of published description of this entity until a report was issued from this center in I960.1 Subsequently, two additional cases have been described,2,3 and another one has been brought to our attention by a personal communication from R. F. Jacox, MD, in February 1963. The purpose of this paper is to re port in detail the clinical and necropsy findings in a fifth case. The patient in this case died during an episode of shock and edema secondary to loss of protein and fluid from the vascular to the extravascular compartments.

generalized edema. Laboratory studies showed the follow ing: hematocrit reading, 65%; white blood cell count, 14,000/cu mm, with a differential count of 64% polymor phonuclear leukocytes, 15% band forms, 20% lymphocytes, and 1% monocytes; urinalysis disclosed 2+ albuminuria. Serum electrolyte values were as follows: sodium, 138 mEq/liter; chloride, 110 mEq/liter; and potassium, 4.4 mEq/liter; carbon dioxide combining power was 23 milli mols/liter, and blood urea nitrogen (BUN) was 13 mg/100 ml. Blood volume determinations confirmed loss of plasma volume. In the first hospital day, 22 units of plasma, 2 units of serum albumin, and large volumes of isotonic sa line were required to maintain the patient's blood pressure. In addition, he received 150 mg prednisolone daily which
was

Report

of

Case

The patient, a 52-year-old white man, was well until July 1958, when he experienced the first of five recurrent episodes of increasingly severe hypovolemic shock; the last attack led to his death in March 1962. The first episode was characterized by profuse diaphoresis and faintness. and subsided spontaneously after several hours. Thereafter

he remained well until November 1958, when he noted the sudden recurrence of faintness, profuse diaphoresis, flush ing, severe thirst, nausea, and vomiting, following an upperrespiratory tract infection. On admission to another hospi tal, he was alert, but both the pulse rate and blood pressure were unobtainable. The skin was cold and dry, and no edema was noted. Initial laboratory studies showed a hema tocrit reading of 69%; white blood cell count, 13,350/cu mm differential count of 51% polymorphonuclear leukocytes, 27% band forms, and 22% lymphocytes. Urinalysis findings were normal, and the specific gravity was 1.028. Serum electrolyte values were as follows: sodium, 128 mEq/liter; chloride, 86 mEq/liter; and potassium, 6.4 mEq/liter. The blood volume was initially measured at 4,120 cc (76% of predicted value) ; plasma volume, 1,610 cc (50% of pre dicted value); and red blood cell volume, 2,570 cc (112% of predicted value). Results from the guaiac test were normal for occult blood in the feces. After multiple transfusions of
From the departments of medicine and pathology, the New York Hospital\p=m-\CornellMedical Center, New York. Reprint requests to 1300 York Ave, New York 10021 (Dr. Hor-

days. By the third hospital day, the patient's blood and plasma volumes had become normal but he was markedly edematous. A spontaneous diuresis then supervened, but the recovery was accompanied by congestive heart failure and pulmonary edema, presumably due to mobilization of interstitial fluid. With the exception of transitory azotemia, anemia, and hyperbilirubinemia, an extensive evaluation revealed no other significant findings, and he was dis charged. In January 1962, the patient was referred to the endo crine clinic of the New York Hospital. Results from physi
20

decreased

progressively

and discontinued

over

the next

with).

cal examination at that time were unremarkable except for a blood pressure of 150/100 mm Hg. He was instructed to return immediately if he experienced the premonitory signs of a fifth episode. In March 1962, an upper-respiratory tract infection de veloped with fever, cough, malaise, and rhinorrhea which lasted for one week. Five days later, he noted recurrence of thirst, polyuria, weakness, myalgia, flushing, and puffiness of his face. Although he had no diaphoresis or faintness, he feared an impending attack and was admitted to this hos pital. No family history of a similar disorder was obtained. On physical examination his temperature was 102.2 F (39 C), the pulse rate was 80 beats per minute and regu lar, the blood pressure was 132/86 mm Hg, and he ap peared perfectly well. The skin was warm, dry, flushed, and not edematous. There were no other significant find ings. The following data were obtained from initial labora tory studies: hematocrit reading, 44%; hemoglobin level, 14.8 gm/100 ml; white blood cell count 6,000/cu mm, with a differential count of 80% polymorphonuclear leukocytes, 3% band forms, 16% lymphocytes, and 1% eosinophils; find-

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ings from urinalysis were normal; the specific gravity was 1.030; results from guaiac tests on the stools were normal; and the sedimentation rate was 13 mm/hr. The initial serum laboratory values were as follows: sodium, 144 mEq/liter and chloride, 107 mEq/liter; carbon dioxide com bining power was 28 millimols/liter; BUN level, 19 mg/100 ml; bilirubin, 0.2 mg/100 ml; cholesterol, 202 mg/100 ml; alkaline phosphatase, 1.7 units (Bodansky) ; total protein, 7.4 gm/100 ml (albumin, 5.2 gm/100 ml; globulin, 2.2 gm/ 100 ml), with a normal pattern on paper electrophoresis; oxaloacetic transaminase, 24 units/ml/hr; pyruvic transami nase, 8 units/ml/hr; and the electrocardiogram was normal. Iodinated I 131 serum albumin blood volume was 4,729 cc (61.5 cc/kg body weight; normal = 77 10 cc/kg) ; and plasma volume was 2,444 cc (34.4 cc/kg; normal == 35.5 cc per kg). For the first 12 hours the patient's hematocrit reading and blood pressure remained stable; after this, his pulse pressure decreased slightly, and he complained of thirst. One hour later he became rapidly hypotensive and serial hematocrit readings confirmed progressive hemoconcentration. In an attempt to maintain the patient's blood volume, transfusions were begun immediately. During the subse quent 39 hours, he received a total of 8,000 cc of plasma protein fraction (Plasmanate), 1,950 cc albumin, and 2,100 cc of dextrose, water, and saline solutions. Large amounts of levarterenol bitartrate and later, angiotensin amide were given intermittently in vain attempts to maintain adequate blood pressure. Despite this therapy, hemoconcentration to a hematocrit reading of 63% followed and he developed generalized firm, nonpitting edema. He was apprehensive, diaphoretic, cyanotic, and had cool skin throughout his course. On the second hospital day, a falling hematocrit reading with venous hypertension, pleural effusions, and signs of congestive heart failure signaled the return of edema fluid to the vascular compartment, which required the use of digitalis, oxygen, and phlebotomy when pulmo nary edema supervened. In spite of supportive measures, including the intravenous administration of hydrocortisone, sodium salicylate, and vasopressor agents, his blood pres sure became unobtainable and he died 59 hours following
admission.

When the patient was admitted to the New York Hospital in March 1962, blood volume studies very early in the course of the attack, prior to the development of shock, revealed a blood volume of 4,729 cc (61.5 cc/kg body weight), not markedly abnormal, on the basis of a normal value of 77 10 cc/kg). The plasma volume at this time was 2,444 cc or 35.5 cc/kg (normal). The rapid and continu ing loss of protein from the vascular bed precluded accurate blood volume determinations during the shock phase; how ever, the progressively increasing hematocrit value and the demonstrated loss of protein and fluid from the vascular compartment helped indirectly to document the marked

hypovolemia.

ml during replacement therapy. Electrocardiograms were normal. The total urinary output was negligible. Routine Laboratory Studies.Findings from urinalysis were normal except for proteinuria on one occasion asso ciated with evidence of maximal concentration of urine. Renal functional studies showed no indication of signifi cant glomerular or tubular disease. Hemograms were remarkable only in the demonstration of hemoconcentration with the progression of each episode; a moderate leukocytosis with a moderate shift to the left accompanied the hemoconcentration. Routine serum elec trolyte values were abnormal only during the November 1958 episode when there was hyponatremia and hyperkalemia; these abnormalities did not recur. Findings from studies of adrenal cortex function were normal. Electrophoresis of serum proteins was normal in all sera examined prior to the onset of the attacks. Following the inception of shock and the infusion of massive amounts of albumin, the electrophoretic pattern reflected the exoge-

During the course of this episode, the serum electrolyte values remained normal; BUN, rose to 26 mg/100 ml; cho lesterol, fell to 89 mg/100 ml; serum albumin, rose from 5.2 to 6.3 gm/100 ml; and globulin, fell from 2.2 to 1.5 gm/100

nously administered albumin. Blood samples for estima tion of kinins were not satisfactory inasmuch as the blood was not immediately mixed with ethanol which is necessary to prevent proteolytic enzyme activity. Special Laboratory Studies Blood volume studies in November 1958 revealed a blood volume of 4,120 cc (76% of predicted value), a plasma volume of 1,610 cc (50% of predicted value), and a red blood cell volume of 2,570 cc (112% of predicted value). Blood volume studies in No vember 1961 again demonstrated loss of plasma volume.

The radioactive iodinated serum albumin studies con firmed the clinical observations, ie, a rapid and massive shift of protein from the vascular compartment to the extravascular space. The half-life for the injected iodinated I 131 serum albumin was 16 hours, a period during which, in the normal control, only partial distribution equilibrium can occur. Depending upon the type of label employed to tag the albumin, the half-life in normal controls varies be tween 10.5 and 17 days.4 Sterling,5 utilizing iodinated I 131 serum albumin, found the half-life to be between 14 and 23 days, with a mean of 18 days. Approximately 90% of the radioactivity found in the ac cumulated fluid in peripheral tissues and in the body cavi ties was protein bound. Plasma obtained by phlebotomy 55 hours after injection of the iodinated I 131 serum albu min contained less than 1% of original iodinated I 131 serum albumin. Approximately 8% of the injected iodi nated I 131 serum albumin appeared in the urine during a 59-hour period compared to 3.1% to 5.4% of the injected iodinated I 131 serum albumin in the first 24 hours in con trol subjects.6 It is also of interest that in spite of the gen eralized nature of this vascular leak, very little evidence of radioactive material was found in the contents of the gas trointestinal tract collected at necropsy. Immunological protein analysis of pleural fluid showed significant amounts of ct-macroglobulins and /3-lipoproteins. The concentration of total proteins and of the estimated globulins in the pleural fluid exceeded that in the plasma. Necropsy Findings.The patient was stocky, well-nour ished, 173 cm (5 ft 8 inches) tall, and 83 kg (183 lb). The skin overlying both thighs was extremely edematous and tense, but nonpitting. The abdominal panniculus was 3 cm thick at the umbilicus. The peritoneal cavity contained a physiologic amount of serous fluid and a few fibrous adhe sions. The left and right pleural cavities contained about 350 and 170 cc of tan, clear, slightly viscous fluid, respec tively, and the pericardial cavity contained about 190 cc of similar fluid. The mesothelial surfaces were smooth and glistening. The heart weighed 410 gm; the myocardium of the walls of the left and right ventricles, at the base were 13 and 3 mm thick, respectively. There was slight, focal atheromatous narrowing of the lumina of all of the large coronary arteries. The cardiac valves, epidardium, and myocardium were all grossly normal. There were scattered, focal, subendocardial petechiae at the base of the left inter ventricular septum. A few atherosclerotic plaques were present on the luminal surface of the wall of the aorta, especially below the level of the ostia of the renal arteries. Microscopically, there was marked edema of the epicardial adipose tissue, and capillaries in the myocardium were engorged with erythrocytes. Scattered throughout the sub endocardial myocardium of the left ventricle, in areas asso ciated with the grossly described petechiae and elsewhere, were discrete areas of myocardial necrosis. In these areas there was myocytolysis, infiltrates of neutrophils and mononuclear cells, occasional erythrocytes, and interstitial edema; extensive or interconnecting foci of necrosis were not present. The lungs together weighed 800 gm, the paren chyma was pink-red and crpitant. The mucosal surfaces of the major bronchi were slightly hyperemic. In sections from both lungs, the bronchioles and alveoli were shown to be filled with deeply staining, homogenous, eosinophilic

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material; arteries, capillaries, and veins were engorged with erythrocytes. Sections from the lower lobes of both lungs showed minimal secondary atelectasis. The liver weighed 1,600 gm, and the parenchyma was tan; microscopically, the lobular architecture was well preserved, but occasional hepatic cord cells contained fat vacuoles. The brain weighed 1,370 gm, and was grossly normal except for the presence of a discrete, 3 X 3-cm area of hyperemia of the arachnoid over the left parietal lobe. Microscopic sections taken from this area showed the presence of hemorrhage in the arach noid and subarachnoid spaces. Specially stained sections

hemoconcentration. He had marked eosinophilia, splenomegaly, and other evidence suggestive of an allergic reaction. The two cases reported by Thom as,9 were thought by some to have a similar type of

of other areas of the arachnoid and of the motor cortex, Ammon's horn, the peduncles, the substantia nigra, the lentiform nucleus, hypothalamus, cerebellum, medulla, and spinal cord were normal. Focal submucosal petechiae were present in the cardia of the stomach. Sections of the duo denum stained for enterochromaffin granules, according to the technique of Gershon and Ross,7 showed no diminution in intracellular chromaffin granules. Each kidney weighed 1 0 gm and was grossly normal. Microscopically, there was focal thickening of the basement membranes of several glomeruli as well as occasional focal hyaline thickening of the walls of arterioles. Sections of the kidney observed with the electron microscope showed no specific or signifi cant changes that were not observed in sections of kidneys from individuals of comparable age. Convoluted and col lecting tubules were normal. The adrenal glands together weighed 17 gm and contained the expected amount of yel low lipid material in the cortices. Microscopically, there was minimal diffuse hyperplasia of the zona fasciculata; cells of the adrenal medulla were positive for the Henle reaction. Sections of skeletal muscle from the psoas, pectoralis major, vastus lateralis, gastrocnemius, sternocleidomastoid, and rectus abdominis showed varying degrees of interstitial edema, most prominent in the sections of the vastus lateralis, rectus abdominis, and psoas. In addition, there were some internalized, plump nuclei, but there were no proliferated hypolemmal nuclei or loss of striation. The gallbladder contained about 30 cc of viscous, dark-green bile admixed with six, soft, dark-green, oval calculi that measured about 6 mm in greatest dimension. The wall of the gallbladder was not appreciably thickened. The pros tate was symmetrically enlarged to about one times normal size and microscopic examination of sections showed adenomatous and fibromuscular hyperplasia. The lymph nodes, spleen, pancreas, thyroid, parathyroid glands, hypophysis, testes, bone marrow, and skin were normal grossly and microscopically. Sections of the heart, kidney, skeletal muscle, and liver, stained by the fluorescent antibody technique with antihuman y-globulin, failed to show localized deposits of y-globulin or complement fixation at any site. The final pathologic diagnoses were as follows: diffuse interstitial edema secondary to (clinical) hypovolemic

shock; multiple serous effusions; pulmonary edema; passive hyperemia of the liver, heart, and kidneys; petechiae in the arachnoid, heart, and stomach; focal necrosis of the subendocardial myocardium; fatty change in the liver (minimal) ; hyperplasia of he adrenal cortices (minimal) : nodular hyperplasia of the prostate; and cholelithiasis.

Comment
most

Plasma loss from the vascular bed without appar ent cause is rare, and not understood. In addition to the patient in the case described above, we are aware of only four other patients1 who had hypo volemic shock and edema in whom no concomitant disease was discovered. Not included in this group is a case described by Preston.8 The patient, in this case, developed edema, but maintained a normal blood pressure and did not show evidence of marked
:i

Hypovolemic shock, not due to hemorrhage, is al always due to physical trauma, eg, burns.

their inclusion in this report. A review of the prodromata, characteristics, and responses to therapy fails to permit classification of these patients into a single, clearly defined syn drome. The case described by Luke2 died in shock, following progressive edema which began as edema of the labia on the third postpartum day. This pa tient had a previous history of urticaria and angioneurotic edema which started in childhood, and she thus differs from the other patients. The episodes described in the case reported here and those in the cases reported by Clarkson, et al1 and Weinbren3 do not resemble angioneurotic edema. Considering those three males and two females, there is no com mon ethnic background, history of exposure to any toxic material, or particular age predeliction. At tacks occurred on an average of one every six to ten months over a period of three to four years, each lasting an average of 5 to 14 days. The only com mon preceding signs and symptoms in three pa tients suggested an upper-respiratory tract infec tion. Marked thrist was noted early in the attack in four patients. Profound muscle weakness was pres ent in all patients, and myalgias, in four. The marked creatinuria and potassium diuresis in Jacox's patient are provocative in the light of the complaints related to muscle weakness. Anorexia, nausea, and vomiting were present in all patients, especially so during the course of an attack. Plasmapheresis and marked hemoconcentration were the most notable laboratory findings in these patients. Studies with Evans blue or iodinated I 131 serum albumin all demonstrated prompt leakage of plasma proteins from the vascular compartment. The plasma samples from three of these patients, when subjected to electrophoresis, had an increase in the concentration of y-globulins. It must be as sumed that this was an absolute increase and not relative to the hemoconcentration since, in our pa tient, y-globulin was also found in the extracellular fluid and other globulin moieties were not propor tionately increased in plasma. The pleural fluid con tained significant concentrations of a2-macroglobulins and /?-lipoproteins. The concentration of total protein, including globulins in the pleural fluid, ex ceeded the protein concentration in the plasma. This was probably the result of back diffusion of water which occurred after the initial shock phase and was also due to the exogenous albumin used in therapy. The mechanism for this sudden and re peated loss of the capacity of the capillaries to con tain molecules as large as albumin and globulins within the vascular bed is not understood. Re views10 '* of the ultrastructure of capillaries and of the effects of pharmacologie agents on increasing capillary permeability1213 point out that several naturally occurring substances present in tissues

edema, but

were

not studied

sufficiently

to

permit

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capable of affecting vascular permeability. Bradykinin is one of these as is histamine. However, an extensive review of the relationship of histamine
are

eg, saline, plasma, or albumin, may be used to coun teract the shock. The resulting accumulation of

to human disease reveals no mention of any disease state in which increased histamine release is asso

ing

edema could be relieved by peritoneal dialysis dur an acute episode and especially during the re

ciated with a similar picture of hypovolemic shock.14 Although plasma proteins leak from the vascular bed in this type of hypovolemic shock, an attempt was made to keep up with the disappearance rate by massive replacement of plasma and albumin. That this regimen was unsuccessful is apparent from the refractoriness exhibited by this group of patients. We did not employ plasma expanders such as dextran 40 or dextran 75. All three patients to whom levarterenol was given appear to have exhibited a greater resistance to therapy and died during the course of an attack. These cases certainly support the current consensus that administration of levarterenol is contraindicated in the therapy of hypovolemic shock. It is apparent that the augmented decrease in the vol ume of the vascular bed, which was caused by sympathomimetic agents, is not physiologic and does not aid in restoring blood pressure to normal, unless there is adequate fluid volume within the vascular compartment.15 Smith and Moore16 reviewed the data which clearly indicated that vasopressors cause a marked reduction in average plasma volume. Fur ther evidence for the vasopressor-induced hypovolemia is shown by the hypotension that frequent ly ensues after discontinuation of the intravenous administration of vasopressor agents. This same

covery

phase.

Ralph F. Jacox. MD, Lt James F. ard Clarkson, MD, and Eugene D. preparation of this report.

McCreedy, MC, USN, Bay Furth, MD assisted in the

Generic and Trade Names of Sterane, Paracortol, Sterolone. Plasma protein fractionPlasmanate. Levarterenol bitartrateLevophed Bitartrate.
tone.

Drugs

PrednisoloneDelta-Cortef. Hydeltra, Meticortelone, Meti-Derm,

Angiotensin amideHypertensin. HydrocortisoneCortef, Cortifan, Cortril, Hycortole, HydrocorDextran 40Rheomacrodex. Iodinated I 131 serum albuminAlbumotope 1-131, Risa-131. DextranExpandex, Plavolex.

References
1. Clarkson, B., et al: Cyclical Edema and Shock Due to Increased Capillary Permeability, Amer J Med 29:193-216 (Aug) 1960. 2. Luke, I.W., and Rubenstein, E.: Fatal Post-Partum Shock Due to Massive Angioneurotic Edema, Amer J Obstet Gynec 83: 322-327 (Feb) 1962. 3. Weinbren, I.: Spontaneous Periodic Edema, Lancet 2:544\x=req-\ 546 (Sept 14) 1963. 4. Berson, S.A., et al: Tracer Experiments With 1-131 Labeled Human Serum Albumin: Distribution and Degradation Studies, J Clin Invest 32:746-768 (Aug) 1953. 5. Sterling, K.: The Turnover Rate of Serum Albumin in Man as Measured by 1-131 Tagged Albumin, J Clin Invest 30:1228-1237 (Nov) 1951. 6. Cohen, S.; Freeman, T.; and McFarlane, A.S.: Metabolism of 1-131 Labeled Human Albumin, Clin Sci 20:161-170 (April) 1961. 7. Gershon. M.D., and Ross. L.L.: Studies on the Relationship of 5-Hydroxytryptamine and the Enterochromaffin Cell to Anaphylactic Shock in Mice, J Exp Med 115:367-382 (Feb) 1962. 8. Preston, G.M.; Rees, J.R.; and Spathis, G.S.: A Man With Cyclical Oedema, Guy's Hosp Rep 111:69-79 (No. 1) 1962. 9. Thomas, W.A.: Generalized Edema Occurring Only at the Menstrual Period, JAMA 101:1126-1127 (Oct 7) 1933. 10. Fawcett D.W.: "The Fine Structure of Capillaries, Arterioles, and Small Arteries," in Reymonds, S.R., and Zweifach, B.W. (eds.): The Microcirculation, Urbana, Ill: University of Illinois Press, 1959. 11. Kisch, B.: Electron Microscopy of the Cardiovascular System Springfield, Ill: Charles C Thomas, Publisher, 1960, p 119. 12. Majno, G., and Palade, G.E.: Studies on Inflammation: I. The Effect of Histamine and Serotonin on Vascular Permeability: An Electron Microscopic Study, J Cell Biology 11:571-605 (Dec) 1961. 13. Majno, G.; Palade, G.E.; and Schoefl, G.I.: Studies on Inflammation: II. The Site of Action of Histamine and Serotonin Along the Vascular Tree: A Topographic Study, Biophys Biochem Cytol 11:617-626 (Dec) 1961. 14. Code, C.F.; Hurn, M.M.; and Mitchell, R.G.: Histamine in Human Disease, Mayo Clin Proc 39:715-737 (Sept) 1964. 15. Kitchen, A.H.: Peripheral Blood Flow and Capillary Filtration Rates, Brit Med Bull 19:155-160 (May) 1963. 16. Smith, L.L., and Moore, F.D.: Refractory Hypotension in Man\p=m-\IsThis Irreversible Shock? Clinical and Biochemical Observations, New Eng J Med 267:733-742 (Oct) 1962. 17. Szakacs, J.E., and Cannon, A.: 1-Norepinephrine Myocarditis, Amer J Clin Path 30:425-434 (Nov) 1958. 18. Szakacs, J.E., and Mehlman, B.: Pathologic Changes Induced by 1-Norepinephrine: Quantitative Aspects, Amer J Cardiol 5:619-627 (May) 1960. 19: Cohn, J.N., and Luria, M.H.: Studies in Clinical Shock and Hypotension, Arch Intern Med 116:562-566 (Oct) 1965.

phenomenon is important in the prophylactic ex pansion of plasma volume given prior to surgery
for

cardium of individuals who received levarterenol.17 IS The clinical and laboratory experience gained from the study of these cases strongly suggests that therapy should be directed toward replacement of intravascular fluid volume by saline suspensions of macromolecular substances, eg, dextran 75, that are capable of exerting a significant oncotic pressure to reverse the hypovolemic shock. There is some ques tion as to whether or not these substances would be retained within the vascular compartment, inas much as plasma proteins with much greater molec ular weights disappeared rapidly into the extracellu lar fluid. However, Cohn and Luria,ui in a report on the use of dextran in the therapy of shock, sug gest that there are significant advantages to its use. They showed an increase in cardiac output and a decrease in peripheral resistance that was signifi cantly greater with administration of dextran than with the administration of sympathomimetic agents. In the event that macromolecular dextrans are not available, large infusions of noncolloidal substances,

pheochromocytoma. Direct toxic effects of the on the myocardium constitute an addi tional contraindication to its use in the quantities frequently employed in the treatment of refractory shock. The changes in the myocardium of this pa tient are not specific. Lesions similar to those pres ent in this patient have been described in the myo
levarterenol

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