Mechanism and treatment of shock associated with acute pancreatitis

Mechanism and Treatment of Shock Associated with Acute Pancreatitis F. LAIRD FACEY, M.D.,* MAX HARRY WEIL, M.D.,~ AND LEONARD ROSO~'~', M.D.,++ Los Angeles, California

From the Shock Research Unit and the Departments of Medicine and Surgery, University of Southern California School of Medicine, and the Los Angeles County Hospital, Los Angeles, California. This investigation was supported by Public Health Service Research Grants HE-05570 and HE-07811 from the National Heart Institute, and by the John A. Hartford Foundation, Inc., New York, New York.

and averaged 76/28 ram. Hg. In the fifth patient the arterial blood pressure was reduced to a degree which escaped clinical detection. Urine flow was markedly reduced in each case. I t averaged 13 ml. per hour at the time of admission to the Shock Research Ward. Three patients were in coma on admission to the hospital and the other two patients lost consciousness within forty-eight hours after hospitalization. Alcoholism in three patients was further complicated by delirium tremens. Biochemical data were consistent with the diagnosis of acute pancreatitis in each case. The serum amyla~_e measured by the modified method of Reinhold ranged from 550 to 2,550 Somogyi units and averaged 1,314 Somogyi units; normal values in our laboratories are less than 80 units. The urinary diastase, measured by the method of Ware, Walberg, and Sterling [3], averaged 4,860 Somogyi units per 100 co. of urine. Less than 600 units per 100 ce. of urine is considered normal in our hospital. Consumption of large amounts of alcohol over a period of years was clearly established by history in four patients. In one of these (case IV) a history of excessive use of a tranquilizer, chlordiazepoxide (Librium®), was also obtained. Heroin addiction was documented in the clinical record of the other subject (case v). No patient had evidence of choledocholithiasis or other disease of the biliary tract either by history or from laboratory data. Bleeding from the upper gastrointestinal tract manifestated by coffee-ground emesis or melena was observed in three of the patients. However, major loss was observed in only one patient (case IV) ; the exact site of loss of blood in this patient was not apparent.

HOCK c o m p l i c a t i n g t h e course of a c u t e p a n c r e a t i t i s is a serious a n d o m i n o u s progn o s t i c sign. I n Siler a n d W u l s i n ' s [1] series of t w e n t y - t w o f a t a l cases of a c u t e p a n c r e a t i t i s , fifteen p a t i e n t s h a d t h e classic f e a t u r e s of a c u t e c i r c u l a t o r y failure. T h e h e m o d y n a m i c a n d m e t a b o l i c a l t e r a t i o n s r e s u l t i n g f r o m shock a s s o c i a t e d w i t h a c u t e p a n c r e a t i t i s h a v e n o t as y e t been c l e a r l y defined. W i t h t h e e s t a b l i s h m e n t of a S h o c k R e s e a r c h W a r d b y t h e Univ e r s i t y of S o u t h e r n C a l i f o r n i a a t t h e Los Angeles C o u n t y H o s p i t a l , we were p r o v i d e d w i t h t h e u n i q u e o p p o r t u n i t y for m a k i n g h e m o d y n a m i c a n d m e t a b o l i c o b s e r v a t i o n s on a g r o u p of c r i t i c a l l y ill p a t i e n t s in w h o m shock c o m p l i c a t e d t h e course of a c u t e p a n c r e a t i t i s .

S

MATERIAL Five patients, four men and one woman, were the subjects of this study. Each patient presented with hypotension, coma, and marked elevation of serum amylase. (Table I.) Ages ranged from twenty-five to fifty-nine years, with the average of forty-two years. Four of the five patients had classic signs of deeompensated shock [2]. The arterial blood pressure in four patients ranged from 70/50 to 84/64 ram. Hg

* Instructor in Surgery, University of Southern California School of Medicine. Attending Surgeon and former Resident Physician-Surgery, Los Angeles County Hospital, Unit I. Associate Professor of Medicine, and Director, Shock Research Unit, University of Southern California School of Medicine; Attending Physician, Los Angeles County Hospital. Associate Professor of Surgery, University of Southern California School of Medicine; Chief Physician of Surgery, and former Resident Physician-Surgery, Los Angeles County Hospital. 374

American .fournal of Surgery

Shock and Acute Panereatitis

375

TABLE I CLINICALDATA

Case

Age (yr.)

Blood Pressure (ram. Hg)

Sensorium

Serum Amylase (Somogyi units)

I n III IV

42 42 45 59

84/64 unobtainable 70/50 70/40

Coma; delirium tremens Coma; delirium tremens Coma; delirium tremens Coma

750 960 550 1,750

v

25

80/60

Coma

2,550

Radiographic examination of the upper gastrointestinal tract demonstrated juxtapyloric gastric ulceration in two patients (cases II and III) with minor hemorrhage. The clinical condition of one patient (case I) was further complicated by pneumonia. Three additional patients (cases II, Iv, and v) had minor pulmonary complications including platelike atelectasis and patchy pneumonitis which were demonstrated on roentgenograms of the chest taken with a portable x-ray machine. Even in the absence of severe pulmonary disease, periphera ! cyanosis was noted, in four of the five patients; tracheostomy was performed in each case. Physical examination of the abdomen demonstrated distention and there was no audible peristalsis. Roentgenographic confirmation of adynamic ileus was obtained in four patients (case I, I1, m, and IV). The patients were initially admitted and treated on general medical and surgical services. Onset of clinical hypotension occurred between two and ten days after admission to the hospital. The patients were admitted to our Shock Research Ward within a median period of a half day after shock became clinically apparent. They were observed and treated in the Shock Research Ward for seventeen to seventytwo hours, with an average of thirty-four hours. The initial hemodynamie and metabolic data presented were obtained within two hours after the patient was admitted to the Shock Research Ward when the patients manifested profound hypotension and clinical features of shock. METHODS OF STUDY A p o l y e t h y l e n e c a t h e t e r 83 cm. long a n d w i t h an i n t e r n a l d i a m e t e r of 1.57 m m . was introduced into the right atrium through a s u r g i c a l l y e x p o s e d basilic vein. C o r r e c t posit i o n was e s t a b l i s h e d b y o b s e r v a t i o n of i n t r a c a r d i a c p r e s s u r e pulses d u r i n g a d v a n c e m e n t of t h e c a t h e t e r into t h e r i g h t v e n t r i c l e a n d its s u b s e q u e n t w i t h d r a w a l to a p o s i t i o n j u s t p r o x Vol. 111, M a r c h 1966

Associated Disease

Chronic alcoholism Chronic alcoholism Chronic alcoholism Chronic alcoholism; tranquilizer excess Narcotic excess

Outcome

Died Survived Survived Survived Survived

i m a l to t h e t r i c u s p i d v a l v e . I n t h e one ills t a n c e in w h i c h this was n o t successful, t h e c a t h e t e r was filled w i t h a 75 p e r c e n t s o l u t i o n of d i a t r i z o a t e ( H y p a q u e ®) a n d a d v a n c e d to t h e c o r r e c t p o s i t i o n u n d e r fluoroscopic control. A second soft r u b b e r c a t h e t e r w i t h a n i n t e r n a l d i a m e t e r of t . 2 m m . a n d a m o l d e d t i p was i n s e r t e d o v e r a guide wire into a s u r g i c a l l y e x p o s e d b r a c h i a l or r a d i a l a r t e r y a n d a d v a n c e d for a d i s t a n c e of 10 em. [4]. T h e c a t h e t e r s were c o n n e c t e d to S t a t h a m 23 A A s t r a i n g a u g e pressure t r a n s d u c e r s a n d flushed i n t e r m i t t e n t l y u n d e r p r e s s u r e w i t h n o r m a l saline s o l u t i o n cont a i n i n g 5 u n i t s of h e p a r i n p e r m i l l i l i t e r [5]. A r t e r i a l a n d c e n t r a l v e n o u s pressures were r e c o r d e d on a d i r e c t w r i t i n g S a n b o r n m u l t i c h a n n e l recorder. C a r d i a c o u t p u t was q u a n t i t a t e d b y t h e t e c h n i c of i n d i c a t o r d i l u t i o n [6] using i n d o c y anine green dye. T h e d y e in c o n c e n t r a t i o n of 2.5 rag. p e r ml. was i n j e c t e d as a single bolus of 1 to 2 ml. into t h e r i g h t a t r i u m . A G i l f o r d M o d e l No. 103 or a W a t e r s X300 p h o t o e l e c t r i c d e n s i t o m e t e r was e m p l o y e d in c o n j u n c t i o n w i t h a H a r v a r d w i t h d r a w a l s y r i n g e for m e a s u r e m e n t of a r t e r i a l d y e c o n c e n t r a t i o n . C o m p u t e r t e c h n i c s were a d a p t e d to t h e m e t h o d of H a m i l t o n et al. [7] for a n a l y s i s of c a r d i a c o u t p u t . C a r d i a c o u t p u t was c o r r e c t e d for surface a r e a a n d expressed as c a r d i a c i n d e x ill liters p e r m i n u t e p e r m e t e r of b o d y surface area. T h e e l e c t r o c a r d i o g r a m (lead n ) was m o n i t o r e d c o n t i n u o u s l y a n d h e a r t r a t e obt a i n e d f r o m it. T o t a l p e r i p h e r o v a s c u l a r res i s t a n c e a n d m e a n c i r c u l a t i o n t i m e were calc u l a t e d b y using s t a n d a r d f o r m u l a s [8]. P l a s m a v o l u m e was d e t e r m i n e d w i t h 1131i o d i n a t e d s e r u m a l b u m i n ( R I S A ) . S a m p l e s of a r t e r i a l b l o o d were collected p r i o r to a n d a t

376

F a c e y , Weil, a n d R o s o f f TABLt~ II CLINICAL LABORATORY DATA

Case

I-Iematocrit (gin. %)

White Blood Cell Count (per cu. mm.)

I II III iv v

56 45 45 42 53

29,000 9,700 5,700 19,100 23,100

Blood Blood Urea Sugar Nitrogen (rag. ~ ) (mg. %)

28 222 16 10 30

62 330 84 142 152

Serum Sodium (mEq./ L.)

Alkaline . . . . Enzymes . . . . . Serutu Serum PhosphaGlutamic Serum Calcium Billrubin tase Albumin Oxal Glutamic Lactic (tug. %) (rag. %) (Bessey- (gin. %) acetic Pyruvie DehydroLowry TransTransgena,se units) aminase aminase

122 160 126 125 143

9.6 7.5

0.4

...

0.5

8.3

fifteen, twenty-five, and thirty-five minutes after the intravenous injection of 10 me. of radioactive tracer; the a m o u n t of tracer was appropriately increased during subsequent measurements of plasma volume. Concentrations were plotted semilogarithmically for extrapolation of radioactive count to zero time. H e m a t o c r i t was measured on heparinized blood b y standard mierohematocrit technic using plain capillary tubes, a microeentrifuge, and manual reader. Blood was sampled with syringes from the arterial catheter for measurement of oxygen saturation, pH, and partial pressure of carbon dioxide. T h e dead space of the syringes was filled with heparin-saline solution containing 5,000 units per milliliter. Initial samples were obtained during ventilation assisted by intermittent positive pressure apparatus with inspired gas containing between 40 and 98 per cent oxygen. The arterial oxygen saturation was measured using a Waters double scale euvette oximeter with periodic confirmation b y gasometric (Van Slyke) technic. This system had an accuracy of 4- 2 per cent in the range of the saturation values t h a t were measured. T h e p H was measured with an expanded scale BeckTABLE I I I CEREBROSPINAL FLIJID DATA

Case

Opening Pressure

i ii IlI IV v

280 i~; 150 ...

Sugar (mg, %)

Chloride (mg. %)

Protein (mg. %)

42 192 loo 150 150

129 133 125 111 124

35 70 48 87 43

Charaeter

Clear Clear Clear ...

0.7 2.7

8.9

0.5

2:5

2.5 2:;

4,7 5.0

83 328

96 56

765 1,490

4.2

1,860

660

1,250

3.9 ~4

80

~

18

66

465

m a n p H meter and a blood microelectrode which provided an accuracy of ± 0.01 p H unit. T h e PC02 was measured b y means of a Severinghaus electrode [9] used in conjunction with the Beckman expanded p H meter, with an accuracy of 4-2 mm. All patients had indwelling urethral catheters for measurement of urine flow. The volume was measured in a calibrated glass cylinder at hourly intervals. Skin and rectal temperatures were measured b y standard thermistor technics. RESULTS

Clinical Laboratory Observations. An

increase in the hematocrit values was observed in each case. (Table II.) Although there was clinical evidence of red blood cell loss in three of the five patients, a selective loss of plasma greater than t h a t of red blood cells was suggested. Leukocytosis was present in three patients. Essentially normal levels of blood urea nitrogen in four patients suggested t h a t circulatory failure was of acute onset• Significant elevations of the blood urea nitrogen, glucose, and sodium concentrations were detected in one patient (case II) and most likely represented failure of fluid intake in the presence of excessive loss of water. T h e serum calcium level was moderately decreased in three patients and within normal limits in only one patient. Although there was clear clinical and historical evidence of alcoholism in four of the five patients results of liver function tests, other t h a n serum enzyme determinations, were not grossly abnormal. (Table ii.) In one patient, bilirubin was increased to 2.7 mg. per cent although it returned to a normal level when remeasured after seventy-two hours. Determinations of serum albumin and alkaline American Journal of Surgery

Shock and Acute Pancreatitis Prior-Cuff

Initiol

[nler~diofe Disc~rge

[40~ARTERIALP R E S S U ~

377

Initiol

[nlermediete Disc~rge

4 T CARDIAC INDEX (I/min/M 2)

i-

3I 4 T CARDIACINDEX(I/min/M2)

N.

..-.-.-o I10 t HEART RATE (beQfs/min)

i

(ml/Kg)~~N,

55 ~ PLASMAVOLUME

25T

~ ,o T .EMATOORIT (vo,~'~ .....

40

g'tt ~~

~

20 T CENTRAL VENOUS PRESSURE (mmHg) N

1

IO I 0

~

N

. 2

FIG. 1. Graphic representation of the h e m o d y n a m i e course based on average measurem e n t s obtained in five p a t i e n t s with panereatitis and hypotension. FIG. 2. Graphic representation of t h e relationship of cardiac index, h e a r t rate, and central venous pressure.

phosphatase were within normal limits m each case. Values for serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, and lactic dehydrogenase were all elevated. Two previous studies of these enzymes reported from this hospital had indicated t h a t such elevations m a y reflect either the state of shock itself [10] or the tissue damage directly resulting from pancreatitis [11] without implicating intrinsic liver disease. Because of the i m p a i r m e n t in sensorium, lumbar puncture with examination of cerebrospinal fluid was performed in each case but no diagnostic abnormality was detected. (Table III,)

Hemodynamic Observations. The hemodynamic course based on the average measurements obtained is shown in Figure 1. A significant reduction in arterial blood pressure and cardiac index was associated with a reduction of plasma volume and an increase in the venous hematocrit. After the intravenous infusion of fluids, the cardiac index, plasma volume, and intra-arterial blood pressure were increased. Concurrently, the increased hematocrit was reduced. Changes in hematocrit reflected changes in plasma volume and served as a clinical guide to the adequacy of volume repletion. Relatively large infusions of fluid were ultimately required to normalize the arterial pressure. This resulted in expansion of the intravascular space to a measured plasma volume considerably in excess of the normal range. Vol. 111, M a r c h 1966

As cardiac index increased, the heart rate was slowed. (Fig. 2.) Venous pressure was essentially unchanged after the administration of large quantities of fluid, indicating the capability of the heart to accept additional volume. T h e calculated peripheral arterial resistance was initially increased, reflectingarterial and arteriolar vasoconstriction. After volume repletion peripheral arterial resistance was returned to normal values. (Fig. 3.) Peripheral skin temperatures measured on the plantar surface of the great toe progressively increased during fluid repletion although the rectal temperature remained relatively unchanged. This selective t e m p e r a t u r e change indicated an i m p r o v e m e n t in blood flow to the distal extremities. Reversal of the state of shock with improvem e n t in cardiac index and a decline in peripheral arterial resistance was also reflected in a striking increase in urinary flow as well as an increase in the velocity of blood flow as indicated b y reduction of the mean circulation time. (Fig. 4.) Metabolic Observations. Metabolic acidosis with a fall in the partial pressure of carbon dioxide was observed in each patient and presumably was related to decreased tissue perfusion. (Table Iv.) A minimal decrease in oxygen saturation during oxygen breathing was attributed to p u l m o n a r y complications. Correction of metabolic acidosis in the four surviving patients was accomplished b y volume repletion with blood, plasma, and saline

378

F a c e y , Weil, a n d R o s o f f

Initial t

Intermediate Disgorge

4 TCARDIAC INDEX (I/rnin/M 2) ........

Initial tt"

Intermediate 1, Discharge 1,

a31 .

~

N

.

25oo m PERIPHERAL ARTERIAL RESISTANCE ~ n e s sec cm-s) 2500 TPERIPHERAL ARTERIAL RESISTANCE 2000 t ,ooo

,

3°°T SKIN(°C )

oo

1oooI

~ ~-~::~

IOO IURINE FLOW ( m l / h ~ 0

58°TRECTAL (°C) ~,7° . . .

36°J"

~

N.

"////////~///////////////////~

......

.........

30 T MEAN CIRCULATION TIME (seconds) . . . . . . .

~

3

J. I0

K

j

N.

4

Fro. 3. Graphic representation of the relationship of peripheral arterial resistance and peripheral skin and rectal temperatures. Fro. 4. Graphic representation of averages of cardiac index, peripheral arterial resistance, urine flow, and mean circulation time in five patients with pancreatitis and hypotension. and dextrose solutions without the addition of alkalinizing solutions. THERAPY

In the four survivors relatively large volumes of colloid and crystalloid solutions were infused during a comparatively short interval of time. (Table v.) The rate and a m o u n t of fluid infused were p a r t l y determined b y changes in central venous pressure with care taken to avoid congestive heart failure. Digitalis and other cardiotonic drugs were not employed since there was no evidence of cardiac failure. In each instance the cardiac index increased with increases in plasma volume and without concomitant elevation in venous pressure. A d j u v a n t t h e r a p y included nasogastrie suction, anticholinergic drugs, and antibiotics. Endotraeheal suction, oxygen, and assisted ventilation with intermittent positive pressure were used as clinically indicated. No cortieosteroids or antitryptie agents were administered. Alpha-beta adrenergic vasopressor drugs [12] such as levarterenol (Levophed ®) and metaraminol (Aramine ®) were not administered to the four survivors. T h e r a p y in the one patient who died (case I) centered on the use of metaraminol administered in sufficient amounts to elevate blood pressure to "normal." Although volume reple-

tion was begun, it was done so only six days after the onset of shock and forty-four hours after admission to the Shock Research Ward. At autopsy extensive pancreatic necrosis, retroperitoneal edema, ileus, and pneumonia were found. COMMENTS

The five patients who were the subjects of this study presented as cases of unexplained coma and circulatory failure. Since the patients were in coma, they were unable to communicate s y m p t o m s referable to the abdomen t h a t might have led clinicians to suspect acute pancreatitis as the diagnosis. Myocardial infarction, diabetic coma, overdose of drugs, and cerebrovascular accident were considered in the differential diagnosis. The hist o r y of chronic alcoholism and the physical signs of delirium tremens called attention to a possible predisposing cause. The remainder of the history, physical examination, routine laboratory studies, and roentgenographic, and eerebrospinal fluid examinations were not diagnostic. The only consistent abnormal laboratory findings were an increase in serum amylase and urinary diastase and a striking increase in hematocrit. Of the routine laboratory measurements, the increased hematocrit was the outstanding finding and indicated t h a t hemoeonAmerican Journal of Surgery

Shock and Acute Pancreatitis TABLE IV METABOLIC OBSERVATIONS Data pH units PCO2 (ram. Hg) HCOz ( m E q . / L . ) Arterial oxygen saturation per cent

Admission

Discharge

7.33 7.42 (7.31-7.35) (7.40-7.42) 27 34 (16-37) (20-38) 15 21 95

99

379

TABLE V AVERAGE VALUES FOR VOLLrME REPLACEMENT IN POUR SURVIVORS Normal Solution

7.40

Total Period First of Circulatory Twenty-Four Instability* Hours (ml.) (ml.)

40 25 100

Glucose, electrolyte, and saline Blood, plasma, and dextran Total

4,936 I, 132 6,068

6,995 1,638 8,633

* Period of circulatory instability averaged thirtyfour hours.

centration due to loss of plasma had occurred, suggesting this as an i m p o r t a n t factor in the pathogenesis of shock. After the patients' admission to the Shock Research W a r d the reduction in plasma volume was confirmed. The decrease observed in cardiac output and arterial blood pressure refleets a corresponding reduction in venous return to the heart. These features are explained b y the deficiency of blood volume available for active circulation. A marked reduction in urinary flout and decreases in skin t e m p e r a t u r e in the extremities indicate a reduction in blood supplied to these organs. T h e metabolic defect which results from this inadequacy of tissue perfusion is metabolic acidosis due to anoxie metabolism and accumulation of acid metabolites. C o m p e n s a t o r y arteriolar vasoconstriction as evidenced b y an increased calculated total peripheral arterial resistance was also a consistent finding. For this reason, except in the sole fatality, alpha-beta adrenergic vasopressor drugs such as levarterenol and metaraminol were not administered. I t was also believed t h a t additional venular constriction would further accentuate intravascular fluid loss due to increases in capillary hydrostatic pressure [13 ]. The pathophysiology of this t y p e of shock is m o s t clearly demonstrated b y the response of these patients to fluid repletion. After infusion of large volumes of a colloid consisting of reconstituted blood plasma, a 5 per cent solution of albumin, or 6 per cent solution of dextran, supplemented b y large quantities of dextrose and electrolyte solutions, cardiac index and arterial pressure increased v e r y significantly. The patients became more alert, urinary flow was restored to normal values, and peripheral vasoconstriction abated. Increases in plasma Vol. 111, March 1966

volume and peripheral skin t e m p e r a t u r e and concurrent decreases in calculated peripheral arterial resistance document the temporal relationship of these changes. There were no p e r m a n e n t neurologic deficits in the four survivors, providing further evidence t h a t the changes in mental alertness were due to a temporary but critical reduction in cerebral blood flow. A decrease in total blood volume has previously been regarded as a p r i m a r y mechanism accounting for shock complicating pancreatitis [14-17]. In experimental studies in which pancreatitis was produced b y injecting bile into the accessory pancreatic duet of dogs, Dos Reis [14] observed a 38 per cent reduction in plasma volume. In a series of fourteen cases of acute panereatitis in patients observed b y K e i t h and W a t m a n [17], the plasma volume was reduced b y an average of 27 per cent. Thal, Kobold, and Hollenberg [18] do not regard plasma volume reduction b y peripancreatie losses as the sole explanation of the shock state. T h e y suggested t h a t a diffuse vascular injury caused b y the systemic actions of pancreatic enzymes results in capillary leakage and generalized vasodilatation. Bradykinin has been suggested as the potent vasoactive substance which affects sites remote from the area of the pancreas during acute panereatitis in m a n and animals [19]. Significant increases in survival time were observed in experimental animals b y Thal, Kobold, and Hollenberg [18] after treatm e n t with inhibitors of these pancreatic enzymes, and clinical investigation of the value of these inhibitors in the t r e a t m e n t of panereatitis has provided some encouraging results. Continued s t u d y of the mechanism of action of these vasoactive substances and an

380

F a c e y , Weil, a n d Rosoff

assessment of the therapeutic value of corresponding enzyme inhibitors are warranted. In the treatment of experimentally produced pancreatitis, Elliott [15] indicated that the survival of animals was more closely related to the adequacy of fluid repletion than to the inhibition of enzyme activity. When intravascular volume was maintained at normal levels after the production of bile panereatitis in studies by Dos Reis [14], fourteen of fifteen dogs survived. In a comparable group of animals in which fluid was not replaced, all but one of the fifteen animals died. Elliott and coworkers [16] found the mortality of experimentally produced panereatitis to be lower in dogs in which the plasma volume was augmented by infusion of concentrated serum albumin. Similarly, infusions of concentrated serum albumin were effective in treatment of acute pancreatitis in eleven patients observed by Kenwell and Wells [20]. The present study confirms the primary role of plasma volume deficits. I t relates the depletion of intravascular volume to the hemodynamie and metabolic disturbances observed and indicates the beneficial effects which followed the prompt administration of fluid. The usefulness of central venous pressure as a guide to volume repletion is demonstrated. Much larger amounts of fluid than the deficit of intravascular volume quantitated b y measurement of intravascular volume were required to reverse circulatory failure. As in the case of shock after hemorrhage [21 ], the surprisingly large fluid requirements are explained b y depletion of extravascular compartments. The differential diagnosis of shock requires routine measurement of serum amylase and, preferably, also measurements of serum calcium and urinary diastase. As Toffler and Spiro [22] have previously pointed out, the clinician would do well to be alerted to the possibility of pancreatitis as a cause of shock in patients who have a past history of alcoholism and who are admitted in coma. Although elevations in serum amylase and urinary diastase are not diagnostic of pancreatitis in the presence of shock, marked elevations in patients in whom shock is of very recent onset are not explained by defective renal clearance of amylase. As Berne and Edmundson [23] have previously emphasized, decreases in serum calcium concentration lend additional support to the diagnosis of acute panereatitis.

Our current approach to the treatment of such patients emphasizes infusion of colloid and crystalloid in amounts sufficient to restore normal cardiovascular function. Blood pressure is elevated, hematocrit is reduced, and oliguria is reversed. Monitoring of central venous pressure guides the rate and volume of fluid infused in order to avoid congestive heart failure [24]. The amount of fluid required for complete reversal of circulatory instability is often in excess of 7 L. in the first twenty-four hours of management. SUMMARY

The mechanism of circulatory shock complicating acute panereatitis is a critical reduction in plasma volume. Serial hemodynamie and metabolic studies were performed on five patients in shock associated with acute pancreatitis. The mean arterial blood pressure and cardiac output were reduced and peripheral arterial resistance was increased. Mean circulation time was markedly prolonged, reflecting decreased velocity of blood flow. Coma, oliguria, hyperamylasemia, and metabolic acidosis were consistent features. Since the state of shock associated with pancreatitis is due to a volume deficit with marked arterial vasoconstriction, volume replacement alone with avoidance of vasoeonstrieting agents is indicated. Prompt plasma volume replacement favors reversal of the hemodynamie and metabolic deficits of this type of shock. Hypotension and coma, the two notable clinical features, were reversed after the infusion of large volumes of colloid and crystalloid solutions. REFERENCES

1. SILER, V. E. and WULSIN, J. H. Consideration of the lethal factors in acute pancreatitis. Arch. Surg., 63: 496, 1951. 2. BERNe, C. J. Diagnosis of compensated hypovolemic shock. Am. J. Surg., 103: 412, 1962. 3. WARE, A. G., WALBERG, C. B., and STERLING, R. E. In: Methods of Clinical Chemistry, vol. 4, p. 15. Edited by Seligson, D. New York, 1963. Academic Press, Inc. 4. SELDINGER, S. 1. Catheter replacement of the needle in pereutaneous arteriography. Acta rad,ioL 39, 368, 1953. 5. WOOD, E. H. Special technics of value in the cardiac catheterization laboratory. Proc, Staff Meet. AJayo Clin., 28: 58, 1953. 6. NICHOLSON, J. W., III and WOOD, E. H. Estimation of cardiac output and Evans blue space in man, using an oximeter. J. Lab. & Clin. Med., 38: 588, 1951.

American Jo2trnal of Surgery

Shock and Acute Pancreatitis 7. HAMILTON, W. F., MOORE, J. W., KINSMAN, .~. M., and SPURLING, R. O. Studies on circulation. IV. Further analysis of the injection method of changes in hemodynamics under physiological and pathological conditions. Am. J. Physiol., 99: 534, 1932. 8. UDHO/I, V. N., WEIL, M. H., SAMBm, M. P., and R0SOFF, L. Hemodynamie studies on clinical shock associated with infection. A~z. Jr. Med., 34: 461, 1963. 9. SEVERINGHAUS, J. W. and BRADLEY, A. F. Electrodes, for blood PO2 and PCO_~ determination. J. Appl. Physiol., 13: 515, 1958. 10. SHUBIN, H. and WEIL, M. H. Acute elevation of serum transaminase and lactic dehydrogenase during circulatory shock. Am. J. Cardiol., 11: 327, 1963. 11. DENNEY, J. L., McAuLEY, C. B., MARTIN, H. E., WARE, A. G., and SEOALOVE, M. Evaluation of the serum glutamic oxalacetic aminopherase (transaminase) test: its use in diagnosis of acute myocardial infarction. J.A.M.A., 161: 614, 1956. 12. WEIL, M. H., SHtrB!N , H., UI)HOjI, V. N., and ROSOFF, L. Effects of vasopressor agents and corticosteroid hormones in endotoxin shock. In: Shock and Hypotension: Pathogenesis and Treatment, a H a h n e m a n n Symposium, p. 470. Edited by Mills, L. C. and Moyer, J. H. New York, 1965. Grune & Strattou, Inc. 13. SHUBIN, H. and WEIL, M. H. The mechanism of shock following suicidal doses of barbiturates, narcotics and tranquilizer drugs, with observations on the effects of treatment. Anz. J. l]fed., 38: 853, 1965. 14. Dos REIS, L. Importance of blood volume changes in acute pancreatitis. An~. Surgeon, 29: 605, 1963.

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15. ELLIOTT, D. W. The mechanism of benefit derived from concentrated h u m a n albumin in experimental acute pancreatitis. S. Forum, 5: 384, 1955. 16. ELLIOTT, D. W., ZOLLINGER, l~_. M., MOORE, R. O., and ELLISON, E. I-I. The use of h u m a n serum albumin in the management of acute pancreatiffs: experimental and clinical observations. Gastroenterology, 28: 563, 1955. 17. KmTH, L. M., JR. and WATMAN, R. N. Blood volume deficits in acute panereatitis. S. Forunz, 5: 380, 1955. 18. THAL, A. P., KOBOLD, E. E., and HOLLENBBRG, M. I. The release of vasoaetive substances in acute pancreatitis. Anz. J. S~rg., 195: 708, 1963 19. I'IOLLENBERG, M. J., KOBOLD, E. E., PRUETT, R., and TI-IAL, A. P. Occurrence of circulating vasoactive substances in h u m a n and experimental panereatitis. S. Forum, 13:302, 1962. 20. KENWELL, H. 1"(. and WELLS, P. B. Acute hemorrhagic pancreafitis: report on eleven consecutive cases treated with h u m a n serum albumin. Surg. Gynec. & Obst., 96: 169, 1953. 21. StoRES, T., COLN, D., CARRICO, J., and LIGHTFOOT, S. Fluid therapy in hemorrhagic shock. Arch. Surg., 88: 688, 1964. 22. TOFFLER, A. H. and SPIRO, H. M. Shock or coma as the predominant manifestation of painless acute pancreatitis. Ann. Int. Med., 57:655, 1962. 23. BERNE, C. J. and EDMUNDSON', I-I. A. Calcium changes in acute pancreatic necrosis. Surg. Gynec. & Obst., 79: 240, 1944. 24. WEIL, M. H., SHI~EIN, H., and ROSOFV, L. Fluid repletion in circulatory shock: central venous pressure a n d other practical guides. J.A.M.A., 192: 668, 1965.