Lethal Pancreatitis: A Diagnostic Dilemma
Lynn M. Peterson, MD, Boston, Massachusetts John I?. Brooks, MD, Boston, Massachusetts
Acute pancreatitis remains a difficult clinical problem because of the lack of a specific therapy, a variable clinical course, and a high mortality rate (10 to 50 per cent) [I-4]. Recent efforts to improve survival of patients with acute pancreatitis have attempted to establish prognostic criteria that select patients at greatest risk of dying or developing serious complications and have instituted more aggressive therapeutic measures (such as peritoneal lavage [I], laparotomy with drainage [z], and pancreatectomy [5]) earlier in the course of the disease [6-91. These efforts have contributed to understanding and managing this disease but are lacking in two respects. First, they lack objective proof of acute pancreatitis against which to measure the prognostic criteria and ultimate therapy; they assume that patients with severe acute pancreatitis have distinct clinical characteristics [8]. Second, they often combine patients with acute pancreatitis regardless of etiologic factors [6-81 because such factors do not appear to affect the morbidity or mortality rates. However, factors such as biliary tract disease or alcoholism provide a clinical setting in which the disease occurs and thus influence the complications that occur and the therapeutic alternatives. In this study we attempted to complement the purely clinical studies of severe acute pancreatitis by correlating the clinical and pathologic features of patients who died from histologically proved acute pancreatitis. The addition of definitive pathologic
findings provides a more precise understanding of the difficulties in managing patients with severe acute pancreatitis and helps clarify therapeutic priorities.
From the Department of Surgery, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts. Reprint requests should be adbessed to Lynn M. Peterson, MD, Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Massachusetts 02115. Presented at the Fifty-Ninth Annual Meeting of the New England Surgical Society, Dixville Notch, New Hampshire, September 29-October 1, 1978.
Eleven patients had caIculous biliary tract disease. This group included six men and five women, aged 55 to 88 years (average 71). Pancreatitis was diagnosed antemortem in ten patients. Serum amylase was helpful in correctly establishing the diagnosis in nine of ten patients in whom it was measured.
Vdume 137, Apru 197s
Methods and Patients
Hospital records of patients who died with acute pancreatitis as a clinical diagnosis or autopsy finding were reviewed. Patients in whom pancreatitis was the antecedent and major cause of death were selected for detailed analysis. Patients were excluded when a clinical diagnosis of acute pancreatitis was not substantiated at autopsy or when pancreatitis was not a significant finding. Of the patients with acute pancreatitis as an autopsy finding, only 27 per cent had pancreatitis of major pathologic significance. The clinical and pathologic information was analyzed with the following questions in mind: (1) Was pancreatitis diagnosed antemortem? (2) Was the measurement of serum amylase useful? (3) Had the patient had previous attacks of pancreatitis? (4) Was an operation performed? (5) What were the lethal mechanisms? (6) Were other significant pathologic findings present? During the twenty-two year period of 1955 to 1977, acute pancreatitis was the major cause,of death in forty patients. Eighteen of these patients died during the first eleven years of the study and twenty-two during the second. The patients included twenty-six men and fourteen women. The patients were classified into the four groups listed in Table I on the basis of the clinical and pathologic data. Group I: Biliary Pancreatllis
491
Peterson and Brooks
TABLE I
Clinical Data Initial Amylase Elevated
Age WI
Previous Pancreatitis
Operation
9110
2
10
7
9/10
1
2
6
617
0
3
0
515
0
0
23
29/32
3
15
Etiologic Group
No. of Patients
Range and Mean .
Correct Diagnosis
I. Biliary pancreatitis II. Alcoholic pancreatitis Ill. Idiopathic pancreatitis IV. Renal failure
11
55-88
10
13
(71) 25-75
10
(52) 49-80
6
(63) 27-86
Total
40
(50) 25-88 160)
Serum amylase was not measured in an 88 year old patient with obstructive jaundice who was believed to have carcinoma of the pancreas; this patient died with a common duct stone and hemorrhagic pancreatitis. One patient had a persistently normal amylase for six weeks despite extensive hemorrhagic pancreatitis. The amylase was normal in five patients, decreasing in two patients, and increasing in two patients at the time of death from pancreatitis. (Figure 1.) Four patients had pathologic evidence of chronic and acute pancreatitis. Two of these patients had well-documented clinical attacks, and two had no history suggesting
previous pancreatitis. Seven patients had neither pathologic nor clinical evidence of previous pancreatitis. Ten patients underwent operation. Three patients were operated on in desperation because of diagnostic uncertainty. A cholecystostomy tube and pancreatic drains were placed in these patients, but they died within 24 hours of operation. The other seven patients were operated on electively. One patient died from the renal and respiratory complications of his pancreatitis after cholecystostomy and drainage of a lesser sac abscess. In six patients operative complications were instrumental in the occurrence of pancreatitis. Three patients had retained common duct
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Ffgure 1. Serial amyiase levels in patients with biiiary pancreatitis. The normal range is shaded.
492
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Figure 2. Serial amyiase levels in patients with alcoholic pancreatitis. Normal range is shaded.
The American Journal o?Surgery
Lethal Pancreatitis
stones with biliary sepsis and inadequate drainage, pancreatic needle biopsies were performed in two patients, and one patient had prolonged bacterial cholangitis which was followed by pancreatitis and death. Six patients had extensive bacterial infection in and around the pancreas with a variety of microorganisms: Escherichia coli, A. aerogenes, P. mirabilis, Serratia, Pseudomonas and enterococcus. Four patients had more than one organism. The organisms in the abscess were also present in bile in three patients who had bile cultures. Three patients had acute renal failure. One patient was treated with peritoneal dialysis followed by hemodialysis but never regained renal function; the other two patients died shortly after developing renal failure. Four patients, including the three patients with renal failure, had significant pulmonary lesions. One patient had pulmonary congestion and bronchopneumonia without renal failure. Three patients had hepatic insufficiency related to persistent biliary obstruction and cholangitis. One patient bled massively from a necrotic inflammed pancreas and was treated unsuccessfully with total pancreatectomy. Group II: Alcoholic Pancreatltls
Thirteen patients had a definite history of prolonged (greater than one year) excessive alcohol consumption, and in most of these patients the lethal attack of pancreatitis was preceded by recent heavy alcohol ingestion. This group included ten men and three women, aged 25 to 75 years (average 52). Pancreatitis was diagnosed clinically in seven patients. The other six patients had an altered state of consciousness but no abdominal complaints or tenderness; three of these patients had hepatic encephalopathy and three acute alcoholic intoxication. Serum amylase was increased in nine of ten patients in whom it was measured; one patient had a normal amylase with severe hemorrhagic pancreatitis. Serial amylase decreased in nine patients and was normal in five patients at the time of death. Amylase increased in two patients. (Figure 2.) Three patients had pathologic changes of chronic pancreatitis in addition to acute pancreatitis, but only one patient had had a clinical attack of pancreatitis before the lethal attack. Two patients underwent operation. Exploratory surgery was performed in one patient on the eleventh hospital day, and a lesser sac abscess secondary to Klebsiella pneumoniae was drained. Exploratory surgery was performed in the other patient on the third hospital day and again two weeks later because of gastric bleeding, when a lesser sac abscess was found. A third patient died with an undrained pancreatic abscess. Nine patients had acute renal failure and acute tubular necrosis at autopsy. Renal failure developed in four patients soon after admission and in five patients between the second and ninth hospital days. Significant pulmonary lesions were present in twelve patients. All nine patients with renal failure had pulmonary congestion, and five also had bronchopneumonia. Three of the four patients without renal failure died in acute respiratory distress and had
volume
137, April 1979
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I
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Figure 3. Serial amyiase levels in pat/ents with idiopathic pancreatitis. Normal range is shaded.
pulmonary congestion pathologically. All three were under sedation because of an agitated state believed secondary to delirium tremens at the time of death. Their agitation may have been due to hypoxemia, but arterial oxygen tensions were not measured. Three patients had severe alcoholic liver disease, and their liver function deteriorated during the course of pancreatitis. One patient bled suddenly and massively from the pancreas and died from hemorrhagic shock. Group Ilk Idiopathic Pancreatltls
Ten patients had no known etiologic or predisposing factor. Two patients had a history of heavy alcohol use, but both had abstained from drinking for more than ten years. Two patients had had chemotherapy for malignancy. This group included seven men and three women, aged 49 to 80 years (average 63). Pancreatitis was not diagnosed in four patients. In two patients diagnostic efforts were restricted because of malignancy. The other two patients had multiple pulmonary emboli believed to account for the clinical findings of shock and respiratory failure. Amylase was appropriately increased in six patients, but remained persistently normal in one patient despite extensive pancreatitis. Serum amylase was normal at the time of death in five patients and increased in only one patient. (Figure 3.) No patient in this group had clinical or pathologic evidence of previous pancreatitis. Three patients underwent
493
Peterson and Brooks
operation; two had multiple drains inserted and the third had exploratory surgery only. These patients died on the first, fourth and fifteenth postoperative days. In four patients autopsy findings of bacterial peritonitis were related to the following factors: extensive sepsis around pancreatic drains, Serratia peritonitis after peritoneal dialysis, perforated gastric ulcer and small bowel perforation with portal vein thrombosis secondary to pancreatitis. Four patients had renal failure, acute tubular necrosis, and severe pulmonary congestion. Another patient with severe pulmonary congestion had underlying cardiac disease and emphysema. Thus five patients had significant pulmonary pathology. Three patients had thromboembolic complications; two had leg vein thrombi with multiple pulmonary emboli, and one had portal vein thrombosis. Group IV: Renal Failure Six patients had renal failure before the onset of pancreatitis. This group included three men and three women, aged twenty-seven to sixty-six years (average fifty). Renal disease included severe nephrosclerosis in two patients, chronic pyelonephritis in two patients, end stage kidneys in one patient and chronic homograft rejection in one patient. Four patients had had renal failure for one to three months and two patients for one to three years. The patient with chronic homograft rejection was receiving immunosuppressive therapy; one patient had hyperparathyroidism, renal failure, and acute pancreatitis. The cause of renal failure was undetermined in the other four patients. No patient in this group had a clinical diagnosis of acute pancreatitis. Three patients had mild abdominal pain but no significant abdominal tenderness. Two patients had nausea and vomiting believed secondary to uremia. Serum amylase was elevated in all five patients in whom it was measured. In one patient serial amylase determinations decreased from 1,800 to 550 units/dl. No patient had clinical or pathologic evidence of previous pancreatitis, and no patient in this group underwent operation. One patient had generalized enterococcal peritonitis but no abscess. Five patients had severe pulmonary congestion, and three of these patients also had bronchopneumonia. Comments Only 57 per cent of the patients studied had a diagnosis of acute pancreatitis before death, yet all had severe acute pancreatitis at autopsy. The apparent reasons for diagnostic failure included (1) an altered state of consciousness in the alcoholic patients, making abdominal examination unreliable; (2) a restricted diagnostic effort due to known malignancy and an unremarkable abdominal examination; and (3) the unreliability of the serum amylase determinations and abdominal symptoms and findings in the patients with renal failure. Tofler and Spiro [IO] reported on nine patients with fatal pancreatitis who presented in coma and shock but had no abdominal
494
pain. Gillespie [ll] similarly
found diagnostic failure in 29 per cent of patients who died from acute pancreatitis. More recently, Bourke [12] noted that 41 per cent of patients who died from pancreatitis did not have an antemortem diagnosis and that the overall mortality rate from acute pancreatitis increased significantly when autopsy findings as well as clinical reports were considered. Thus, patients with severe acute pancreatitis do not always have typical or striking abdominal complaints or findings. Serum amylase was an accurate diagnostic tool. It was significantly elevated in twenty-nine of thirtytwo (90 per cent) patients in whom it was measured. However, there was no correlation between serial amylase levels and the severity or course of the disease. In fifteen patients with severe acute pancreatitis the serum amylase was normal, and in six patients the amylase was decreasing at the time of death. The amylase level was increasing in only five patients at the time of death. Thus, in contrast to other diseases in which decreasing enzyme levels often indicate improvement, a decrease in serum amylase does not necessarily indicate improvement in acute pancreatitis. Only three patients had had previous clinical attacks of pancreatitis. Four other patients had pathologic changes of chronic as well as acute pancreatitis. The patients with previous pancreatitis had alcoholic and biliary related pancreatitis wherein persistence of the offending agent contributed to recurrence. Thus, thirty-seven of these forty patients died during their first clinical attack of pancreatitis. Ranson and Pasternack [B] found that patients with “severe” pancreatitis had significantly fewer episodes of pancreatitis than those with “mild” pancreatitis, and the Medical Research Council [13] reported no deaths in patients with previous pancreatitis. Hence, the first attack of this disease deserves special attention and intensive care. Opinions differ regarding the role of operation in acute pancreatitis. Only one patient in this series who died without an operation might have survived if his pancreatic abscess had been drained. Operation failed in four patients with biliary tract disease and pancreatitis because of incomplete biliary decompression; two patients had common duct stones without biliary intubation, and two had cholecystostomies that functioned only partially. Patients with biliary tract disease and pancreatitis should have common duct stones removed if their general condition and local findings permit; otherwise intubation of the common duct is a suitable alternative. Cholecystostomy may not be dependable when bil-
The American Journal of Surgery
Lethal Pancreatitis
iary tract disease is associated with acute pancreatitis. Intraabdominal sepsis played a major role in lethality in fourteen patients. The incidence of intraabdominal infection was higher in patients with (55 per cent) than in those without biliary tract disease (28 per cent). Three patients with biliary tract disease and peripancreatic sepsis had antemortem bile cultures, and in each patient the offending organism was present in bile. Thus sepsis was more important in the lethality of pancreatitis in the presence of biliary tract disease, and bile cultures provided important information regarding antibiotic selection. Gregg [14] also found that patients with biliary tract disease and pancreatitis frequently had infected bile and that pancreatic juice obtained endoscopically contained the same microorganisms that were present in bile. Acute renal failure due to acute tubular necrosis occurred during the course of pancreatitis in sixteen patients. Although glomerulitis has been reported [15] in patients with relapsing pancreatitis, no patient in this series had a glomerular lesion. Although the renal tubular lesion is reversible, the mortality in patients with acute pancreatitis and acute renal failure has been reported as high as 95 per cent [3]. The occurrence of renal failure may not only reflect the severity of pancreatitis but may also aggravate the pathologic process within the pancreas. Reduced tubular reabsorption of protein has been demonstrated in patients with acute pancreatitis causing increased urinary excretion of amylase. Urinary excretion of the proteolytic and phospholipolytic enzymes that are critical in the local pathologic process may also be increased. When renal function is compromised and enzyme excretion reduced, an important defense mechanism could be impaired. All sixteen patients with acute renal failure and five of the six patients with chronic renal failure had severe pulmonary congestion pathologically. Three patients with alcoholic, one patient with biliary, and one patient with idiopathic pancreatitis had severe pulmonary congestion without renal failure. Thus the development of severe pulmonary lesions in patients who died with severe pancreatitis was more common in patients with (95 per cent) than in those without (27 per cent) renal failure. Warshaw et al [16] suggested that respiratory failure and pulmonary congestion in patients with pancreatitis is due to damage of the alveolar-capillary membrane and that the lesion improves with intubation and controlled ventilation with positive end-expiratory pressure. There was no correlation between the presence of severe pulmonary congestion and the presence of a septic
Volume 137, April 1979
BILIARY
IDIOPATHIC
ALCOHOLIC
RENAL
Figure 4. Lethal mechanisms in patients with acute pancreatttis. The stippled bars represent peripancreatic sepsis, the white bars represent renal iailure, and the black bars respiratory failure.
process in or around the pancreas. Hence, the development of respiratory failure alone in patients with acute pancreatitis is not an indication for pancreatic exploration. Other findings that contributed significantly to mortality were present in thirteen patients. Of the six patients with significant hepatic parenchymal lesions, three had biliary tract disease and cholangitis, and three were alcoholics with cirrhosis. Three patients had nonpancreatic peritonitis caused by peritoneal dialysis, a perforated gastric ulcer, and “spontaneous” enterococcal peritonitis (in a patient with chronic renal failure). Three patients had leg vein thrombi with multiple pulmonary emboli, and two patients died after massive hemorrhage from the pancreas. The lethal mechanisms in patients with biliary tract disease differed from those with alcohol-related pancreatitis. (Figure 4.) The incidence of local sepsis was greater (55 versus 24 per cent) but the incidence of renal failure (27 versus 70 per cent) and respiratory failure (36 versus 92 per cent) smaller in the patients with biliary tract disease than in the patients with alcoholic pancreatitis. The incidence of these lethal mechanisms in patients with idiopathic pancreatitis appeared intermediate between these two groups, whereas patients with chronic renal failure had a low incidence of local sepsis and a high incidence of respiratory failure. Thus, although the overall mortality in acute pancreatitis may be the same for different types of patients, the lethal mechanisms and course of the disease depends to some extent on the underlying etiologic factors. Conclusions
Acute pancreatitis may be lethal because of diagnostic failure and a consequent lack of appropriate
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and Brooks
therapy. Therapy should minimally include adequate parenteral fluid support, gastric suction, and close observation. Serum amylase should be measured if the slightest suspicion of pancreatitis exists and should possibly be measured as a part of the routine chemical battery in patients seen in the emergency room. Amylase is not a useful prognostic indicator, and serial amylase determinations do not help monitor the course of the disease. The first attack of pancreatitis carries the greatest risk of death. Antibiotics appear most important in patients with pancreatitis associated with biliary tract disease. Operations carried out in patients with pancreatitis and biliary tract disease should provide adequate biliary decompression; cholecystostomy may not be sufficient. Impairment of renal and pulmonary function are the most important serious complications of acute pancreatitis but are potentially reversible. Neither complication indicates the presence of a septic pancreatic process or the need for pancreatic exploration. Summary
Clinical and pathologic information from forty patients who died with pathologically severe acute pancreatitis was correlated. Patients were classified into four etiologic groups: those with biliary pancreatitis (11 patients), alcoholic pancreatitis (13 patients), idiopathic pancreatitis (10 patients), and renal failure (6 patients). Antemortem diagnosis was made in only 57 per cent of the patients studied. The diagnosis was determined before death in 91 per cent of the biliary patients but in none of the renal patients. Thirty-seven patients died from their first clinical attack of pancreatitis. Operation in patients with biliary pancreatitis failed when biliary decompression was not provided. Peripancreatic sepsis was a frequent lethal mechanism in patients with biliary pancreatitis, but renal and respiratory failure were
496
more common in patients titis.
with alcoholic pancrea-
References 7. Gliedman ML, Bolocki H, Rosen RG: Acute pancreatitis. Curr Probl Surg 1970. 2. Lawson DW, Daggeti WM, Cireffa JM, Cony RJ, Bartlett MK: Surgical treatment of acute necrotizing pancreatitis. Ann Surg 172: 605, 1970. Frey C: me operative treatment of pancreatitis. Arch Surg 98: 406, 1969. Peterson LM, Collins JJ, Wilson RE: Acute pancreatitis occurring after operation. Surg Gynecol Obstet 127: 23, 1968. Norton L. Eiseman B: Near total pancreatectomy for hemorrhagic pancreatitis. Am J Surg 127: 191, 1974. Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC: Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 139: 69, 1974. 7. Ranson JHC, Rifkind KM, Turner JW: Prognostic signs and nonoperative peritoneal lavage in acute pancreatitis. Surg Gynecol Obstet 143: 209, 1976. 8. Ranson JHC, Pasternack BS: Statistical methods for quantifying the severity of clinical acute pancreatitis. J Surg Res 22: 79, 1977. 9. Jacobs ML, Daggett WM, Ciretta JM, Vasu MA, Lawson DW. Warshaw AL, Nardi G, Bartlett MK: Acute pancreatitis: analysis of factors influencing survival. Ann Surg 185: 43, 1977. 10. Tofler AH, Spiro HM: Shock or coma as the predominant manifestation of painless acute pancreatitis. Ann intern Med 57: 655, 1962. 11. Gillespie WJ: Observations on acute pancreatitis. JR Co// Surg Edinb 20: 36, 1975. 12. Bourke JB: Incidence and mortality of acute pancreatitis. Br Med J2: 1668, 1977. 13. Welbourn RB, Armitage P, Giimore OJA, MacKay C, Trapnell JE, Williamson RCN, Cox AG: Death from acute pancreatitis. Lancet 2: 632, 1977. 14. Gregg JA: Detection of bacterial infection of the pancreatic ducts in patients with pancreatitis and pancreatic cancer during endoscopic cannulation of the pancreatic duct. Gastroenterol73: 1005. 1975. 15. Dickmeyer, JP, Wolfson W, Kowell A, Dornfeld L: Reversible crescentic glomerulonephritis following an acute exacerbation of chronic relapsing pancreatitis. Arch lntem Med 137: 1065.1977. 16. Warshaw AL, Lesser PB, Rie M, Cullen DJ: The pathogenesis of pulmonary edema in acute pancreatitis. Ann Surg 182: 505, 1975.
The American Journal 01 Surgery
Lynn M. Peterson, MD, Boston, Massachusetts John I?. Brooks, MD, Boston, Massachusetts
Acute pancreatitis remains a difficult clinical problem because of the lack of a specific therapy, a variable clinical course, and a high mortality rate (10 to 50 per cent) [I-4]. Recent efforts to improve survival of patients with acute pancreatitis have attempted to establish prognostic criteria that select patients at greatest risk of dying or developing serious complications and have instituted more aggressive therapeutic measures (such as peritoneal lavage [I], laparotomy with drainage [z], and pancreatectomy [5]) earlier in the course of the disease [6-91. These efforts have contributed to understanding and managing this disease but are lacking in two respects. First, they lack objective proof of acute pancreatitis against which to measure the prognostic criteria and ultimate therapy; they assume that patients with severe acute pancreatitis have distinct clinical characteristics [8]. Second, they often combine patients with acute pancreatitis regardless of etiologic factors [6-81 because such factors do not appear to affect the morbidity or mortality rates. However, factors such as biliary tract disease or alcoholism provide a clinical setting in which the disease occurs and thus influence the complications that occur and the therapeutic alternatives. In this study we attempted to complement the purely clinical studies of severe acute pancreatitis by correlating the clinical and pathologic features of patients who died from histologically proved acute pancreatitis. The addition of definitive pathologic
findings provides a more precise understanding of the difficulties in managing patients with severe acute pancreatitis and helps clarify therapeutic priorities.
From the Department of Surgery, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts. Reprint requests should be adbessed to Lynn M. Peterson, MD, Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Massachusetts 02115. Presented at the Fifty-Ninth Annual Meeting of the New England Surgical Society, Dixville Notch, New Hampshire, September 29-October 1, 1978.
Eleven patients had caIculous biliary tract disease. This group included six men and five women, aged 55 to 88 years (average 71). Pancreatitis was diagnosed antemortem in ten patients. Serum amylase was helpful in correctly establishing the diagnosis in nine of ten patients in whom it was measured.
Vdume 137, Apru 197s
Methods and Patients
Hospital records of patients who died with acute pancreatitis as a clinical diagnosis or autopsy finding were reviewed. Patients in whom pancreatitis was the antecedent and major cause of death were selected for detailed analysis. Patients were excluded when a clinical diagnosis of acute pancreatitis was not substantiated at autopsy or when pancreatitis was not a significant finding. Of the patients with acute pancreatitis as an autopsy finding, only 27 per cent had pancreatitis of major pathologic significance. The clinical and pathologic information was analyzed with the following questions in mind: (1) Was pancreatitis diagnosed antemortem? (2) Was the measurement of serum amylase useful? (3) Had the patient had previous attacks of pancreatitis? (4) Was an operation performed? (5) What were the lethal mechanisms? (6) Were other significant pathologic findings present? During the twenty-two year period of 1955 to 1977, acute pancreatitis was the major cause,of death in forty patients. Eighteen of these patients died during the first eleven years of the study and twenty-two during the second. The patients included twenty-six men and fourteen women. The patients were classified into the four groups listed in Table I on the basis of the clinical and pathologic data. Group I: Biliary Pancreatllis
491
Peterson and Brooks
TABLE I
Clinical Data Initial Amylase Elevated
Age WI
Previous Pancreatitis
Operation
9110
2
10
7
9/10
1
2
6
617
0
3
0
515
0
0
23
29/32
3
15
Etiologic Group
No. of Patients
Range and Mean .
Correct Diagnosis
I. Biliary pancreatitis II. Alcoholic pancreatitis Ill. Idiopathic pancreatitis IV. Renal failure
11
55-88
10
13
(71) 25-75
10
(52) 49-80
6
(63) 27-86
Total
40
(50) 25-88 160)
Serum amylase was not measured in an 88 year old patient with obstructive jaundice who was believed to have carcinoma of the pancreas; this patient died with a common duct stone and hemorrhagic pancreatitis. One patient had a persistently normal amylase for six weeks despite extensive hemorrhagic pancreatitis. The amylase was normal in five patients, decreasing in two patients, and increasing in two patients at the time of death from pancreatitis. (Figure 1.) Four patients had pathologic evidence of chronic and acute pancreatitis. Two of these patients had well-documented clinical attacks, and two had no history suggesting
previous pancreatitis. Seven patients had neither pathologic nor clinical evidence of previous pancreatitis. Ten patients underwent operation. Three patients were operated on in desperation because of diagnostic uncertainty. A cholecystostomy tube and pancreatic drains were placed in these patients, but they died within 24 hours of operation. The other seven patients were operated on electively. One patient died from the renal and respiratory complications of his pancreatitis after cholecystostomy and drainage of a lesser sac abscess. In six patients operative complications were instrumental in the occurrence of pancreatitis. Three patients had retained common duct
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Ffgure 1. Serial amyiase levels in patients with biiiary pancreatitis. The normal range is shaded.
492
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Figure 2. Serial amyiase levels in patients with alcoholic pancreatitis. Normal range is shaded.
The American Journal o?Surgery
Lethal Pancreatitis
stones with biliary sepsis and inadequate drainage, pancreatic needle biopsies were performed in two patients, and one patient had prolonged bacterial cholangitis which was followed by pancreatitis and death. Six patients had extensive bacterial infection in and around the pancreas with a variety of microorganisms: Escherichia coli, A. aerogenes, P. mirabilis, Serratia, Pseudomonas and enterococcus. Four patients had more than one organism. The organisms in the abscess were also present in bile in three patients who had bile cultures. Three patients had acute renal failure. One patient was treated with peritoneal dialysis followed by hemodialysis but never regained renal function; the other two patients died shortly after developing renal failure. Four patients, including the three patients with renal failure, had significant pulmonary lesions. One patient had pulmonary congestion and bronchopneumonia without renal failure. Three patients had hepatic insufficiency related to persistent biliary obstruction and cholangitis. One patient bled massively from a necrotic inflammed pancreas and was treated unsuccessfully with total pancreatectomy. Group II: Alcoholic Pancreatltls
Thirteen patients had a definite history of prolonged (greater than one year) excessive alcohol consumption, and in most of these patients the lethal attack of pancreatitis was preceded by recent heavy alcohol ingestion. This group included ten men and three women, aged 25 to 75 years (average 52). Pancreatitis was diagnosed clinically in seven patients. The other six patients had an altered state of consciousness but no abdominal complaints or tenderness; three of these patients had hepatic encephalopathy and three acute alcoholic intoxication. Serum amylase was increased in nine of ten patients in whom it was measured; one patient had a normal amylase with severe hemorrhagic pancreatitis. Serial amylase decreased in nine patients and was normal in five patients at the time of death. Amylase increased in two patients. (Figure 2.) Three patients had pathologic changes of chronic pancreatitis in addition to acute pancreatitis, but only one patient had had a clinical attack of pancreatitis before the lethal attack. Two patients underwent operation. Exploratory surgery was performed in one patient on the eleventh hospital day, and a lesser sac abscess secondary to Klebsiella pneumoniae was drained. Exploratory surgery was performed in the other patient on the third hospital day and again two weeks later because of gastric bleeding, when a lesser sac abscess was found. A third patient died with an undrained pancreatic abscess. Nine patients had acute renal failure and acute tubular necrosis at autopsy. Renal failure developed in four patients soon after admission and in five patients between the second and ninth hospital days. Significant pulmonary lesions were present in twelve patients. All nine patients with renal failure had pulmonary congestion, and five also had bronchopneumonia. Three of the four patients without renal failure died in acute respiratory distress and had
volume
137, April 1979
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Figure 3. Serial amyiase levels in pat/ents with idiopathic pancreatitis. Normal range is shaded.
pulmonary congestion pathologically. All three were under sedation because of an agitated state believed secondary to delirium tremens at the time of death. Their agitation may have been due to hypoxemia, but arterial oxygen tensions were not measured. Three patients had severe alcoholic liver disease, and their liver function deteriorated during the course of pancreatitis. One patient bled suddenly and massively from the pancreas and died from hemorrhagic shock. Group Ilk Idiopathic Pancreatltls
Ten patients had no known etiologic or predisposing factor. Two patients had a history of heavy alcohol use, but both had abstained from drinking for more than ten years. Two patients had had chemotherapy for malignancy. This group included seven men and three women, aged 49 to 80 years (average 63). Pancreatitis was not diagnosed in four patients. In two patients diagnostic efforts were restricted because of malignancy. The other two patients had multiple pulmonary emboli believed to account for the clinical findings of shock and respiratory failure. Amylase was appropriately increased in six patients, but remained persistently normal in one patient despite extensive pancreatitis. Serum amylase was normal at the time of death in five patients and increased in only one patient. (Figure 3.) No patient in this group had clinical or pathologic evidence of previous pancreatitis. Three patients underwent
493
Peterson and Brooks
operation; two had multiple drains inserted and the third had exploratory surgery only. These patients died on the first, fourth and fifteenth postoperative days. In four patients autopsy findings of bacterial peritonitis were related to the following factors: extensive sepsis around pancreatic drains, Serratia peritonitis after peritoneal dialysis, perforated gastric ulcer and small bowel perforation with portal vein thrombosis secondary to pancreatitis. Four patients had renal failure, acute tubular necrosis, and severe pulmonary congestion. Another patient with severe pulmonary congestion had underlying cardiac disease and emphysema. Thus five patients had significant pulmonary pathology. Three patients had thromboembolic complications; two had leg vein thrombi with multiple pulmonary emboli, and one had portal vein thrombosis. Group IV: Renal Failure Six patients had renal failure before the onset of pancreatitis. This group included three men and three women, aged twenty-seven to sixty-six years (average fifty). Renal disease included severe nephrosclerosis in two patients, chronic pyelonephritis in two patients, end stage kidneys in one patient and chronic homograft rejection in one patient. Four patients had had renal failure for one to three months and two patients for one to three years. The patient with chronic homograft rejection was receiving immunosuppressive therapy; one patient had hyperparathyroidism, renal failure, and acute pancreatitis. The cause of renal failure was undetermined in the other four patients. No patient in this group had a clinical diagnosis of acute pancreatitis. Three patients had mild abdominal pain but no significant abdominal tenderness. Two patients had nausea and vomiting believed secondary to uremia. Serum amylase was elevated in all five patients in whom it was measured. In one patient serial amylase determinations decreased from 1,800 to 550 units/dl. No patient had clinical or pathologic evidence of previous pancreatitis, and no patient in this group underwent operation. One patient had generalized enterococcal peritonitis but no abscess. Five patients had severe pulmonary congestion, and three of these patients also had bronchopneumonia. Comments Only 57 per cent of the patients studied had a diagnosis of acute pancreatitis before death, yet all had severe acute pancreatitis at autopsy. The apparent reasons for diagnostic failure included (1) an altered state of consciousness in the alcoholic patients, making abdominal examination unreliable; (2) a restricted diagnostic effort due to known malignancy and an unremarkable abdominal examination; and (3) the unreliability of the serum amylase determinations and abdominal symptoms and findings in the patients with renal failure. Tofler and Spiro [IO] reported on nine patients with fatal pancreatitis who presented in coma and shock but had no abdominal
494
pain. Gillespie [ll] similarly
found diagnostic failure in 29 per cent of patients who died from acute pancreatitis. More recently, Bourke [12] noted that 41 per cent of patients who died from pancreatitis did not have an antemortem diagnosis and that the overall mortality rate from acute pancreatitis increased significantly when autopsy findings as well as clinical reports were considered. Thus, patients with severe acute pancreatitis do not always have typical or striking abdominal complaints or findings. Serum amylase was an accurate diagnostic tool. It was significantly elevated in twenty-nine of thirtytwo (90 per cent) patients in whom it was measured. However, there was no correlation between serial amylase levels and the severity or course of the disease. In fifteen patients with severe acute pancreatitis the serum amylase was normal, and in six patients the amylase was decreasing at the time of death. The amylase level was increasing in only five patients at the time of death. Thus, in contrast to other diseases in which decreasing enzyme levels often indicate improvement, a decrease in serum amylase does not necessarily indicate improvement in acute pancreatitis. Only three patients had had previous clinical attacks of pancreatitis. Four other patients had pathologic changes of chronic as well as acute pancreatitis. The patients with previous pancreatitis had alcoholic and biliary related pancreatitis wherein persistence of the offending agent contributed to recurrence. Thus, thirty-seven of these forty patients died during their first clinical attack of pancreatitis. Ranson and Pasternack [B] found that patients with “severe” pancreatitis had significantly fewer episodes of pancreatitis than those with “mild” pancreatitis, and the Medical Research Council [13] reported no deaths in patients with previous pancreatitis. Hence, the first attack of this disease deserves special attention and intensive care. Opinions differ regarding the role of operation in acute pancreatitis. Only one patient in this series who died without an operation might have survived if his pancreatic abscess had been drained. Operation failed in four patients with biliary tract disease and pancreatitis because of incomplete biliary decompression; two patients had common duct stones without biliary intubation, and two had cholecystostomies that functioned only partially. Patients with biliary tract disease and pancreatitis should have common duct stones removed if their general condition and local findings permit; otherwise intubation of the common duct is a suitable alternative. Cholecystostomy may not be dependable when bil-
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Lethal Pancreatitis
iary tract disease is associated with acute pancreatitis. Intraabdominal sepsis played a major role in lethality in fourteen patients. The incidence of intraabdominal infection was higher in patients with (55 per cent) than in those without biliary tract disease (28 per cent). Three patients with biliary tract disease and peripancreatic sepsis had antemortem bile cultures, and in each patient the offending organism was present in bile. Thus sepsis was more important in the lethality of pancreatitis in the presence of biliary tract disease, and bile cultures provided important information regarding antibiotic selection. Gregg [14] also found that patients with biliary tract disease and pancreatitis frequently had infected bile and that pancreatic juice obtained endoscopically contained the same microorganisms that were present in bile. Acute renal failure due to acute tubular necrosis occurred during the course of pancreatitis in sixteen patients. Although glomerulitis has been reported [15] in patients with relapsing pancreatitis, no patient in this series had a glomerular lesion. Although the renal tubular lesion is reversible, the mortality in patients with acute pancreatitis and acute renal failure has been reported as high as 95 per cent [3]. The occurrence of renal failure may not only reflect the severity of pancreatitis but may also aggravate the pathologic process within the pancreas. Reduced tubular reabsorption of protein has been demonstrated in patients with acute pancreatitis causing increased urinary excretion of amylase. Urinary excretion of the proteolytic and phospholipolytic enzymes that are critical in the local pathologic process may also be increased. When renal function is compromised and enzyme excretion reduced, an important defense mechanism could be impaired. All sixteen patients with acute renal failure and five of the six patients with chronic renal failure had severe pulmonary congestion pathologically. Three patients with alcoholic, one patient with biliary, and one patient with idiopathic pancreatitis had severe pulmonary congestion without renal failure. Thus the development of severe pulmonary lesions in patients who died with severe pancreatitis was more common in patients with (95 per cent) than in those without (27 per cent) renal failure. Warshaw et al [16] suggested that respiratory failure and pulmonary congestion in patients with pancreatitis is due to damage of the alveolar-capillary membrane and that the lesion improves with intubation and controlled ventilation with positive end-expiratory pressure. There was no correlation between the presence of severe pulmonary congestion and the presence of a septic
Volume 137, April 1979
BILIARY
IDIOPATHIC
ALCOHOLIC
RENAL
Figure 4. Lethal mechanisms in patients with acute pancreatttis. The stippled bars represent peripancreatic sepsis, the white bars represent renal iailure, and the black bars respiratory failure.
process in or around the pancreas. Hence, the development of respiratory failure alone in patients with acute pancreatitis is not an indication for pancreatic exploration. Other findings that contributed significantly to mortality were present in thirteen patients. Of the six patients with significant hepatic parenchymal lesions, three had biliary tract disease and cholangitis, and three were alcoholics with cirrhosis. Three patients had nonpancreatic peritonitis caused by peritoneal dialysis, a perforated gastric ulcer, and “spontaneous” enterococcal peritonitis (in a patient with chronic renal failure). Three patients had leg vein thrombi with multiple pulmonary emboli, and two patients died after massive hemorrhage from the pancreas. The lethal mechanisms in patients with biliary tract disease differed from those with alcohol-related pancreatitis. (Figure 4.) The incidence of local sepsis was greater (55 versus 24 per cent) but the incidence of renal failure (27 versus 70 per cent) and respiratory failure (36 versus 92 per cent) smaller in the patients with biliary tract disease than in the patients with alcoholic pancreatitis. The incidence of these lethal mechanisms in patients with idiopathic pancreatitis appeared intermediate between these two groups, whereas patients with chronic renal failure had a low incidence of local sepsis and a high incidence of respiratory failure. Thus, although the overall mortality in acute pancreatitis may be the same for different types of patients, the lethal mechanisms and course of the disease depends to some extent on the underlying etiologic factors. Conclusions
Acute pancreatitis may be lethal because of diagnostic failure and a consequent lack of appropriate
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and Brooks
therapy. Therapy should minimally include adequate parenteral fluid support, gastric suction, and close observation. Serum amylase should be measured if the slightest suspicion of pancreatitis exists and should possibly be measured as a part of the routine chemical battery in patients seen in the emergency room. Amylase is not a useful prognostic indicator, and serial amylase determinations do not help monitor the course of the disease. The first attack of pancreatitis carries the greatest risk of death. Antibiotics appear most important in patients with pancreatitis associated with biliary tract disease. Operations carried out in patients with pancreatitis and biliary tract disease should provide adequate biliary decompression; cholecystostomy may not be sufficient. Impairment of renal and pulmonary function are the most important serious complications of acute pancreatitis but are potentially reversible. Neither complication indicates the presence of a septic pancreatic process or the need for pancreatic exploration. Summary
Clinical and pathologic information from forty patients who died with pathologically severe acute pancreatitis was correlated. Patients were classified into four etiologic groups: those with biliary pancreatitis (11 patients), alcoholic pancreatitis (13 patients), idiopathic pancreatitis (10 patients), and renal failure (6 patients). Antemortem diagnosis was made in only 57 per cent of the patients studied. The diagnosis was determined before death in 91 per cent of the biliary patients but in none of the renal patients. Thirty-seven patients died from their first clinical attack of pancreatitis. Operation in patients with biliary pancreatitis failed when biliary decompression was not provided. Peripancreatic sepsis was a frequent lethal mechanism in patients with biliary pancreatitis, but renal and respiratory failure were
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more common in patients titis.
with alcoholic pancrea-
References 7. Gliedman ML, Bolocki H, Rosen RG: Acute pancreatitis. Curr Probl Surg 1970. 2. Lawson DW, Daggeti WM, Cireffa JM, Cony RJ, Bartlett MK: Surgical treatment of acute necrotizing pancreatitis. Ann Surg 172: 605, 1970. Frey C: me operative treatment of pancreatitis. Arch Surg 98: 406, 1969. Peterson LM, Collins JJ, Wilson RE: Acute pancreatitis occurring after operation. Surg Gynecol Obstet 127: 23, 1968. Norton L. Eiseman B: Near total pancreatectomy for hemorrhagic pancreatitis. Am J Surg 127: 191, 1974. Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC: Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 139: 69, 1974. 7. Ranson JHC, Rifkind KM, Turner JW: Prognostic signs and nonoperative peritoneal lavage in acute pancreatitis. Surg Gynecol Obstet 143: 209, 1976. 8. Ranson JHC, Pasternack BS: Statistical methods for quantifying the severity of clinical acute pancreatitis. J Surg Res 22: 79, 1977. 9. Jacobs ML, Daggett WM, Ciretta JM, Vasu MA, Lawson DW. Warshaw AL, Nardi G, Bartlett MK: Acute pancreatitis: analysis of factors influencing survival. Ann Surg 185: 43, 1977. 10. Tofler AH, Spiro HM: Shock or coma as the predominant manifestation of painless acute pancreatitis. Ann intern Med 57: 655, 1962. 11. Gillespie WJ: Observations on acute pancreatitis. JR Co// Surg Edinb 20: 36, 1975. 12. Bourke JB: Incidence and mortality of acute pancreatitis. Br Med J2: 1668, 1977. 13. Welbourn RB, Armitage P, Giimore OJA, MacKay C, Trapnell JE, Williamson RCN, Cox AG: Death from acute pancreatitis. Lancet 2: 632, 1977. 14. Gregg JA: Detection of bacterial infection of the pancreatic ducts in patients with pancreatitis and pancreatic cancer during endoscopic cannulation of the pancreatic duct. Gastroenterol73: 1005. 1975. 15. Dickmeyer, JP, Wolfson W, Kowell A, Dornfeld L: Reversible crescentic glomerulonephritis following an acute exacerbation of chronic relapsing pancreatitis. Arch lntem Med 137: 1065.1977. 16. Warshaw AL, Lesser PB, Rie M, Cullen DJ: The pathogenesis of pulmonary edema in acute pancreatitis. Ann Surg 182: 505, 1975.
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