Long Peritoneal Lavage Decreases Pancreatic Sepsis in Acute Pancreatitis

JOHN H. C. RANSON, B.M., B.CH., and RUSSELL S. BERMAN, B.S. Late infection of devitalized pancreatic and peripancreatic tissue has become the major cause of morbidity in severe acute pancreatitis. Previous experience found that peritoneal lavage for periods of48 to 96 hours may reduce early systemic complications but did not decrease late pancreatic sepsis. A fortunate observation led to the present study of the influence of a longer period of lavage on late sepsis. Twenty-nine patients receiving primary nonoperative treatment for severe acute pancreatitis (three or more positive prognostic signs) were randomly assigned to short peritoneal lavage (SPL) for 2 days (15 patients) or to long peritoneal lavage (LPL) for 7 days (14 patients). Positive prognostic signs averaged 5 in both groups but the frequency of five or more signs was higher in LPL (71%) than in SPL (47%). Eleven patients in each group had early computed tomographic (Cl') scans. Peripancreatic fluid collections were shown more commonly in LPL (82%) than in SPL (54%) patients. Longer lavage dramatically reduced the frequency of both pancreatic sepsis (22% LPL versus 40% SPL) and death from sepsis (0% LPL versus 20% SPL). Among patients with fluid collections on early CT scan, LPL led to a more marked reduction in both pancreatic sepsis (33% LPL versus 83% SPL) and death from sepsis (0% LPL versus 33% SPL). The differences were even more striking among 17 patients with five or more positive prognostic signs. In this group the incidence of pancreatic sepsis was 30% LPL versus 57% SPL and of death from sepsis 0% (LPL) versus 43% (SPL) (p = 0.05). In these patients, overall mortality was also reduced (20% LPL versus 43% SPL). When 20 patients treated by LPL were compared with 91 other patients with three or more positive prognostic signs who were treated without lavage or by lavage for periods of 2 to 4 days, the frequency of death from pancreatic sepsis was reduced from 13% to 5%. In those with five or more signs, the incidence of sepsis was reduced from 40% to 27% (p = 0.03) and of death for sepsis from 30% to 7% (p = 0.08). These findings indicate that lavage of the peritoneal cavity for 7 days may significantly reduce both the frequency and mortality rate of pancreatic sepsis in severe acute pancreatitis.

From the Department of Surgery, New York University School of Medicine, New York, New York

T n HE THERAPEUTIC VALUE of peritoneal lavage in patients with acute pancreatitis has been contro-

versial. Controlled clinical trials of lavage carried Presented at the 101st Annual Meeting of the Southern Surgical Association, Hot Springs, Virginia, December 3-6, 1989. Address reprint requests to John H. C. Ranson, M.D., Professor of Surgery, New York University Medical Center, 530 First Avenue, New York, NY 10016.

out for periods of 2 to 4 days have produced conflicting results.'-5 Our own clinical experience has been that the institution of lavage in patients with severe acute pancreatitis is frequently followed by a dramatic improvement in cardiovascular and respiratory function. Use of lavage for periods of 2 to 4 days appeared to be associated with a marked reduction in early death from this disease.6 Unfortunately the overall hospital mortality rate was only slightly reduced. The reason appeared to be that lavage did not change the frequency or mortality of late infection in devitalized pancreatic and peripancreatic tissue. A chance observation in July 1979 raised the possibility that a longer period of peritoneal lavage might reduce the frequency of late pancreatic sepsis in severe acute pancreatitis. The initial patient had severe alcohol-associated acute pancreatitis with seven positive prognostic signs. We had previously limited the period of peritoneal lavage to a maximum of 4 days. However, due to a misunderstanding, this patient was treated by lavage of the peritoneal cavity for 8 days. The patient's management was complicated by the fact that he and his family adamantly refused blood transfusion for religious reasons. He eventually died on the 53rd hospital day due to acute bacterial endocarditis. At autopsy his pancreatitis appeared healed with no pancreatic fluid collection or infection. Because, up to that time, all patients with more than six positive prognostic signs had developed pancreatic sepsis,7 the next patient who had similar signs received peritoneal lavage for 7 days. This second patient had severe gallstone-associated pancreatitis with eight positive prognostic signs. She recovered completely with no pancreatic sepsis or persistant cyst. The present study was, therefore, initiated to evaluate whether a longer period of peritoneal lavage might indeed be effective in reducing late pancreatic sepsis in patients with severe acute pancreatitis.

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Materials and Methods

TABLE 2. Features Used to Classify Findings on

Patients Patients with a diagnosis of acute pancreatitis who received their initial treatment at New York University Medical Center, Bellevue, or the Manhattan Veterans' Administration hospitals between September 1979 and October 1988 were eligible for study. The severity of acute pancreatitis was estimated by the previously described prognostic signs listed in Table 1 .8 Only those who had three or more positive signs were considered. Five patients in whom the diagnosis of acute pancreatitis was made at laparotomy during the first 48 hours of treatment were excluded because earlier experience has indicated that early abdominal surgery influenced the risk of pancreatic infection.6' This report describes 39 other patients with three or more positive prognostic signs whose early management included peritoneal lavage. The diagnosis of acute pancreatitis was confirmed by computed tomographic (CT) studies and operative or autopsy findings in 30 patients. In nine patients the diagnosis rested on clinical findings and elevated amylase measurements. In two of these patients, as described below, early CT findings and the clinical course raised doubt about the diagnosis of severe pancreatitis. In 28 patients the pancreas and peripancreatic retroperitoneum were imaged by CT during the first 10 days of treatment. In 23 patients this study was obtained within 48 hours of admission. The findings on CT were graded according to the features listed in Table 2.9 The patient characteristics are listed in Tables 3 and 4, which also include the two pilot patients treated before the study period. In the overall group, there were 17 women and 22 men. Their ages ranged from 22 to 77 years (mean, 53.1 years). Pancreatitis was associated with alcohol abuse in 20 patients. Eleven patients had biliary stones, three of whom also consumed excessive amounts of alcohol. Three patients had hyperlipoproteinemia without alcohol abuse and, in eight, the cause of pancreatitis was undetermined. TABLE 1. The I11 Early Objective Signs Used to Classify the Severity of Pancreatitis At admission

Age

more

or

diagnosis

than 55 years

White blood cell count Blood

glucose

more

more

mm

than 200 mg%

Serum lactic dehydrogenase Serum

than 16,000/cu

more

than 350 lUlL

glutamic oxaloacetic transaminase

more

than 250

Frankel units%

During initial 48 hours Hematocrit fall greater than 10 percentage points Blood

urea

nitrogen rise

more

than 5

mg%/,

Serum calcium level less than 8 mg%

mmHg mEq/L Estimated fluid sequestration more than 6000

Arterial P0

709

less than 60

Base deficit greater than 4

mL

Sigma-

Early Computed Tomography CT Grade A Pancreas and peripancreatic tissues radiographically normal. B Pancreatic enlargement alone without inflammatory changes in peripancreatic tissues. C Inflammatory changes confined to the pancreas and peripancreatic fat. D One peripancreatic fluid collection. E Two or more peripancreatic fluid collections.

Treatment All patients were initially treated by nasogastric suction, intravenous fluids, and standard supportive measures. Broad-spectrum antibiotics were administered to all patients. Catheters for peritoneal lavage were introduced into the peritoneal cavity using a formal, 4- to 5-cm incision carried out under local infiltration anesthesia. Lavage was initiated within 48 hours of hospital admission. The fluid used was an approximately isotonic balanced electrolyte solution containing 15 gIL of dextrose (Dianeal®, Baxter Health Care Corp., Deerfield, IL). Eight milliequivalents of potassium, 1000 USP units of heparin, and 250 mg of ampicillin were added to each 2 L of fluid. An alternative antibiotic was used if a history of penicillin allergy was present. Hypertonic fluid with 42.5 gIL of dextrose was used for part of the lavage in some patients. In general 2 L of lavage fluid were run into the peritoneal cavity under gravity during a 15-minute period. It was left intraperitoneally for approximately 30 minutes and then drained out by gravity. This cycle was usually repeated hourly. In some patients smaller volumes of fluid and a shorter cycle were used because of exacerbation of respi'ratory distress caused by increased abdominal distension. Patients were arbitrarily assigned to short lavage for 2 days or to long lavage for 7 days according to whether their chart number was even or odd. Excluded patients. Eight patients managed by nonoperative peritoneal lavage during the study period are excluded from the formal study group. Three received short lavage and five received long lavage. Three patients (two short and one long lavage) who died within the first 5 days of treatment from respiratory or cardiovascular failure are excluded because they did not survive long enough to evaluate whether late pancreatic sepsis would develop. Two short lavage patients died of respiratory failure on days 3 and 5 of treatment. Autopsy in one confirmed severe pancreatitis without sepsis but was denied in the second patient. The long lavage patient died of cardiovascular collapse despite support that included intra-aortic balloon counterpulsation. Laparotomy on day 4 and autopsy the next day showed severe pancreatitis without infection. Two patients were excluded because, despite having more than three positive prognostic signs, they did not

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RANSON AND BERMAN

Ann. Surg. * June 1990

TABLE 3. Short Lavage Patients

Age

Sex

59 64 76 51 76 68 70 41 65 43 22 67 57 37 32

F F F M F F M M F M M M M M M

Etiology

Positive Prognostic Signs

GB GB

Days

CT Grade

10 8 8 5 5 5 5

? GB & ETOH GB GB ? ETOH GB & ETOH ? ETOH ? ETOH LIPID ETOH

Abscess or Pseudocyst

E E

Resp.

ICU

Hosp.

Abscess Abscess Abscess

18 23 37 0 31

Pseudocyst Abscess

1 24 0 0 3 0 35 0 0 0

56 24 74 6 35 9 93 3 5 90 4 67 3 10 6

56 24 118 70 87 79 93 35 23 113 21 101 14 25 25

4 2 2

5 3 10

5 3 71

-

4 4 4 4 4

C D C C D D D

3 3 3

C C

Abscess Abscess

Outcome

Dead-sepsis Dead-sepsis Alive p drainage Alive Alive Alive p drainage Dead-sepsis Alive Alive Alive p drainage Alive Alive p drainage Alive Alive Alive

Excluded Patients 47

36 62

M M M

ETOH ETOH GB & ETOH

6 5 5

E D A

-

Dead-early respiratory failure Dead-early respiratory failure Alive-CBD stone ? pancreatitis

GB, biliary stones; ETOH, alcohol; LIPID, hyperlipidemia.

appear to have severe pancreatitis. Both had a normal pancreas on CT scan within 48 hours of admission. The short lavage patient eventually was found to have a common duct stone and may have had cholangitis with ele-

vated amylase levels. The long lavage patient completed only 6 days of lavage because of mild clinical and CT findings. Both recovered without pancreatic complications.

TABLE 4. Long Lavage Patients

Age

Sex

Etiology

Positive Prognostic Signs

36 36 56

F F M M F M F F M M F M F F

GB ETOH ETOH ETOH GB ETOH ETOH ? ETOH ? LIPID ? LIPID ETOH

8 6 6 6 6 5 5 5 5 5 4 3 3 3

41

60 56 59 64 51 68 64 29 36 36

Days

CT Grade E E D E D

Abscess or Pseudocyst

Resp.

ICU

Hosp.

54

0 28 0 0 0 0

66 76 8 10 8 81 9 22 14 31 9 9 7 7

119 110 10 42 71 130 84 58 59 31 18 93 15 26

6 44

13 53

97 53

37 113

37 113

37 113

5 13 0

5 23

5 51 23

Abscess Abscess

E D E

Abscess

D C C

Pseudocyst

0 0 0 5 86 0 4

Outcome

Alive p drainage Alive p drainage Alive Alive Alive Dead-late pneumonia Alive Alive p drainage Alive MI CABG Dead CVA Alive Alive p drainage Alive Alive

Excluded Patients 69 36

F M

GB ETOH

7

53 55

M F

ETOH ?

7 6

51 77 66

M F M

ETOH GB ETOH

6 5 4

8 E E

Abscess -

A

GB, biliary stones; ETOH, alcohol; LIPID, hyperlipidemia.

7

Alive-before study Dead-before study endocarditis Dead-sepsis long by choice Dead-brain injury long by choice Dead-early-CV failure Alive-long by choice Alive-6 day lavage ? severe pancreatitis

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LONG PERITONEAL LAVAGE IN PANCREATITIS

TABLE 5. Comparability ofPatient Groups Study Group Patients

Lavage

Short

Long

Short

Long

Patients Mean age (range) Percentage of women Percentage of biliary Mean positive prognostic signs Percentage of .5 positive signs Percentage of CT grade E Percentage of CT grades D

15 55 (22-76) 40% 27% 5 47% 18% 36%

14 49 (29-68) 57% 14% 5 71% 45% 36%

18 54 (22-76) 33% 22% 5 56% 21% 36%

21 52 (29-77) 52% 19% 5.4 76% 50% 29%

Finally three long lavage patients are excluded from the study group because their chart number should have resulted in a short period of lavage. They received 7 days of lavage because this was believed to be indicated by the severity of their clinical course. The two pilot patients are clearly excluded from the study group but are included in the overall reported experience. Statistical methods. Data were analyzed using the Fisher's Exact Test using the Statgraphics Statistical Graphics System® (Gerard E. Dallal, Malden, MA) method of calculation. Results Comparability of Patient Groups In Table 5 patients receiving short lavage are compared to those receiving long lavage. Among patients in the study group, those receiving long lavage were slightly younger, included more women, and a smaller proportion with gallstones as the only identified etiology. The severity of pancreatitis as estimated by the mean number of positive prognostic signs was equal in the two groups. However the percentage of patients with five or more positive signs in the long lavage group was 71% compared to only 47% in those treated by short lavage. Eleven patients in each study group underwent early CT examination. Forty-five TABLE 6. Study Group Results

Patients Long lavage Patients Deaths Abscess Abscess death Short lavage Patients Deaths Abscess Abscess death *

p

All Patients

=

0.051.

All

3-4 Signs

.5 Signs

per cent of those studied in the long lavage group had the most severe, grade E, CT findings, compared to only 18% in the short lavage group. Comparison of the overall patients reported in the two treatment groups show similar

findings.

Morbidity The morbidity of individual patients is shown in Tables 3 and 4 and is summarized in Tables 6 and 7. Among study group patients the incidence of pancreatic sepsis was 21% after long lavage, compared to 40% after short lavage. Furthermore, while 20% of patients in the short lavage group died of pancreatic sepsis, there were no deaths from this cause in patients receiving 7 days of lavage (p = 0.12). The differences were most marked in those patients who had five or more positive prognostic signs or who had early CT scans showing peripancreatic fluid collections (grade D or E). In patients with five or more positive prognostic signs, long lavage reduced the incidence of late pancreatic sepsis from 57% to 30% and of death from sepsis from 43% to zero (p = 0.051). In patients with CT scans grade D or E, long lavage reduced the incidence of late pancreatic sepsis from 83% to 33% (p = 0.083) and of death from sepsis from 33% to zero (p = 0.14). The sample sizes are small and these differences do not achieve statistical significance. One patient in each group developed a late pancreatic pseudocyst without sepsis. Each recovered after cyst drainage procedures.

CT Grade D

TABLE 7. Total Experience

or E

All

Patients 14 2 (14%)

3 (21%) 0 15 3 (20%) 6 (40%) 3 (20%)

4

0 0 0 8 0 2 (25%) 0

10 2 (20%) 3 (30%) 0* 7 3 (43%) 4 (57%) 3 (43%)*

9 0 3 (33%) 0 6 2 (33%) 5 (83%) 2 (33%)

Long lavage Patients Deaths Abscess Abscess death Short lavage Patients Deaths Abscess Abscess death

21 6 (29%) 4 (19%) 1 (4.8%)

18 5 (28%) 6 (33%) 3 (17%)

3-4 Signs 5 0 0 0

8 0 2 (25%) 0

.5 Signs

CT Grade D or E

16 6 (38%) 4 (25%) 1 (6%)

11 2 (18%) 4 (36%) 1 (9%)

10 5 (50%)

8 4 (50%) 5 (63%) 2 (25%)

4 (40%) 3 (30%)

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RANSON AND BERMAN

There were two deaths in the long lavage group that were not related to pancreatic sepsis. The first of these was an alcoholic man with five positive prognostic signs. He had underlying severe chronic obstructive pulmonary

disease. He responded well to treatment of his pancreatitis but had persistent pulmonary insufficiency that led to tracheostomy and long-term ventilatory support. He was eventually transferred to a pulmonary care unit. At that time, 5 weeks after admission, he tolerated oral feedings and had no clinical or CT evidence of pancreatitis. He was eventually weaned from the respirator but died on the 130th hospital day from recurrent pneumonia. The second patient was a 68-year-old man with diabetes, hypertension, chronic renal insufficiency, and peripheral vascular disease that had led to a previous lower extremity amputation. He suffered a major stroke and died on the 31 st hospital day. Computed tomography was not available at the time of his treatment and autopsy was denied. There was, however, no clinical evidence to suggest pancreatic sepsis at the time of death. Because of these two deaths, the overall mortality rates in the two groups were similar. It should be noted, however, that in patients with five or more positive prognostic signs, the overall mortality rate was reduced to 20% after long lavage compared to 43% in the short lavage group. All deaths in the short lavage group were related to pancreatic sepsis. The periods ofventilator respiratory support, intensive care, and hospital stay are also shown in Tables 3 and 4. No clear differences between the groups were apparent. The morbidity and mortality of all patients treated initially at our institution during the study period by peritoneal lavage without laparotomy is summarized in Table 7. It includes three patients who should have been assigned to short lavage but who received long lavage because this was considered indicated by the responsible physician. One of these patients, who had very severe pancreatitis, complete renal shut down and brittle diabetes, died after pancreatic sepsis on the 37th hospital day. Three patients excluded from the study group died during the first 5 days due to cardiorespiratory failure without evidence of pancreatic sepsis. As in the study group patients, long lavage was associated with a dramatic reduction in pancreatic sepsis and in deaths from this cause. Again the improvements were most marked in patients with five or more positive prognostic signs and in those with severe pancreatitis by CT examination. In these categories of patients, long lavage was associated with reductions not only in sepsis and death from sepsis but also with substantially reduced overall mortality. Discussion Evaluation of the treatment of patients with acute pancreatitis is difficult because of wide variation in the natural history of this disease or group of diseases and because

Ann. Surg. * June 1990

only small numbers of patients with severe pancreatitis receive their primary treatment at any single institution. Improvements in supportive care and in the management of specific complications appear to have resulted in reduced overall mortality rate.2"0 However no specific measure has been convincingly shown to prevent complications or reduce their virulence. Interest in the possibility that peritoneal lavage might benefit patients with acute pancreatitis was initiated by an observation by Wall" in 1965. He initiated peritoneal dialysis in three patients judged to have severe acute pancreatitis, two of whom had frank renal failure. Marked clinical improvement was noted after the initiation of peritoneal dialysis and two patients survived. After this a number of reports appeared, all of which suggested that peritoneal lavage was of benefit to patients with severe acute pancreatitis. 12-15 In 1985 Reynaert16 reviewed 203 reported patients treated by peritoneal lavage for severe pancreatitis with an overall mortality rate of 22.6%. Unfortunately the criteria used to identify patients with severe acute pancreatitis varied considerably. Furthermore the timing and duration of peritoneal lavage were not standardized and, in some patients, placement of lavage catheters was combined with formal intra-abdominal surgical procedures. In 1976 we2 reported a small controlled clinical trial of peritoneal lavage that suggested that morbidity was reduced by this measure. In 1980 Stone3 reported a larger controlled trial in which 29 of 34 patients treated with lavage showed "a decided improvement in the overall condition" compared to only 13 of 36 patients treated without lavage. Eleven patients in this study underwent formal early laparotomy. Further interpretation of this group is also clouded by the fact that 17 nonlavage group patients were later transferred to lavage therapy. However mortality in the final group of 51 patients treated with lavage was 15.7% compared to 31.6% in those treated without lavage.3 Two other small controlled clinical trials4'5 and a large cooperative study' found no benefit from peritoneal lavage in severe acute pancreatitis. The large cooperative trial included 91 patients, 45 of whom received peritoneal lavage for 3 days. No difference was found between the lavage and nonlavage groups in overall mortality nor in the cause or timing of death. These findings may have been influenced by the fact that 34 of the 46 nonlavage patients underwent diagnostic lavage of the peritoneal cavity for prognostic assessment. Furthermore patients in the study were cared for in 24 different hospitals that may have had differing patterns of treatment. Our own initial experience with peritoneal lavage for the management of severe acute pancreatitis was summarized in 1978.6 At that time the course of 103 patients with three or more positive prognostic signs was reviewed.

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LONG PERITONEAL LAVAGE IN PANCREATITIS

This included 24 patients whose early management included laparotomy. Twenty-four of the one hundred three patients had received lavage of the peritoneal cavity for periods of 2 to 4 days. A number of observations were made at that time. First overall mortality was not affected by lavage but was influenced by early laparotomy. It was 66.7% in six patients who underwent laparotomy and placement of lavage catheters alone and 66.7% in 18 patients who underwent other early operative procedures. The mortality rate was 16.7% in 18 patients who underwent lavage using catheters introduced under local anesthesia and 16.4% in 61 patients who received standard nonoperative treatment without peritoneal lavage. Peritoneal lavage did, however, appear to influence the cause and timing of death. No lavaged patient died during the first 10 days of treatment, while 10 of 22 (45%) deaths in nonlavaged patients occurred during this early period, primarily as a result of cardiovascular or respiratory failure. Almost all deaths in lavaged patients were due to late pancreatic sepsis. It was our conclusion that peritoneal lavage for periods of 2 to 4 days was a valuable adjunct to the management of early cardiovascular and respiratory complications of severe acute pancreatitis but did not influence the occurrence of the sequellae of pancreatic and peripancreatic necrosis, specifically sepsis. It was also noted at that time that in clinical reports of acute pancreatitis published during the period 1962 to 1974, death had been attributed to shock or pulmonary complications in 66% to 80% of patients17-2' and most such deaths had occurred during the first 14 days of treatment.2123 Death was due to pancreatic sepsis in 14% to 35% of cases,'8"19'2 and these deaths usually occurred after of 450 the first 2 weeks of treatment. 7,2123 In our seriessfS patients reported in 1978, death was due to cardiovascular, respiratory, or cerebrovascular insufficiency in 10 patients (32%). These deaths occurred on days 1 to 16 (median, day 5). Twenty-two deaths (68%) were associated with intra-abdominal sepsis and occurred on days 8 to 131 (median, day 23). It was clear that, with improvements in early supportive care of patients and possibly the use of peritoneal lavage, the major cause of morbidity and death in acute pancreatitis had become infection of devitalized pancreatic and peripancreatic tissue.24 As described above the present study was stimulated by a chance observation in a patient with seven positive prognostic signs who received 8 days of peritoneal lavage in 1979. He did not develop pancreatic sepsis, although this was anticipated on the basis of earlier experience. Long lavage in a second patient with eight positive signs suggested that the initial observation may not have been due to chance alone. Accordingly the present controlled trial was initiated to evaluate whether 7 days of peritoneal lavage reduced the frequency or severity of late pancreatic sepsis compared to shorter lavage for 2 days.

713

Patient Selection

There is no satisfactory method for the precise identification at the outset of disease of those patients who will develop pancreatic infection. A number of tests, such as serum ribonuclease, C-reactive protein or Alpha- 1 macroglobulin levels, or the use of contrast-enhanced CT studies, have been reported to be valuable in recognizing pancreatic or peripancreatic necrosis.25 These tests are, in general, of diagnostic rather than prognostic value. They are not, in general, helpful in identifying, during the first 2 days of illness, those patients who may later develop pancreatic necrosis or infection. The prognostic signs listed in Table 1 were developed to identify the overall risk of complications and death in acute pancreatitis. Although not specifically designed for this purpose, there is a relationship between the number of signs present and the occurrence of late pancreatic sepsis.7 Among 260 patients with 0 to 2 positive signs, 2.7% developed pancreatic sepsis and 0.4% died of this cause. Of 61 patients with more than three positive signs, 34% developed pancreatic infection and 25% died of sepsis.7 The risk of infection rises with increasing numbers of positive signs. Although the signs were subsequently refined to more accurately identify the risk of late sepsis,26 the signs listed in Table 1 were used to select patients for the present study. Any patient with three or more positive signs was eligible for inclusion. Only 39 patients have been treated by nonoperative peritoneal lavage during a 9-year period. It may be noted that in our earlier report 65% of patients who had more than three positive prognostic signs had only three or four positive signs. In the present group of patients only 33% of those treated by lavage had only three or four positive signs. This reflects a reluctance by primary physicians to submit patients with pancreatitis of only moderate severity to peritoneal lavage in view of its uncertain benefits. The introduction of CT scanning has, for the first time, permitted noninvasive imaging of the pancreas and peripancreatic retroperitoneum. We have previously reported that there is a relationship between early CT appearances as categorized in Table 2 and the risk of late sepsis.9 The risk of late sepsis was zero in patients with grade A or B findings, 11.8% in grade C, 16.7% in grade D, and 60.9% in grade E. Computed tomography was not available throughout this study but early CT findings are reported when available. It is possible that the addition of contrast enhancement may improve the value of CT scanning in predicting late sepsis.27 However current data indicate only that it is of value in recognition, rather than prediction, of pancreatic necrosis.

Timing and Technique of Peritoneal Lavage Peritoneal lavage has been started as soon as the diagnosis of severe acute pancreatitis is made and not more

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RANSON AND BERMAN

than 48 hours after the initiation of treatment in all patients. For this reason patients transferred to our institution after initial therapy elsewhere are not included in the present report. The catheter for lavage is introduced by cutdown to the peritoneum under local anesthesia to reduce the risk of visceral injury. No such injury has occurred in this series of patients. Because formal laparotomy increases the risk of late sepsis,6'7 patients who underwent early laparotomy are excluded from the present study. Hazards of peritoneal lavage include increased respiratory distress due to abdominal distension by lavage fluid, hyperglycemia, and fluid overload if the lavage fluid is not returned from the peritoneal cavity. In some patients it was necessary to reduce the volume and timing of the lavage cycle to prevent undue respiratory compromise. In general the volume of peritoneal effluent exceeds that of the lavage fluid. If needed the tendency to a net fluid loss by the patient during lavage may be increased by using hypertonic lavage fluid. When such fluid is used, blood glucose levels must be carefully monitored. Two patients have developed late incisional hernias at the site of lavage catheter placement. However no other serious complications of lavage have been observed in the present group of patients.

Efficacy of Long Peritoneal Lavage As shown in Table 6, prolonged lavage of the peritoneal cavity for 7 days appears to result in a dramatic reduction in the occurrence of late pancreatic sepsis and of death from this cause when compared to short lavage for 2 days. The changes are most dramatic in patients with five or more positive prognostic signs or with CT scans of grades D or E. The number of patients in these groups is small and the differences do not achieve statistical significance. Because there were two deaths in the long lavage group that were not related to pancreatic sepsis, the overall mortality rate in the two groups is similar. It is, however, reduced from 43% to 20% in those with five or more positive prognostic signs. To evaluate further whether 7 days of lavage was really different from shorter lavage or no lavage at all, the frequency of pancreatic sepsis and of death from sepsis has been studied in 20 long lavage patients compared to that in 16 short lavage patients combined with previously reported patients with three or more positive prognostic signs who received nonoperative lavage for 2 to 4 days (17 patients) or were managed by standard nonoperative measures (58 patients).6 The findings in this analysis are shown in Figure 1. Patients who died during the first few days of treatment without developing sepsis are not included. The overall frequency of pancreatic sepsis in the two groups is approximately equal, although deaths from sepsis

Ann. Surg. - June 1990

LONG LAVAGE (LL) vs. ALL OTHER NONOPERATIVE TREATMENT (OT) POSITIVE PROGNOSTIC SIGNS .3 3-4 .5 40

40|

-

0% Abscess Death

30

4i

-

27

30

~~~2020~~~2 13

13

10 7 0

Treatment: Patients:.

LL OT LL OT LL OT 20 91 5 61 15 30 FIG. 1. The incidence of pancreatic sepsis and death from pancreatic sepsis in patients treated by 7 day lavage compared to all other nonoperative treatments. *p = 0.03.

were reduced from 13% to 5% by long lavage. These findings are, however, related to the relatively small number of long lavage patients with only three or four positive signs. In this group long lavage reduced the incidence of sepsis and death after sepsis from 13% and 5%, respectively, to zero. In patients with five or more positive signs, long lavage reduced the incidence of sepsis from 40% to 27% (p = 0.03) and of death from this cause from 30% to 7% (p = 0.08). The possible mode of action of peritoneal lavage is obscure, but its efficacy has usually been attributed to the removal of toxic materials in the peritoneal exudate in This is, in part, due to an obacute pancreatitis. servation in 1962 that hemodialysis did not improve survival in severe acute pancreatitis.30 The conclusion that peritoneal lavage acts by removing substances in the peritoneal exudate rather than dialysable material from the blood may not be appropriate. Studies of the peritoneal exudate found during acute pancreatitis have shown that this exudate contains many substances including amylase, lipase, phospholipase-A, protease-antiprotease complexes, trypsinogen, proteolytic pro-enzymes, prostoglandinlike activity, and kinin-forming enzymes.3'1-52 Furthermore the exudate has been shown to produce systemic hypotension,353753 histamine release,46 increased vascular permeability,38 and inhibition of hepatic mitochondrial function.54 While removal of such material might explain the dramatic immediate clinical improvement, which is sometimes observed after the initiation of peritoneal lavage, it is not clear why prolonged lavage should influence pancreatic or peripancreatic necrosis or the risk of infection of such devititalized tissue. Studies of peritoneal lavage in the treatment of pancreatitis in dogs,28'2955-57 guinea pigs,58 and rats59 have shown immediate improvement and reduced mortality.

'28-30

Vol.211 * No.6

LONG PERITONEAL LAVAGE IN PANCREATITIS

Furthermore lavage is reported to have reduced necrosis of the pancreas and peripancreatic fat in some of these experimental studies. 28,29,55,57,60 Experimental studies suggest that the addition of protease inhibitors to lavage fluid may increase the therapeutic efficacy of this measure.57'59'6' However in a controlled clinical trail including 55 patients treated by peritoneal lavage,62 no benefit was observed in those patients randomized to receive aprotinin in their lavage fluid. Evidence that periods of lavage that are longer than 2 to 4 days may be beneficial in human acute pancreatitis has been provided by studies from Germany. Gebhardt and Gall63 in 1981 advocated operative debridement of necrotic tissue combined with postoperative irrigation and sump drainage of the peritoneal cavity. Mortality, in their report, was 54% in 84 patients treated for necrotising pancreatitis without postoperative peritoneal irrigation compared to 37% when irrigation was added. Beger64 has also advocated operative debridement of necrotic tissue and combines this with postoperative lavage of the lesser omental sac. Lavage was continued for an average of 25 days (range, 5 to 90 days) and it was found that markedly elevated levels of pancreatic trypsin, amylase, and phospholipase-A were present in the lavage effluent for periods of 10 to 15 days after operation. If active pancreatic enzymes are released for similarly prolonged periods in unoperated patients, this may provide an explanation for the benefits of long lavage observed in the present study. In Beger's report, the overall mortality rate was 8.1% in 74 patients who had an average of 4.5 positive prognostic signs treated in this way. It is possible that these excellent results may, in large part, be due to prolonged peritoneal lavage. In contrast a controlled clinical trial in Finland65 compared laparotomy with postoperative pancreatic drainage to laparotomy and postoperative lavage of the lesser omental sac for a mean of 6.8 days (range, 4 to 12 days). Twenty-four patients were included in this study and had an average of 4.7 to 4.5 positive prognostic signs (Table 1). No reduction in the frequency of pancreatic infection was observed and the overall mortality rate was higher in the lavage group (36%) than in the drainage group (17%). It must be emphasized that all patients in this last study underwent laparotomy and that lavage was begun on day 4.1 ± 3.6 of symptoms. Infection of devitalized pancreatic and peripancreatic tissue has become the major cause of morbidity and death in severe acute pancreatitis. The present controlled clinical trial and retrospective comparison to earlier experience strongly suggests that lavage of the peritoneal cavity for periods of 7 days may dramatically reduce the incidence and mortality from pancreatic sepsis in severe acute pancreatitis. The number of patients treated by prolonged peritoneal lavage is not large. However the morbidity of

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long lavage is small and these findings indicate the need for wider evaluation of this therapeutic approach.

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DISCUSSION

The p value for significance of differences observed between the long and short lavage is 0.05, and for comparison between 7-day lavage and other nonoperative treatment the value is 0.03. If one is a purist, 0.01 p values with Fischer's t test may be preferable. However the general trend of the study seems, as you have seen from his data, to favor the 7-day lavage group. It would seem from just a guess that Dr. Ranson would need to double his experience and maintain the present trend to achieve the perfect nervana of 0.01 significance. I have trouble understanding the mechanics of how peritoneal lavage prevents retroperitoneal fat infection and necrosis, especially because the lesser sac is not opened. It might be relevant to note that in our cases of pancreaticoduodenectomy in which the retroperitoneum is widely exposed, the most common cause of death used to be hemorrhage from

DR. JOHN W. BRAASCH (Burlington, Massachusetts): I suspect that John Ranson asked me to discuss this paper because he knew my mind wouldn't be cluttered by an extensive experience with acute hemorrhagic pancreatitis, and he is correct. At least I have not had an extensive experience. The variations in test subjects, in which there are many in this study, have been controlled by Dr. Ranson by the use of his criteria, by the use of a grading system for CT scans, and by various patient exclusion criteria, which included early deaths, mild disease, or mistakes in patient treatment assignment. These exclusions do not appear to favor any one group, as far as I can tell, but they do make a reviewer's mind uneasy.