Serum phospholipase A2 and pulmonary changes in acute fulminant pancreatitis

Resuscitation, 10 (1982) 79-37 Elsevier Scientific Publishers Ireland Ltd.

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SERUM PHOSPHOLIPASE A, AND PULMONARY FULMINANT PANCREATITIS

T. SCHReDER’,

M. LEMPINEN,

E. KIVILAAKSO

CHANGES

and P. NIKKIb

*Second Department of Surgery and bDepartment of Anaesthesia, Central Hospital, Haartmaninkatu 4, 00290 Helsinki 29, (Finland) (Received

IN ACUTE

Helsinki University

March 22nd, 1982)

SUMMARY

Twenty-three patients with acute fulminant pancreatitis were studied. The diagnosis was confirmed at laparotomy in every case. Blood samples for the assay of phospholipase Az were collected for 14 days, and the pulmonary status of the patients was followed by monitoring the blood gases and the inspired oxygen fraction and studying a derived variable, the alveolar to arterial oxygen tension difference -the arterial oxygen tension ratio (A-aDO,/Pa&). The serum phospnolipase Az activities correlated with the changes in pulmonary function and with the outcome of the disease. Eight patients succumbed and they showed higher phospholipase Az activities and A-aD&/Paq ratios than the five patients who survived after major complications and the ten patients who survived without major complications. The results suggest that in acute fulminant pancreatitis serum phospholipase Az activity correlates with the severity of the pulmonary changes. Furthermore, it seems to reflect the prognosis.

INTRODUCTION

In human acute hemorrhagic pancreatitis; the prognosis is largely dependent upon the development of severe systemic complications and their management. (Shader and Paxton, 1966; Kellum, De Meester, Elkins and Zuidema, 1972; Halmagyi, Karis and Stenning, 1974; Ranson, Turner, Roses, Rifkind and Spencer, 1974; Baumann, Kobviantz, Danczkay and Address all correspondence and reprint requests to: Tom Schroder, M.D., Second Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki 29, Finland. 0300-9672/82/0000 -0000/$02.75 & 1982 Elsevier Scientific Publishers Ireland Ltd.

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Heinzehnann, 1977; Jacobs, Dagett, Civetta, Vasu, Lawson, Warshaw, Nardi and Bartlett, 1977; Johnson and Tong, 1977; Carey, 1979; von Dammann, Wichert and Schreiber, 1979; Kimura, Toung, Margolis, Permutt and Cameron, 1979). Some of these complications could, at least in part, be explained by the action of the lipolytic enzyme phospholipase AZ released from the pancreas during the illness. Experimentally an intravenous infusion of phospholipase AZ has-been shown to cause pulmonary changes identical to those seen in experimental pancreatitis (Morgan, Jenny and Haessler, 1968). It has been proposed that circulating phospholipase A2 splits the phospholipids of alveolar surfactant, thus leading to impairment of pulmonary function (Maciver, Metcalfe, Possmayer, Harding and Passi, 1977), manifested as atelectasis, reduced compliance and functional residual capacity and increased pulmonary shunting and hypoxemia. In the present study, serum phospholipase AZ activities were measured in 23 patients with acute hemorrhagic pancreatitis. Special attention was paid to the relationship of phospholipase AZ activity to the occurrence of complications as well as to the general course and outcome of the disease. PATIENTS

AND METHODS

The series consisted of 23 patients (age 43 f 14, mean f S.D.) with acute hemorrhagic pancreatitis treated at the 2nd Department of Surgery, Helsinki University Central Hospital, between March, 1979 and July, 1980. All the patients were treated at the multidisciplinary Intensive Care Unit of the hospital. The diagnosis was verified at laparotomy in all cases. Treatment of the patients with acute hemorrhagic pancreatitis All patients were operated on. The choice of treatment selected was between’either peritoneal lavage (13 patients) or subtotal pancreatic resection (10 patients). Postoperatively the patients were treated in the intensive care unit for 7-69 days (mean 17 days). The routine treatment included: (1) antibiotics: tobramycin (Nebcina@) 80-120 mg t.d.s., according to the serum concentration, and clindamycin (Dalacin@) 150 mg q.i.d.; (2) cimetidine (Tagamet@) 150-200 mg q.i.d. i.v., and oral antacids via a nasogastric tube in amounts sufficient to maintain intragastric acidity continuously above pH 5; (3) ventilatory support, consisting of additional inspired oxygen, continuous positive airway pressure (CPAP 5- 10 cmH,O) with a face mask, and intubation with positive end expiratory pressure (PEEP 5- -20 cmH,O) and intermittent mandatory ventilation (IMV) as needed. Total parenteral nutrition was given to all patients until they could eat by themselves. Follow-up of the patients with acute hemorrhagic pancreatitis On admission, assays for urine amylase and hemoglobin and white blood cell count were made. Next morning and on days 3, 5, 7, and 14 blood samples were collected for the assay of routine laboratory tests in acute

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pancreatitis (Schroder , Kivilaakso, Kinnunen and Lempinen, 1980), and phospholipase AZ. The blood gases were determined as needed using standard laboratory technique, and the inspired oxygen fraction (FI02) was measured polarographically during sampling. The alveolar to arterial oxygen differencearterial oxygen tension ratio (AaDoJPaO,) was derived from blood gas and FI02 values using the equation (PA02 = FIOz X (barometric pressure PacOJR), assuming that the respiratory exchange ratio R = 0.8. P&C) For $0, = 1.0, PA02 was calculated as BP - 47(pu,q) - PaCO,. The serum phospholipase AZ was determined as reported previously (Schrijder, Lempinen, Nordling and Kinnunen, 1981), and the other assays were performed according to the hospital routine. The early prognostic signs, as listed by Ranson, Rifkind and Turner (1976),.were somewhat modified to suit our hospital routine. Analysis of patients with acute fulminant pancreatitis Tne patients were divided according to the general course and outcome of the disease into three groups as follows: Group 1. Non-survivors (eight patients); Prognostic signs 3.3 f 1.4 (mean f SD.); Therapy subgroups: resection four patients, lavage 4 patients. Group 2. Survivors after major complications and prolonged hospitalization (over 6 weeks) (five patients); Prognostic signs 2.6 + 0.6 (mean f S.D.); Therapy subgroups: resection 1 patient, lavage 4 patients. no severe complications, hospitalization less than Group 3. Survivors, 6 weeks (10 patients); Prognostic signs 2.5 f 1.4 (mean * S.D.); Therapy subgroups: resection five patients, lavage 5 patients. Statistical treatment of the data was performed by Student’s t-test for paired and unpaired variants. The results are given as means + S.E.M. or S.D.

RESULTS

Eight of the 23 patients died (35%). Five patients (22%) developed major complications leading to further operations and to prolonged hospitalization. Ten patients (43%) recovered without severe complications. Phospholipase A z In all but one patient the serum phospholipase AZ activity was elevated on admission (23 + 13 run01 ml-’ - min-‘). The only patient with a normal value was a 61-year-old woman in group 3. However, even she showed elevated values from the day following admission onwards. The serum phospholipase AZ activities in the different groups are shown in Fig. 1. The highest activities were found among the eight patients who ??

0

1

3

5

7

14 days

Fig\ 1. The diagram shows the serum phospholipase A, activities of the patients. Group 2: 5 patients with X---X ---X, Group 1: 3 patients who died; ??---- .0---o, major complications; ?? . -. -me-. - a, Group 3: 10 patients without complications. Bars indicate S.E.M.

died (group l), whereas lower but still markedly elevated values were seen in the five patients who survived after major complications (group 2). Phospholipase AZ activities were lowest in the 10 patients who survived without complications (group 3). On admission, there were no significant differences in phospholipase AZ activities between these groups. However, on day 3 group 3 had significantly (P < 0.01) lower values than groups 1 or 2. By .c 60 E

r

t

0.

.’

0

1

3

5

: ,..

:

7

; ;...:

;

-4

.

14 days

Fig. 2. The diagram shows the serum phospholipase A, x a- . x . - ax, Subtotal pancreatic resection, 10 patients; ?? -4, 13 patients. Bars indicate S.E.M.

activities

of the patients. Peritoneal lavage,

83

1

I

1

2

4

6

I

v

,

1

8

10

12

14

days

Fig. 3. The diagram shows the A-aDo,/Pao, values of the patients. ?? --, Group 1: 8 patients who died; o- - -o- - -0, Group 2 : 5 patients with major complications; A. - .A. - .A, Group 3 : 10 patients without complications. Bars indicate S.E.M.

day 14, the differences between the groups were even more distinct (group 1 vs. group 2 P < 0.01; group 2 vs. group 3 P < 0.01). No significant difference was observed in serum phospholipase Az activity between the patients treated by peritoneal lavage and those treated by subtotal pancreatic resection (Fig. 2). Pulmonary changes As seen in Fig. 3, the three groups did not differ in regard to A-aDo, / Pa& values at the time of admission or even on day 3, but on day 7 the patients in groups 1 (who died) and 2 (survivors with major complications) had significantly higher values than those in group 3. The same trend continued on day 14. In group 1, all eight patients needed ventilatory support and PEEP (mean 13.5, range 6-22 cmH,O) for prolonged periods. In group 2, four out of five patients needed ventilator with PEEP (mean 7, range O-12 cmH,O), whereas in group 3 none of the patients needed ventilation except for the first 36 h postoperatively. Figures 4,5 and 6 are examples illustrating the course of phospholipase AZ activity and A-aDoJPao, values during the illness of three patients, one of each group. In the patient of group 1, both the phospholipase and AaDO, / 5.0 4.0 Phospholipase

3.0

A2 nmol ml mm I

2.0

“U ,O

2

4

days

ok,

4. The

patient in

diagram group

1.

6

8

AaW2

I

Pa02

‘.O

shows the phospholipase A, activities and A--aDo,lPao,

Values of a

5.0 4.0

AaOOp Pa02

3,0

i

2.0 1.0

0

2

4

6

8

10

14

16

18

days

Fig. 5. The diagram shows the phospholipase patient in group 2.

A, activities

and A~Do,lPao,

values of a

Pao, values remained persistently high. This patient was connected to a ventilator for 12 days and died 15 days after admission. The patient of group 2 recovered after prolonged treatment and major complications. There was a substantial initial increase of phospholipase Az activity and A-aDoJPaO, ratio, but both values slowly decreased during the recovery phase. The patient of group 3 serves as an example of the course of pancreatitis without complications. DISCUSSION

In 1960, phospholipase Az was identified as one of the pancreatic digestive enzymes (Vogel and Zieve, 1960). It is activated by trypsin in the presence of the detergent substances of bile, such as lysolecithin. Gjone, Ofstad, Marton and Amundsen (1967) reported that in experimental pancreatitis the pancreatic exudate contains phospholipase Az activity. This enzyme is a potent toxin and, when released into the circulation, may cause severe damage to remote organs.

7 4.0 Aa

Phospholipase

I

Pa02

A2 nmol ml min

I

days

Fig. 6. The diagram shows the phospholipase patient in group 3.

A, activities

and A--aDo,/Pao,

values of a

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The role of this enzyme in the pathophysiology of acute pancreatitis nas been studied by Schmidt and Creutzfeldt (1969) and by Creutzfeldt and Schmidt (1970). These workers reported that intrapancreatic infusion of phospholipase A2 with small amounts of bile caused severe necrosis in the pancreas, with a microscopic appearance very similar to that seen in human pancreatitis. The surfactant in lung alveoli contains phospholipids, which are substrates for phospholipase A?. Thus, activated and released pancreatic phospholipase A2 can hydrolyze the surfactant phospholipide so causing alveolar collapse. Changes in the surfactant in experimental pancreatitis in the dog have been reported (Maciver et al., 1977). These changes may have been caused by phospholipase A2 activity. The findings of Morgan, Jenny and Haessler (1963) support this theory; they demonstrated similar changes in the lungs of dogs following intravenous infusion of phospholipase A2. Human pancreas contains phospholipase A2 in large amounts (Zieve, Vogel and Kelly, 1963). In 1961, Zieve and Vogel (1961) showed that the activity of this enzyme was elevated in the serum of patients with acute pancreatitis. They studied only a few patients and did not seek any correlation between the severity of the disease and the activity of the enzyme. Schmidt and Creutzfeldt (1969) reported that in a patient who died of acute pancreatitis, the pancreatic phospholipid composition was dominated by lysocompounds, while the lecithin and cephalin fractions were reduced, suggesting the presence of phospholipase A2 activity. Since then there has been much speculation concerning the role of this enzyme in the development of complications in remote organs in acute pancreatitis (Nevalainen, 1980). Previous studies indicated that serum phospholipase A2 activities are higher in patients with acute fulminant pancreatitis than in the milder forms of the disease with spontaneous recovery (Schroder et al., 1980). We have also reported that pulmonary changes in experimental pancreatitis can be reduced by the use of phospholipase A2 inhibitors (Schriider, Kinnunen and Lempinen, 1978; SchrSder, Lempinen, Nordling and Kinnunen, 1981). In the present series of patients with acute fulminant pancreatitis, serum phospholipase activity seemed to correlate with the course of the disease. It increased when major complications arose and with prolongation of the course of the disease. Furthermore, the highest phospholipase A2 activities were found in the non-survivors. In contrast, the modality of therapy seemed not to influence phospholipase A2 activity, there being no difference between patients treated by resection or lavage. The changes in phospholipase A2 activity seemed to parallel the pulmonary changes, as seen from concomitant changes in the A-aD02/PaOz ratio. This ratio reflects a pulmonary venous admixture that includes both true shunt and ventilation-to-perfusion abnormalities. The most typical changes in acute fulminant pancreatitis are atelectases, with resultant reduced functional residual capacity and pulmonary compliance leading to increased venous admixture and hypoxemia. Elevation of the diaphragm due to

86

increased intraabdominal pressure certainly contributes to the occurrence of atelectasis. There must also, however, be intrapulmonary causes at the alveolar level. Our data seem to favor the theory that increased activities of phospholipase A2 in the serum may impair the function of pulmonary surfactant, thus leading to alveolar collapse, increased pulmonary resistance, increased pulmonary pressure, and venous admixture. To conclude, our results suggest that the outcome of acute fulminant pancreatitis correlates with serum levels of phospholipase AZ. Furthermore, the serum phospholipase seems to be related to the severity of the pulmonary dysfunction. REFERENCES Baumann, C.B., Kovbiantz, A., Danczkay and 2. Heinzelmann, (1977) Respiratorische Komplikationen bei Pancreatitis acuta. Helv. Chir. Acta, 44, 509-513. Carey, L.C. (1979) Extra-abdominal manifestations of acute pancreatitis. Surgery, 86, 337-342. Creutzfeldt, W. and Schmidt, H. (1970) Aethiology and pathogenesis of pancreatitis (Current concepts). Stand. J. Gastroenterol., Suppl., 5,47-62. von Dammann, H.G., Wichert, P.V. and Schreiber, H.W. (1979) Prognostische Indizes bei der akuten Pankreatitis. Eine postoperative Studie. Zentrabl. Chir., 104.397-404. Gjone, E., Ofstad, E:, Marton, P.F. and Amundsen, E. (1967) Phospholipase activity in pancreatic exudate in experimental acute pancreatitis. Stand. J. Gastroenterol., 2, 181-185. Halmagyi, D.F.J., Karis, J.H. and Stenning, F.G. (1974) Pulmonary hypertension in acute hemorrhagic pancreatitis. Surgery, 76,637+42. Jacobs, M.L., Daggett, W.M., Civet& J.M., Vasu, A., Lawson, D.W., Warshaw, A.L., Nardi, G.L. and Bartlett, M.K. (1977) Acute pancreatitis: Analysis of factors influencing survival. Ann. Surg., 185,43-51. Johnson, D.A. and Tong, N.T. (1977) Pancreatic encephalopathy. South Med. J., 70, 165--167. Kellum, J.M. Jr., DeMeester, T.R., Elkins, R.C. and Zuidema, G.D. (1972) Respiratory insufficiency secondary to acute pancreatitis. Ann. Surg., 175, 657-662. Kimura, T., Toung, J.K., Margolis, S., Permutt, S. and Cameron, J.L. (1979) Respiratory failure in acute pancreatitis. Ann. Surg., 189,509-514. Maciver, A.G., Metcalfe, I.L., Possmayer, F., Harding, P.G.R and Passi, R.B. (1977) Alteration of surfactant chemistry in experimental hemorrhagic pancreatitis. J. Surg. Res., 23,311-314. Morgan, A.P., Jenny, M.E. and HaessIer, H. (1968) Phospholipids, acute pancreatitis and the lungs: Effect of lecithinase infusion on pulmonary surface activity in dogs. Ann. Surg., 167,329-335. NevaIainen, T.J. (1980) Review: The role of phospholipase in acute pancreatitis. Stand. J. Gastroenterol., 15, 641- 650. Ranson, J.H.C., Turner, J.W., Roses, D.F., Rifkind, KM. and Spencer, F.C. (1974) Respiratory complications in acute pancreatitis. Ann. Surg., 179, 557-566. Ranson, J.H.C., Rifkind, KM. and Turner, J.W. (1976) Prognostic signs and nonoperative peritoneal lavage in acute pancreatitis. Surg. Gynecol Obstet., 143, 209-219. Schmidt, H. and Creutzfeldt, W: (1969) The possible role of phospholipase A in the pathogenesis of acute pancreatitis Stand. J. Gastroenterol., 4, 39-48. Schriider, T., Kinnunen, P.K.J. and Lempinen, M. (1978) Xylocaine treatment in experimental pancreatitis in pigs. Stand. J. Gastroenterol., 13, 863-865,

87 Schrijder, T., Kivilaakso, E., Kinnunen, P.K.J. and Lempinen, M. (1980) Serum phospholipase A, in human acute pancreatitis. Stand. J. Gastroenterol., 15,633-636. SchrBder, T., Lempinen, M., Nordling, S. and Kinnunen, P.K.J. (1981) Chloropromazine treatment of experimental pancreatitis in pigs. Eur. Surg. Res., 13, 143-151. Shader, A.E. and Paxton, J.R. (1966) Fatal pancreatitis. Am. J. Surg., 111, 369-373. Vogel, W.C. and Zieve, L. (1960) A lecithinase A in duodenal contents of man. J. Clin. Invest., 39,1295-1301. Zieve, L. and Vogel, W.C. (1961) Measurements of lecithinase A in serum and other body fluids. J. Lab. Clin. Med., 67,586-599. Zieve, L., Vogel, W.C. and Kelly, W.D. (1963) Species difference in pancreatic lipolytic and amylolytic enzymes. J. Appl. Physiol., 18, 77-82.