Annals of
Ann Hematol (1991) 63:39-41
Hematology 9 Springer-Verlag 1991
Original article Pancreatitis in acute hemolysis W. Druml, A.N. Laggner, K. Lenz, G. Grimm, and B. Schneewei6 1st Department of Medicine, University of Vienna, Vienna, Austria Received January 31, 1991/Accepted April 15, 1991
Summary. Forty cases o f hemolysis (drop o f hematocrit > 12%/12 h) were retrospectively analyzed for hyperamylasemia and pancreatic complications. In 15 subjects the serum amylase level was > 360 U/l, i.e., three times the n o r m a l range, in ten the amylase level exceeded 900 U/1. Excluding patients in circulatory shock a n d / o r hepatic coma, acute pancreatitis as defined by an elevation o f serum amylase and clinical signs (epigastric pain) was present in four, with additional ultrasound findings (pancreatic swelling) a n d / o r l a p a r a t o m y / p o s t m o r t e m findings in a further six subjects (total ten patients = 25%) with various causes o f hemolysis: a u t o i m m u n e hemolysis 2, microangiopathic hemolytic anemia 2, toxicemia, G - 6 - P D H deficiency, septic abortion, malaria, Wilson's disease, and h y p o p h o s p h a t e m i a , one case each. In all subjects acute renal failure and in seven an activation o f intravascular coagulation was seen. Three patients died (33% vs 47% o f all hyperamylasemic patients and 46% o f the whole group), but none o f the deaths was attributed to pancreatitis. Pancreatic p o s t m o r t e m findings were diffuse edema and patchy parenchymal necrosis in two cases and petechial bleeding in one case. We conclude that acute pancreatitis is a complication o f massive hemolysis, occurring at a prevalence o f above 20%. It m a y progress f r o m diffuse edema and i n f l a m m a t i o n to focal necrosis, rarely if ever to gross hemorrhage, and does not contribute to the high mortality o f massive hemolysis. Back pain in hemolysis might originate f r o m the pancreas rather than from the kidneys.
Key words: Hemolysis - Pancreatitis - Microcirculation - Diffuse intravascular coagulation - Acute renal failure
Besides the c o m m o n association with biliary tract disease and ethanol abuse, the etiology o f acute pancreatitis includes multiple rare causes, such as drugs, infections, Address for correspondence: W. Druml, I. Med. Univ. Klinik, Lazarettgasse 14, A-1090 Vienna, Austria
hyperparathyroidism, hyperlipidemia, shock, trauma, or pregnancy [11]. Treating patients with massive acute intravascular hemolysis, we noted a striking frequency o f pancreatic complications. To define a possible causal relationship between hemolysis and pancreatitis, we analyzed a large series o f patients admitted to our institution because o f massive hemolysis. The results indicate that, in fact, pancreatitis is a complication o f intravascular hemolysis.
Patients and methods Forty patients consecutively admitted to our medical intensive care unit with acute massive hemolysis of various causes were analyzed retrospectively. Massive hemolysis was defined as a fall of hematocrit of 12% or more within 12 h, the clinical picture being dominated by the hemolytic process. Causes of hemolysis were iso/autoimmune hemolysis (10), intoxication (9), microangiopathic hemolytic anemia (9), parainfectious (6), Wilson's disease (3), G-6-PDH deficiency (2), and hypophosphatemia (1). Because of the massive intravascular red cell destruction, all patients were ahaptoglobinemic and showed a pronounced hemoglobinuria with dark-red to black urine if renal function was preserved. Depending on survival time and associated complications, serum bilirubin rose to a maximum of 37.6 to 1302.6 pmol/1 (normally < 17.1)/~mol/1. Similarily, the reticulocyte count was variably elevated from 15 to 200 G/1. In 15 patients (38%) an elevation of serum amylase to > 360 U/1 (3 x the upper limit of normal controls, a range usually not exceeded in the presence of renal dysfunction) was observed. The characteristics of these patients are given in Table 1. In ten subjects the serum amylase level was higher than 900 U/1. A pancreatitis was diagnosed in the presence of elevated serum amylase level and at least one of the following features: clinical signs (abdominal pain and distension, epigastric tenderness; cases 1-4, "possible pancreatitis") and ultrasound findings (swelling of the pancreas) and/or laparatomy findings and/or postmortem findings (cases 5-10, "obvious pancreatitis"). Subjects without clinical symptoms (no. 15) or those presenting in shock (patients 11, 12, and 14) or hepatic coma (no. 13) were excluded. Causes of hemolysis in the ten patients (25% of the case series) with acute pancreatitis were autoimmune hemolytic anemia 2, nos. 2,8), microangiopathic hemolytic anemia (2, nos. 1,7), parainfectious (2, nos. 4,6), acid ingestion in case 10, G-6-PDH deficiency in case 5, Wilson's disease in case 3, and, possibly, hypophosphatemia in case 9.
40 Table 1. Pancreatitis in massive hemolysis: Patients No. Cause of hemolysis
Sex Age Fall in free Hb LDH (years) He (%) mg/dl U/1
Amylase Associated U/1 complications
Additional pancreatic findings
Outcome
f m
23 12
25 24
520 488
4200 5850
515 1024
ARF ARF, DIC
C: epigastric pain C: epigastric pain
Survived Survived (splenectomy)
f f
13 25
14 13
38 120
1900 1230
375 651
C: epigastric pain C: epigastric pain
Survived Survived
m
29
20
400
4700
6350
ARF ARF, DIC, coma ARF, DIC,
Death (brain edema)
f
34
17
613
3540
4020
ARF, DIC
m
45
19
267
2860
8116
35
15
802
83
27
2060
5610
900
I0
Autoimmuue m hemolysis Hypophosf phatemia Acid intox, f
ARF, DIC, coma ARF
US: diffuse swelling PM: petech, bleeding C: epigastric pain US: diffuse swelling PM: patchy necrosis
27
14
414
4440
1820
11
Acid intox,
36
12
180
12
42
30
3900
7350
750
17
12
770
2380
920
14
Perfringens m septicemia Autoimmune f hemolysis Acid intox, f
51
14
860
1465
935
15
G-6-PDH def. m
36
16
676
8250
400
1 2 3 4 5 6 7 8 9
13
HUS Autoimmune hemolysis Wilson's dis. Malaria G-6-PDH deficiency Septic abortion TTP
f
1 5 5 0 0 2100
1 3 6 5 0 1660
ARF, DIC ARF, DIC, coma ARF, DIC, coma ARF, DIC, shock, coma ARF, hepatitis, coma ARF, DIC, shock ARF
Survived Death (brain edema)
C: epigastric pain PM: patchy necrosis C: epigastric pain L: diffuse swelling C: epigastric pain US: diffuse swelling PM: not done
Death (hemorrhagic shock) Survived
Death (toxic shock)
PM: not done
Death (septic shock)
PM: patchy necrosis PM: not done
Death (brain edema) (liver failure) Death (toxic shock)
none
Survived
Survived
C, Clinical; US, ultrasound; L, laparatomy; PM, postmortem findings; G-6-PDH, glucose-6-phosphate dehydrogenase; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura; ARF, acute renal failure; DIC, diffuse intravascular coagulation
Clinical signs of pancreatitis were present in noncomatose patients within 48 h after admission or the hemolytic crisis, i.e., abdominal distention and epigastric pain, diminished bowel sounds, and marked tenderness to deep epigastric palpation. In patient 9 an exploratory laparatomy was performed because of intense abdominal pain. Apart from a mild diffuse edema of the pancreas, no macroscopic abnormalities were seen. Signs of pancreatitis persisted in the surviving patients for a mean of 12 days: 21 (no. 6), 12 (nos. 3,10), 10 (nos. 2,9), and 4 days (no. 1), respectively. Plasma amylase concentration was already elevated at admission and rose to a maximum (mean 2071 U/l, median 935 U/l, normal range 40-120 U/I; Table 1) within 4 days. Leukocytosis, frequently seen in acute pancreatitis, was not used as a diagnostic criterion because the leukocyte count is usually elevated in hemolysis. In all patients with hemolysis-associated pancreatitis, acute renal failure (as defined by an acute elevation of serum creatinine 3 times above normal) was evident, and in seven subjects a diffuse intravascular coagulation (as defined by a prolongation of prothrombin time, a decrease in fibrinogen concentration and platelet count, and a positive ethanol test and/or elevation of fibrinogen degradation products) was observed. Coagulation activation was maximal during the hemolytic crisis, and renal failure - as well as pancreatitis - became apparent during the first 48 h. Two subjects required respiratory support; six patients were comatose. Therapy for pancreatitis included nasogastric suction, parenteral nutrition, gastric ulcer prophylaxis with histamine antagonists, and, in two cases, continuous somatostatin infusion. Prognosis: Three of the ten patients with acute pancreatitis (33%) died within 5 - 7 days after admission. All were subjects with "obvious pancreatitis" (mortality: 3 of 6 = 50%) and causes of death were brain edema in two and hemorrhagic shock in one. Five other patients with hyperamylasemia died: two of brain edema, two of toxic shock, and one of septic shock. Mortality of the 15 hyper-
amylasemic patients was 47%, comparable to that of the whole group of 40 subjects (46%) or of nonpancreatitis patients (44%). None of the deaths was attributed to the pancreatitis. Postmortem findings in three patients with "obvious pancreatitis" included a diffuse swelling and patchy parenchymal necrosis in two and petechial bleeding in an edematous pancreas in one. Massive hemorrhage was not present in any case.
Discussion We present evidence that acute pancreatitis is a complicat i o n of massive hemolysis with a prevalence of a b o u t 25%. Pancreatic p a t h o l o g y may progress from mild inf l a m m a t i o n a n d e d e m a to massive swelling, patchy p a r e n c h y m a l necrosis, a n d focal bleeding. H e m o r r h a g i c necrosis of the pancreas was not observed, a n d pancreatitis did n o t affect mortality. Pancreatitis developed in cases with massive intravascular red cell destruction only a n d was n o t seen in milder forms o f hemolysis. O n l y one case report to date has linked the developm e n t of pancreatitis to massive intravascular hemolysis. Walker et al. presented two patients o n chronic h e m o d i a lysis t r e a t m e n t in w h o m hemolysis occurred because o f hypotonic dialysate c o m p o s i t i o n [12]. These patients c o m p l a i n e d o f epigastric p a i n a n d developed paralytic ileus, a n d their serum amylase c o n c e n t r a t i o n s rose to 10000 a n d 17600 U/1 respectively. S y m p t o m s resolved within 8 days.
41 Several features support the hypothesis that acute pancreatitis is a direct consequence of hemolysis and not of associated factors or complications. Pancreatitis developed during a broad spectrum of underlying diseases and thus independently of the cause of red cell destruction and immediately during hemolytic crisis. Clearly, the patients were polymorbid, but pathogenetic factors known to be associated with pancreatitis were absent, and subjects with circulatory shock were excluded from analysis. C o m m o n findings in most of the patients with pancreatitis were acute renal failure and activation of intravascular coagulation, both well-defined complications of hemolysis [5]. Renal failure per se may cause a rise in serum amylase level, but this rarely exceeds more than 2.5 times the upper limit of normal and is not associated with clinical or ultrasound signs of pancreatitis [3]. The limit of 360 U/1 for serum amylase in our study was chosen to exclude cases with hyperamylasemia due to impaired renal function. Thus, renal failure and other causes of hyperamylasemia of extrapancreatic origin might have contributed to the quantitative elevation of serum amylase but do not explain the occurrence of pancreatitis. Chronic renal failure is associated with a higher prevalence o f pancreatitis than expected in the general population, the exact rates in acute renal failure being unknown [1, 9]. The time course of the occurrence of pancreatitis during or immediately after red cell destruction and before the development of an uremic state does not favor any contribution of acute uremia to the pathogenesis of pancreatitis in hemolysis but suggests a c o m m o n pathway in the development of both organ dysfunctions. In most patients an activation of intravascular coagulation was evident [51. Clearance of fibrinogen-fibrin split products is reduced during hemolysis because of the blockage o f the reticuloendothelial system by cell detritus which, in a vicious circle, promotes further coagulation system activation [8]. Both the accumulation of activated coagulation factors and decreased reticuloendothelial clearance maintain the formation of microthrombi and associated microvascular disturbance, resulting in the functional impairment of several organs [2]. Organ dysfunctions may further be promoted by the local vasoconstriction effects of hemolysate due to inhibition of endothelium-derived relaxing factor [61. Moreover, hemoglobin and/or degradation products thereof may accelerate oxygen free-radical formation and thus cell injury [10]. A combination of these and, in individual cases associated factors such as anemia and hypotension may contribute to the development of injury to the pancreas, an organ extremely susceptible to microcirculatory impairment (13). Chronic hemolysis is known to increase the incidence o f pigment stones [7]. Biliary concrements do not develop in acute red cell destruction and were not demonstrated in any of our patients. Thus, a biliary origin of pancreatitis is unlikely. None of the patients with hemolysis died of acute pancreatitis. The death rate in the pancreatitis group (33%) was comparable to that in all hyperamylasemic patients (47%) and in nonpancreatitis patients (44%), or in
the whole patient series (46%), and is determined mainly by the severity of the underlying disease process. With a prevalence of about 25%, acute pancreatitis in massive hemolysis should, in fact, be expected at a higher frequency than in other etiologic factors commonly referred to in textbooks, such as hyperparathyroidism, hyperlipidemia, and trauma [4, 11]. Possibly because of the low incidence of massive hemolysis, this association has not been investigated previously. In a patient presenting with acute hemolysis who develops epigastric pain one should be aware of the possibility of the occurrence of pancreatitis and should take a cautious approach with respect to any st~rgical intervention (as highlighted by our case 9, in whom a laparatomy was performed). Modern imaging techniques, such as a CT scan of the pancreatic region, may help to resolve diagnostic dilemmas, especially in intensive-care patients with additional complications. Whether the " b a c k pain" frequently observed during massive hemolysis originates from the kidneys, as suggested in many textbooks, or in fact from the pancreas, as our observations indicate, remains to be proven. We conclude that massive hemolysis has to be added to the list of rare causes of pancreatitis, and that acute pancreatitis should be included among the well-defined complications of intravascular red cell destruction. References
1. Araki T, Ueda M, Taketa K, Kosaka K (1989) Pancreatic-type hyperamylasemia in end-stage renal disease. Dig Dis Sci 34: 1425-1427 2. Baker WF (1989) Clinical aspects of disseminated intravascular coagulation. Semin Thromb Hemost 15:1-57 3. Berk JE, Fridhandler L, Ness RL (1979) Amylase and isoamylase activities in renal insufficiency. Ann Intern Med 90:351-353 4. Bess MA, Edis A J, van Heerden JA (1980) Hyperparathyreoidism and pancreatitis. Chance or causal association? JAMA 243:246-247 5. Goldfinger D (1977) Acute hemolytic transfusion reactions a fresh look at pathogenesis and considerations regarding therapy. Transfusion 17:85-98 6. Martin W, Villani GM, Jothianandan D, Furchgott RF (1985) Selective blockage of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 232:708-716 7. Merendino KA, Manhas DR (1973) Man-made gallstones: a new entity following cardiac valve replacement. Ann Surg 177: 696-699 8. Rabiner SF, Friedman LH (1968) The role of intravascular hemolysis and the reticuloendothelial system in the production of a hypercoagulable state. Br J Haematol 126:1127-1132 9. Rutzky EA, Robards M, van Dyke JA, Bostand SG (1986) Acute pancreatitis in patients with end-stage renal disease without transplantation. Arch Intern Med 146:1741-1744 10. Sadrzadeh SMH, Graf E, Panter S, Hallaway PE, Eaton JW (1984) Hemoglobin. A biologic Fenton reagent. J Biol Chem 259:14354-14356 11. Steer ML (1986) Etiology and pathophysiology of acute pancreatitis. In: Go VLW (ed) The exocrine pancreas: biology, pathology, and diseases. Raven, New York, pp 465-474 12. Walker JF, Cronin C J, Donohoe JF, Carmody M, o'Dwyer WF (1981) Acute severe intravascular hemolysis: an unrecognized cause of pancreatitis. Br Med J 282:1929 13. Warshaw AL, O'Hara PJ (1978) Susceptibility of the pancreas to ischemic injury in shock. Ann Surg 188:t97-201
Ann Hematol (1991) 63:39-41
Hematology 9 Springer-Verlag 1991
Original article Pancreatitis in acute hemolysis W. Druml, A.N. Laggner, K. Lenz, G. Grimm, and B. Schneewei6 1st Department of Medicine, University of Vienna, Vienna, Austria Received January 31, 1991/Accepted April 15, 1991
Summary. Forty cases o f hemolysis (drop o f hematocrit > 12%/12 h) were retrospectively analyzed for hyperamylasemia and pancreatic complications. In 15 subjects the serum amylase level was > 360 U/l, i.e., three times the n o r m a l range, in ten the amylase level exceeded 900 U/1. Excluding patients in circulatory shock a n d / o r hepatic coma, acute pancreatitis as defined by an elevation o f serum amylase and clinical signs (epigastric pain) was present in four, with additional ultrasound findings (pancreatic swelling) a n d / o r l a p a r a t o m y / p o s t m o r t e m findings in a further six subjects (total ten patients = 25%) with various causes o f hemolysis: a u t o i m m u n e hemolysis 2, microangiopathic hemolytic anemia 2, toxicemia, G - 6 - P D H deficiency, septic abortion, malaria, Wilson's disease, and h y p o p h o s p h a t e m i a , one case each. In all subjects acute renal failure and in seven an activation o f intravascular coagulation was seen. Three patients died (33% vs 47% o f all hyperamylasemic patients and 46% o f the whole group), but none o f the deaths was attributed to pancreatitis. Pancreatic p o s t m o r t e m findings were diffuse edema and patchy parenchymal necrosis in two cases and petechial bleeding in one case. We conclude that acute pancreatitis is a complication o f massive hemolysis, occurring at a prevalence o f above 20%. It m a y progress f r o m diffuse edema and i n f l a m m a t i o n to focal necrosis, rarely if ever to gross hemorrhage, and does not contribute to the high mortality o f massive hemolysis. Back pain in hemolysis might originate f r o m the pancreas rather than from the kidneys.
Key words: Hemolysis - Pancreatitis - Microcirculation - Diffuse intravascular coagulation - Acute renal failure
Besides the c o m m o n association with biliary tract disease and ethanol abuse, the etiology o f acute pancreatitis includes multiple rare causes, such as drugs, infections, Address for correspondence: W. Druml, I. Med. Univ. Klinik, Lazarettgasse 14, A-1090 Vienna, Austria
hyperparathyroidism, hyperlipidemia, shock, trauma, or pregnancy [11]. Treating patients with massive acute intravascular hemolysis, we noted a striking frequency o f pancreatic complications. To define a possible causal relationship between hemolysis and pancreatitis, we analyzed a large series o f patients admitted to our institution because o f massive hemolysis. The results indicate that, in fact, pancreatitis is a complication o f intravascular hemolysis.
Patients and methods Forty patients consecutively admitted to our medical intensive care unit with acute massive hemolysis of various causes were analyzed retrospectively. Massive hemolysis was defined as a fall of hematocrit of 12% or more within 12 h, the clinical picture being dominated by the hemolytic process. Causes of hemolysis were iso/autoimmune hemolysis (10), intoxication (9), microangiopathic hemolytic anemia (9), parainfectious (6), Wilson's disease (3), G-6-PDH deficiency (2), and hypophosphatemia (1). Because of the massive intravascular red cell destruction, all patients were ahaptoglobinemic and showed a pronounced hemoglobinuria with dark-red to black urine if renal function was preserved. Depending on survival time and associated complications, serum bilirubin rose to a maximum of 37.6 to 1302.6 pmol/1 (normally < 17.1)/~mol/1. Similarily, the reticulocyte count was variably elevated from 15 to 200 G/1. In 15 patients (38%) an elevation of serum amylase to > 360 U/1 (3 x the upper limit of normal controls, a range usually not exceeded in the presence of renal dysfunction) was observed. The characteristics of these patients are given in Table 1. In ten subjects the serum amylase level was higher than 900 U/1. A pancreatitis was diagnosed in the presence of elevated serum amylase level and at least one of the following features: clinical signs (abdominal pain and distension, epigastric tenderness; cases 1-4, "possible pancreatitis") and ultrasound findings (swelling of the pancreas) and/or laparatomy findings and/or postmortem findings (cases 5-10, "obvious pancreatitis"). Subjects without clinical symptoms (no. 15) or those presenting in shock (patients 11, 12, and 14) or hepatic coma (no. 13) were excluded. Causes of hemolysis in the ten patients (25% of the case series) with acute pancreatitis were autoimmune hemolytic anemia 2, nos. 2,8), microangiopathic hemolytic anemia (2, nos. 1,7), parainfectious (2, nos. 4,6), acid ingestion in case 10, G-6-PDH deficiency in case 5, Wilson's disease in case 3, and, possibly, hypophosphatemia in case 9.
40 Table 1. Pancreatitis in massive hemolysis: Patients No. Cause of hemolysis
Sex Age Fall in free Hb LDH (years) He (%) mg/dl U/1
Amylase Associated U/1 complications
Additional pancreatic findings
Outcome
f m
23 12
25 24
520 488
4200 5850
515 1024
ARF ARF, DIC
C: epigastric pain C: epigastric pain
Survived Survived (splenectomy)
f f
13 25
14 13
38 120
1900 1230
375 651
C: epigastric pain C: epigastric pain
Survived Survived
m
29
20
400
4700
6350
ARF ARF, DIC, coma ARF, DIC,
Death (brain edema)
f
34
17
613
3540
4020
ARF, DIC
m
45
19
267
2860
8116
35
15
802
83
27
2060
5610
900
I0
Autoimmuue m hemolysis Hypophosf phatemia Acid intox, f
ARF, DIC, coma ARF
US: diffuse swelling PM: petech, bleeding C: epigastric pain US: diffuse swelling PM: patchy necrosis
27
14
414
4440
1820
11
Acid intox,
36
12
180
12
42
30
3900
7350
750
17
12
770
2380
920
14
Perfringens m septicemia Autoimmune f hemolysis Acid intox, f
51
14
860
1465
935
15
G-6-PDH def. m
36
16
676
8250
400
1 2 3 4 5 6 7 8 9
13
HUS Autoimmune hemolysis Wilson's dis. Malaria G-6-PDH deficiency Septic abortion TTP
f
1 5 5 0 0 2100
1 3 6 5 0 1660
ARF, DIC ARF, DIC, coma ARF, DIC, coma ARF, DIC, shock, coma ARF, hepatitis, coma ARF, DIC, shock ARF
Survived Death (brain edema)
C: epigastric pain PM: patchy necrosis C: epigastric pain L: diffuse swelling C: epigastric pain US: diffuse swelling PM: not done
Death (hemorrhagic shock) Survived
Death (toxic shock)
PM: not done
Death (septic shock)
PM: patchy necrosis PM: not done
Death (brain edema) (liver failure) Death (toxic shock)
none
Survived
Survived
C, Clinical; US, ultrasound; L, laparatomy; PM, postmortem findings; G-6-PDH, glucose-6-phosphate dehydrogenase; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura; ARF, acute renal failure; DIC, diffuse intravascular coagulation
Clinical signs of pancreatitis were present in noncomatose patients within 48 h after admission or the hemolytic crisis, i.e., abdominal distention and epigastric pain, diminished bowel sounds, and marked tenderness to deep epigastric palpation. In patient 9 an exploratory laparatomy was performed because of intense abdominal pain. Apart from a mild diffuse edema of the pancreas, no macroscopic abnormalities were seen. Signs of pancreatitis persisted in the surviving patients for a mean of 12 days: 21 (no. 6), 12 (nos. 3,10), 10 (nos. 2,9), and 4 days (no. 1), respectively. Plasma amylase concentration was already elevated at admission and rose to a maximum (mean 2071 U/l, median 935 U/l, normal range 40-120 U/I; Table 1) within 4 days. Leukocytosis, frequently seen in acute pancreatitis, was not used as a diagnostic criterion because the leukocyte count is usually elevated in hemolysis. In all patients with hemolysis-associated pancreatitis, acute renal failure (as defined by an acute elevation of serum creatinine 3 times above normal) was evident, and in seven subjects a diffuse intravascular coagulation (as defined by a prolongation of prothrombin time, a decrease in fibrinogen concentration and platelet count, and a positive ethanol test and/or elevation of fibrinogen degradation products) was observed. Coagulation activation was maximal during the hemolytic crisis, and renal failure - as well as pancreatitis - became apparent during the first 48 h. Two subjects required respiratory support; six patients were comatose. Therapy for pancreatitis included nasogastric suction, parenteral nutrition, gastric ulcer prophylaxis with histamine antagonists, and, in two cases, continuous somatostatin infusion. Prognosis: Three of the ten patients with acute pancreatitis (33%) died within 5 - 7 days after admission. All were subjects with "obvious pancreatitis" (mortality: 3 of 6 = 50%) and causes of death were brain edema in two and hemorrhagic shock in one. Five other patients with hyperamylasemia died: two of brain edema, two of toxic shock, and one of septic shock. Mortality of the 15 hyper-
amylasemic patients was 47%, comparable to that of the whole group of 40 subjects (46%) or of nonpancreatitis patients (44%). None of the deaths was attributed to the pancreatitis. Postmortem findings in three patients with "obvious pancreatitis" included a diffuse swelling and patchy parenchymal necrosis in two and petechial bleeding in an edematous pancreas in one. Massive hemorrhage was not present in any case.
Discussion We present evidence that acute pancreatitis is a complicat i o n of massive hemolysis with a prevalence of a b o u t 25%. Pancreatic p a t h o l o g y may progress from mild inf l a m m a t i o n a n d e d e m a to massive swelling, patchy p a r e n c h y m a l necrosis, a n d focal bleeding. H e m o r r h a g i c necrosis of the pancreas was not observed, a n d pancreatitis did n o t affect mortality. Pancreatitis developed in cases with massive intravascular red cell destruction only a n d was n o t seen in milder forms o f hemolysis. O n l y one case report to date has linked the developm e n t of pancreatitis to massive intravascular hemolysis. Walker et al. presented two patients o n chronic h e m o d i a lysis t r e a t m e n t in w h o m hemolysis occurred because o f hypotonic dialysate c o m p o s i t i o n [12]. These patients c o m p l a i n e d o f epigastric p a i n a n d developed paralytic ileus, a n d their serum amylase c o n c e n t r a t i o n s rose to 10000 a n d 17600 U/1 respectively. S y m p t o m s resolved within 8 days.
41 Several features support the hypothesis that acute pancreatitis is a direct consequence of hemolysis and not of associated factors or complications. Pancreatitis developed during a broad spectrum of underlying diseases and thus independently of the cause of red cell destruction and immediately during hemolytic crisis. Clearly, the patients were polymorbid, but pathogenetic factors known to be associated with pancreatitis were absent, and subjects with circulatory shock were excluded from analysis. C o m m o n findings in most of the patients with pancreatitis were acute renal failure and activation of intravascular coagulation, both well-defined complications of hemolysis [5]. Renal failure per se may cause a rise in serum amylase level, but this rarely exceeds more than 2.5 times the upper limit of normal and is not associated with clinical or ultrasound signs of pancreatitis [3]. The limit of 360 U/1 for serum amylase in our study was chosen to exclude cases with hyperamylasemia due to impaired renal function. Thus, renal failure and other causes of hyperamylasemia of extrapancreatic origin might have contributed to the quantitative elevation of serum amylase but do not explain the occurrence of pancreatitis. Chronic renal failure is associated with a higher prevalence o f pancreatitis than expected in the general population, the exact rates in acute renal failure being unknown [1, 9]. The time course of the occurrence of pancreatitis during or immediately after red cell destruction and before the development of an uremic state does not favor any contribution of acute uremia to the pathogenesis of pancreatitis in hemolysis but suggests a c o m m o n pathway in the development of both organ dysfunctions. In most patients an activation of intravascular coagulation was evident [51. Clearance of fibrinogen-fibrin split products is reduced during hemolysis because of the blockage o f the reticuloendothelial system by cell detritus which, in a vicious circle, promotes further coagulation system activation [8]. Both the accumulation of activated coagulation factors and decreased reticuloendothelial clearance maintain the formation of microthrombi and associated microvascular disturbance, resulting in the functional impairment of several organs [2]. Organ dysfunctions may further be promoted by the local vasoconstriction effects of hemolysate due to inhibition of endothelium-derived relaxing factor [61. Moreover, hemoglobin and/or degradation products thereof may accelerate oxygen free-radical formation and thus cell injury [10]. A combination of these and, in individual cases associated factors such as anemia and hypotension may contribute to the development of injury to the pancreas, an organ extremely susceptible to microcirculatory impairment (13). Chronic hemolysis is known to increase the incidence o f pigment stones [7]. Biliary concrements do not develop in acute red cell destruction and were not demonstrated in any of our patients. Thus, a biliary origin of pancreatitis is unlikely. None of the patients with hemolysis died of acute pancreatitis. The death rate in the pancreatitis group (33%) was comparable to that in all hyperamylasemic patients (47%) and in nonpancreatitis patients (44%), or in
the whole patient series (46%), and is determined mainly by the severity of the underlying disease process. With a prevalence of about 25%, acute pancreatitis in massive hemolysis should, in fact, be expected at a higher frequency than in other etiologic factors commonly referred to in textbooks, such as hyperparathyroidism, hyperlipidemia, and trauma [4, 11]. Possibly because of the low incidence of massive hemolysis, this association has not been investigated previously. In a patient presenting with acute hemolysis who develops epigastric pain one should be aware of the possibility of the occurrence of pancreatitis and should take a cautious approach with respect to any st~rgical intervention (as highlighted by our case 9, in whom a laparatomy was performed). Modern imaging techniques, such as a CT scan of the pancreatic region, may help to resolve diagnostic dilemmas, especially in intensive-care patients with additional complications. Whether the " b a c k pain" frequently observed during massive hemolysis originates from the kidneys, as suggested in many textbooks, or in fact from the pancreas, as our observations indicate, remains to be proven. We conclude that massive hemolysis has to be added to the list of rare causes of pancreatitis, and that acute pancreatitis should be included among the well-defined complications of intravascular red cell destruction. References
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