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Myonecrosis, myoglobinuria and acute renal failure induced by south american rattlesnake (Crotalus durissus terrificus) envenomation in brazil
Tox/k'o~.Vol.23, No. 4, 139.631-636, 1'~$. Printed In Great ~ d n .
0041-0101/115$3.00+ .00 © 1985Peflamoa Pres*Ltd.
MYONECROSIS, MYOGLOBINURIA AND ACUTE RENAL FAILURE INDUCED BY SOUTH AMERICAN RATTLESNAKE (CROTALUS DURISSUS TERRIFICUS) ENVENOMATION IN BRAZIL M. M. AZEVEDO-MARQUES 1, P. CuPo, a T. M. COIMBRA, 3 S. E. HERING, 2 M. A. ROSSP and C. J. LAUREs Departments of 1Internal Medicine, 2Pediatrics, 4pathology and SBiochemistry, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, 14100 Ribeirao Preto, SP, Brazil, and 2Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
(Accepted for publication I8 December 1984) M. M. AZEVEDO-MARQUES,P. ~ , T. M. COIMBRA, S. E. HERINO, M. A. ROSSI and C. J. LAunE. Myonecrosis, myoglobinuria and acute renal failure induced by South American rattlesnake (Crotalus durlm~ts terrOr,us) envenomation in Brazil. Toxicon 23, 631-636, 1985. The venom of the Brazilian rattlesnake Crotalus durissus terr(/'tcus is know to have hemolytic and neurotoxic physiopathological activities which may cause acute renal failure with hemoglobinuria and/or methemoglobinuHa. As far as we know, no report has been published on the ability of the venom of this rattlesnake species to cause rhabdomyolysis. In the present paper we demonstrate that the venom of Brazilian snakes of the genus Crotalus can induce systemic myonecrosis. Clinical, laboratory and anatomo-patholngical data for two patients referred to the University Hospital of the Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, 24 hr after a rattlesnake bite, are presented. In both cases, exaggerated elevation of serum levels of the enzymes creatine phosphokinase, lactate dehydrngenase and glutamic-oxaloacetic transaminase were detected, as well as data suggesting acute hypercatabolic renal failure. Immunoelectrophoresis of the serum and urine of these patients, carried out against specific anti-mynglobin serum (lkhringwerke), demonstrated mynglobinemia and myoglobinurla, confirming injury to muscle tissue. Electron microscopy of a calf muscle biopsy taken from the leg contralateral to the bite from one patient revealed foci of myonecrosis.
INTRODUCTION IT HAS BEEN established in Brazil that the venom of the rattlesnake Crotalus durissus
terrO~cus has hemolytic and neurotoxic physiopathological activities in man, with frequent occurrence of renal failure accompanied by acute tubular necrosis. Local damage at the site of the bite has been reported to be minimal or absent, a feature in which the South American rattlesnake C. durissus terrificus differs from the snakes of the same genus in other American regions, whose venom has local proteolytic activity (ROSENFELD, 1971). The renal lesions caused by C. durissus terrificus bites in humans have been described by AMORIM and MELLO 0952, 1954) as "nephrosis of the intermediate nephron", with the presence of hemoglobin cylinders inside the renal tubules, later identified as consisting of methemogiobin (ROSENFELD et aL, 1968). Experiments carried out by AMOPdM et ai. (1969), in which envenomation by C. durissus terr~cus was reproduced in dogs, revealed constant hemoglobinuria and renal lesions identical to those reported for human envenomation (AMORIM and MELLO, 1952). Thus, the existence of 631
M . M . A Z E V E D O - M A R Q U E S et al.
632
hemogiobinuria as an expression of the hemolytic activity of the venom of the South American rattlesnake Crotalus durissus terrificus, in the absence of hematuria, was emphasized. None of the above reports mentioned a myotoxic activity of the venom. The present report concerns two patients, victims of bites by C. durissus, very probably from the subspecies terrificus, who developed acute hypercatabolic renal failure and for whom the presence of myonecrosis and myoglobinuria was demonstrated. These observations are similar to those reported for patients with rhabdomyolysis and acute myogiobinuric renal failure caused by the bite of sea-snakes in Asia (MARSDENand REID, 1961; REID, 1961). CASE R E P O R T S
Patient 1 A 7-year-old boy (V.A.S.) from the State of Minas Gerais, Brazil, was admitted to the University Hospital of the Faculty of Medicine of Ribeir~o Preto 24 hr after being bitten by C. durissus and after receiving anti-ophidian serum (Butantan Institute) s.c. 20 rain after the accident at a dose sufficient to neutralize 100 mg of C. durissus terrificus venom and 200 mg of B. jararaca venom. When first examined in our hospital the patient was pale, hydrated and semiconscious, suffering alternating periods of agitation and somnolence. His limbs were cold and slightly cyanotic. There was bilateral palpebral ptosis and the pupils were mydriatic, more intensely so on the left, with slow photomotor reflexes. Semiologic cardiopulmonary examination showed no changes, with 120/90 mm Hg blood pressure and 40 respiratory cycles/min. Eye fundoscopy showed blurring of the optic disc on the right. Neurologic examination disclosed hypoactive deep reflexes. No lesions were present at the site of the bite. Anticrotalus serum (Butantan Institute) sufficient to neutralize 250 mg of C. durissus terrificus venom by the i.v. route was immediately administered to the patient. Diuresis was 1 5 - 2 0 ml/hr. The urine, dark brown in color, showed no red cells in the sediment, but the benzidine test was positive. The results of the blood tests carried out after admission are shown in Table 1. Owing to a rapid increase in serum urea and creatinine levels, as well as in blood pressure, peritoneal dialysis was started 24 hr after admission. During this treatment the child suffered serious complications, with alimentary bleeding and respiratory failure requiring artificial respiration. Death occurred on the 13th day of hospitalization. Diuresis was constantly low, and absent during the last three days. TABLE 1. SERUM MEASUREMENTS CARRIED OUT ON THE TWO PATIENTS ON THE DAY FOLLOWING Crotalus ENVENOMATION Days after CPK LDH TGO Urea Creatinine Uric acid Phmphorus Potmudum Calcium He~noglobtn the bite (50-320)*(100-225)* (15-40)* (10-30)* (0.5-1.1)*(4.0-9.0)* (2.5-4.5)* (3.5-4.5)* ( 9 - !1)* (mU/ml) ( m U / m l ) ( m U / m l ) (ms,b) (rng~) (mg~) (mg~) (mEq/l) (mg~) (g~ ) Pat/ent 1
(V.A.S.) 1 2 4 5 12 Pat/ent 2 (J.R.) 1 2 3 •5
105,000 98,000 3700 900 180
6500 14,000 12,000 I0,000 1780
300,000 280,000 80,000 15,800
10,000 5000 2800
~50 6500 750 300 1~
101.9 296.0 1~.0 1~.8 112.1
2.2 3.8 2.4 3.0 2.4
119.0 ~2.0 270.0 ~5.0
4.6 5.9 7.0 9.1
18.0
19.0
18.0 15.0 13.0
10.0 5.0 6.4
10.2
10.0
14.0 12.6
11.0 7.0
6.6 5.8 4.3 5.3 6.0
6.0 6.5 8.7 10.0 9.6
10.5
4.6 5.0 5.2 4.3
8.0 7.5 6.5 9.1
13.7 12.3 12.7 11.7
*Values in parentheses are the normal ranges (Technicon SMA 12/60 and SMA Plus Auto-Analyzer).
11.4 11.2 9.7
633
FIG. I. PATIENT I (V.A.S.). Serum (I) and urine (2) immunoelectrophoresis against anti-human myoglobin serum 24 hr after the bite. The anode position is on the fight.
634
FIG. 2. ELECTRONMICROGRAPHSOF A MUSCLEBIOPSYFROMTHE CALFCONTRALATERALTO THE SITE OF THE BITE OF PATIENT I ('V.A.S.).
(A) Disor~aniT~tion and lysis o f myofilaments ( ~ ' ) , contraction bands formation (cb) a n d dilation o f sarcoplasmic reticulum (st). (B) Myofibrillar disintegration with loss o f cross striations (~), contraction bands formation (cb) a n d mitochondrial swelling (mi).
Myonecrosis Induced by Rattl~nAk¢ Venom
635
Throughout, the patient suffered episodes of isolated or generalized muscular tremors in the limbs. Serum and urine immunoelectrophoresis carried out against anti-human myogiobin serum revealed the presence of myogiobinemia and myogiobinuria (Fig. 1). Electron microscopy of the muscle biopsy from the calf contralateral to the site of bite showed foci of myonecrosis with myofibrillar disintegration, disorganization and lysis of myofilaments, loss of cross striations, dilation of the sarcoplasmic reticulum, contraction bands formation and mitochondrial swelling (Fig. 2A and B). At autopsy the kidney showed acute tubular disease characterized by epithelial degeneration and necrosis, basement membrane disruption (tubulorrhexis) and irregular patches of reddish granular casts (heine casts). The other autopsy findings included multiple acute erosions of the esophageal, gastric and duodenal mucosae, cerebral edema, moderate fatty change in the liver, rhabdomyolysis and bilateral confluent bronchopneumonia.
Patient 2 A 51-year-old male (J.R.) from the State of Minas Gerais was admitted to the University Hospital of the Faculty of Medicine of Ribeir$o Preto 24 hr after envenomation by C. durissus, and after being given an undetermined dose of antiophidian serum (Butantan Institute) 4 hr after the accident by the s.c. route. At first he showed a satisfactory general condition, was oriented, somnolent, hydrated and had no gross respiratory or cardiocirculatory changes. He complained of muscle weakness. Bilateral palpebral ptosis, decreased muscle strength and hypoactive deep reflexes were present. Eye fundoscopy showed a slight blurring of the papilla on the left towards the temporal side. Blood pressure was 120/80 nun Hg and no lesions were present at the site of the bite. The patient presented with oliguria immediately after the bite. Upon admission, anticrotalus serum (Butantan Institute) at a dose sufficient to neutralize 200 mg of C. durissus terrificus venom was administered i.v. The results of the laboratory tests carded out after admission are shown in Table 1. Peritoneal dialysis was started 5 hr after admission and maintained throughout the remainder of the patient's life. The patient started to suffer nausea, vomiting and alimentary bleeding. On the 2nd day of hospitalization, after virtually no diuresis, he suffered prolonged apnea and cardiac arrests which were reversed with oxygenation, external cardiac massage and i.e. administration of epinephrine, sodium bicarbonate and calcium giuconate. The patient fell into a coma. Sporadic tremors were noted in the pectoral muscles and lower limbs, which later became generaliTed and occurred sometimes simultaneously with a temperaure up to 39°C. He showed loss of muscle tone and periods of muscle contractures. On the 4th day in hospital, extrasystoles and ventricular fibrillation were detected and death occurred on the 5th day. Throughout the patient remained anuric and showed progressively higher serum urea and creatinine levels, despite continuous peritoneal dialysis. Serum and urine immunoelectrophoresis, carried out against anti-human myoglobin serum, revealed myogiobinemia and myogiobinuria. At autopsy the kidneys showed acute tubular necrosis with tubulorrbexis and heine casts. Other autopsy findings included erosions of the gastric mucosa, cerebral edema, hepatic fatty changes and bilateral bronchopneumonia. DISCUSSION
Upon adrni~ion, both patients exhibited obvious clinical signs of serious Crotalus durissus terrificus envenomation (ROSENFELD, 1971), rapidly developing acute hypercatabolic renal failure requiring early installation of dialysis. Both patients showed
636
M . M . AZEVEDO-MARQUES et ai.
tremors during hospitalization, which at times were restricted to a muscle group, and at others were generalized and accompanied by myalgia. The presence of urine dark brown in color without red cells and of high serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH) and oxaloacetic transaminase (TGO) levels (Table 1) suggests a diagnosis of rhabdomyolysis, which was confirmed by the detection of myoglobin in the serum and urine of both patients (Fig. 1) and by electron microscopy of a biopsy from patient 1 (Fig. 2). In studies of human poisoning by the sea snake Enhydrina schistosa, MARSDEN and REID (1961), REID (1961) and SITPRIJA et ai. (1971) reported extensive necrosis of skeletal muscle, with myoglobinuria and acute renal failure. HOOD and JOHNSON(1974) reported the case of an Australian patient who developed massive rhabdomyolysis, myoglobinuria and acute tubular necrosis after being bitten by the elapid Notechis scutatus scutatus. A muscle biopsy taken during the 2nd week after the bite showed focal necrosis of muscle fibers. These studies reported the systemic myonecrotic action of snake venom, which attacks several skeletal muscles and produces intense myoglobinuria. A survey of the Brazilian literature is devoid of reports on the myotoxic action of Crotalus venom or of rhabdomyolysis occurring after snake bites in general. The electron microscopy findings in the biopsy obtained from patient 1 from the limb contralateral to the site of the bite demonstrated the distant myonecrotic action of the venom of the South American rattlesnake Crotalus durissus. Myoglobinuria, whether alone or in association with the hemolytic and nephrotoxic effects of the venom, appears to be an important factor in the pathogenesis of acute renal failure after bites by Crotalus durissus in Brazil. Although the snakes responsible for the two cases were not captured, it is known that Crotalus durissus terrOTcus is the rattlesnake species most commonly encountered in southeastern Brazil, where the patients herein reported were living when they suffered the bites. REFERENCES AMORIM, M. DE F. and M~LLO, R. F. (1952) Nefrose do nefron intermedi6xio no envenenamento crot~tlico humano. Estudo amitomo-patol6gico. Mems Inst. 8utantan 24, 281. AMORIM, M. DE F. and MELLO, R. F. (1954) Intermediate nephrosis from snake poisoning in man. A m . J. Path. 30, 479. AMORIM, M. DE F., MELI.O, R. F. and SAUNA, F. (1969) Les6es renais induzidas experimentalmente no c~o pelo veneno croffdico. Meres Inst. Butantan 34, 137. HOOD, V. L. and JOHNSON, J. R. (1974) Acute renal failure with myoglobinuria following tiger snake bite. Aust. N . Z . J . Meal. 4, 415. MAgSDEN, A. T. H. and REID, H. A. (1961) Pathology of sea-snake poisoning. Br. Med. J. 1, 1290. REID, H. A. (1961) Myoglobinuria and sea-snake bite poisoning. Br. Med. J. 1, 1284. ROS~FELD, G. (1971) Symptomatology, pathology and treatment of snake bites in South America. In: Venomous Animals and their Venoms, Vol. II, p. 345 (BucHERL, W., BUCXLEY, E. E. and DEULOWU, V., Eds.). New York: Academic Press. ROSENFELD, (3, NAHAS, L. and KEI.EN, E. M. A. (1968) Coagulant, proteolytic and hemolytic properties of some snake venoms. In: Venomous Animals and their Venoms, Vol. l, p. 217 (BUCHERL, W., BUCKLEY,E. E. and DEULOFEU, V., Eds.). New York: Academic Press. SITPltUA, V., SRmHIBHAVH, R. and BENYAJATI, C. (1971) Haemodialysis in poisoning by sea-snake venom. Br. Med. J. 3, 218.
0041-0101/115$3.00+ .00 © 1985Peflamoa Pres*Ltd.
MYONECROSIS, MYOGLOBINURIA AND ACUTE RENAL FAILURE INDUCED BY SOUTH AMERICAN RATTLESNAKE (CROTALUS DURISSUS TERRIFICUS) ENVENOMATION IN BRAZIL M. M. AZEVEDO-MARQUES 1, P. CuPo, a T. M. COIMBRA, 3 S. E. HERING, 2 M. A. ROSSP and C. J. LAUREs Departments of 1Internal Medicine, 2Pediatrics, 4pathology and SBiochemistry, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, 14100 Ribeirao Preto, SP, Brazil, and 2Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
(Accepted for publication I8 December 1984) M. M. AZEVEDO-MARQUES,P. ~ , T. M. COIMBRA, S. E. HERINO, M. A. ROSSI and C. J. LAunE. Myonecrosis, myoglobinuria and acute renal failure induced by South American rattlesnake (Crotalus durlm~ts terrOr,us) envenomation in Brazil. Toxicon 23, 631-636, 1985. The venom of the Brazilian rattlesnake Crotalus durissus terr(/'tcus is know to have hemolytic and neurotoxic physiopathological activities which may cause acute renal failure with hemoglobinuria and/or methemoglobinuHa. As far as we know, no report has been published on the ability of the venom of this rattlesnake species to cause rhabdomyolysis. In the present paper we demonstrate that the venom of Brazilian snakes of the genus Crotalus can induce systemic myonecrosis. Clinical, laboratory and anatomo-patholngical data for two patients referred to the University Hospital of the Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, 24 hr after a rattlesnake bite, are presented. In both cases, exaggerated elevation of serum levels of the enzymes creatine phosphokinase, lactate dehydrngenase and glutamic-oxaloacetic transaminase were detected, as well as data suggesting acute hypercatabolic renal failure. Immunoelectrophoresis of the serum and urine of these patients, carried out against specific anti-mynglobin serum (lkhringwerke), demonstrated mynglobinemia and myoglobinurla, confirming injury to muscle tissue. Electron microscopy of a calf muscle biopsy taken from the leg contralateral to the bite from one patient revealed foci of myonecrosis.
INTRODUCTION IT HAS BEEN established in Brazil that the venom of the rattlesnake Crotalus durissus
terrO~cus has hemolytic and neurotoxic physiopathological activities in man, with frequent occurrence of renal failure accompanied by acute tubular necrosis. Local damage at the site of the bite has been reported to be minimal or absent, a feature in which the South American rattlesnake C. durissus terrificus differs from the snakes of the same genus in other American regions, whose venom has local proteolytic activity (ROSENFELD, 1971). The renal lesions caused by C. durissus terrificus bites in humans have been described by AMORIM and MELLO 0952, 1954) as "nephrosis of the intermediate nephron", with the presence of hemoglobin cylinders inside the renal tubules, later identified as consisting of methemogiobin (ROSENFELD et aL, 1968). Experiments carried out by AMOPdM et ai. (1969), in which envenomation by C. durissus terr~cus was reproduced in dogs, revealed constant hemoglobinuria and renal lesions identical to those reported for human envenomation (AMORIM and MELLO, 1952). Thus, the existence of 631
M . M . A Z E V E D O - M A R Q U E S et al.
632
hemogiobinuria as an expression of the hemolytic activity of the venom of the South American rattlesnake Crotalus durissus terrificus, in the absence of hematuria, was emphasized. None of the above reports mentioned a myotoxic activity of the venom. The present report concerns two patients, victims of bites by C. durissus, very probably from the subspecies terrificus, who developed acute hypercatabolic renal failure and for whom the presence of myonecrosis and myoglobinuria was demonstrated. These observations are similar to those reported for patients with rhabdomyolysis and acute myogiobinuric renal failure caused by the bite of sea-snakes in Asia (MARSDENand REID, 1961; REID, 1961). CASE R E P O R T S
Patient 1 A 7-year-old boy (V.A.S.) from the State of Minas Gerais, Brazil, was admitted to the University Hospital of the Faculty of Medicine of Ribeir~o Preto 24 hr after being bitten by C. durissus and after receiving anti-ophidian serum (Butantan Institute) s.c. 20 rain after the accident at a dose sufficient to neutralize 100 mg of C. durissus terrificus venom and 200 mg of B. jararaca venom. When first examined in our hospital the patient was pale, hydrated and semiconscious, suffering alternating periods of agitation and somnolence. His limbs were cold and slightly cyanotic. There was bilateral palpebral ptosis and the pupils were mydriatic, more intensely so on the left, with slow photomotor reflexes. Semiologic cardiopulmonary examination showed no changes, with 120/90 mm Hg blood pressure and 40 respiratory cycles/min. Eye fundoscopy showed blurring of the optic disc on the right. Neurologic examination disclosed hypoactive deep reflexes. No lesions were present at the site of the bite. Anticrotalus serum (Butantan Institute) sufficient to neutralize 250 mg of C. durissus terrificus venom by the i.v. route was immediately administered to the patient. Diuresis was 1 5 - 2 0 ml/hr. The urine, dark brown in color, showed no red cells in the sediment, but the benzidine test was positive. The results of the blood tests carried out after admission are shown in Table 1. Owing to a rapid increase in serum urea and creatinine levels, as well as in blood pressure, peritoneal dialysis was started 24 hr after admission. During this treatment the child suffered serious complications, with alimentary bleeding and respiratory failure requiring artificial respiration. Death occurred on the 13th day of hospitalization. Diuresis was constantly low, and absent during the last three days. TABLE 1. SERUM MEASUREMENTS CARRIED OUT ON THE TWO PATIENTS ON THE DAY FOLLOWING Crotalus ENVENOMATION Days after CPK LDH TGO Urea Creatinine Uric acid Phmphorus Potmudum Calcium He~noglobtn the bite (50-320)*(100-225)* (15-40)* (10-30)* (0.5-1.1)*(4.0-9.0)* (2.5-4.5)* (3.5-4.5)* ( 9 - !1)* (mU/ml) ( m U / m l ) ( m U / m l ) (ms,b) (rng~) (mg~) (mg~) (mEq/l) (mg~) (g~ ) Pat/ent 1
(V.A.S.) 1 2 4 5 12 Pat/ent 2 (J.R.) 1 2 3 •5
105,000 98,000 3700 900 180
6500 14,000 12,000 I0,000 1780
300,000 280,000 80,000 15,800
10,000 5000 2800
~50 6500 750 300 1~
101.9 296.0 1~.0 1~.8 112.1
2.2 3.8 2.4 3.0 2.4
119.0 ~2.0 270.0 ~5.0
4.6 5.9 7.0 9.1
18.0
19.0
18.0 15.0 13.0
10.0 5.0 6.4
10.2
10.0
14.0 12.6
11.0 7.0
6.6 5.8 4.3 5.3 6.0
6.0 6.5 8.7 10.0 9.6
10.5
4.6 5.0 5.2 4.3
8.0 7.5 6.5 9.1
13.7 12.3 12.7 11.7
*Values in parentheses are the normal ranges (Technicon SMA 12/60 and SMA Plus Auto-Analyzer).
11.4 11.2 9.7
633
FIG. I. PATIENT I (V.A.S.). Serum (I) and urine (2) immunoelectrophoresis against anti-human myoglobin serum 24 hr after the bite. The anode position is on the fight.
634
FIG. 2. ELECTRONMICROGRAPHSOF A MUSCLEBIOPSYFROMTHE CALFCONTRALATERALTO THE SITE OF THE BITE OF PATIENT I ('V.A.S.).
(A) Disor~aniT~tion and lysis o f myofilaments ( ~ ' ) , contraction bands formation (cb) a n d dilation o f sarcoplasmic reticulum (st). (B) Myofibrillar disintegration with loss o f cross striations (~), contraction bands formation (cb) a n d mitochondrial swelling (mi).
Myonecrosis Induced by Rattl~nAk¢ Venom
635
Throughout, the patient suffered episodes of isolated or generalized muscular tremors in the limbs. Serum and urine immunoelectrophoresis carried out against anti-human myogiobin serum revealed the presence of myogiobinemia and myogiobinuria (Fig. 1). Electron microscopy of the muscle biopsy from the calf contralateral to the site of bite showed foci of myonecrosis with myofibrillar disintegration, disorganization and lysis of myofilaments, loss of cross striations, dilation of the sarcoplasmic reticulum, contraction bands formation and mitochondrial swelling (Fig. 2A and B). At autopsy the kidney showed acute tubular disease characterized by epithelial degeneration and necrosis, basement membrane disruption (tubulorrhexis) and irregular patches of reddish granular casts (heine casts). The other autopsy findings included multiple acute erosions of the esophageal, gastric and duodenal mucosae, cerebral edema, moderate fatty change in the liver, rhabdomyolysis and bilateral confluent bronchopneumonia.
Patient 2 A 51-year-old male (J.R.) from the State of Minas Gerais was admitted to the University Hospital of the Faculty of Medicine of Ribeir$o Preto 24 hr after envenomation by C. durissus, and after being given an undetermined dose of antiophidian serum (Butantan Institute) 4 hr after the accident by the s.c. route. At first he showed a satisfactory general condition, was oriented, somnolent, hydrated and had no gross respiratory or cardiocirculatory changes. He complained of muscle weakness. Bilateral palpebral ptosis, decreased muscle strength and hypoactive deep reflexes were present. Eye fundoscopy showed a slight blurring of the papilla on the left towards the temporal side. Blood pressure was 120/80 nun Hg and no lesions were present at the site of the bite. The patient presented with oliguria immediately after the bite. Upon admission, anticrotalus serum (Butantan Institute) at a dose sufficient to neutralize 200 mg of C. durissus terrificus venom was administered i.v. The results of the laboratory tests carded out after admission are shown in Table 1. Peritoneal dialysis was started 5 hr after admission and maintained throughout the remainder of the patient's life. The patient started to suffer nausea, vomiting and alimentary bleeding. On the 2nd day of hospitalization, after virtually no diuresis, he suffered prolonged apnea and cardiac arrests which were reversed with oxygenation, external cardiac massage and i.e. administration of epinephrine, sodium bicarbonate and calcium giuconate. The patient fell into a coma. Sporadic tremors were noted in the pectoral muscles and lower limbs, which later became generaliTed and occurred sometimes simultaneously with a temperaure up to 39°C. He showed loss of muscle tone and periods of muscle contractures. On the 4th day in hospital, extrasystoles and ventricular fibrillation were detected and death occurred on the 5th day. Throughout the patient remained anuric and showed progressively higher serum urea and creatinine levels, despite continuous peritoneal dialysis. Serum and urine immunoelectrophoresis, carried out against anti-human myoglobin serum, revealed myogiobinemia and myogiobinuria. At autopsy the kidneys showed acute tubular necrosis with tubulorrbexis and heine casts. Other autopsy findings included erosions of the gastric mucosa, cerebral edema, hepatic fatty changes and bilateral bronchopneumonia. DISCUSSION
Upon adrni~ion, both patients exhibited obvious clinical signs of serious Crotalus durissus terrificus envenomation (ROSENFELD, 1971), rapidly developing acute hypercatabolic renal failure requiring early installation of dialysis. Both patients showed
636
M . M . AZEVEDO-MARQUES et ai.
tremors during hospitalization, which at times were restricted to a muscle group, and at others were generalized and accompanied by myalgia. The presence of urine dark brown in color without red cells and of high serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH) and oxaloacetic transaminase (TGO) levels (Table 1) suggests a diagnosis of rhabdomyolysis, which was confirmed by the detection of myoglobin in the serum and urine of both patients (Fig. 1) and by electron microscopy of a biopsy from patient 1 (Fig. 2). In studies of human poisoning by the sea snake Enhydrina schistosa, MARSDEN and REID (1961), REID (1961) and SITPRIJA et ai. (1971) reported extensive necrosis of skeletal muscle, with myoglobinuria and acute renal failure. HOOD and JOHNSON(1974) reported the case of an Australian patient who developed massive rhabdomyolysis, myoglobinuria and acute tubular necrosis after being bitten by the elapid Notechis scutatus scutatus. A muscle biopsy taken during the 2nd week after the bite showed focal necrosis of muscle fibers. These studies reported the systemic myonecrotic action of snake venom, which attacks several skeletal muscles and produces intense myoglobinuria. A survey of the Brazilian literature is devoid of reports on the myotoxic action of Crotalus venom or of rhabdomyolysis occurring after snake bites in general. The electron microscopy findings in the biopsy obtained from patient 1 from the limb contralateral to the site of the bite demonstrated the distant myonecrotic action of the venom of the South American rattlesnake Crotalus durissus. Myoglobinuria, whether alone or in association with the hemolytic and nephrotoxic effects of the venom, appears to be an important factor in the pathogenesis of acute renal failure after bites by Crotalus durissus in Brazil. Although the snakes responsible for the two cases were not captured, it is known that Crotalus durissus terrOTcus is the rattlesnake species most commonly encountered in southeastern Brazil, where the patients herein reported were living when they suffered the bites. REFERENCES AMORIM, M. DE F. and M~LLO, R. F. (1952) Nefrose do nefron intermedi6xio no envenenamento crot~tlico humano. Estudo amitomo-patol6gico. Mems Inst. 8utantan 24, 281. AMORIM, M. DE F. and MELLO, R. F. (1954) Intermediate nephrosis from snake poisoning in man. A m . J. Path. 30, 479. AMORIM, M. DE F., MELI.O, R. F. and SAUNA, F. (1969) Les6es renais induzidas experimentalmente no c~o pelo veneno croffdico. Meres Inst. Butantan 34, 137. HOOD, V. L. and JOHNSON, J. R. (1974) Acute renal failure with myoglobinuria following tiger snake bite. Aust. N . Z . J . Meal. 4, 415. MAgSDEN, A. T. H. and REID, H. A. (1961) Pathology of sea-snake poisoning. Br. Med. J. 1, 1290. REID, H. A. (1961) Myoglobinuria and sea-snake bite poisoning. Br. Med. J. 1, 1284. ROS~FELD, G. (1971) Symptomatology, pathology and treatment of snake bites in South America. In: Venomous Animals and their Venoms, Vol. II, p. 345 (BucHERL, W., BUCXLEY, E. E. and DEULOWU, V., Eds.). New York: Academic Press. ROSENFELD, (3, NAHAS, L. and KEI.EN, E. M. A. (1968) Coagulant, proteolytic and hemolytic properties of some snake venoms. In: Venomous Animals and their Venoms, Vol. l, p. 217 (BUCHERL, W., BUCKLEY,E. E. and DEULOFEU, V., Eds.). New York: Academic Press. SITPltUA, V., SRmHIBHAVH, R. and BENYAJATI, C. (1971) Haemodialysis in poisoning by sea-snake venom. Br. Med. J. 3, 218.