Abstract
An unusual case of a patient developing severe coagulopathy disorder and a clinical picture of cerebral hemorrhage and acute renal failure after young Bothrops jararacussu snake bite is reported. The mechanisms of snake venom-induced injury are discussed and similar cases in literature are revised and compared. The use of bothropic-Crotalus antivenom in severe B. jararacussu envenomation is discussed.
INTRODUCTION
Snake bite is a significant public health hazard in tropical countries due to its frequency, morbidity and mortality. The World Health Organization estimates that 125,000 individuals/year die after snake envenoming in the world, mostly in Asia Citation[[1]]. Recent data from the Brazilian Health Ministry showed a prevalence of 19,000 to 22,000 snake bites/year with a mortality rate around 0.45% Citation[[2]]. The country's incidence rate is 13.5 cases/100,000 inhabitants/year, being higher in the mid-western Brazil (33 cases/100,000 inhabitants/year) Citation[[2]].
Snakes of the genus Bothrops account for nearly 90% of venomous snakebites in South America, with a mortality rate of 0.31% in patients receiving antivenom Citation[[2]]. These snakes are found in Brazilian humid tropical forests, in rural regions and the surroundings of big cities, where rodents are easily found (Southern and Southeastern regions of Brazil and in the States of Bahia, Goiás and Mato Grosso, South of Bolivia, Paraguay and Northeastern Argentina) Citation[2-5].
The adult Bothrops jararacussu is a large snake, that can reach 1.5 to 2.2 m of length by 22 cm of circumference Citation[[4]]. B. jararacussu venom has a high mortality when compared to other snakes of the genus Bothrops and comparable to Crotalus durissus terrificus venom Citation[[6]]. Fortunately, B. jararacussu envenoming is unusual. Among 1718 snakebites followed for twelve years, only 0.82% were caused by B. jararacussu Citation[[7]]. In another study, a 20-year follow-up in São Paulo, Brazil, only 29 cases of B. jararacussu envenoming were observed Citation[[4]].
Bothrops venom has proteolytic, coagulant and hemorrhagic effects Citation[[2]], Citation[[8]]. Local manifestations are pain and edema at the bite area. Severe cases can develop soft tissue necrosis, abscess, compartmental syndrome and even loss of the injured limb Citation[[3]], Citation[[8]]. The most frequent systemic complications after the bite are bleeding, acute renal failure, sepses and more rarely hypotension or shock Citation[[2]], Citation[[8]].
Coagulation disorders are one of the most usual manifestations after Bothrops envenoming. The incidence of coagulopathy after this kind of snake bite is high, ranging from 48% to 75% Citation[[4]], Citation[9-12]. Hemorrhagic manifestations are observed at the bite site, gums, the nasopharyngeal area, the gastrointestinal tract, the urinary tract and the central nervous system Citation[[4]].
There are few reports of intracerebral hemorrhage after snake bite in literature Citation[[13]], with only 8 cases reported after Bothrops poisoning Citation[[7]], Citation[[9]], Citation[13-15].
This paper reports a fatal case of cerebral hemorrhage and acute renal failure after Bothrops jararacussu bite. The possible mechanisms of injury are discussed and other cases found in literature are revised.
CASE REPORT
In October 1998, a 64 year old woman was admitted at the Hospital de Doenças Tropicais de Goiánia (Tropical Diseases Hospital, Goiánia, Brazil), 10 hours after a bite in the left ankle by a young Bothrops jararacussu snake. The snake was identified by a herpetologist (NJSJ) of the “Núcleo Regional de Ofiologia de Goiánia-Universidade Católica de Goiás”.
At hospital admission the patient complained of severe pain at the bite site. She was confused, with isocoric and photoreactive pupils, without motor or sensitive deficits or neck rigidity. There was extremities cyanosis (2+/4+). The patient presented cool sudoresis, dyspnea (2+/4+), pale (+/4+) and lightly icteric mucous and was hydrated. Blood pressure was 160/100 mmHg and heart rate was 130 beats/min. Pulmonary auscultation disclosed decreased vesicular murmur at bases. Respiratory rate was 35 inspirations/min. There were no abdominal abnormalities. There were two punctiforms marks at the lateral side of the left ankle and important inflammatory signs spreading to the knee. There was also a 2 cm bloody blister close to the bite site. She was given 12 vials of Bothrops antivenom and 5,000 U of antitetanic serum IV.
The laboratory examination disclosed: hemoglobin 14.2 g/dL, hematocrit 40%, leukocyte 30,400/uL (rods 16%, neutrophil 71%, eosinophils 0%), platelets 126,000/uL, clotting time > 30 min, sodium 124 mEq/L, potassium 3.6 mEq/L, calcium 8.5 mg/dL, magnesium 2 mg/dL, phosphorus 1.1 mg/dL, urea 62 mg/dL, creatinine 2.4 mg/dL, bicarbonate 8.8 mmol/L, creatine phosphokinase 426 U/L, lactic dehydrogenase 4552 UI/L, total bilirubin 3.1 mg/dL (indirect bilirubin 2.3 mg/dL), albumin 3.8 g/dL, glutamic oxalacetic transaminase 326UI/L, glutamic pyruvic transaminase 80 UI/L, arterial gas (O2 nasal catheter, 4l/min): pH 7.10, pO2 72 mmHg, pCO2 28 mmHg, O2 saturation 89%, urinalysis: pH 5.5, density 1020, proteins 3+/4+, leukocytes 6/hpf, red blood cells: too numerous to count, hemoglobin 4+/4+.
Approximately 15 hours after the bite the patient was comatose, anisocoric (right pupil > left pupil) and with neck rigidity and was transferred to the intensive care unit. She required mechanical ventilation and was hemodynamically unstable (blood pressure 80/40 mmHg and heart rate of 160 beats/min), requiring high dose of dopamine (10 μg/kg/min) to maintain blood pressure. Urine output was 50 mL/h, grossly bloody. The inflammatory signs at the bite site became more intense, spreading throughout the left leg. Intravenous ceftriaxone and ampicillin were provided.
Eighteen hours after the bite, the patient was anuric, unresponsive to furosemide 80 mg IV bolus, with generalized edema. She presented epistaxes, hematemeses, bleeding at blood collection and bite sites and diffuse hemorrhagic suffusions. Fundoscopy disclosed diffuse retina bleeding. Laboratory values were: hemoglobin 11 g/dL, hematocrit 35%, clotting time > 30 minutes, sodium 138 mEq/L, potassium 3.3 mEq/L, urea 98 mg/dL, creatinine 3.7 mg/dL, bicarbonate 15 mmol/L, arterial blood gas (FiO2 100%): pH 7.31, pO2 56 mmHg, pCO2 29 mmHg, O2 saturation 87%. Due to severe bleeding diathesis, additional IV antivenom and therapy with packed red cells, cryoprecipitate and fresh plasma were prescribed. However, the patient's clinical picture continued to deteriorate and 28 hours after the bite she had a ventricular tachycardia followed by cardiorespiratory arrest.
DISCUSSION
A fatal case of envenomation by a young Bothrops jararacussu in which the patient suffered multiple manifestations of coagulopathy, acute renal failure and a clinical picture strongly suggestive of intracerebral hemorrhage is reported.
Adult Bothrops snakes usually bite the legs, inject higher venom amount and their venom is more proteolytic and less pro-coagulant compared to young Bothrops snakes Citation[[4]]. Coagulopathy is observed more frequently in poisoning by young (58%) than adult snakes (41%), probably as a result of the elevated procoagulant enzyme observed in the young animals venom Citation[[16]].
Our patient sought medical care ten hours after the snakebite. Thus, the antivenom administration was delayed, allowing the venom to express its proteolytic and mainly its coagulant effects. On hospital admission, the patient was confused, which could be interpreted as an early sign of cerebral injury. Fifteen hours after the bite she was comatose, anisocoric and with diffuse retinal bleeding, a picture suggesting intracerebral hemorrhage. Unfortunately, the patient's clinical status did not allow specific radiologic exams to be performed.
Intracerebral hemorrhage after snake bite has been sporadically reported in different regions of the world and it is an important prognostic factor, associated with high mortality Citation[[17]]. A careful literature revision disclosed only 8 other cases of intracerebral hemorrhage after Bothrops accidents, with a mortality rate of 75% Citation[[7]], Citation[[9]], Citation[13-15]. These cases are summarized in . Severe intracerebral hemorrhage after envenoming by Pseudonaja (brown snake), Echis carinatus, Vipera russelli, Notechis scutatus (tiger snake) and Trimeresurus (Green pit viper) have also been reported with high mortality Citation[17-25]. Cases of ischemic cerebral injury have been reported after Crotalus, E. carinatus and V. russelli bites Citation[26-30]. (see )
Table 1. Cases of Bothrops Snake Bite-Induced Central Nervous System Injury
Table 2. Cases of Snake Bite-Induced (Other Than Bothrops) Central Nervous System Injury
Intracerebral hemorrhage after snakebite is related to inadequate early care and/or the occurrence of severe coagulopathy Citation[[17]], Citation[[24]], Citation[[31]]. In this case, the patient received medical care after 10 hours and had significant clinical manifestations of coagulopathy disorders. Consistently, Ribeiro et al. reported fatal intracerebral hemorrhage in four Bothrops snakebite cases with marked coagulopathy Citation[[9]]. The bites of other snakes known to cause intracerebral hemorrhage such as E. carinatus and V. russelli, also produce significant coagulopathy Citation[[18]], Citation[[20]]. These cerebral hemorrhagic disorders have been related to blood incoagulability and low platelet count associated with diffuse vasospasm and cerebral capillary endothelial damage caused by hemorrhagins and possibly by other toxins found in the snake venom Citation[[21]], Citation[[30]].
The intracerebral hemorrhages after Pseudonaja bites in Australia have been related to subcutaneous or intravenous adrenalin, routinely administered for the prophylaxis of adverse reactions to antivenom Citation[[23]], Citation[[25]]. However, more recent controlled and randomized studies question the actual role of adrenalin as a cause of this kind of bleeding Citation[[24]], Citation[[32]].
Acute renal failure (ARF) is a severe complication after Bothrops snakebite. Its prevalence ranges from 2 to 10% Citation[33-35] and its mortality rate is approximately 15.6% Citation[[36]]. Renal dysfunction usually occurs early and it is severe and oliguric, requiring dialysis. In the present case, renal lesion developed extremely fast, since the patient had a marked increase in serum creatinine as early as 10 hours after the bite. The most common renal structural lesion found in Bothrops-induced ARF is acute tubular necrosis, but cases of bilateral renal cortical necrosis have also been reported Citation[36-39]. The probable mechanisms of renal injury in Bothrops envenomation are fibrin microthrombi deposition at the glomerular capillary tuff, hemoglobinuria and direct tubular nephrotoxicity Citation[[37]], Citation[39-40].
Local lesions as edema, blisters and necrosis are caused by the activity of proteases, hyaluronidases and phospholipases of Bothrops venom, as well as the release of inflammatory mediators, resulting from hemorrhagins on the endothelium and venom procoagulant activity Citation[[2]], Citation[[41]]. These changes progress rapidly and severely, as observed in the present case.
The specific treatment for B. jararacussu envenomation is the intravenous administration of bothropic, bothropic-Crotalus or bothropic-Lachesis antivenom Citation[[2]]. If clotting time does not improve within 24 hours of antivenom therapy, additional antivenom should be given Citation[[2]], Citation[[17]]. Dos Santos et al experimentally demonstrated that the combination of bothropic and Crotalus antivenom was more efficient to neutralize the procoagulant, myotoxic and lethal activities of B. jararacussu venom than the single treatment with bothropic antivenom Citation[[42]]. In the present case bothropic antivenom given in adequate amount and route, followed by an early booster dose did not prevent the severe systemic injury caused by the venom. The clinical outcome of the patient reported in this paper suggests that the concomitant therapy with bothropic and Crotalus antivenom may be required after severe B. jararacussu envenomation.
In summary, a rare case of fatal intracerebral hemorrhage and acute renal failure after B. jararacussu snake bite is reported. Data obtained reinforce early and aggressive treatment should be provided after B. jararacussu bite, using the IV antivenom therapy in adequate doses after the correct identification of the offending snake. The combined administration of Bothrops and Crotalus antivenom should be considered in cases of severe envenomation.
ACKNOWLEDGMENTS
We thank Lívia Cais Burdmann for grammatical review of the manuscript.
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