Document Type: Original Article

Authors

1 Addiction Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of infectious diseases, Intensive care unit, Mashhad University of Medical Sciences, Mashhad, Iran

3 Addiction Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran. AJA University of Medical Sciences, Tehran, Iran

4 AJA University of Medical Sciences, Tehran, Iran

Abstract

Background: The goal of antivenom administration for snake-bitten patients is to achieve therapeutic response (initial control), which means reversal of the venom-induced effects through neutralizing the venom. The aim of this study was to identify snakebite prognostic factors of weak therapeutic response prior to antivenom administration.
Methods: This was a retrospective study of patients with viperidae snakebite envenomation who were admitted to Mashhad Toxicology Centre during 2007-2011. Demographic features, clinical manifestations and snakebite severity score (SSS) were collected prior to antivenom administration. Total number of antivenom vials administered to achieve therapeutic response and duration of hospitalization were also recorded. Potential factors in snakebite prognosis were analyzed by comparing in two groups of achieving therapeutic response with less than 5 vials and over 5 to calculate odds ratio. 
Results: Total of 108 patients (male/female: 85/23) with mean (SD) age of 34.5 (17.0) were studied. The most common manifestations included fang marks (100%), pain (100%), ecchymosis (89%), swelling (83%), blister formation (48%) and thrombocytopenia (25%). In univariate analysis, thrombocytopenia (P=0.01), spontaneous bleeding (P=0.02), coagulopathic disturbances (P=0.007), swelling (P=0.003), progressive swelling (P=0.005), ecchymosis (P=0.05) and respiratory distress (P= 0.05) were significantly correlated to weak therapeutic response. Swelling and spontaneous bleeding were the strongest snakebite prognostic factors, as respectively they put the patients at 12.4 and 10.4 fold risks for difficult achievement of therapeutic response.
Conclusions: In snakebite, some clinical manifestations in the first hours of admission and prior to antivenom administration are associated with weak therapeutic response. Identifying these prognostic factors, can assist health care providers to better estimate the patient’s needs and predict the final consequences. 

Keywords

INTRODUCTION

Snakebite in Iran is a major health problem, which affects approximately 4500-6500 individuals with 3-9 deaths each year according to recent reports of Iranian Ministry of Health and Medical Education (1). In Khorasan Razavi catchment area, 30 to 70 snakebites occur annually which are mainly because of two viperidae snakes, Echis Carinatus and Vipera Lebentia (1-3). Most of these victims were being admitted to Imam Reza Hospital, Mashhad Medical Toxicology Centre (MTC), a multidisciplinary reference department for management of poisoned patients in northeastern Iran. Less than 1% mortality rate has been reported among them (1,3).

Viperidae envenomations are mostly known to cause coagulopathic disturbances (mucosal and internal hemorrhages, thrombocytopenia and decrease in coagulation factors) in addition to local effects (pain, progressive edema, erythema, ecchymosis, bulla and blister) and other systemic effects (nausea, vomiting, dyspnea, neurologic abnormalities, hypotension, shock) (4,5). Extensive or progressive local effects, severe systemic and hemostatic abnormalities are the main indications of antivenom administration (3,4). Annual internal reports (MTC) showed that approximately 90% of these patients received antivenom during admission. The goal of antivenom administration for snake-bitten patients is to achieve therapeutic response (initial control) which means reversal of the venom-induced effects (cessation of edema progression and improvement of systemic manifestations) through neutralizing the venom.

Razi™ polyvalent antivenin is the only commercially available treatment for snakebite in Iran and is approved by Iranian Ministry of Health and Medical Education (5).  It is a F(ab’)2 antivenom product which is derived from equine hyperimmune serum and capable of neutralizing the venom of 6 most common snakes in Iran including 5 viper species (Echis carinatus sochureki, Vipera lebetina obtusa, Vipera albicornuta, Agkistrodon halys, Pseudocerastes persicus) and an elapid species (Naja naja oxiana) (6,7). This product has been efficiently used in treatment of snakebite with limited adverse effects. The manufacturer has recommended administering 1-2 vial attack doses until stabilizing the patient or reversal of venom effects (5,6). However, local experience through past 4 decades in MTC revealed that morbidities and mortalities are higher with such lower initial doses (3). Therefore, according to a locally developed grading scale (Table 1), for patients with moderate envenomation up to 4 vials, for severe cases 5-9 vials and for very severe cases 10-15 vials were being administered to achieve therapeutic response. Half of the initial dose was also being added if no response was attained in the first hours (3). Notwithstanding, in recent years, as a more conservative practice, lower attack doses (Although most of venom-induced effects will be subsided after average of 4-5 vials antivenom (3,8), some victims might experience progression of effects and require higher doses. Identification of characteristics of these patients will help clinicians to better estimate and decide the amount of antivenom needed and the duration of admission. Furthermore, it assists health policy makers to more accurately predict sufficient antivenom supplies for such patients. The objective of this study was to investigate snakebite prognostic factors of weak therapeutic response prior to antivenom administration.

Table 1. Snakebite severity grading

Grading

Local manifestation

Systemic manifestation

Minimal

Fang marks, no pain and swelling

None

Moderate

Swelling from bite site to adjacent joint, progressive swelling

None

Severe

Swelling involving entire bitten limb, blister/bulla formation, ecchymosis

None

Very Severe

Swelling beyond the bitten limb, extensive local necrosis, compartment syndrome

Incoagulable blood, increased protimes, thrombocytopenia, spontaneous bleeding, hemodynamic instability, shock, respiratory failure, acute renal failure, rhabdomyolysis, loss of consciousness

METHODS

This was a retrospective cross-sectional study of definite or suspected cases of viperidae snakebite envenomation according to taken snake corpse or patient’s clinical manifestations who were admitted to MTC during 2007-2011. Exclusively those patients who received antivenom as part of their treatment were enrolled. Demographic features, clinical manifestations and laboratory examinations prior to antivenom administration, snakebite severity score (SSS) (9), total number of antivenom vials administered, duration of admission of each patient according to available medical records were collected. To be included in the data analysis, each record had to include complete documentation to assess all potential factors and allow calculation of SSS. Snakebite severity score is a validated measure for evaluation of crotaline snakebites (a subfamily of viperidae snakes) severity according to local edema, hematologic tests, and gastrointestinal, neurologic, respiratory and cardiovascular signs (9). The ultimate SSS score ranges between 0-20, while snakebites with 0-3 scores can be interpreted as mild, with 4-7 scores as moderate and over 8 as severe (9).

Data analysis was performed with SPSS version 11.5. All potential factors in snakebite prognosis such as age, gender, bite site, venom induced manifestations and severity of snakebite were investigated independently according to mean number of administered antivenom vials and duration of admission by univariate analysis and also linear regression model to find the strength of their relationship. Moreover, we considered 5 vials antivenom as cutoff point of difficult achievement of therapeutic response (weak therapeutic response). Accordingly, the potential factors were further analyzed by comparing in two antivenom groups (≤5 and >5 vials).

RESULTS

In this 5-year study, 108 patients were included which 79% of them were male. The mean (SD, range) age was 34.5 (17.0, 6-78) years. The antivenom except one patient, who developed mild hypersensitivity reactions, was administered with excellent safety and the median (range) of antivenom vials administered was 5 (1-25) during median of 2 days (1-7) admission (Table 2). Most patients had mild to moderate envenomation according to SSS and the median of SSS was 2 (0-8). Approximately all patients were bitten in extremities with similar frequency in upper (50%) and lower (49%) and the anatomical location of bites were predominantly hand (44%) and foot (29%).

Table 2. Demographic data and clinical findings of 108 patients.

Feature

Scale

Report

Results

Gender

Male/Female

No. (%)

85/23 (78.7/21.3)

Age

Year

Mean ± SD

34.5 ± 17.0

Antivenom

No. vials

Median (IQR)

5.0 (5.0-10.0)

Weak therapeutic response

Patient

No. (%)

38 (35.2)

Adverse reactions

Patient

No. (%)

1 (0.9)

Duration of admission

Day

Median (IQR)

2.0 (2.0-3.0)

SSS

Score

Median (IQR)

2.0 (1.0-3.0)

PT

Second

Median (IQR)

13.0 (12.5-13.67)

PTT

Second

Median (IQR)

28.0 (26.0-31.0)

INR

IU

Median (IQR)

1.1 (1.0-1.2)

Platelet count

Count/L

Mean ± SD

184.2±57.9

The most common manifestations included fang marks (100%) (Figure 1), pain (100%), ecchymosis (88.9%), swelling (83.3%), blister formation (48.1%) (Figure 2), thrombocytopenia (25%), nausea/vomiting (13%), dizziness (12%), respiratory distress (12%), abdominal pain (9.3%), tachycardia (7.4%), hypotension (5.6%), spontaneous internal or mucosal bleeding (5.6%), fever (4.6%), increased protimes which is recently known as venom-induced consumption coagulopathy (VICC) (10) (3.7%), and neurologic abnormalities (2.8%).

Figure 1. A severely envenomated patient following viperidae (Echis carinatus) snakebite. (with permission)

A. The patient was unable to open her eyes due to extensive edema. Ecchymosis and blister formation were also present. Arrows show the bite site (fang marks). The edge of edema was marked on the victim’s face with a blue line. The patient later developed thrombocytopenia and VICC.

B. Same patient in the 4th day post-bite after administration of 24 vials of snake antivenom and other supportive treatments.

Figure 2. Severe edema, blister formation and dermal necrosis following viperidae snakebite. (with permission) 

Through univariate analysis, it was ascertained that patients with significantly longer duration of admission had cardiovascular manifestations (P= 0.03), GI manifestations (P=0.03), progressive swelling (P=0.04) and more severe envenomation (P=0.01) prior to antivenom administration (Table 2). Moreover, it was demonstrated that patients with progressive swelling (P=0.01), respiratory distress (P=0.02), ecchymosis (P=0.04), thrombocytopenia (P=0.001), spontane-ous bleeding (P=0.04), coagulopathic abnormalities in general (P=0.001) and also those with more extensive swelling (P<0.001) and severer envenomation according to SSS (P<0.001) significantly needed more antivenom to recover (Table 3). Putting these factors to stepwise linear regression model, after excluding confounding factors, revealed that a patient with swelling requires 4.2 fold, with progressive swelling 3.1 fold, with respiratory distress 3.2 fold and with coagulopathic disturbances 1.7 fold more antivenom to confine venom effects (number of antivenom vials= 1.8 + 4.2 [swelling] + 3.1[progressive swelling] + 3.2 [respiratory distress] + 1.7[coagulopathic disturbances], P= 0.02).

Table 3. Univariate analysis of potential snakebite prognostic factors according to amount of antivenom, duration of admission and snakebite severity

Factor

 

Frequency

Antivenom

Duration of Admission

SSS

Gender

Male