Safety of subcutaneous adrenaline as prophylaxis against acute adverse reactions to anti-venom serum in snakebite

Objectives To study the safety of low dose subcutaneous adrenaline given as prophylaxis against acute adverse reactions to anti-venom serum (AVS) in patients bitten by snakes. Methods Patients admitted with snakebite envenoming who satisfied inclusion criteria were given 0.25 ml of 1:1000 adrenaline subcutaneously immediately before administration of AVS. They were observed for adverse effects, and pulse and blood pressure (BP) were monitored. Results 51 patients [35 males, mean age 34.8 years (SD 14)] were included in the study. Adverse reactions to AVS occurred in 15 (29.4%) patients. There was one death from suspected cerebral haemorrhage, and 3 (5.9%) patients developed small haematomas at the subcutaneous injection site. There were no significant changes in mean pulse or BP following administration of subcutaneous adrenaline. Conclusions Low dose subcutaneous adrenaline did not cause significant changes in pulse rate or BP. Although the death was unlikely to be directly related to subcutaneous adrenaline, we suggest further studies on the safety of this prophylactic treatment before its routine use.


Introduction
Antivenom serum (AVS) is the only effective treatnent for snakebite envenoming.Adverse effects of AVS are common, and include anaphylaxis.On average, about half the patients who receive AVS available in Sri Lanka develop adverse reactions to it (1,2,3) and reaction rates as high as 68% have been reported (4).We recently showed that low dose adrenaline given subcutaneously immediately before administration of AVS to snakebite victims significantly reduces incidence of such acute adverse reactions (1).Its use in this manner has now been recommended in the Cochrane database (5).A major concern regarding use of adrenaline is the risk of intracerebral haemorrhage (6), a result of coagulopathy induced by some snake venoms and hypertension produced by adrenaline.In the study mentioned above (1), no significant adverse effects attributable to adrenaline were reported, but patients who were at high risk for adverse effects from adrenaline were excluded.Adrenaline given intravenously causes hypertension.Although this does not seem to occur with subcutaneous administration (7), fatal intracranial bleeding has been reported (8).The objective of this study was to further assess the safety of low dose subcutaneous adrenaline.

Methods
We prospectively studied consecutive patients with snakebite envenoming at the Colombo North Teaching Hospital, from April 2000 to October 2001.After informed consent, patients who satisfied inclusion criteria were given 0.25 ml of 1:1000 adrenaline subcutaneously into the forearm immediately before administration of polyspecific AVS (Haffkine Laboratories, Mumbai, India) by intravenous infusion.Patients were excluded if they were pregnant, aged over 70 years, had hypertension, ischaemic heart disease, arrhythmias or cerebrovascular disease.They were observed for adverse effects, and pulse and blood pressure (BP) were recorded before, and every 5 min for 20 min, and every 10 min for up to 60 min after adrenaline was given.In patients who developed adverse reactions to AVS, subsequent pulse and BP measurements were not included for analysis as these values were likely to be influenced by the reaction.Ethical approval was obtained for our study from the Ethics Committee, University of Kelaniya.
The patient who died was a 65-year old man, bitten by unidentified snake.On admission there was swelling at the site of bite (right foot) and coagulopathy (whole blood Papers clotting time > 20 min).He was given subcutaneous adenaline followed by 10 vials of AVS.He developed a reaction to AVS (severe rigors, and tightening sensation in his throat and chest) 55 min after the infusion was started.AVS was stopped, and he was given 0.5ml 1:1000 adrenaline intramuscularly, 200 mg hydrocortisone intravenously and 25 mg promethazine intramuscularly.He recovered, and as the clotting time was less than 10 minutes by that time, no further AVS was given.About 10 hours later he became drowsy and unresponsive.His limbs were flaccid, tendon reflexes were present and plantar responses were extensor bilaterally.There was no neck stiffness.Optic fundi could not be visualised because of cataracts.Intracerebral haemorrhage was suspected, and as facilities for CT scan were not available in our hopsital, he was transferred to the National Hospital, Colombo.He died before CT could be performed.His relatives did not consent to post-mortem examination.
ous administration is 43 min (9).Based on this it is likely that almost all of the drug would be eliminated from the body 4 hours after administration, and that effects would have worn off by then, perhaps sooner.In another study (10), plasma adrenaline concentrations fell by 3 hours after subcutaneous administration, and effects lasted 90 min.These findings make the death of our patient unlikely to be directly related to subcutaneous adrenaline.Nevertheless, further studies on the safety of prophylactic adrenaline shoud be performed before its routine use can be recommended in snakebite.

Comment
Low dose subcutaneous adrenaline did not cause significant changes in mean pulse rate or BP in our patients.This is in agreement with previous findings (7).The subcutaneous haematomas can be attributed to the injection.The patient who died, in addition to receiving subcutaneous adenaline about 11 hours before death, had snake venom induced coagulopathy, and developed a reaction to AVS which was treated with intramuscular adrenaline about one hour after the subutaneous dose.A recent study suggests that the half-life of adrenaline after subcutane-

Figure .
Figure.Mean systolic and diastolic blood pressures of patients who received low dose subcutaneous adrenaline.Vertical bars denote one standard deviation.