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Low-Dose Adrenaline, Promethazine, and Hydrocortisone in the Prevention

of Acute Adverse Reactions to Antivenom following Snakebite: A Randomised,
Double-Blind, Placebo-Controlled...

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DOI: 10.1371/journal.pmed.1000435 · Source: PubMed

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Low-Dose Adrenaline, Promethazine, and
Hydrocortisone in the Prevention of Acute Adverse
Reactions to Antivenom following Snakebite: A
Randomised, Double-Blind, Placebo-Controlled Trial
H. Asita de Silva1*, Arunasalam Pathmeswaran1, Channa D. Ranasinha1, Shaluka Jayamanne2,
Senarath B. Samarakoon2, Ariyasena Hittharage3, Ranjith Kalupahana3, G. Asoka Ratnatilaka3,
Wimalasiri Uluwatthage4, Jeffrey K. Aronson5, Jane M. Armitage6, David G. Lalloo7, H. Janaka de Silva1
1 Clinical Trials Unit, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka, 2 Polonnaruwa General Hospital, Polonnaruwa, Sri Lanka, 3 Kurunegala Teaching
Hospital, Kurunegala, Sri Lanka, 4 Hambantota General Hospital, Hambantota, Sri Lanka, 5 Department of Primary Health Care, University of Oxford, Oxford, United
Kingdom, 6 Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom, 7 Liverpool School of Tropical Medicine, Liverpool, United Kingdom

Abstract
Background: Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in
South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We
investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals
in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.

Methods and Findings: In total, 1,007 patients were randomized, using a 26262 factorial design, in a double-blind,
placebo-controlled trial of adrenaline (0.25 ml of a 1:1,000 solution subcutaneously), promethazine (25 mg intravenously),
and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching
placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe
adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence
of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions
to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients
were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with
placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25–67) at 1 h and by 38% (95% CI
26–49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding
hydrocortisone negated the benefit of adrenaline.

Conclusions: Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake
antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although
the need to improve the quality of available antivenom cannot be overemphasized.

Trial registration: http://www.ClinicalTrials.gov NCT00270777

Please see later in the article for the Editors’ Summary.

Citation: de Silva HA, Pathmeswaran A, Ranasinha CD, Jayamanne S, Samarakoon SB, et al. (2011) Low-Dose Adrenaline, Promethazine, and Hydrocortisone in the
Prevention of Acute Adverse Reactions to Antivenom following Snakebite: A Randomised, Double-Blind, Placebo-Controlled Trial. PLoS Med 8(5): e1000435.
doi:10.1371/journal.pmed.1000435
Academic Editor: Ken Winkel, University of Melbourne, Australia
Received May 4, 2010; Accepted March 31, 2011; Published May 10, 2011
Copyright: ß 2011 de Silva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by a grant from the University of Kelaniya, Sri Lanka (grant no: RP/03/04/08/01/2005). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Abbreviations: BP, blood pressure; OR, odds ratio
* E-mail: [email protected]

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 Prevention of Reactions to Antivenom

Introduction and poor recruitment rates, and were approved at each step by the
ethics review committee that approved the study. At any given
Globally an estimated 421,000 envenomings and 20,000 deaths time, no more than three hospitals participated in the study.
occur each year due to snakebite, although the incidence may be All patients who presented after snakebite were screened for
as high as 1,841,000 envenomings and 94,000 deaths [1]. eligibility by attending clinical staff (Table 1). Those over age 12 y
Populations with the highest burden (in rural areas of South Asia, requiring antivenom were eligible for randomisation. All partic-
Southeast Asia, and sub-Saharan Africa) experience high morbid- ipants provided written informed consent; for those unable to give
ity and mortality because of poor access to often suboptimal health consent or less than 16 y of age, a relative provided written
services; scarcity of antivenom, which is the only specific treatment informed consent.
for snakebite, may also be a problem [2]. The incidence of The primary aim was to determine whether low-dose adrenaline
snakebite in Sri Lanka (based on hospital data) is about 200 per (0.25 ml of a 1:1,000 solution subcutaneously; i.e., 250 micro-
100,000 individuals per year [1,3], one of the highest in the world. grams), promethazine (25 mg intravenously), or hydrocortisone
In the North-Central and North-Western Provinces of the country, (200 mg intravenously), alone or in combination, given as
which have the highest incidence of bites by highly venomous pretreatment, significantly reduced severe adverse reactions to
snakes, three regional hospitals reported 1,851 snakebite admis- antivenom compared with placebo (0.9% NaCl) up to and
sions, with 11 deaths due to snakebite during 2000 [4]. including 48 h. All time points relate to time after starting the
Antivenom is the mainstay of treatment for snakebite. Adverse antivenom infusion. Adverse reactions to antivenom were
reactions to the snake antivenoms available in Sri Lanka and other predefined as mild, moderate, and severe based on an interna-
countries in South Asia, which contains equine proteins, are tional classification of anaphylaxis reactions [17] (Table 2). We
common: both acute (anaphylactoid or pyrogenic) and delayed also assessed the safety of the pretreatment medication, looking
(serum sickness type) reactions occur [5]. Acute reactions cause the specifically for complications that might be caused by adrenaline:
greatest problem: in most cases, symptoms are mild (urticaria, arrhythmias, increased systolic blood pressure (BP) (.30 mm Hg
nausea, vomiting, headache, and fever), but in up to 40% of cases, increase), and intracerebral haemorrhage.
severe systemic anaphylaxis may develop, including bronchospasm Patients were randomized with equal probability to one of eight
and hypotension [6–9]. In Sri Lanka, only Indian-manufactured different treatments in a 26262 factorial blinded design, using a
polyvalent antivenoms are available. The rates of adverse reactions triple-dummy technique (Figure 1). Stratified block randomization
to these antivenoms are high, ranging from 43% to 81% [10–12]. was done by hospital site. For each site, computer-generated
Increasing the safety of treating individuals with snakebite using random allocation sequences were prepared independently by the
antivenom therefore has a high priority. trial statistician. All trial medications were prepared at the Clinical
Prophylactic use of hydrocortisone and antihistamines before Trials Unit, Faculty of Medicine, University of Kelaniya, and
infusion of antivenom is widely practised, although the theoretical packaged in identical sealed envelopes. Syringes containing
basis for this treatment is unclear and there is limited evidence of adrenaline and adrenaline placebo were clearly marked to ensure
efficacy. Subcutaneous adrenaline (epinephrine) significantly that they were not administered intravenously. The envelopes,
reduced the incidence of acute adverse reactions in one with unique, centre-specific identification numbers, were stored on
prospective study [10], but this study was of inadequate size to site.
establish the safety of pretreatment with adrenaline [13]. A Patients were seen by ward doctors within 10 min of admission
retrospective study in Papua New Guinea suggested that and examined. Baseline investigations, such as electrocardiogra-
adrenaline pretreatment significantly reduced acute adverse phy and assessment of blood clotting, were done as indicated.
reaction rates to antivenom but that promethazine or hydrocor- Randomization occurred after clinical assessment by ward doctors
tisone had no effect [14]. This study has subsequently been and after written informed consent had been obtained. Patients
criticised for its poor design [15]. Other studies investigating the remained under the care of consultant physicians following
use of pretreatment with hydrocortisone or promethazine have management protocols based on current treatment guidelines that
failed to demonstrate any clear benefit [12,16]. In view of this had been approved by the study team. The ward team made all
uncertainty about the safety and efficacy of pretreatment to reduce clinical decisions relating to patient care and administered the
or prevent adverse reactions to antivenom, we conducted a large pretreatment medication and antivenom. Monitoring for acute
randomized, placebo-controlled, double-blind trial to determine reactions was carried out independently by groups of three
whether low-dose adrenaline, promethazine, and hydrocortisone, medically qualified clinical research coordinators dedicated to
alone and in all possible combinations, are significantly better than each site who were blind to the interventions. Participants were
placebo in preventing acute adverse reactions to antivenom in observed continuously for the first 2 h and then reviewed at 4-h
snakebite victims. intervals until 48 h.
Patients were given ten vials of antivenom dissolved in 500 ml of
Methods isotonic saline as an intravenous infusion over 1 h. Antivenom
treatment was repeated as deemed necessary by attending
Subjects and Procedures clinicians, according to clinical judgement. However, patients
The study was developed for secondary referral hospitals in were not given further doses of trial medication, even if antivenom
areas in Sri Lanka with a high incidence of snakebite (Text S1). It was repeated. Patients were monitored using a clinical observation
was initiated in March 2005 at Anuradhapura, Kurunegala, and protocol developed jointly by consultant physicians and study
Polonnaruwa hospitals. Polonnaruwa and Kurunegala hospitals coordinators for acute adverse reactions to antivenom and any
participated throughout the study to its conclusion in April 2008. adverse reactions to the study drugs. Study-related patient
The study was terminated in Anuradhapura in June 2005. information was recorded in standardised clinical record forms.
Recruitment was subsequently moved to Embilipitiya hospital Patients were kept in hospital for at least 96 h after the infusion
for the period November 2005 to May 2006, and thereafter to of antivenom. If a reaction developed during infusion, or if a
Hambantota hospital until the conclusion of the trial. These patient developed cardiac arrhythmias, ischaemic changes on the
changes were made for a combination of administrative reasons electrocardiogram, a rise in BP (for systolic, an increase of

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 Prevention of Reactions to Antivenom

Table 1. Inclusion and exclusion criteria. adverse reactions would correspond to a substantial benefit. Using
the proposed design, a sample size of 1,000 gave 80% power to
detect a 25% relative reduction in adverse reactions from the
Inclusion Criteria Exclusion Criteria current reaction rate by any one treatment, at p,0.01.
Analysis. The prespecified primary outcome measure was the
Patients above 12 y of age Patients who are pregnant or nursing
frequency of severe reactions to antivenom up to and including
Patients admitted to hospital Patients who are currently taking beta- or 48 h after antivenom administration in those allocated to each
after snakebite in whom alpha-adrenoceptor antagonists, or tricyclic
treatment compared to those not allocated to that treatment.
antivenom is indicated antidepressants
Secondary outcomes were rates of severe reactions within 1 or 6 h,
Patients who give informed Patients in whom adrenaline may be
consent contraindicated (this may include patients with
rates of any adverse reactions up to and including 48 h, and acute
the following): (1) history of ischaemic heart adverse reactions to study treatments separately (prespecified as
disease or stroke, (2) uncontrolled arrhythmias, intracerebral haemorrhage, or an increase in systolic
hypertension, (3) tachyarrhythmias BP.30 mm Hg). The 26262 factorial design used for this trial
facilitates primary analyses to determine the main effects of the
doi:10.1371/journal.pmed.1000435.t001
three treatments, and allows investigation of two-way and three-
way interactions.
Analyses were undertaken on an intention-to-treat basis using
.30 mm Hg, or for diastolic, an increase of .20 mm Hg, from
logistic regression, and took into account clustering by trial site.
pretreatment level), a fall in BP (for systolic, a decrease of .20 mm
The final model included the three trial medications and all three
Hg, or for diastolic, a decrease of .10 mm Hg, from pretreatment
two-way interaction terms. Odds ratios (ORs) and 95% confidence
level), or anaphylaxis after the study drug and antivenom,
intervals for the effects of each treatment and the two-way
appropriate treatment (‘‘rescue medication’’) was given solely at interactions were calculated. This superseded our original
the discretion of the attending clinicians. Reactions to antivenom intention to compare event rates for those who received a
were treated by stopping the antivenom infusion temporarily, and particular drug versus those not given that drug, and to repeat
giving, alone or in any combination, 0.25 ml (mild reactions) or these analyses with stratification by other treatments administered
0.5 ml (moderate and severe reactions) of 1:1,000 adrenaline to check for interactions between trial medications. This change
intramuscularly, 25 mg of promethazine intravenously, or 200 mg was made on the advice given by the statistical reviewer for the
of hydrocortisone intravenously (rescue medication). journal.
Ethics committee approval was received from the Ethics Review No allowance was to be made for multiple comparisons in the
Committee, Faculty of Medicine, University of Kelaniya. An primary analyses but for secondary and, particularly, for tertiary
independent data monitoring committee was provided with comparisons, allowance was made for multiple hypothesis testing,
interim analyses when information from groups of 200 new taking into account the nature of the events (including timing,
patients became available. In the light of these analyses and the duration, and severity) and evidence from other studies.
results of any other new relevant information, the data monitoring
committee was instructed to advise the principal investigator if, in
Results
the committee’s view, there was proof beyond reasonable doubt
that the data showed that any part of the protocol under From March 2005 to April 2008, 4,677 patients who presented
investigation became clearly indicated or contraindicated, either after snakebite to trial hospitals were screened, and 1,007 eligible
for all participants or for a specific subgroup of trial participants, patients were randomized (53 at Anuradhapura, 16 at Embilipi-
or if it appeared that no clear outcome would be obtained. tiya, 152 at Hambantota, 353 at Kurunegala, and 433 at
However, no data monitoring committee–driven changes to Polonnaruwa) (Text S2). The main reason for exclusion was lack
protocol were made as a result of interim analyses. of clinical indication for antivenom. Recruitment was stopped
when the target sample size of 1,000 was reached in April 2008.
Statistical Analysis All the randomized patients completed the study and were
Sample size calculations. We estimated that acute adverse evaluated; there were no protocol deviations.
reactions would occur in about 40% of patients who received Table 3 shows the baseline demographic and other clinical
antivenom and that a reduction of over 25% in the rate of acute characteristics in the three treatment groups and shows good
balance between the groups. The median time from snakebite to
administration of antivenom was similar at the different hospitals
(median time ranged from 3.9 to 4.6 h). More than 70% of
Table 2. Classification of acute adverse reactions to patients were transferred from smaller rural hospitals. Some of
antivenom. them had received antivenom (20% of all study patients),
hydrocortisone (25% of all study patients), or promethazine
(9.7% of all study patients) before transfer to a trial hospital. None
Mild Moderate Severe
of the patients had been given adrenaline. This did not have a
Facial oedema Abdominal pain Drowsiness or altered consciousness significant effect on the trial outcomes. The biting snake species
Pruritus Nausea Systolic BP , 80 mm Hg was identified in only 25% of the cases.
Urticaria Vomiting Cyanosis
In total, 752 patients (75%) developed acute reactions to
antivenom within 48 h of administration (Table 4), of which 667
Fevera Bronchospasm Confusion
reactions (almost 90%) occurred in the first hour (Figure 2). Of
Rigora Stridor these, 9% were mild reactions, 48%, moderate, and 43%, severe;
a
Not in original classification [17] but added to capture all of the systemic
83% of severe reactions occurred in the first hour. After the first
reactions. hour the category of reaction changed in 128 patients (12.7%);
doi:10.1371/journal.pmed.1000435.t002 this change in reaction category took place before the end of 6 h

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 Prevention of Reactions to Antivenom

Figure 1. Trial profile.

doi:10.1371/journal.pmed.1000435.g001

in 93 of these 128 patients (Figure 2). There was a change in all patients with mild or no acute reactions, 47% of all patients
reaction category after 6 h in only 35 patients, and this included with moderate reactions, and 50% of all patients with severe
the one patient whose reaction category changed from moderate reactions.
to severe during the second 24 h of observation. Patients were Adrenaline reduced the rate of severe adverse reactions
given rescue medication at the discretion of the attending compared with placebo at 1 h by 43% (OR 0.57, 95% CI 0.43–
clinicians and managed as clinically indicated. In all, 40% of 0.75; p,0.001); and by 38% over 48 h (OR 0.62, 0.51–0.74;
patients received rescue medication within the first hour: 27% of p,0.001) (Tables 5 and 6). Neither hydrocortisone nor prometh-

Table 3. Patient baseline characteristics by treatment allocation.

Characteristic Adrenaline Hydrocortisone Promethazine Total (n = 1,007)

Yes (n = 502) No (n = 505) Yes (n = 510) No (n = 497) Yes (n = 505) No (n = 502)

Male, n (%) 392 (78.1) 384 (76.0) 388 (76.1) 388 (78.1) 383 (75.8) 393 (78.3) 776 (77.1)
Age in years, mean 36.0 (13.6) 37.1 (13.5) 36.0 (13.4) 37.1 (13.7) 36.8 (13.8) 36.3 (13.4) 36.5 (13.6)
(standard deviation)
Time between bite and 4.3 (2.8–6.8) 4.3 (2.9–6.8) 4.3 (2.8–6.7) 4.3 (3.0–7.2) 4.2 (2.8–7.9) 4.4 (3–6.9) 4.3 (2.9–6.8)
antivenom in hours,
median (interquartile
range)
Direct admission, n (%) 136 (27.1) 134 (26.5) 141 (27.7) 129 (26.0) 155 (30.7) 115 (22.9) 270 (26.8)
History of previous 51 (10.2) 54 (10.7) 54 (10.6) 51 (10.3) 60 (11.8) 45 (9.0) 105 (10.4)
snakebite, n (%)
Snake identified (%) 135 (26.9) 124 (24.6) 126 (24.7) 133 (26.7) 124 (24.6) 135 (26.9) 259 (25.7)
Antivenom given before 102 (20.3) 103 (20.4) 96 (18.8) 109 (21.9) 95 (18.8) 110 (21.9) 205 (20.4)
transfer, n (%)
Hydrocortisone given 127 (25.3) 128 (25.4) 131 (25.7) 124 (25.0) 117 (23.2) 138 (27.5) 255 (25.3)
before transfer, n (%)
Promethazine given 47 (9.4) 51 (10.1) 45 (8.8) 53 (10.7) 46 (9.1) 52 (10.3) 98 (9.7)
before transfer, n (%)
History of allergy, n (%) 37 (7.4) 45 (8.9) 39 (7.7) 43 (8.7) 42 (8.3) 40 (8.0) 82 (8.1)
History of bronchial 25 (5.0) 32 (6.3) 32 (6.3) 25 (5.0) 30 (5.9) 27 (5.4) 57 (5.7)
asthma, n (%)

doi:10.1371/journal.pmed.1000435.t003

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 Prevention of Reactions to Antivenom

Table 4. Outcomes during first hour and 48 h by treatment allocation.

Total
Outcome Reaction Adrenaline Hydrocortisone Promethazine (n = 1,007)
Yes Yes
(n = 502) No (n = 505) (n = 510) No (n = 497) Yes (n = 505) No (n = 502)

Reaction during first hour None, n (%) 185 (36.9) 155 (30.7) 170 (33.3) 170 (34.2) 182 (36.0) 158 (31.5) 340 (33.8)
Mild, n (%) 43 (8.6) 41 (8.1) 39 (7.7) 45 (9.1) 29 (5.7) 55 (11.0) 84 (8.3)
Moderate, n (%) 154 (30.7) 161 (31.9) 164 (32.2) 151 (30.4) 167 (33.1) 148 (29.5) 315 (31.3)
Severe, n (%) 120 (23.9) 148 (29.3) 137 (26.9) 131 (26.4) 127 (25.2) 141 (28.1) 268 (26.6)
Any reaction, n (%) 317 (63.1) 350 (69.3) 340 (66.7) 327 (65.8) 323 (64.0) 344 (68.5) 667 (66.2)
a
OR (95% CI) for severe 0.57 (0.43–0.75) 0.86 (0.60–1.24) 0.81 (0.51–1.30)
reaction
ORa (95% CI) for any 0.76 (0.64–0.91) 1.04 (0.85–1.28) 0.81 (0.65–1.02)
reaction
Reaction during 48 h None, n (%) 135 (26.9) 120 (23.7) 126 (24.7) 129 (26.0) 128 (25.4) 127 (25.3) 255 (25.3)
Mild, n (%) 29 (5.8) 37 (7.3) 30 (5.9) 36 (7.2) 22 (4.4) 44 (8.8) 66 (6.6)
Moderate, n (%) 184 (36.7) 180 (35.6) 188 (36.9) 176 (35.4) 197 (39.0) 167 (33.3) 364 (36.2)
Severe, n (%) 154 (30.7) 168 (33.3) 166 (32.5) 156 (31.4) 158 (31.3) 164 (32.7) 322 (32.0)
Any reaction, n (%) 367 (73.1) 385 (76.3) 384 (75.3) 368 (74.0) 377 (74.6) 375 (74.7) 752 (74.7)
a
OR (95% CI) for severe 0.62 (0.51–0.74) 0.80 (0.53–1.21) 0.87 (0.50–1.52)
reaction
ORa (95% CI) for any 0.85 (0.71–1.00) 1.07 (0.87–1.32) 1.00 (0.74–1.35)
reaction
Rescue medication during 206 (41.0) 191 (37.8) 186 (36.5) 211 (42.5) 194 (38.4) 203 (40.4)
first hour
X2 = 1.09; p = 0.30 X2 = 3.77; p = 0.052 X2 = 0.43; p = 0.51
Time (min) to rescue 30.7 (2.2) 25.9 (1.6) 31.1 (2.1) 25.4 (1.7) 30.7 (2.1) 25.8 (1.7)
medication, mean
(standard error)
t = 1.78; p = 0.08 t = 2.13; p = 0.03 t = 1.86; p = 0.06

All time points relate to time after starting the antivenom infusion.
a
For predictors of severe reaction, ORs were calculated using the main effects and all two-way interactions of the trial medications; for predictors of any reaction, ORs
were calculated using only the main effects of the trial medications because there were no significant interactions.
doi:10.1371/journal.pmed.1000435.t004

azine had any significant effect on the risk of severe adverse cant difference in the use of rescue medication between the
reactions at 1 h or 48 h (Tables 5 and 6). The same pattern was treatment groups.
observed at 6 and 24 h (Tables S1 and S2, respectively). There was
some evidence that the effect of allocation to hydrocortisone in Discussion
addition to adrenaline negated the benefit of adrenaline (OR 1.50,
95% CI 1.09–2.07; p = 0.013). Furthermore, adrenaline, but Reactions to antivenom present considerable challenges to
neither hydrocortisone nor promethazine, reduced the rate of all clinicians treating snakebite. The frequency of early reactions
reactions, especially at 1 h (Table 4). varies markedly between individual antivenoms and between
Adrenaline and promethazine seemed to be safe (Table 7): only different batches of antivenom from the same manufacturer,
13 (1.3%) patients died. All deaths were considered by the occurring with a frequency that ranges from less than 0.5% up to
supervising physician to be consequences of envenoming or 87%, although only a small proportion of reactions are life
complications that developed during intensive care treatment for threatening [7]. The high reaction rates of 75% observed in this
envenoming (one death from pneumonia, four from sepsis, three study are in line with the rates of between 43% and 81% that were
from shock, three from acute renal failure, and two from observed in three previous Sri Lankan studies [10–12].
respiratory failure). There were significantly more deaths among Given such high rates of antivenom reactions in some settings, it
those who received hydrocortisone compared to no hydrocortisone is not surprising that pharmacological prophylaxis has been
(ten [2%] versus three [0.6%]; OR 3.3, 95%CI 1.28–8.52; advocated to reduce acute adverse reactions to antivenom. Before
p = 0.014) (Table 8). In all, 261 patients had a significant rise in BP this study, only the routine use of adrenaline was supported by any
(increase in systolic BP of .30 mm Hg and/or increase in diastolic evidence. Low-dose subcutaneous adrenaline given immediately
BP of .20 mm Hg) within 48 h, but there was no significant before antivenom to snakebite victims significantly reduced the
association between rise in BP and trial medications, individually incidence of acute adverse reactions to the antivenom from 43% to
or combined at 30 or 60 min (Table 7). No patient had an 11% [10]. However, the study included only 102 participants,
intracerebral haemorrhage or arrhythmia. There was no signifi- primarily observed for the first hour after infusion, and could not

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 Prevention of Reactions to Antivenom

Figure 2. Progression of type of reaction over 48 h. Numbers within boxes indicate the number of patients according to the highest category
of reaction they had experienced by that time. Numbers above the boxes indicate the number of patients who experienced a higher category of
reaction during the preceding interval. Those who changed from no reaction to a reaction category are indicated by numbers highlighted in yellow.
Those who changed from mild reaction to a higher category are indicated by numbers highlighted in green. Those who changed from moderate to
severe reaction are indicated by numbers highlighted in turquoise. For example the above numbers can be interpreted as follows. At 1 h, there were
315 patients with moderate reaction, and by 6 h, 336 patients were classified as moderate reactions; 33 patients who had had no reaction in 1 h had
a moderate reaction during this interval, six patients who had had mild reaction in 1 h had a moderate reaction during this interval, and 18 patients
who had had moderate reaction in 1 h had a severe reaction during this interval: 336 = (315+33+6)218.
doi:10.1371/journal.pmed.1000435.g002

Table 5. Risk of severe reaction during the first hour by treatment: main effects and two-way interactions adjusted for clustering
by trial site.

Logistic Regression Model, Main Effects and Two-

Treatment Severe Reaction Way Interactions

Yes No Total OR 95% CI p-Value

Adrenaline 28 95 123 0.57 0.43–0.75 ,0.001

Hydrocortisone 39 88 127 0.86 0.60–1.24 0.430
Promethazine 37 89 126 0.81 0.51–1.30 0.378
Adrenaline and hydrocortisone 33 93 126 1.50 1.09–2.07 0.013
Adrenaline and promethazine 25 97 122 1.17 0.85–1.61 0.327
Hydrocortisone and promethazine 31 95 126 0.97 0.64–1.47 0.896
Adrenaline, hydrocortisone, and promethazine 34 97 131
Triple placebo 41 85 126
Total 268 739 1,007

There were no three-way interactions. Data are from five hospitals. All time points relate to time after starting the antivenom infusion.
doi:10.1371/journal.pmed.1000435.t005

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 Prevention of Reactions to Antivenom

Table 6. Risk of severe reaction up to and including 48 h by treatment: main effects and two-way interactions adjusted for
clustering by trial site.

Logistic Regression Model, Main Effects and Two-

Treatment Severe Reaction Way Interactions

Yes No Total OR 95% CI p-Value

Adrenaline 33 90 123 0.62 0.51–0.74 ,0.001

Hydrocortisone 41 86 127 0.80 0.53–1.21 0.296
Promethazine 43 83 126 0.87 0.50–1.52 0.629
Adrenaline and hydrocortisone 43 83 126 1.76 1.24–2.50 0.002
Adrenaline and promethazine 33 89 122 1.16 0.80–1.69 0.441
Hydrocortisone and promethazine 37 89 126 1.00 0.65–1.55 0.999
Adrenaline, hydrocortisone, and promethazine 45 86 131
Triple placebo 47 79 126
Total 322 685 1,007

There were no three-way interactions. Data are from five hospitals. All time points relate to time after starting the antivenom infusion.
doi:10.1371/journal.pmed.1000435.t006

establish safety, a major concern regarding the use of adrenaline as were mild or moderate, and the trial was not designed to study
a prophylactic agent [13], particularly the risk of intracerebral the efficacy of chlorphenamine alone, making it difficult to
haemorrhage [18,19]. Although a recent study from Papua New interpret the results.
Guinea suggested that adrenaline pretreatment was effective [14], In contrast to these small studies, our trial enrolled just over
the retrospective design, lack of standardised definitions, and a 1,000 patients, and 752 patients experienced reactions. Our
selective statistical analysis that did not correct for multiple prespecified primary end point was the development of severe
comparisons make it difficult to draw firm conclusions from this reactions to antivenom during the first 48 h after its administra-
study. tion. However, our data clearly showed that more than 80% of
Prophylactic use of hydrocortisone and antihistamines before severe reactions occurred during the first hour after antivenom
infusion of antivenom is widely implemented. However, one small administration, and only a negligible number of severe reactions
randomized controlled trial demonstrated no benefit from the occurred more than 6 h after antivenom administration. Further-
routine use of antihistamines [16]. Hydrocortisone takes several more, about 40% of patients were given rescue medication (i.e.,
hours to act and may be ineffective as a prophylactic against adrenaline, hydrocortisone, or promethazine as rescue medication
acute adverse reactions that develop almost immediately after irrespective of the randomization) in the first hour after antivenom
antivenom treatment. One small study (52 patients) showed that administration. Such early administration of rescue medication
intravenous hydrocortisone alone was ineffective in preventing may have diluted the effects of the randomization on reactions at
acute adverse reactions to antivenom, but demonstrated a trend the later time points, but should not have affected rates of
towards hydrocortisone reducing reactions when given with reactions at 1 h, and we therefore chose to focus on severe
intravenous chlorphenamine [12]. However, all of the reactions reactions during the first hour. Previous studies have used a variety

Table 7. Heart rate, blood pressure, and number of patients with rise in blood pressure at 30 min and 60 min after pretreatment
administered.

Time after
Pretreatment Measure Adrenaline Hydrocortisone Promethazine

Yes (n = 502) No (n = 505) Yes (n = 505) No (n = 502) Yes (n = 505) No (n = 502)

30 min Heart rate 94.9 (0.91) 94.9 (0.93) 96.2 (0.95) 93.7 (0.89) 95.2 (0.94) 94.6 (0.90)
Systolic BP 114.9 (0.97) 111.5 (1.01) 113.9 (0.98) 112.6 (1.00) 113.5 (1.02) 112.9 (0.95)
Diastolic BP 70.3 (0.68) 68.9 (0.66) 70.3 (0.68) 69.0 (0.65) 69.4 (0.67) 69.9 (0.67)
Number of patients 63 (12.6) 52 (10.3) 63 (12.4) 52 (10.4) 66 (13.1) 49 (9.8)
with rise in BPa
60 min Heart rate 93.4 (0.85) 93.0 (0.88) 94.2 (0.88) 92.3 (0.85) 93.4 (0.85) 93.1 (0.87)
Systolic BP 117.1 (0.85) 114.2 (0.94) 115.6 (0.93) 115.6 (0.87) 116.5 (0.91) 114.7 (0.89)
Diastolic BP 71.5 (0.61) 69.8 (0.64) 71.2 (0.65) 70.2 (0.61) 70.8 (0.63) 70.6 (0.63)
Number of patients 84 (16.7) 64 (12.7) 82 (16.1) 66 (13.3) 85 (16.8) 63 (12.6)
with rise in BPa

All values are mean (standard error).

a
An increase in systolic BP of .30 mm Hg and/or diastolic BP of .20 mm Hg higher than baseline.
doi:10.1371/journal.pmed.1000435.t007

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 Prevention of Reactions to Antivenom

Table 8. Risk of death by treatment: main effects adjusted for clustering by trial site.

Treatment Death Logistic Regression Model, Main Effects

Yes No Total OR 95% CI p-Value

Adrenaline 0 123 123 0.85 0.39–1.85 0.681

Hydrocortisone 2 125 127 3.30 1.28–8.52 0.014
Promethazine 0 126 126 1.16 0.80–1.68 0.220
Adrenaline and hydrocortisone 3 123 126
Adrenaline and promethazine 2 120 122
Hydrocortisone and promethazine 4 122 126
Adrenaline, hydrocortisone, and promethazine 1 130 131
Triple placebo 1 125 126
Total 13 994 1,007

Data from five hospitals.

doi:10.1371/journal.pmed.1000435.t008

of different definitions for reactions, and we chose to use an reactions between a 30-min infusion and intravenous injection
established international grading [17] in an attempt to standardise over 10 min. Using a small test dose of antivenom to detect
this; rates of severity of reactions are therefore not directly patients who may develop acute adverse reactions to the
comparable to previous studies. The factorial design enabled us to antivenom has no predictive value and can itself cause
investigate both direct effects and interactions between the anaphylactic reactions [6,25].
different medications in the most efficient manner. The high rate of adverse reactions to antivenom observed in our
We found that administration of adrenaline significantly and study is common to large areas of South Asia, and is an example of
substantially reduced the risk of severe adverse reactions in the first how poor manufacturing and quality control by antivenom
hour and that this was still apparent at 48 h, but neither producers causes substantial problems for patients and their doctors.
hydrocortisone nor promethazine had any clear effect. We have This highlights the importance of addressing issues of poor quality
also unequivocally demonstrated that a dose of subcutaneous and potentially unsafe antivenom. Even well-manufactured anti-
adrenaline of 250 micrograms is safe after snakebite, even where venom may be associated with severe adverse reaction rates of up to
there is coagulopathy. While pretreatment with hydrocortisone or 5% [15]. We therefore welcome the recent World Health
promethazine did not reduce severe reaction rates to antivenom Organization guidelines on production, control, and regulation of
significantly, hydrocortisone negated the beneficial effects of antivenom [26]. The need for concerted action by local health and
adrenaline when these treatments were given together. However, regulatory authorities, the World Health Organization, and other
given the multiple comparisons and post-hoc nature of this finding, stakeholders, including technology transfer programmes between
it should be interpreted cautiously. Hydrocortisone was also antivenom manufacturers, to improve the quality of antivenom can
associated with an increased risk of death, but this finding was not be overemphasized. Ultimately, the prevention of antivenom
based on very small numbers. Given that hydrocortisone has no reactions will depend on improving the quality of antivenom. The
benefit and may even be harmful, we would discourage its current increasing recognition of the considerable burden of snakebite and
widespread empirical use as a pretreatment before antivenom its treatment will hopefully lead to such improvements. Until these
administration.
overdue improvements come about, we have shown that pretreat-
The mechanism of reactions to antivenom is uncertain. Acute
ment with low-dose adrenaline is an effective and safe therapy to
reactions may be due to type 1 (IgE-mediated) hypersensitivity, but
prevent acute reactions to antivenom. This finding may be of
antivenom reactions often occur in those with no previous
particular relevance in areas where adverse reactions to antivenom
exposure to equine proteins. Although some commercial anti-
are common. Meanwhile, we continue to reiterate that the need for
venoms have anticomplement activity in vitro, complement
careful observation of patients receiving antivenom and prompt
activation has never been clearly demonstrated in patients with
treatment of acute reactions when they occur remains undimin-
antivenom reactions [6,20,21]. Early reactions are most likely to
ished.
be due to a combination of type 1 hypersensitivity, complement
activation, and the effect of aggregates of immunoglobulin or
immunoglobulin fragments, including Fc, which can be found in Supporting Information
even highly refined antivenoms [22]. Although theoretically Table S1 Risk of severe reaction during the first 6 h by
cleaving of the IgG molecule into smaller fragments should reduce treatment. Main effects and two-way interactions adjusted for
the incidence of antivenom reactions, this has not been shown in clustering by trial site.
clinical studies, and the major influence on reaction rates appears Found at: doi:10.1371/journal.pmed.1000435.s001 (0.04 MB
to be the manufacturing process [7]: there is emerging evidence DOC)
that the use of caprylic acid, which results in a more pure IgG
preparation, may reduce reaction rates [23,24]. Slow infusion of Table S2 Risk of severe reaction during first 24 h by treatment.
antivenom intravenously (rather than administration by bolus Main effects and two-way interactions adjusted for clustering by
injection) has also been advocated as a way of reducing reaction trial site.
rates, although the only small comparative study of methods of Found at: doi:10.1371/journal.pmed.1000435.s002 (0.04 MB
administration found no difference in the rates and severity of DOC)

PLoS Medicine | www.plosmedicine.org 8 May 2011 | Volume 8 | Issue 5 | e1000435

 Prevention of Reactions to Antivenom

Text S1 Study protocol. Michael Dewey, statistical reviewer for PLoS Medicine, who proposed an
Found at: doi:10.1371/journal.pmed.1000435.s003 (0.10 MB improved method of analysis.
DOC)
Text S2 CONSORT checklist.
Author Contributions
Found at: doi:10.1371/journal.pmed.1000435.s004 (0.22 MB ICMJE criteria for authorship read and met: HAdS AP CDR SJ SBS AH
DOC) RK GAR WU JKA JMA DGL HJdS. Agree with the manuscript’s results
and conclusions: HAdS AP CDR SJ SBS AH RK GAR WU JKA JMA
DGL HJdS. Designed the experiments/the study: HAdS CDR AH JKA
Acknowledgments JMA DGL HJdS. Analyzed the data: HAdS AP JKA JMA DGL. Collected
We thank the directors and medical and nursing staff of the study hospitals data/did experiments for the study: HAdS SJ SBS AH RK GAR WU.
for their help and support, clinical research coordinators for their hard Enrolled patients: HAdS SJ SBS AH RK GAR WU. Wrote the first draft
work, and the independent data monitoring committee (Charles Warlow of the paper: HAdS CDR HJdS. Contributed to the writing of the paper:
[Western General Hospital, Edinburgh; Chair], Saman Gunatilake HAdS AP CDR SJ SBS JKA DGL HJdS. Provided comments on the
[University of Sri Jayawardenapura], and Rajitha Wickremasinghe manuscript: JMA. Participated in the design; supervised the study: HJdS.
(University of Kelaniya]). We also gratefully acknowledge input from

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 Prevention of Reactions to Antivenom

Editors’ Summary
Background. Of the 3,000 or so snake species in the world, and nearly half of all the patients were given rescue medication
about 600 are venomous. Venomous snakes, which are during the first hour. Compared with placebo, pretreatment
particularly common in equatorial and tropical regions, with adrenaline reduced severe reactions to the antivenom by
immobilize their prey by injecting modified saliva (venom) 43% at one hour and by 38% over 48 hours. By contrast,
into their prey’s tissues through their fangs—specialized neither hydrocortisone nor promethazine given alone reduced
hollow teeth. Snakes also use their venoms for self-defense the rate of adverse reactions to the antivenom. Moreover,
and will bite people who threaten, startle, or provoke them. adding hydrocortisone negated the beneficial effect of
A bite from a highly venomous snake such as a pit viper or adrenaline.
cobra can cause widespread bleeding, muscle paralysis,
irreversible kidney damage, and tissue destruction (necrosis) What Do These Findings Mean? These findings show
around the bite site. All these effects of snakebite are that pretreatment with low-dose adrenaline is safe and
potentially fatal; necrosis can also result in amputation and reduces the risk of acute severe reactions to snake
permanent disability. It is hard to get accurate estimates of antivenom, particularly during the first hour after infusion.
the number of people affected by snakebite, but there may They do not provide support for pretreatment with
be about 2 million envenomings (injections of venom) and promethazine or hydrocortisone, however. Indeed, the
100,000 deaths every year, many of them in rural areas of findings suggest that the addition of hydrocortisone could
South Asia, Southeast Asia, and sub-Saharan Africa. negate the benefits of adrenaline, although this finding
needs to be treated with caution because of the design of
Why Was This Study Done? The best treatment for snakebite the trial, as does the observed increased risk of death
is to give antivenom (a mixture of antibodies that neutralize the associated with pretreatment with hydrocortisone. More
venom) as soon as possible. Unfortunately, in countries where generally, the high rate of acute adverse reactions to
snakebites are common (for example, Sri Lanka), antivenoms are antivenom in this trial highlights the importance of
often of dubious quality, and acute allergic reactions to them improving the quality of antivenoms available in Sri Lanka
frequently occur. Although some of these reactions are mild (for and other parts of South Asia. The researchers note that the
example, rashes), in up to 40% of cases, anaphylaxis—a recent World Health Organization guidelines on production,
potentially fatal, whole-body allergic reaction—develops. The control, and regulation of antivenom should help in this
major symptoms of anaphylaxis—a sudden drop in blood regard but stress that, for now, it is imperative that
pressure and breathing difficulties caused by swelling of the physicians carefully monitor patients who have been given
airways—can be treated with adrenaline. Injections of antivenom and provide prompt treatment of acute reactions
antihistamines (for example, promethazine) and hydrocortisone when they occur.
can also help. In an effort to prevent anaphylaxis, these drugs are
also widely given before antivenom, but there is little evidence Additional Information. Please access these Web sites via
that such ‘‘prophylactic’’ treatment is effective or safe. In this the online version of this summary at http://dx.doi.org/10.
randomized double-blind controlled trial (RCT), the researchers 1371/journal.pmed.1000435.
test whether low-dose adrenaline, promethazine, and/or
hydrocortisone can prevent acute adverse reactions to N The MedlinePlus Encyclopedia has pages on snakebite and
antivenom. In an RCT, the effects of various interventions are on anaphylaxis (in English and Spanish)
compared to a placebo (dummy) in groups of randomly chosen N The UK National Health Service Choices website also has
patients; neither the patients nor the people caring for them pages on snakebite and on anaphylaxis
know who is receiving which treatment until the trial is
completed.
N The World Health Organization has information on
snakebite and on snake antivenoms (in several languages);
its Guidelines for the Production, Control and Regulation
What Did the Researchers Do and Find? The researchers of Snake Antivenom Immunoglobulins are also available
randomized 1,007 patients who had been admitted to
secondary referral hospitals in Sri Lanka after snakebite to N The Global Snakebite Initiative has information on
receive low-dose adrenaline, promethazine, hydrocortisone, or snakebite
placebo alone and in all possible combinations immediately N A PLoS Medicine Research Article by Anuradhani Kasturir-
before treatment with antivenom. The patients were atne and colleagues provides data on the global burden of
monitored for at least 96 hours for adverse reactions to the snakebite
antivenom; patients who reacted badly were given adrenaline,
promethazine, and hydrocortisone as ‘‘rescue medication.’’
N A PLoS Medicine Neglected Diseases Article by José Marı́a
Gutiérrez and colleagues discusses the neglected problem
Three-quarters of the patients had acute reactions—mostly of snakebite envenoming
moderate or severe—to the antivenom. Most of the acute
reactions occurred within an hour of receiving the antivenom,

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