Toxicon 54 (2009) 9981011

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Toxicon
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Epidemiological, clinical and therapeutic aspects of Bothrops asper bites

o*
Rafael Otero-Patin
Facultad de Medicina, Universidad de Antioquia, Medelln, Colombia

a r t i c l e i n f o a b s t r a c t

Article history: Bothrops asper inicts the majority of snakebites in Central America and in the northern
Received 18 February 2009 regions of South America, mostly affecting young agricultural workers in rural settings.
Received in revised form 29 June 2009 This species is capable of provoking severe envenomings associated with local and
Accepted 1 July 2009
systemic manifestations. The main clinical features are: local edema, ecchymoses, blisters,
Available online 8 July 2009
dermonecrosis, myonecrosis, debrinogenation, thrombocytopenia, systemic bleeding,
hypotension and renal alterations. In addition, soft-tissue infection, acute renal failure,
Keywords:
compartmental syndrome, central nervous system hemorrhage and, in pregnant women,
Bothrops asper
Envenoming abortion, fetal wastage and abruptio placentae have been described as complications.
Epidemiology Intravenous administration of antivenom constitutes the mainstay in the therapy. Anti-
Clinical features venoms composed of either whole IgG or F(ab0 )2 fragments, manufactured in Brazil,
Antivenom Colombia, Costa Rica and Mexico, have been tested in controlled clinical trials, and rational
Therapy protocols for antivenom administration have been developed. In addition to antivenom
Ancillary treatment therapy, a number of ancillary interventions are recommended in the treatment of B. asper
bites.
2009 Elsevier Ltd. All rights reserved.

1. Epidemiological background
The incidence of snakebites, regardless of the species
involved, varies from country to country and between
regions in a country, depending on factors as diverse as
climate, ecological parameters, biodiversity, distribution of
venomous snakes, human population density, economic
activities, and types of dwellings, among others. In Latin
America, the overall incidence of snakebite envenomings
ranges from 5 to 62 cases/100,000 population per year,
depending on the country (roughly corresponding from
130,000 to 150,000 cases in the whole region, with an
estimated number of 2300 deaths) (Chippaux, 2006;
Kasturiratne et al., 2008). A large number of cases, espe-
cially in Costa Rica, Nicaragua, Honduras, Panama,
Colombia, Venezuela and Ecuador, are inicted by Bothrops
asper, where it is responsible for 5080% of the snakebites
(Dao, 1971; Ayerbe, 2009; Gutierrez, 1995; Gutierrez et al.,
* Tel./fax: 57 4 2685062.
E-mail address: rafaotero@une.net.co
2006a,b; Otero et al., 1992a, 2001a; Sasa and Vazquez,
2003; Warrell, 2004; Otero, 2007; Otero-Patin o, 2008).
In Latin America, Panama presents the highest incidence
of snakebites in the region (5462 cases/100,000 pop-
ulation; 2000 bites per year), mostly by B. asper, whereas
the incidence and total number of cases per year in other
countries vary. An incidence of 1214 cases/100,000 pop-
ulation, corresponding to a total number of 22,000 bites, is
described in Brazil, most of them inicted by Bothrops sp.
species different from B. asper. In Costa Rica, 550-600 bites
are reported every year, predominantly by B. asper, with an
incidence of 16 cases/100,000 population. In turn, Mexico,
Peru (by different Bothrops spp.) and Colombia report an
incidence of approximately 6 cases/100,000 population,
with a total number of cases of 2600 for Colombia (Meier
and White, 1995; Chippaux, 2006; Fan et al., 2004;
Gutierrez et al., 2006a,b; Sasa and Vazquez, 2003; Otero
et al., 1992a, 2001a; Otero, 2007; Otero-Patin o, 2008;
Kasturiratne et al., 2008). Nevertheless, as occurs for other
snake species in Africa and Asia, there are important
regional differences within a single country. In Panama, for
instance, the provinces of Panama Este, Veraguas, Cocle and

0041-0101/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.toxicon.2009.07.001
 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
Chiriqu present incidences higher than 100 snakebites/
100,000 population/year (communication from the
Ministry of Health, Panama).
Although a number of bites (corresponding to 1020% of
the total number of cases) occur inside or around houses,
the majority of these accidents are an occupational hazard
occurring in agricultural elds in rural communities
(8590% of the cases), mostly affecting agricultural workers
(Gutierrez et al., 2006a,b; Otero et al., 1992a, 2001a; Sasa
and Vazquez, 2003). These accidents mostly affect young
adults (1545 years old, 54% of cases), predominantly males
(76%); however, a signicant number of cases occur in
children (30%). Regarding the anatomical region of the
bites, 70% of the cases occur in the lower extremities
(Meier and White, 1995; Chippaux, 2006; Gutierrez et al.,
2006a,b; Sasa and Vazquez, 2003; Otero et al., 1992a,
2001a; Otero, 2007; Otero-Patin o, 2008; Kasturiratne
et al., 2008).
As in the case of incidence, the fatality rate also varies
between countries and between regions within a country.
Such differences in mortality are due to ethno-anthropo-
logical factors, geographical difculties for early transfer of
patients to hospitals, the availability of therapeutic
resources and primary care programs in remote places
where bites occur, the snake species causing the accidents,
and the intra-species variability in venom composition
(related to age, size, sex, diet, and geographical parame-
ters). In Brazil, a case fatality rate for snakebites of 0.5% has
been described (Bothrops spp. 0.30.4%; Crotalus spp. 1.3%;
Lachesis spp. 0.8%) (Fan et al., 2004; Frana and Malaque,
2003). In Costa Rica and Panama, fatality rate is also less
than 1%, with mortality rates of less than 0.15/100,000
Fig. 1. Variability of color pattern in B. asper specimens from the Departments of Antioquia and Choco, Colombia. Photos: D. A. Warrell and R. Otero.
999
population in Costa Rica (Fernandez and Gutierrez, 2008)
and 0.6/100,000 population in Panama in 2006 (data from
the Ministry of Health, Panama). Interestingly, Brazil, Costa
Rica and Panama are countries where the Ministries of
Health distribute antivenoms free of charge for patients in
all the Hospitals and Health Centers.
In Colombia, the fatality rate of snakebite envenoming is
35%, whereas 610% of patients suffer some type of
sequelae, mainly as a result of dermonecrosis and myo-
necrosis. The antivenom supply in Colombia has tradi-
tionally been insufcient (Silva-Haad, 1989; Otero et al.,
1992a,b,c). In 1995, the Colombian Ministry of Health
applied a legislation, that was approved by the Congress in
1993, which modied the social security system. Since
then, the responsibility of antivenom purchase relies in
health and insurance institutions and not in the central
government. As a consequence, there have been serious
problems in the supply of antivenoms, both in terms of
quantity and quality (Otero, 2004; Otero et al., 2000a,
2001a,b, 2002a,b).
B. asper (Fig 1) is responsible for 5080% of snakebites,
and 6090% of deaths secondary to snakebites, in Central
America and northern South America, thus having a heavy
public health impact in these regions (Mekbel and
Cespedes, 1963; Vargas-Baldares, 1978; Gutierrez, 1995;
Chippaux, 2006; Gutierrez et al., 2006a,b; Otero et al.,
2002a; Otero, 2007; Otero-Patin o, 2008; Sasa and Vaz-
quez, 2003). This irritable, fast-moving, unpredictable
species can grow to about 250 cm and inicts bites in any
anatomical region, including above the knee level, some-
times inducing severe local and systemic envenoming
(Hardy, 1994; Warrell, 2004). Because of its irritability,
1000 o / Toxicon 54 (2009) 9981011
R. Otero-Patin

during the stroke of the bite, venom may be ejected
before the fangs penetrate the skin, and yellow drops of
venom can be observed around the fang marks (our
unpublished observations). B. asper is widely distributed
in humid lowland regions of Mexico, Central America,
Venezuela, Colombia and Ecuador (Campbell and Lamar,
2004; Sasa et al., 2009) and readily adapts to agricultural
settings, thus being in close contact with agricultural
workers and human dwellings (see Sasa et al., 2009). This
species is popularly known as cuatronarices, equis,
mapana, rabiseca, boquidora, dama (Embera ethnic group)
or tapa (Cuna ethnic group) in Colombia; cuatronarices,
equis pachona, equis rabo de hueso and pudridora in
Ecuador; equis in Panama; terciopelo and barba amarilla
in Central America (Otero et al., 1992a,b, 2000a, 2001a;
Otero, 1994, 2007; Campbell and Lamar, 2004; Gutierrez
et al., 2006a,b).
More than 110 years after Calmette developed sero-
therapy for the treatment of snakebite envenoming, this
resource remains the mainstay in the treatment (Bon, 1996;
Theakston et al., 1992, 2003; Otero-Patin o et al., 1998;
Otero, 2007). Unfortunately, antivenoms are often
unavailable in remote rural places of developing countries,
being this one of the factors responsible for the delayed
treatment of envenomed patients (Theakston et al., 2003;
o et al., 1998; Gutierrez et al.,
Otero et al., 1992c; Otero-Patin
2006a). In many tropical areas of Latin America, at least
4050% of patients receive traditional medicine attention
as rst treatment (plants, chemical products, physical
methods, prayers, etc.). This and other factors cause a delay
in the arrival of patients to hospitals and other health
centers, which usually occurs six or more hours after the
bite, thus affecting the prognosis of these cases (Otero et al.,
1992a, 1996, 1999, 2000a,b, 2001a,b; Otero-Patin o et al.,
1998; Otero-Patin o, 2008). Death is usually prevented
when the patients receive adequate antivenom therapy
within the rst two hours of the bite. On the other hand,
almost all cases ending in death or developing sequelae are
associated with a delayed onset of specic treatment more
than two hr after the bite (RR 2.5). Medical attention
beyond this time interval is a critical factor to develop acute
renal failure (ARF) and hemorrhage in the central nervous
system (CNS) in B. asper bites (P 0.02), and is also asso-
ciated with an increased risk of developing compartmental
syndrome, local necrosis and other sequelae (P < 0.001) in
patients bitten by adult specimens (more than one meter
body length) (Otero, 1994, 2007; Otero et al., 2002a).
2. Clinical aspects and diagnosis
Clinical features of envenoming by B. asper are similar in
Central and South America. They include edema (95% of the
cases), the classical sign of local bothropic envenoming,
detectable as early as 5 min after the bite; local hemorrhage
(34%), evident as bleeding or ecchymosis during the rst
530 min; blisters (12%), dermonecrosis and myonecrosis
(10%), apparent only six or eight hours after the bite.
Debrinogenation (6070%) is the classic sign of systemic
envenoming, which usually occurs within 3060 min.
In rare cases of patients receiving antivenom within
3045 min after the bite, who had normal blood coagulation
on admission, it has been observed that they may
present unclottable blood 6 h after beginning of specic
treatment (our unpublished observations). Thrombocyto-
penia (1530% of cases) and hypotension (1014%) are also
observed, as well as systemic bleeding (mainly gingival
bleeding and hematuria, 2530%, or through recent
wounds). As described for bites by various Bothrops species,
other systemic hemorrhagic manifestations include vaginal,
rectal, through veni-puncture sites or CNS bleeding,
epistaxis and hemoptysis (Rosenfeld, 1971; Kamiguti and
Cardoso, 1989; Kerrigan, 1991; Kamiguti et al., 1996; Frana
and Malaque, 2003; Gutierrez and Lomonte, 2003; Otero,
1994, 2007; Otero et al., 1992a,b, 2002a).
The progression and extension of edema and the pres-
ence of necrosis dene the local envenoming grade. Alter-
ation of blood coagulation, bleeding and the presence of
life-threatening complications such as shock, ARF and
damage of vital organs, dene the systemic envenoming
grade (Table 1, Figs. 25) (Otero, 2007). In B. asper cases, 15%
of patients present severe systemic envenoming and 10%
severe local envenoming (necrosis, edema extending to the
trunk). On the other hand, 40% of cases have mild and 45%
moderate local envenoming, together with systemic
envenoming in 23% and 25% of them, respectively. Addi-
tionally, 36% of patients present only local envenoming,
without systemic manifestations (Otero et al., 1992a; Otero,
1994, 2007). On the basis of previous studies performed in
Colombia in B. asper bites, only patients with severe
envenoming are at risk of death and sequelae (Otero et al.,

Table 1
Clinical gradation of envenoming in B. asper bites.

Grade Clinical local signs Clinical systemic signs

Non-envenoming Mild pain, negligible edema and hemorrhage
Mild envenoming Swelling involving one or two segments of the bitten limb
(e.g., foot and leg), circumference of extremity increased
<4 cm, ecchymosis; scarce or no bleeding in the bite site, no necrosis
Moderate Swelling involving two or three segments of the bitten limb
envenoming (e.g., foot, leg, thigh), circumference of extremity increased
>4 cm; local bleeding, no local necrosis, blisters in few cases
Severe Swelling extending beyond the bitten limb (to trunk); blisters;
envenoming local bleeding; necrosis or compartmental syndrome.
See text for cases of bites by specimens >1 m body length
Normal vital signs and blood coagulation.
Incoagulable or normal blood, no systemic bleeding,
no hemodynamic alterations
Incoagulable blood, systemic bleeding (gingival,
hematuria, recent wounds, etc.), no hemodynamic
alterations, no renal failure
Incoagulable blood, multiple systemic bleeding,
hypotension or shock, disseminated intravascular
coagulation or renal failure, cerebral hemorrhage or
multi-systemic failure

Adapted from Silva-Haad (1989); Bolan os (1984); Wingert and Wainschel (1975); Reid et al. (1963a,b); and as recommended by Otero (1994, 2007); Otero
and Mesa (2001, 2005); Otero et al. (1992a, 1996, 1999, 2002a, 2006); Otero-Patino et al. (1998, 2007).
 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
Fig. 2. Twelve-year-old patient with swelling involving foot and leg (mild
local envenoming), 12 h after B. asper bite, without systemic envenoming.
1992a, 1996, 1999, 2006; Otero-Patin o et al., 1998, 2007).
Nevertheless, the clinical grading described has a temporal
validity on admission, because the envenoming is
a dynamic process which usually progresses in 1015% of
the cases after the beginning of antivenom therapy (Otero
et al., 1996, 1999, 2006; Otero-Patin o et al., 1998, 2007).
The ontogenetic variations in venom composition have
implications in the clinical manifestations of these enve-
nomings. As the venom of adult specimens has a higher
content of myotoxic phopholipases A2 (Alape-Giron et al.,
2008), snakebites by B. asper specimens larger than one
meter body length (adult specimens) involve a higher risk
of severe envenoming with dermonecrosis and myonec-
rosis (Otero et al., 1996, 1999, 2002a; Otero, 2007; Otero-
Patin o et al., 1998, 2007). Similar observations were made
by Hardy (1994). In contrast, the venoms of juvenile spec-
imens and offsprings induce higher lethal, hemorrhagic
and debrinogenating activities at the experimental level
(Gutierrez et al., 1980; Saldarriaga et al., 2003) in agree-
ment with their higher content of metalloproteinases
(Alape-Giron et al., 2008). Thus, bites inicted by juvenile
specimens tend to induce more frequently severe coagul-
opathy and bleeding in patients, with relatively low serum
Fig. 3. Five-year-old patient, with swelling involving foot, leg and thigh, 8 h
after B. asper bite. In addition, this patient presented coagulopathy and
hematuria (moderate local and systemic envenoming).
1001
Fig. 4. Thirty-year-old patient with swelling extending beyond the affected
limb (to trunk), many hemorrhagic blisters, necrosis, coagulopathy and
gingival bleeding 24 h after B. asper bite. She had acute renal failure and
necrotizing fasciitis as complications (severe local and systemic
envenoming).
venom-antigen concentrations as demonstrated by ELISA
(Otero et al., 1996; Otero, 2007). Similarly, Bothrops jararaca
bites inicted by specimens >100 cm length induce
necrosis, whereas bites by juvenile specimens are associ-
ated with coagulopathy and bleeding (Ribeiro and Jorge,
1989, 1990; Ribeiro et al., 2001). Additionally, there have
been documented cases of ARF secondary to acute tubular
necrosis (ATN) in Colombia in bites inicted by juvenile
(<50 cm) B. asper specimens, both in children and adults
(Otero et al., 2006; Otero, 2007).
Mean venom yield of B. asper in Colombia corresponds,
in terms of dry weight, to 130 mg, with a maximum of
1000 mg (1.0 g) by manual milking of a 175 cm female adult
specimen (our unpublished observations). In Costa Rica,
Bolan os (1984) reported an average venom yield of 458 mg
(dry weight) and a maximum of 1530 mg. On the other
hand, as has been described for Bothrops atrox and B. jar-
araca from Brazil, females of B. asper are larger and heavier
than males, and present a higher venom yield (ve times
Fig. 5. Two-year-old patient bitten three times at the leg 12 h before by
B. asper. She presented swelling involving three segments of the lower
extremity, blisters, extense ecchymosis, necrosis, cyanosis and lack of
voluntary movement of toes (suggesting compartmental syndrome),
hematuria and coagulopathy, without shock and acute renal failure (severe
local and moderate systemic envenoming). The limb was amputated.
1002 o / Toxicon 54 (2009) 9981011
R. Otero-Patin

higher in the case of B. jararaca) (Belluomini et al., 1991; urinary sodium (FeNa), a good indicator of the proximal
Furtado et al., 2006; Otero, 1995, 2007; our unpublished renal tubule function, can help to discriminate between
observations). This aspect must be taken into consideration pre-renal (hypovolemia) or renal failure secondary to acute
in B. asper bites as a possible source of variation in the tubular necrosis, which induces loss of the ability of the
clinical presentation and severity of these envenomings. proximal tubule to reabsorb sodium, with the consequent
For a complete evaluation of the patient, according to the natriuresis. Additionally, an endogenous creatinine clear-
complexity level and the available resources of health ance of <60 ml/min/1.73 m2 indicates ARF (Otero et al.,
centers, clinicians must rely on laboratory examinations, 2002a; Otero, 2007; Pinho et al., 2005).
such as blood coagulation tests (whole blood clotting test The use of immunoassays (ELISAs), for the determination
(WBCT), or the 20 min WBCT), prothrombin time (PT), of serum venom-antigen and antivenom concentrations in
partial thromboplastin time (PTT), brinogen concentra- patients bitten by Bothrops snake species, have currently
tion, D-dimer concentration, and brinogen/brin degra- only value for retrospective studies, as they have not been
dation products (FDP) concentration on admission and at 6, adapted at the hospital setting to estimate venom-antigen
12, 24, 48, 72 and 96 h after the onset of antivenom therapy concentration in blood at the time of admission. ELISA has
(Lee and White, 1913; Miller et al., 1978; Otero, 1994, 2007; been successfully used in various studies to quantify venom-
Otero and Mesa, 2005; Otero et al., 1992a, 1996, 1999, 2006; antigen and antivenom concentrations in clinical samples.
Otero-Patin o et al., 1998, 2007; Sano-Martins et al., Such studies have demonstrated that serum venom-antigen
1994; Warrell, 1995, 2004). Nevertheless, owing to its low concentrations are higher in patients with severe
cost, simplicity and good correlation with plasma brinogen envenoming (w128 to 192 ng venom/ml) than in patients
concentration, the 20 min WBCT is an effective and reliable with moderate (w39 to 142 ng venom/ml) or mild
method for evaluation of coagulation status in the primary envenomings (w8 to 15 ng venom/ml) (Otero et al., 2006;
care centers without laboratory resources (Frana and Otero-Patin o et al., 2007; Frana et al., 2003).
Malaque, 2003; Otero, 2007). In addition, platelet and
leukocyte counts are indicated, since 1530% of envenomed
3. Complications of envenoming
patients present thrombocytopenia, and since leukocytosis
and neutrophilia (6075% of patients) are common ndings
The most frequent complications described in patients
(Otero et al., 1992a). Determination of hemoglobin concen-
envenomed by B. asper are:
tration and hematocrit is also indicated (50% of patients
(a) Soft-tissue infection (1130% of the cases), charac-
develop anemia), together with the assessment of acute
terized by impetigo/cellulitis/abscesses/fasciitis, predomi-
phase reactants (C reactive protein, erythrocyte sedimen-
nantly cellulitis and abscesses caused by gram-negative
tation rate), plasma creatine kinase activity (a myonecrosis
rods (Morganella morganii, Proteus rettgeri, Klebsiella spp.,
indicator which remains elevated for several days, mainly in
Enterobacter spp., Aeromonas hydrophila) or Staphylococcus
severe cases), serum electrolyte concentration, urinary
aureus (Figs. 6 and 7). Infection occurs most frequently in
sediment and serum creatinine concentration (an indicator
moderate/severe local envenomings when extensive
of renal function) at 24 h intervals at least during 24 days.
edema, hemorrhage, myotoxicity and necrosis occur, which
Moreover, monitoring of arterial oxygen saturation (pulse
may create a favorable environment for multiplication of
oxymetry) is recommended in severe cases instead of arte-
bacteria present in the mouth, fangs and venom of the
rial blood sampling for pH and arterial gases (Amaral et al.,
snake (Andrade et al., 1989; Arroyo et al., 1980; Jorge et al.,
1986; Otero et al., 2002a; Otero, 2007), since the latter is
1990, 1994, 1998, 2004; Gutierrez and Lomonte, 2003;
a dangerous intervention in patients with incoagulable
Saravia-Otten et al., 2007; Otero et al., 1992a, 1996, 1999,
blood due to the risk of hematomas. Thus, a meticulous
2002a, 2006; Otero-Patin o et al., 1998, 2007; Saldarriaga
laboratory monitoring of envenomed patients is an excel-
and Otero, 1995; Theakston et al., 1990). Culture of aspirates
lent tool for an adequate assessment of the severity of
is a valuable guide to identify infecting organisms. Arthritis,
envenoming and the success of therapy.
Alteration in coagulation tests occurs in moderate and
severe envenomings, but not in all mild cases, since only
one-half of them develop a concomitant systemic enve-
noming. Acute phase reactants usually rise within the rst
48 h of treatment; if the elevation persists on the third day,
clinicians must correlate this alteration with leukocyte
counts (persistent leukocytosis and neutrophilia) and
platelet count (persistent thrombocytopenia) to discard
infection as a likely complication (Otero, 1994, 1995, 2007;
Otero and Mesa, 2005). When serum brinogen
concentration is low (less than 150 mg/dl), erythrocyte
sedimentation rate is also altered (Miller et al., 1978; Otero
et al., 1992a). Macro or micro-hematuria may occur in
moderate and severe cases, whereas the nding of eryth-
rocyte casts in urinary sediment examination is an
indicator of acute glomerulonephritis, a typical complica- Fig. 6. Cellulitis and abscess by M. morganii, complicating moderate local
tion of severe envenoming. The fractional excretion of envenoming by B. asper.
 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
Fig. 7. Baby fteen months of age, with necrotizing fasciitis and sepsis
(bacteremia, pneumonia) by S. aureus 48 hr after severe local envenoming
by B. asper.
osteomyelitis, sepsis, pneumonia and meningitis are less
frequent complications, but have been described in B. asper
envenomings (Figs. 8 and 9).
(b) Acute renal failure (ARF), which develops in 1117%
of patients, sometimes without oliguric phase (<400 ml/
day/1.73 m2), hypertension, hyperkalemia and metabolic
acidosis. Clinically and pathophysiologically, ARF can be
pre-renal, or can be associated with acute glomerulone-
phritis, acute tubular necrosis or acute cortical necrosis
(Soe et al., 1990), the latter being unresponsive to dialysis
during 34 weeks (Amaral et al., 1986; Otero, 2007; Otero
et al., 1992a, 2002a, 2006; Warrell, 1995). These types of
renal damage have been demonstrated in autopsies in
Costa Rica in patients bitten by B. asper and constitute,
along with CNS hemorrhage, the main causes of death in
those patients (Vargas-Baldares, 1978; Mekbel and
Cespedes, 1963; Otero et al., 2002a; Otero, 2007).
Fig. 8. Radiograph of the left hand of a young man taken 14 days after
B. asper bite on the proximal phalanx of the rst nger. The patient received
polyvalent antivenom within the rst hr of the bite. He presented septic
arthritis treated with broad spectrum antibiotics since the third day.
Arthritis was then drained surgically (purulent liquid, no bacteria) at the
sixth day. Observe the conspicuous narrowing of the rst meta-
carpophalangeal articular space and subluxation of the rst phalanx, as
sequelae.
1003
(c) Compartmental syndrome (CPS), occurring in 3% of
patients. In severe local envenoming, extensive swelling can
lead to CPS, mainly when the bite is on a nger, hand, foot or
in the anterior tibial compartment (Fig. 10) (Garn et al.,
1979; Hayden, 1983; Fan and Cardoso, 1995; Otero et al.,
2002a). If a CPS is suspected, the intracompartmental
pressure (IP) must be documented by means of the Stryker
pressure monitor or a similar equipment. It is elevated and
associated with CPS if the IP is >30 mm Hg in children or
>45 mm Hg in adults (Gomez and Dart, 1995; Warrell, 1995;
Otero et al., 2002a). Since a needle (no. 1618) is used in this
procedure, it is contraindicated in patients with non-clot-
ting blood (within the rst 624 h of treatment) or with
severe thrombocytopenia, owing to the risk of a large
hematoma, thus increasing the morbidity as a consequence
of this intervention (Otero et al., 2002a; Otero, 2007).
(d) CNS hemorrhage, which occurs in 23% of B. asper bite
victims and constitutes one of the most serious systemic
complications of these envenomings. It can be intracerebral,
intraventricular (Fig. 11), intramedullar (hematomyelia),
subarachnoid, cerebellar, subdural or extradural, as
described also for Bothrops moojeni (Kouyoumdjian et al.,
1991), B. atrox, Echis ocellatus and Calloselasma rhodostoma
(Kerrigan, 1991; Warrell, 1995; Otero et al., 2002a). It can be
spontaneous or may occur after a cephalic trauma following
the bite (our unpublished observations). Clinical symptoms
correspond to the localization of bleeding. For instance,
depending on the site of hemorrhage, manifestations can be
Fig. 9. Radiograph of the left leg of a 12-year-old boy taken 28 days after
a B. asper bite. The patient, presenting moderate envenoming on admission,
was treated with polyvalent antivenom and G crystalline penicillin per i.v.
route in the local hospital, during three days. Notice the large periosteal
reaction, several sequestrations into the cortex of bula and pathologic
fractures, corresponding to chronic osteomyelitis. Finally, he was treated
with surgery (sequestrectomy), immobilization and oxacillin during six
months, with recovery.
1004 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
Fig. 10. Patient 12-year-old who sought medical attention 36 h after severe
B. asper bite on a hand, and treated initially by traditional healers. He
developed a compartmental syndrome with lack of all voluntary movements
of the hand, ngers and of sensitivity in the palmar region, with blisters and
skin necrosis of dorsum of the hand and forearm. Local swelling affected
three segments of the limb and trunk. The IP into forearm was 73 mm Hg.
Additionally, the patient presented anuria (acute renal failure secondary to
acute tubular necrosis, requiring hemodialysis), coagulopathy, pleural effu-
sion and pneumonia. Finally, the extremity was amputated when the clinical
condition improved.
as diverse as focalization (palsy) and sensitive decit signs,
convulsions, intracranial hypertension, unconsciousness
and meningeal irritation signs (Otero et al., 1992a, 2002a;
Kerrigan, 1991). Hemorrhage into the pituitary gland, with
secondary panhypopituitarism, has been described for
Daboia russelli bites in Asia (Warrell, 1995) but no cases of
this complication have been reported for B. asper bites.
(e) Other systemic bleeding complications, such as
hemarthrosis (nger joints, knee, with risk of septic
arthritis) and any hematoma distant from the bite site
(sublingual, submandibular, subcapsular in the liver,
retroperitoneal) have been also described in B. asper bite
envenomings (Otero et al., 1992a, 2002a, 2006; Otero-
Patin o et al., 2007; Otero, 2007; Warrell, 2004). Diagnosis
Fig. 11. Cerebral hemorrhage affecting left parietal lobe and ventricle (uid
level), with midline deviation and coagulopathy, 48 h after B. asper bite. The
patient (18-year old), who was treated initially (30 h) by traditional healers,
died. Reproduced with permission from Elsevier.
can be established by means of appropriate imaging (Rx,
computed tomography, magnetic resonance, angiography,
ultrasound, etc.).
(f) Other complications of B. asper bites are: hematic or
serous pleural effusion in severe cases, affecting chest and
upper extremities (Fig. 12). On the basis of the molecular
mass of snake venom toxins and on the potential effect of
metalloproteinases and other toxins on the placenta, it is
highly likely that various venom components can cross the
placental barrier in patients bitten by B. asper, causing fetal
envenoming and pregnancy complications such as abortion,
fetal wastage and abruptio placentae (1% of cases). Never-
theless, there are reports of envenomed patients who have
nished pregnancy in good condition without complica-
tions after B. asper bites, certainly requiring strict control of
the mother and also a complete evaluation (renal, CNS,
hematological) of the newborn (Zugaib et al., 1985;
Pantanowitz and Guidozzi, 1996; Otero et al., 1992a, 2002a,
2006). Thromboses in cerebral or other arteries (femoral,
mesenteric, etc.) have been described for B. lanceolatus bites
in the Lesser Antillean island of Martinique (Thomas et al.,
1995) for Daboia russelli in Asia (Ameratunga, 1972), and for
Porthidium lansbergii (one case) in Colombia (Otero, 2002a),
but are rare (<0.1%) in B. asper bites.
4. Specic treatment
First aid measures must be limited to immobilization of
the extremity, and rapid transfer of patient to the hospital.
Tourniquets, suction devices, multiple punctures around the
wound or incisions increase the risk of ischemia and
necrosis, the former two, and of hemorrhage and infection,
the latter (Busch et al., 2000; Hardy, 2003). Therefore, these
interventions are strongly contraindicated. The black stone,
a traditional treatment very common in Africa and in some
afroamerican communities from northwestern South
America (Colombia), is not an adequate treatment for
snakebites, as indicated by clinical and experimental
Fig. 12. Radiograph of the chest of a seven-year-old patient, taken 12 h after
a bite inicted on precordial area by an adult specimen of B. asper. 2 h after
the bite, 15 vials of a polyvalent antivenom were administered. Observe the
severe left pleural effusion with mediastinum deviation. Adequate drainage
by a thoracic cannula was started (hematic liquid). Photo courtesy of Dr.
Carlos Paredes (Colombia).
 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
evidence (Otero et al., 1992a; Chippaux et al., 2007). Patients
with severe envenoming should be preferably treated in an
intensive care unit (ICU). Those with mild or moderate
envenoming can be treated in the emergency room during
the rst 24 h, the latter with monitoring of vital signs (Otero,
2007; Otero and Mesa, 2001). Then, the treatment is
followed and nished in a hospitalization ward.
The rational basis for specic antivenom therapy
(selection of antivenom and dosage) in a particular region or
country depends on: (a) The biology, epidemiology and
clinical manifestations of snakebites; (b) the venom yield of
different snake species; (c) the toxicological prole of
venoms; (d) the in vitro/in vivo evaluation of the neutral-
izing ability of the antivenoms available against those
venoms; and (e) the information generated by controlled
clinical trials performed to evaluate efcacy and safety of
antivenoms, together with immunoassays (ELISA) to quan-
tify serum venom-antigen and antivenom concentrations
(Theakston et al., 1992; Otero, 1998, 2007; Otero et al., 1996,
1999; Otero-Patin o, 2008; Cardoso et al., 1993). Three kinds
of antivenoms, based on the type of active substance, are
currently produced in the world: (a) equine-derived, whole
IgG antivenoms obtained by ammonium sulphate or cap-
rylic acid fractionation of plasma; (b) equine-derived F(ab0 )2
fragments, obtained by pepsin digestion of IgG and ammo-
nium sulphate precipitation; and (c) Fab fragments obtained
by papain digestion of ovine-derived IgG, only produced in
North America and Europe (Otero, 2002; Lalloo and Theak-
ston, 2003; Theakston et al., 2003; Gutierrez et al., 2006a).
Following recommendations by the World Health
Organization (WHO, 1981; Theakston et al., 2003), every
country or region must perform preclinical studies to
evaluate the neutralizing ability of the available antivenoms,
either locally manufactured or imported, against the most
relevant toxicological effects of the snake venoms of highest
epidemiological importance in those countries and regions.
In Colombia, two whole IgG polyvalent antivenoms, manu-
factured by Instituto Nacional de Salud (INS, neutralizing
potency 70 mg B. asper venom per 10 ml vial) and Probiol
(neutralizing potency 25 mg B. asper venom) and one F(ab0 )2
antivenom (Bioclon, Mexico, neutralizing potency 30 mg
B. asper venom), are produced and/or distributed. In addition,
antivenoms from Brazil (Instituto Butantan, polyspecic
pepsin-digested Bothrops antivenom), Costa Rica (Instituto
Clodomiro Picado, polyvalent caprylic acid-fractionated
whole IgG antibothropic, anticrotalic, antilachesic
antivenom) and Venezuela (Centro de Biotecnologa,
Universidad Central de Venezuela, polyvalent pepsin-
digested antivenom), with differences in potency, have
neutralizing capacity against B. asper venom from Colombia,
as demonstrated experimentally (Otero et al., 1995, 1997,
2002b) and clinically (Otero et al., 1996, 1999, 2006;
Otero-Patin o et al., 1998). In Central America, the polyvalent
antivenom of Instituto Clodomiro Picado (neutralizing
potency 30 mg B. asper venom per 10 ml vial of antivenom)
has been successfully used since 1970 for the treatment of
envenomings by B. asper and other viperid species in this
region (Gutierrez, 1995).
During the last 15 years, six collaborative randomized/
controlled clinical trials (phases III and IV) were performed
in patients envenomed by Bothrops sp bites, including the
1005
determination of serum venom-antigen and antivenom
concentrations by ELISA, using the antivenoms mentioned
above (manufactured in Colombia, Brazil, Costa Rica and
Mexico), with neutralizing potencies ranging from 30 to
70 mg B. asper venom from Colombia/10 ml vial (Otero
et al., 1996, 1999, 2006; Otero-Patin o et al., 1998, 2007).
Additionally, a post-marketing study also evaluated the
total needs of antivenom (quantity, safety) for the country
(Otero et al., 2001b). Taken together, these studies have
improved the design of rational protocols for the treatment
of Bothrops sp. bites, in order to evaluate the safety of those
products, to elucidate some factors involved in the early
adverse reactions (EARs) to antivenoms, and to improve the
production and distribution of these immunobiologicals.
As recommended in Brazil for B. jararaca and B. atrox
bites (Amaral et al., 1991; Frana and Malaque, 2003),
antivenom doses currently suggested in Colombia for the
treatment of B. asper bites should neutralize no less than
100, 200 or 300 mg of venom in case of mild (2 vials of
polyvalent antivenom from INS; 4 vials of polyvalent anti-
venom from Probiol or Bioclon), moderate (4 vials INS; 8
vials Probiol or Bioclon) and severe envenomings (6 vials
INS; 12 vials Probiol or Bioclon), respectively (Table 2)
(Otero, 2007). Additionally, all patients bitten by B. asper
larger than one meter (adult specimens), who seek medical
attention within the rst two hr, must receive the highest
antivenom dose (not less than 612 vials, independently of
the envenoming grade at this time), due to the risk of
severe local/systemic envenoming (Otero et al., 2002a;
Otero, 2007). For the polyvalent antivenom from Costa Rica,
similar doses to those of Probiol and Bioclon products are
indicated for B. asper bites.
Table 2
Specic treatment of B. asper bites, according to the envenoming grade.
Grade Neutralization Vials of
of B. asper venom (mg)a antivenom (n)
Non- No antivenom
envenoming needed. Observe
the patient
during 6 h. Repeat
blood coagulation test.
Mild No less 2 of A or 4 of B
envenoming than 100 mg
Moderate No less 4 of A or 8 of B
envenoming than 200 mg
Severe No less 6 of A or 12 of B
envenoming than 300 mg
a
Adapted from Brazilian Ministry of Health and Butantan Institute
recommendations for Bothrops bites (Amaral et al., 1991; Frana and
Malaque, 2003). Patients bitten by B. asper specimens whose total length
exceeds one meter and seek medical attention within the rst two hr of
the bite must be treated as severe case, independently of the envenoming
grade on admission, because of the statistical association with severe
envenoming, mainly necrosis (Otero, 2007; Otero et al., 2002a, 2006;
Otero-Patin o et al., 2007). The same recommendation is valid for B. asper
bites on the head, face, neck, chest and genitals (Otero, 2007), due to the
risk of CNS/eyes damage, airway obstruction, pleural effusion and
necrosis. Antivenom A: polyvalent Instituto Nacional de Salud (INS),
Bogota (neutralizing potency against B. asper venom 70 mg/vial).
Antivenom B: polyvalent Laboratorios Probiol, Bogota (neutralizing
potency 25 mg/vial); or polyvalent Antivipmyn Tri, Instituto Bioclon,
Mexico (neutralizing potency 30 mg/vial); or polyvalent Instituto
Clodomiro Picado, Costa Rica (neutralizing potency 30 mg/vial).
1006 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
Results of efcacy obtained in Colombia, with the
antivenoms described above, were similar in various clin-
ical trials. Briey, cessation of local and systemic bleeding
(different of hematuria) should occur within the rst
612 h (mainly within 23 h) of treatment in 100% of
patients, and recovery of blood coagulability (WBCT, PT,
PTT, brinogen) within 1224 h after the onset of anti-
venom therapy in 90100% of the patients. These simple
clinical and laboratory parameters are recommended as
criteria of efcacy of the initial antivenom dose. Without
specic antivenom, coagulopathy can persist during 811
days (Kornalik and Vorlova, 1990). If these criteria are not
fullled, an additional dose of three vials of the same
antivenom should be administered at 12 or 24 h of treat-
ment, respectively, or at any time when there is evidence of
recurrence of coagulopathy or bleeding (Otero et al., 1996,
1999, 2006; Otero-Patin o et al., 1998, 2007; Otero, 2007).
Hematuria stops in 90% of patients who present this sign
within 1224 h and in 100% of patients in 4872 h (Otero,
2007; Otero-Patin o et al., 2007). The use of edema
progression as a criterion to recommend additional
antivenom doses is discussed below.
Besides the clinical and laboratory criteria of efcacy
described, immunoassays also indicate that serum venom-
antigen concentrations signicantly decreased at the end of
the antivenom infusion and remained undetectable during
4896 h in most patients (Otero et al., 1996, 1999).
Nevertheless, 1030% of patients had recurrence of anti-
genaemia, without clinical signicance (Otero et al., 2006;
Otero-Patin o et al., 1998, 2007). Interestingly, there were
some patients (510%) who corrected WBCT and brinogen
levels at a faster rate than PT, or viceversa, because toxins
that induce clotting of brinogen and activation of
prothrombin are different (Kamiguti and Cardoso, 1989;
Sano-Martins et al., 1994; Otero et al., 2006; Otero, 2007;
Otero-Patin o et al., 2007).
Skin or conjunctival sensitivity tests should not be
performed because they have no predictive value for the
occurrence of early adverse reactions (EARs) (Malasit et al.,
1986; Cupo et al., 1991; Warrell, 1995; Otero-Patin o et al.,
1998; Otero et al., 2006). Antihistamines or other
premedications should not be used and all patients have to
be regarded as potentially reactive to antivenom therapy.
Antivenom must be diluted in 0.9% NaCl solution (100 ml
for children and 250 ml for adults) and the intravenous
infusion should be completed within 3060 min. Patients
should be carefully observed for 24 h for the development
of EARs. As previously described (WHO, 1981; Lalloo and
Theakston, 2003), these appear within the rst 24 h of
antivenom therapy, predominantly during the infusion and
within the rst 2 h of treatment (Otero et al., 1996, 1999,
2006; Otero-Patin o et al., 1998, 2007, 2008). Antivenom
administration by means of bolus injection is not recom-
mended, because it may induce a rapid hypotension, an
effect attributable to the presence of phenol as preservative
in many antivenoms (Garca et al., 2002).
5. Adverse reactions to antivenom therapy
EARs might correspond to type I hypersensitivity reac-
tions, which involve IgE-mediated degranulation of mast
cells and basophils, with rapid release (within minutes) of
preformed mediators, such as histamine, TNFa and IL-4.
Arachidonic acid metabolites, such as leukotriene D4 and
prostaglandin D2 are synthesized and released more slowly
(30 min to hours). The cross-linking of two molecules of IgE
antibodies specic for the equine IgG (their relevant
allergen) on the specic receptors of cell surface (FcER1), is
the triggering mechanism involved in anaphylactic
reactions, for degranulation of mast cells and basophils.
Nevertheless, histamine release can also be triggered by
agents that act on other receptors of the mast cell/basophil
plasma membrane; for example, the complement-derived
fragments C3a and C5a (anaphylatoxins) generated
through complement activation by heterologous IgG may
induce mast cell/basophil degranulation. Such acute
reactions to these agents, which do not involve IgE anti-
bodies, are referred to as anaphylactoid reactions (Fan and
Frana, 1992; Roitt et al., 2001; Otero, 2007). The majority
of EARs (>90%) after antivenom infusion are anaphylactoid,
whereas less than 10% of EARs correspond to true
anaphylactic reactions. Pyrogenic reactions may occur after
the administration of antivenoms containing bacterial
endotoxins (Otero-Patin o et al., 1998).
The incidence of EARs varies depending on the product.
It is relatively low using some F(ab0 )2 preparations
(1236%) and caprylic acid-fractionated IgG antivenoms
(1129%). The former antivenoms are produced in Brazil,
Mexico and Venezuela, and the latter are produced in Costa
Rica (Otero et al., 1996, 1999, 2006; Otero-Patin o et al.,
1998, 2007; Smalligan et al., 2004). The incidence of EARs is
associated with the physico-chemical characteristics of
antivenoms. Factors such as albumin contamination, high
load of protein and presence of protein aggregates are likely
to contribute to EARs (Otero, 2007; Otero et al., 1999;
Otero-Patin o et al., 2007), thus stressing the need of good
fractionation protocols that yield highly puried F(ab0 )2 or
IgG products. It has been demonstrated that antivenoms
made of whole IgG obtained by ammonium sulphate
precipitation have higher in vitro anticomplementary
activity and, accordingly, induce a relatively high incidence
of EARs (2582%). In contrast, a lower incidence of EARs has
been described after administration of caprylic acid-
fractionated whole IgG and F(ab0 )2 preparations (Smalligan
et al., 2004; Otero-Patin o et al., 1998, 2007; Otero et al.,
1996, 1999, 2006).
EARs are classied as mild (characterized by cutaneous
or gastrointestinal reactions, chills, fever), moderate
(associated with mild hypotension, facial angioneurotic
edema), and severe (characterized by airway angioedema,
shock, cardiac arrest, bronchospasm) (Otero-Patin o et al.,
1998). These reactions should be treated as recommended
by Fan and Frana (1992) and Otero-Patin o et al. (1998,
2007). Briey, the antivenom infusion has to be stopped
and adrenaline (0.01 mg/kg in children and 0.30.5 mg in
adults) should be administered subcutaneously for mild/
moderate EARs and intravenously for severe EARs.
Although some authors recommend intramuscular (i.m.)
rather than subcutaneous (s.c.) adrenaline in terms of
bioavalability, it must be kept in mind the risk of deep
hematomas associated with i.m. injections in patients
having coagulopathy. Additionally, patients must receive
 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
hydrocortisone i.v. 100200 mg every 6 h during 24 h
(510 mg/kg/day in children) or any equivalent cortico-
steroid, and one i.v. dose of antihistamine. Once EAR
symptoms have subsided or ameliorated (usually within
15 min), antivenom infusion should be continued with
caution. If EARs repeat, a parallel continuous infusion of
adrenaline (1.0 mg diluted in 250 ml 0.9% NaCl solution)
should be administered during the antivenom infusion
(Otero, 2007).
After discharge from the hospital, patients should be
asked to return for re-evaluation within the next four
weeks, and need to be instructed about the possible
development of serum sickness within 524 days after
antivenom infusion (Otero-Patin o et al., 1998; Otero, 2007).
This complication occurs in 3075% of patients receiving
heterologous immunoglobulins, as a result of the devel-
opment of antibodies by the patient against equine IgG or
F(ab0 )2, with formation of antigenantibody complexes and
complement activation (Lalloo and Theakston, 2003). The
circulating immune complexes are deposited in the walls of
microvessels in various tissues (skin, lymphatic nodes,
kidney, peripheral nerves, serous membranes) leading to
increased vascular permeability and thus to a type III
hypersensitivity reaction or immune complex disease
(Roitt et al., 2001). Fever, arthralgia, pruritus, urticaria,
enlargement of lymphatic nodes, proteinuria and a drop in
serum complement activity are the usual symptoms and
signs of serum sickness; in rare cases glomerulonephritis
and peripheral neuropathy can also occur.
The development of serum sickness is associated with the
antivenom dose administered, i.e. with the total load of
heterologous proteins received by the patient (Roitt et al.,
2001; LoVecchio et al., 2003; Otero 2007). This late adverse
reaction is treated with antihistamines and, if necessary, with
a short cycle of corticosteroids. As most patients affected by
snakebites live in remote rural communities, there is under-
registration of this adverse reaction in tropical areas of Latin
America, where only 2030% of patients come back for re-
evaluation (Otero, 2007).
6. Ancillary treatment
The support or ancillary treatment of envenomings by
B. asper includes: the correction of hypovolemia; the early
administration of wide-spectrum antibiotics in moderate/
severe bites (clindamycin ceftriaxone; or clindamy-
cin ciprooxacin; or sulbactam/ampicillin); tetanus
prophylaxis at the second day of treatment (after normal-
ization of blood coagulation tests due the risk of i.m.
hematoma in incoagulated patients); the surveillance of
edema progression; the evaluation of an adequate response
to antivenom therapy; the early detection of local and
systemic complications (infection, CPS, ARF, CNS hemor-
rhage); surgical procedures; and rehabilitation. The details
of such ancillary treatment are the following:
(a) For the adequate correction of hypovolemia, two
peripheral venous lines should be canalized, one for anti-
venom administration and the other to infuse crystalloids
(normal saline solution or Ringer lactate solution), as
needed (1530 ml/kg or more in 3060 min) to restore
circulating volume. The measurement of the arterial
1007
oxygen saturation is recommended, in order to assess the
need to provide oxygen therapy. Then, i.v. liquids have to
satisfy 12 times the daily needs of water, glucose and
electrolytes. In all cases, urinary output should be
measured hourly, in severe cases, by means of a bladder
catheter. Normally, adolescents and adults eliminate more
than 0.5 ml/kg/h (3040 ml/h) and children more than
1.02.0 ml/kg/h. In severe envenomings, especially when
there is anuria, the management of i.v. liquids is more
difcult and, preferably, the patient should have a central
venous catheter for continuous measurement of the central
venous pressure (Otero, 1994, 2007; Otero and Mesa, 2001,
2005). If, after a second bolus of i.v. liquids, urinary output
does not normalize, furosemide (12 mg/kg i.v., maximal
dose 5 mg/kg/day) should be administered. If anuria
persists, an i.v. infusion of dopamine (2.55.0 mg/kg/min)
during 6 h may be recommended to normalize renal
plasmatic ow and glomerular itration (Hardman et al.,
2001; Otero, 2007; Otero and Mesa, 2001). Finally, if an
adequate response is not achieved, concentrations of serum
creatinine and electrolytes, and an electrocardiogram,
should be assessed because the patient is likely to develop
an ARF in these circumstances, possibly secondary to ATN.
Some criteria to perform dialysis (20% of patients with ARF
secondary to Bothrops sp bites need dialysis) are metabolic
acidosis, persistent and unresponsive anuria with hyper-
volemia, elevation of serum creatinine concentration above
5 mg/dl, and hyperkalemia (>6 mEq/l) (Otero et al., 1992a,
2002a; Pinho et al., 2005; Otero, 2007).
(b) The early use of antibiotics in moderate/severe
bothropic envenomings (not prophylaxis, a term that
implies the use of antibiotics before the trauma), is
controversial for several reasons: 1) there have been few
controlled clinical trials addressing this issue; 2) the
venoms of different snake species differ in their proteo-
lytic and necrotizing effects and, consequently, in their
potential to promote infection; 3) the snake responsible
for the accident is often not identied; 4) the time interval
to seek medical attention at the hospital is often pro-
longed (>6 to 12 h), thus being too late for beginning
antibiotic administration, considering that bacteria of high
pathogenicity might have been injected with the venom in
the affected tissues; 5) the groups of patients with mild,
moderate and severe envenomings described in several
studies are not comparable; 6) antibiotics used were
inadequate for the bacteria that cause infections in viperid
bites; 7) the indiscriminate use of broad spectrum
antibiotics promotes the development of bacterial resis-
tance (Goldstein, 1992; Clark et al., 1993; Weed, 1993;
Kerrigan et al., 1997; Blaylock, 1999; LoVecchio et al., 2002;
Jorge et al., 1994, 1998, 2004; Jorge and Ribeiro, 1997; Broder
et al., 2004; Cuesta et al., 2008; Hardman et al., 2001).
However, despite the uncertainty derived from these
considerations, envenomings by B. asper, and other large
snakes (>1 m) distributed in Latin America such as B. atrox,
B. jararacussu and Lachesis muta (up to 34 m body length),
are often associated with severe local effects and infection.
Thus, the antibiotic schedule mentioned above for
moderate/severe local envenomings inicted by B. asper
should be followed during hospitalization of the patient and
thereafter, whenever required (Otero, 2007; Otero et al.,
1008 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
2002a; Saravia-Otten et al., 2007). Adequate samples for
cultures (blood, exudates, pus, blister contents) should be
collected in order to identify the bacteria and to assess its
corresponding antibiotic sensitivity (Otero et al., 2002a).
(c) Edema progression and bleeding should be moni-
tored every hour during the rst 24 h, and every 6 h during
the second day. As mentioned above, the halting of local
and systemic hemorrhage is a good criterion of venom
neutralization by the antivenom within the rst 612 h of
treatment, although most of patients stop bleeding within
the rst two hr. In contrast, in spite of adequate venom
neutralization by antivenom, edema may continue to
progress during 1248 h, with the possible development of
CPS. Thus, edema progression stops within 612 h in
6070% of patients; within 1224 h in 2535% of patients;
and in 2448 h in the remaining 5%. Edema is largely an
auto-pharmacological phenomenon triggered by venom-
induced release of endogenous mediators that can persist
activated several hours after venom neutralization
(Gutierrez and Lomonte, 2003; Olivo et al., 2007; Otero
et al., 1996; Otero-Patin o et al., 1998; Otero, 2007; see also
Teixeira et al., 2009). For this reason, it is better to exclude
edema progression as a criterion to assess therapeutic
success and to determine whether additional antivenom
doses should be administered, at least during the rst 24 h
(Otero et al., 1996). If edema progression persists during the
second day, after excluding secondary infection, an addi-
tional dose of antivenom should be administered.
(d) The CPS is clinically suspected by the presence of
tight edema, dysesthesia, alteration of deep sensitivity
(propioceptive) in the extremity, limitation of movement,
with or without slow capillary lling. It occurs during the
rst two days of envenoming, mainly within the rst 12 h
(phase of rapid increment of edema) (Otero, 2007).
Diagnosis must be conrmed by measurement of IP, as
described above. However, during the rst 12 h of treat-
ment, the measurement of IP is not recommended owing to
the risk of hematoma under the fascia in a coagulopathic
patient. Therefore, an alternative is the administration of an
i.v. infusion of the osmotic diuretic mannitol (12 g/kg) in
3060 min (half-life 1.7 h), which generally induces a fast
reduction of IP within 2 h (our observations). This has been
reported to reduce the need of fasciotomy in many cases
(Gomez and Dart, 1995; Hardman et al., 2001; Warrell,
1995; Otero et al., 2002a).
Mannitol is contraindicated if there is: 1) Persistent
anuria with hypervolemia; 2) oliguria with hypovolemia; 3)
active bleeding into the CNS; 4) edema or pulmonary
hemorrhage (Hardman et al., 2001; Otero, 2007). The use of
fasciotomy has been a controversial subject. For CPS
following trauma, the pathophysiology appears to depend
on increased pressure, but for venom-induced CPS, the
central factor is likely to be the direct venom effect on the
tissue, and not only the resulting increase in compartment
pressure (Dart, 2004). As demonstrated in animal experi-
ments (Tanen et al., 2003, 2004; Stewart et al., 1989), most
authors consider that the early administration of high
antivenom doses is better than fasciotomy in terms of nal
results (muscle function). Morbidity, disguration/scars
and complications (infection, bleeding) increase with this
surgical intervention; it must be deferred only for those
patients with high IP which does not decrease after
mannitol administration (Russell et al., 1975; Garn et al.,
1979; Stewart et al., 1989; Warrell, 1995, 2004; Otero et al.,
2002a; Dart, 2004).
(e) Intramuscular injections should be avoided during
the rst 2448 h of treatment, or while coagulopathy
persists. For an analgesic effect, tramadol or meperidine
(12 mg/kg i.v. every 612 h), or acetaminophen per oral
route are recommended. Morphine should not be used
because it causes a decrease of venous return and hypo-
tension, which are particularly problematic in hypovolemic
patients. Nonsteroidal anti-inammatory drugs (NSAIDs)
are not recommended, because they inhibit platelet
aggregation and may exert renal, hepatic and gastrointes-
tinal deleterious actions (Otero, 2007; Otero and Mesa,
2005; Hardman et al., 2001; Mycek et al., 2000). An
adequate antivenom dose administered early in the course
of envenoming usually induces a fast reduction of pain,
because it interferes with the activation that venom toxins
induce on inammatory cascades (Otero, 2007).
(f) The affected extremity must rest at the level of bed,
i.e., neither elevated nor pendant. Wound cleaning may be
performed with saline solution and a soft antiseptic every
day; then, it can be covered with sterile gauzes moistened
with saline solution without bandage. Blister contents must
be aspirated with sterile syringe at 1224 h intervals,
because they contain high venom-antigen concentrations
that can be reabsorbed. The search for infection is recom-
mended, ordering cultures when necessary. Careful
debridement of necrotic soft-tissue, as well as amputations,
must be performed under anesthesia and in a sequence
indicated by clinical evolution, usually after the third day
(Otero, 2007). At this time, covering with gauzes, antibac-
terial or healing ointments and bandages, is indicated.
Surgical drainage of soft-tissue abscesses and necrotizing
fasciitis should be as extensive as necessary, especially in
the latter. Drainage should be followed by cultures for
aerobic and anaerobic bacteria. After the second week,
a rehabilitation program is essential for some patients who
develop local complications (skin grafts, physical exercises,
prosthesis, etc.) (Otero, 2007). Finally, in patients present-
ing soft-tissue infection, especially in moderate and severe
cases, and when the bite was on anatomical sites covered
by a thin layer of soft-tissue, i.e., tibial compartment,
ngers or head, a radiographic assessment of the affected
limb is recommended at two and four weeks after the bite,
in order to discard osteomyelitis.
7. Prevention
An adequate primary health care, together with
permanent prevention programs, constitute the most
viable and effective strategy to reduce the high impact of
snakebites in Latin America in terms of morbidity,
mortality and sequelae. Some of the essential components
for the successful implementation of this strategy are: a)
effective education programs on snakes, snakebites,
prevention and treatment, offered to the communities and
health workers by using diverse communication methods;
b) adequate channels for the early supply and distribution
of antivenoms and other basic drugs which are necessary
 o / Toxicon 54 (2009) 9981011
R. Otero-Patin
for the attention of patients at health institutions of
different complexity; c) the promotion of an interdisci-
plinary approach for confronting this health problem; d)
the involvement of the communities in the various
components of the strategy; e) an expedite network of
communications and transportation to ensure the timely
transfer of patients to health facilities; f) a suitable and
effective distribution and delegation of functions of the
health personnel according to the grade of envenoming of
patients; g) a well-designed epidemiological surveillance
system; h) a strategic alliance between universities and
health authorities to develop research and educational
programs; and i) an adequate nancial support to the
different components of these programs, mainly from the
Ministries of Health, which should establish national
policies and evaluate the performance of these initiatives
(Otero et al., 1992c, 2001a; Gutierrez et al., 2006a).
Acknowledgements
Some results presented in this work correspond to
clinical trials performed in Colombia with the support of
COLCIENCIAS, the University of Antioquia, the University of
Costa Rica, Instituto Butantan from Brazil, Instituto Bioclon
from Mexico, the Direcciones Seccionales de Salud of the
departments of Antioquia, Choco and Amazonas
(Colombia) and CYTED (project 206AC0281). The partici-
pation of one hundred hospitals from Colombia in these
clinical studies is greatly acknowledged. The author thanks
Jose Mara Gutierrez, Instituto Clodomiro Picado, University
of Costa Rica, for the revision of the manuscript.
Conict of interest
The author declares that there are no conicts of
interest regarding this manuscript.
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