Hifumi et al. Journal of Intensive Care (2015) 3:16
DOI 10.1186/s40560-015-0081-8

REVIEW

Open Access

Venomous snake bites: clinical diagnosis andtreatment
Toru Hifumi1*, Atsushi Sakai2, Yutaka Kondo3, Akihiko Yamamoto4, Nobuya Morine5, Manabu Ato6, Keigo Shibayama4,
Kazuo Umezawa7, Nobuaki Kiriu8, Hiroshi Kato8, Yuichi Koido8, Junichi Inoue9, Kenya Kawakita1 and Yasuhiro Kuroda1

Abstract
Snake bites are life-threatening injuries that can require intensive care. The diagnosis and treatment of venomous
snake bites is sometimes difficult for clinicians because sufficient information has not been provided in clinicalpractice. Here we review the literature to present the proper management of bites by mamushi, habu, andyamakagashi snakes, which widely inhabit Japan and other Asian countries. No definite diagnostic markers or kits
are available for clinical practice; therefore, definitive diagnosis of snake-venom poisoning requires positive
identification of the snake and observation of the clinical manifestations of envenomation. Mamushi (Gloydius
blomhoffii) bites cause swelling and pain that spreads gradually from the bite site. The platelet count gradually
decreases due to the platelet aggregation activity of the venom and can decrease to <100,000/mm3. If thevenom gets directly injected into the blood vessel, the platelet count rapidly decreases to <10,000/mm3 within 1
h after the bite. Habu (Protobothrops flavoviridis) bites result in swelling within 30 min. Severe cases manifest not
only local signs but also general symptoms such as vomiting, cyanosis, loss of consciousness, and hypotension.
Yamakagashi (Rhabdophis tigrinus) bites induce life-threatening hemorrhagic symptoms and severe disseminatedintravascular coagulation with a fibrinolytic phenotype, resulting in hypofibrinogenemia and increased levels offibrinogen degradation products. Previously recommended first-aid measures such as tourniquets, incision, andsuction are strongly discouraged. Once airway, breathing, and circulation have been established, a rapid, detailed
history should be obtained. If a snake bite is suspected, hospital admission should be considered for further
follow-up. All venomous snake bites can be effectively treated with antivenom. Side effects of antivenom should
be prevented by sufficient preparation. Approved antivenoms for mamushi and habu are available. Yamakagashi
antivenom is used as an off-label drug in Japan, requiring clinicians to join a clinical research group for its use inclinical practice.
Keywords: Mamushi, Habu, Yamakagashi, Antivenom

Introduction
Throughout the world, snake bites remain life-threatening
injuries [1-4], sometimes requiring intensive care [5]. Similar to malaria, dengue hemorrhagic fever, tuberculosis, andparasitic diseases, the risk of snake bite is always present[1]. In 2009, the World Health Organization (WHO) added
snake bites to the list of neglected tropical diseases, which
includes dengue hemorrhagic fever, cholera, and Japanese
encephalitis. The mortality associated with snake bites ismuch greater than that of other neglected tropical diseases* Correspondence: hifumitoru@gmail.com
1
Emergency Medical Center, Kagawa University Hospital, 1750-1 Ikenobe,
Miki, Kita, Kagawa 761-0793, Japan
Full list of author information is available at the end of the article[1]. Moreover, the 2014 dengue fever outbreak in Tokyo,
Japan, was promoted by climate change and intensive
interaction between people; these factors may thus contribute to outbreaks of other tropical diseases in the future.
Venomous snakes of the same genus as mamushi(Gloydius), habu (Protobothrops), and yamakagashi(Rhabdophis) inhabit Japan and other Asian countries[6-8]. The incidence of bites by these venomous snakes
is reported as approximately 1,000 cases with 10 deaths
annually for mamushi (Gloydius blomhoffii) [9], 100
cases annually for habu (Protobothrops flavoviridis) [10],and 34 cases with 4 deaths over the past 40 years foryamakagashi (Rhabdophis tigrinus) [6].

© 2015 Hifumi et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

Hifumi et al. Journal of Intensive Care (2015) 3:16

The diagnosis and treatment of venomous snake bites issometimes difficult for clinicians because sufficient information, including the administration of antivenom
therapy, has not been provided in clinical practice[6,11]. Here we clarify the proper management of bitesby mamushi, habu, and yamakagashi, including snake
characteristics, venom activity and symptoms, clinicaldiagnosis, and treatment.

Review
Snake characteristics
Mamushi (G. blomhoffii)

Mamushi is a pit viper that is seen in a wide variety ofcolors (Figure 1). As mamushi is a small snake (about 60cm), its attack range is only about 30 cm [11]. The fangs
are about 5 mm long, with very thin tips (Figure 2a).
This snake lives near rivers, ponds, and paddy fields andis active in the daytime in spring and autumn and atnight in the summer. In Japan, G. blomhoffii is seen from
Kyushu to Hokkaido, and the distinct species Gloydius
tsushimaensis (Tsushima Mamushi) is found on Tsushimaisland, Nagasaki.
Habu (P. flavoviridis)

Five types of pit vipers inhabit Okinawa and Amami.
Habu, one of these pit vipers, varies in color by region(Figure 3). Even though this nocturnal snake is not
active in the daytime, many people are bitten when
disturbing snakes while farming. At night, this snake
comes out in search of food near houses, sometimes
entering them. Accidents often occur during handling.
Habu snakes often climb trees. Habu is the most dangerous

Page 2 of 9of these three snakes because it is large, reaching up to 2 m
in length, and is the most aggressive. Habu fangs aretubular and 1.5–2 cm in length (Figure 2b). Dry bites
can occur because the venom-releasing pore of thehabu snake is located approximately 0.1 cm from the tipof the venom fang [12].
Yamakagashi (R. tigrinus)

Yamakagashi is a rear-fanged venomous snake that lives
near rivers, ponds, and paddy fields, the same habitat as
mamushi. Snakes of the same genus, such as Rhabdophis
lateralis and Rhabdophis subminiatus, are distributed
throughout Russia and Asia [13,14]. Yamakagashi grows
to about 1 m in the plains and 1.5 m in the hills andmountains. The color varies by region (Figure 4). The larger snakes have short, 2-mm long fangs located slightly
back from the front of the mouth. Like viper fangs, thefangs of yamakagashi are not tubular, and the venom
gland duct opens at the base of the fang (Figure 2c). Because yamakagashi fangs are not grooved, envenomation
does not occur in most bites; therefore, this snake has long
been considered non-venomous [13,15].
Venom activity and clinical symptoms
Mamushi (G. blomhoffii)

Several enzymes, including a protease, phospholipase
A2 (PlA2), and bradykinin-releasing-enzyme are contained in the mamushi venom [16]. The effects of these
enzymes are described in Table 1. Local pain and swelling are the main symptoms at the bite site; subcutaneous bleeding and blisters are sometimes observed. The
swelling and pain spread gradually from the bite site

Figure 1 Color variation in mamushi. (a) Common color; (b, c) color variations; (d) melanistic variant. Photographs courtesy of the Japan
Snake Institute.

Hifumi et al. Journal of Intensive Care (2015) 3:16

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Figure 2 Locations of fangs in mamushi, habu, and yamakagashi snakes. (a) Mamushi fangs are about 5 mm long, with very thin tips. The
snakes often have two fangs on each side; (b) habu fangs are 1.5 to 2 cm long; (c) yamakagashi fangs are only about 2 mm long and are locatedslightly back in the mouth. Photographs courtesy of the Japan Snake Institute (a, c) and the Okinawa Prefectural Institute of Health andEnvironment (b).

(Table 2). Most patients are bitten on the hand or foot,but the spread of swelling to the trunk is often observed [17].
With severe swelling, hypotension can occur. In thesecases, increased levels of creatine phosphokinase (CPK)and blood myoglobin due to rhabdomyolysis are remarkable and can cause acute renal failure [11,17]. In addition
to hypotension, renal hemorrhage and direct action of thevenom on the kidney can cause acute renal failure. In
severe cases, the plasma potassium level can increase
due to muscle tissue damage and metabolic acidosis,
causing cardiac arrest shortly after the bite [18,19]. A
rise in the level of the CPK isozyme cardiac muscle
conformer (MB) and necrosis of the myocardium havebeen reported, which may be due to the direct action ofvenom on the cardiac muscle [20].

Figure 3 Color variations in habu from different geographical locations. Habu from (a) Amami Oshima; (b) Tokunoshima; and (c, d)Okinawa. Photographs courtesy of the Okinawa Prefectural Institute of Health and Environment.

Hifumi et al. Journal of Intensive Care (2015) 3:16

Page 4 of 9

Figure 4 Color variation in yamakagashi from different geographical locations. Yamakagashi from (a) Kanto and Tohoku; (b) Chubu andKinki; and (c) Chugoku and Sikoku; (d) melanistic variant. Photographs courtesy of the Japan Snake Institute.

As the venom is absorbed from the bite site, the platelet
count gradually decreases due to the platelet aggregation
activity of the venom, sometimes decreasing to <100,000/
mm3 [21]. Cases in which the platelet count rapidly
Table 1 Enzymes in the snake venoms
EnzymeMamushi Habu Yamakagashi

Non-hemorrhagic metalloproteinase +

+

HR1

+

+

HR2

+

+

Phospholipase A2++

TAME esterase++

L-amino acid oxidase++

Hyaluronidase++

Phosphodiesterase++

Phosphomonoesterase++

ATPase++5′-nucleotidase++

Endonuclease++NAD-nucleosidase+±

Alginine ester hydrolase++

Thrombin-like enzyme++

Endopeptidase++

Bradykinin-releasing enzyme

+

+

+

decreases to <10,000/mm3 within 1 h after the bite areoften seen [22]. The venom is thought to be injected directly into the blood vessel during the bite, as the tips ofthe mamushi fangs are very thin. The platelet aggregationand hemorrhagic activities are very strong, causing ecchymosis and gastrointestinal bleeding. However, even insevere cases, little change in prothrombin time (PT), activated partial thromboplastin time (APTT), or fibrinogenlevels is observed [11]. The vasodilatation activity of thevenom is strong, sometimes causing hypotension [23].
The venom contains small amounts of neurotoxin,
which causes diplopia, blurred vision, and a divergent
squint due to action on the nervus oculomotorius, but
respiratory muscle paralysis is not seen. These ocularsymptoms remit within several days to about 2 weeks [24].
Habu (P. flavoviridis)±+ indicates the presence of the enzyme, − indicates the absence of the
enzyme, blank space indicates unknown whether the venom contains thegiven enzyme, HR 1 hemorrhagic factor-1, HR-2 hemorrhagic factor-2, TAME
p-toluenesulfonyl-L-arginine methyl ester, ATPase adenosine triphosphatase,
NAD nicotinamide adenine dinucleotide.

The toxicity of habu venom is about half that of mamushi
venom, but the amount of habu venom is approximately
10 times that of mamushi venom. Since habu venom contains many enzymes similar to those found in mamushi
venom (except the neurotoxin), a similar range of symptoms are observed in patients with habu bites (Table 1).
Habu venom causes extreme local swelling, necrosis, andbleeding at the bite site (Table 2). Most habu bites start toswell within 30 min after the bite [7]. In addition, severecases manifest not only with local signs but also withgeneral symptoms such as vomiting, cyanosis, loss of
consciousness, and hypotension. Habu bites frequently
cause compartment syndrome (CS) because of the large
volume of venom injected, regardless of its lower

Hifumi et al. Journal of Intensive Care (2015) 3:16

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Table 2 Typical symptoms and laboratory data to be evaluatedMamushi

Habu

Yamakagashi

Typicalsymptoms

Local pain, swelling, severely decreased platelet
counta, diplopia, blurred vision, nauseab,vomitingb, stomachacheb, diarrheab, cyanosisb

Local swelling, necrosis, bleeding at the bite site,
vomitingb, cyanosisb, loss of consciousnessb,
hypotensionb, compartment syndrome

Nasal bleeding, gum
bleeding, bleeding fromthe bite site, headacheb

Laboratory data
to be evaluatedroutinely

CBC, CK, BUN, Cre, Na, K, Cl, Fibrinogen, FDP, d-dimer, PT, APTT

Typicallaboratory
findings

CK↑

Laboratory data
to be evaluatedadditionally

Myoglobin, CK-MB

FDP >100 μg/mLa

Plt <10,000/μL

Fibrinogen <100 mg/dL
Myoglobin

AT-III, TAT, PIC

CBC complete blood count, Plt platelet count, CK creatine kinase, BUN blood urea nitrogen, Cre creatinine, FDP fibrinogen degradation products, PT prothrombin
time, APTT activated partial thromboplastin time AT-III antithrombin III, TAT thrombin-antithrombin III complex, PIC plasmin-α2-plasmin inhibitor complex.
a
Venom is injected into the blood vessel directly.
b
In severe cases.

toxicity compared to mamushi venom. In addition, following the bite, patients tend to bind the wound excessively
tightly due to fear of the venom spreading to the whole
body, thereby exacerbating CS. Thus, many cases of CS arereported following habu bites.
Yamakagashi (R. tigrinus)

Yamakagashi venom (metalloproteinase) has strong blood
coagulation activity, with a prothrombin-activating effectand a weak thrombin-like effect [25]. Once yamakagashi
venom enters the blood, it activates prothrombin continuously, causing excessive coagulation. Disseminated fibrin
formation ensues, and fibrinolysis is activated, resulting in
hypofibrinogenemia and increased levels of fibrinogendegradation products (FDP) [5]. This venom induces
life-threatening hemorrhagic symptoms and severe disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype that is typically observed in patients withacute, severe blunt trauma [26], acute leukemia (particularly in acute promyelocytic leukemia) [27], and massive
obstetric hemorrhage [28]. DIC progresses to acute renal
failure due to the obstruction of glomeruli by thrombi.
Because the fangs of this snake are very short, thevenom is injected subcutaneously or intradermally.
However, pain, swelling, and inflammation are minimal
at the bite site because the venom does not act on thetissues directly. The typical symptom is hemorrhage,
including nasal bleeding, gum bleeding, and bleedingfrom the bite site (Table 2). In severe cases, headache isalso a characteristic symptom [5].
Diagnosis

There are no definite diagnostic markers or kits available
in clinical practice; therefore, definitive diagnosis of snakevenom poisoning requires positive identification of thesnake and observation of the clinical manifestations of envenomation [3]. On initial assessment, CBC, BUN, Cre,Na, K, Cl, CK, and coagulation markers (fibrinogen, FDP,
d-dimer, PT, and APTT) should be examined (Table 2).
Mamushi (G. blomhoffii)

Because mamushi hide in the grass and fallen leaves,
identification is difficult, even in the daytime. Patientsusually feel only a pain similar to that of a splinter because the fangs are about 5 mm long and very thin.
Thus, patients and physicians often mistake this bite for
an insect bite or sting, especially when bitten at night[11]. The mamushi bite usually leaves two very small
wounds that are 1 cm apart [11]. These snakes often
have two fangs on each side; therefore, three or four fang
marks are often observed. As small bite marks may bedifficult to observe, diagnosis by bite wounds alone isdifficult [11]. In many cases, blood test data do notchange for several hours after the bite. If symptoms suchas swelling are seen, it is necessary to perform frequent
blood tests. With increased swelling, CK and blood myoglobin levels rise, followed by a rise in BUN and creatininelevels. A remarkable rise in myoglobin level is an indicator
for the diagnosis of mamushi bite and suggests the risk ofacute renal failure.
In cases where venom was injected into the blood vessel
directly, platelet counts rapidly decrease to <10,000/mm3
but fibrinogen levels do not decrease [22]. Such cases are
difficult to diagnose because the local symptoms are mild.
However, if swelling, hypotension, or ocular symptoms
such as double vision or squint are observed, the identityof the snake is most likely mamushi. In severe cases,
nausea, vomiting, stomachache, diarrhea, cyanosis, andtachycardia are sometimes observed.
Grade classification for mamushi bites is clinicallyused to determine the severity of injuries as follows[17,29]: Grade I, redness and swelling around the bittenarea; Grade II, redness and swelling of the wrist or footjoint; Grade III, redness and swelling of the elbow orHifumi et al. Journal of Intensive Care (2015) 3:16

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Table 3 Indication and incidence of side effects in antivenom
Mamushi

Habu

Yamakagashi

Mamushi grade ≧ III

N/A

Fibrinogen <100 mg/dL

Anaphylaxis

2.4%–9.0%

11%0%Serum sickness disease

N/A

24.2%

N/A

Indication
Side effects

N/A not applicable.

knee joint; Grade IV, redness and swelling of the wholeextremity; and Grade V, redness and swelling in parts
beyond the extremity or exhibiting systemic symptoms.
Habu (P. flavoviridis)

There are no standardized diagnostic or severity criteria
for habu bites. Local swelling may help determine whether
the patient was bitten by a habu. Because habu bites resultin swelling within 30 min, the circumference of theaffected limb may be one indicator of severity. Twenty
percent of habu bites are dry. This incidence is higher
than that of bites by other snakes, such as the saw-scaled
viper (Echis carinatus) with 8% dry bites and the rattlesnake in Central California with 10.9% dry bites [30-32].
While most dry bite cases do not require admission, Levine
recommends repeating laboratory test within 6 h [4].
Yamakagashi (R. tigrinus)

Yamakagashi bites have been diagnosed based on detailed
descriptions of snakes by patients and hemorrhagic symptoms including severe hypofibrinogenemia (<100 mg/dL)[6]. In one study, about 80% of the reported patientsdeveloped persistent bleeding from the bite site on
admission [5]. DIC with a fibrinolytic phenotype
develops early; therefore, evaluating the DIC score ismandatory for the diagnosis of this injury [33]. Assessment of the levels of antithrombin III (AT-III), thrombinantithrombin III complex (TAT) and plasmin-α2-plasmin
inhibitor complex (PIC) may help to evaluate the clinicalcondition.
Treatment

Previously recommended first-aid measures are strongly
discouraged [3]. The use of tight ligatures and arterial
tourniquets in the first-aid treatment of snakebite has
been universally condemned by modern snakebite experts due to the increase of potential adverse effects
and the lack of effectiveness [34-36]. No human study
has shown the efficacy of incision and suction as afirst-aid tool with regard to improvement of survival oroutcome [37].
Once airway, breathing, and circulation have been
established, a rapid, detailed history should be obtained[3,37]. If a snake bite is suspected, hospital admission
should be considered for further follow-up.

Antivenom therapy

Snake antivenoms are manufactured by immunizing horses
against unbound venom. Antivenom treatment is the definitive therapy, but not all cases warrant such therapy(Table 3). Antivenom is administered intravenously toachieve rapid onset of action [7,11]. Subcutaneous or intramuscular injection for the purpose of avoiding side effects
is not recommended.
Because snakes inject the same amount of venom into
adults and children, the same dose/volume of antivenom
must be administered to children.
Preparedness for anaphylaxis should be consideredwhen administering the antivenom. Premedication withan antihistamine and/or epinephrine should be used when
the perceived benefit is greater than the risk of adverse
effects [5]. As for the use of hydrocortisone as premedication for snake antivenom, the efficacy has notbeen determined [38].
Another major adverse effect of antivenom is serum
sickness disease, which usually occurs 4–10 days after
antivenom administration [39]. Rashes, itching, joint
pain, fever, lymphadenopathy, malaise, and renal failure
are typical symptoms [39,40]. Serum sickness disease is
the prototypical type III hypersensitivity reaction, involving excessive immune complex formation [41]. Althoughmany patients have mild symptoms, the reaction canlead to multiple organ failure. Such severe reactions
most often occur in patients with severe snakebites that
require large amounts of antivenom. Systematic corticosteroids are the main treatment of choice, starting at adose of 60 mg per day and tapering over 2 weeks to
avoid rebound [3,42]. Plasmapheresis is used to obtainrapid effectiveness, particularly in severe cases [43,44].
Mamushi and habu antivenom are approved drugs,
whereas yamakagashi antivenom is used as an off-label
drug in Japan. Therefore, clinicians are required to join aclinical research group to use yamakagashi antivenom inclinical practice [6].
Efficacy of antivenom
Mamushi (G. blomhoffii)

Studies have evaluated the efficacy of antivenom andcepharanthine (CEP) in a single-center cohort study[45,46]. Makino et al. evaluated 114 cases and reported
that patients administered antivenom had a significantly

Hifumi et al. Journal of Intensive Care (2015) 3:16

shorter hospital stay than those administered CEP (p <0.01). However, in severe cases (grades of mamushi bites
IV/V), the percentage of patients administered antivenom was higher than that of patients administered
CEP (50% vs. 33%, p = 0.06) [45]. In contrast, Kochi etal. evaluated 50 cases and reported that patients administered antivenom had a significantly longer hospital staythan those administered CEP because of the greater
severity of cases in the antivenom group [46]. Thus,
evaluating the efficacy of antivenom and CEP without
adjusting for the severity of mamushi bites limited thesestudies [45,46].
Until 1990, antivenom was most often administeredsubcutaneously or intramuscularly to avoid adverse reactions. Due to its slow absorption in the human body,mamushi antivenom was mistakenly assumed to be ineffective by clinical doctors [47]. Intravenous administrationof antivenom had started in the 1990s, and proper reevaluation of the antivenom was expected. Hifumi et al.
conducted large, multi-center, population-based studies[17], reporting 234 mamushi bites. Among the severecases (grades III/IV/V), patients administered antivenom
had a significantly shorter hospital stay than those administered CEP (p = 0.024). In contrast, for the mild cases(grades I/II), there was no significant difference in the duration of hospital stay between the two groups (p = 0.77).
Therefore, the authors concluded that antivenom is effective in shortening the duration of hospital stay for patientswith severe mamushi bites [17]. We propose a new clinicaldecision algorithm for mamushi bites as shown in Figure 5.
We recommend antivenom administration in patientswith mamushi grade ≧III on the basis of our previously reported data [17].

Page 7 of 9large-scale studies of the prognosis. Okinawa prefecture
is known to have a large population of habu, and therate of antivenom use is high. There have been no
deaths from habu bites in the last 10 years in this area
(2004–2013, no deaths in 551 cases) [48]. However, between 1965 and 1969, there were approximately 24
deaths among 1,770 cases in Okinawa due to the lack ofantivenom [48]. Therefore, antivenom therapy is currently
considered useful for habu bites [49,50].

Yamakagashi (R. tigrinus)

Hifumi et al. conducted a retrospective survey analyzing
data from 34 patients (19 of whom were treated withantivenom) between 1973 and 2013 [5]. Univariate analysis revealed no significant difference in baseline characteristics and laboratory data between those treatedwith and without antivenom. Hospital mortality was significantly lower in patients treated with antivenom thanin those treated without (0% vs. 26.7%; p = 0.03). Moreover, the number of patients with renal failure requiring
hemodialysis was significantly lower among those treatedwith antivenom (5.3% vs. 40.0%; p = 0.03).
Therefore, antivenom is a specific, definitive, and effective
treatment. Administration of yamakagashi antivenom
following bites can lead to complete clinical recovery
without progression to multiple organ dysfunction syndrome (MODS), even in the presence of severe DIC. Thus,
antivenom effectively treats the acute symptoms and canprevent disease progression. Fibrinogen levels <100 mg/dL
are considered appropriate for antivenom administrationin clinical practice [13,51].

Habu (P. flavoviridis)

Antivenom side effects
Mamushi (G. blomhoffii)

No definitive indication for the use of antivenom has
been provided in clinical practice. Although antivenom
is considered effective following habu bites, there are no

A recent national survey reported that the incidence ofadverse reactions to antivenom was 2.4%–9.0%, including
mild cases [9,17].

Figure 5 The clinical decision algorithm for Mamushi bites. IV fluid, intravenous fluid administration.

Hifumi et al. Journal of Intensive Care (2015) 3:16

Page 8 of 9

Habu (P. flavoviridis)

Yamakagashi (R. tigrinus)

Miyagi reported that habu antivenom induced early allergic reactions in approximately 11% and serum sickness
disease in approximately 24.2% of patients [7]. The reason
this antivenom has higher rates of allergic reactions thanthe other two antivenoms produced using horses remains
unknown.

Yamakagashi bites induce DIC, for which heparin has beenused [5]. However, heparin use is contraindicated considering the pathophysiology of DIC involving fibrinolysis.
Although other adjunct DIC treatments, such as proteaseinhibitors and fresh frozen plasma (FFP), are clinicallyused, the only definitive therapy available is antivenom.

Yamakagashi (R. tigrinus)

Although the number of the included patients is small (34cases) to make any comprehensive assessment, the initial
anaphylactic reaction rate (including severe reactions) was
zero [5,6].
Other treatments
Mamushi (G. blomhoffii)

CEP, a biscoclaurine (bisbenzylisoquinoline) amphipathic
alkaloid isolated from Stephania cepharantha Hayata,
has been proposed as a possible alternative therapy toantivenom because it lessens the inflammation and pain
caused by snake bites [9]. CEP and other extracts fromthe same plant are widely used in clinical practice (primarily in Japan) to treat a variety of acute and chronic diseases
such as alopecia areata [52], radiotherapy-induced leucopenia [53], malaria [54], and septic shock [55]. However,
CEP does not have the ability to neutralize circulating
venom [56]; therefore, CEP should not be used instead ofantivenom for treating mamushi bites (Figure 5). A previously proposed clinical decision algorithm for mamushi
bites (supported by the pharmaceutical company) recommends the routine use of CEP [57]; however, the routine
use of CEP is clearly unnecessary considering its limited
effectiveness.
Because no cases of tetanus associated with mamushi
bites have been reported, routine use of tetanus toxoid
in patients with mamushi bites is not recommended(Figure 5).
Habu (P. flavoviridis)

Because myonecrosis and CS are often observed, our goalin treatment is not only to save lives but to improvefunctional outcomes [58,59]. Habu bites caused 14 casesof CS in 2009 [60]. Fasciotomy is required when the compartment pressure reaches 30 mmHg. However, whenpressures only moderately exceeds 30 mmHg, somepeople advocate management with further antivenom,
elevation, and reassessment within a few hours; in suchcases, fasciotomy is only considered if pressures fail todecrease within several hours [3,32]. This protocol may
be the preferable option for mildly symptomatic patients.
The initial use of intravenous fluids is also effective for
improving circulatory dysfunction and preventing renal
dysfunction caused by CS.

Conclusions
In this review, we have provided information to clarify theclinical diagnosis of snake bites. Antivenom therapy is
warranted for venomous snake bites.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
TH, AS, and YK wrote the manuscript. KS, KU, NK, HK, YK, JI, and KK
participated and cooperated with the research group. TH, AY, MA, and YK
revised and edited the manuscript. All authors read and approved the final
manuscript.
Acknowledgements
This study was supported by Health Science Grants (H25-Shinkou-Shitei-007,
2013–2015) from the Ministry of Health, Labour and Welfare of Japan.
Author details
1
Emergency Medical Center, Kagawa University Hospital, 1750-1 Ikenobe,
Miki, Kita, Kagawa 761-0793, Japan. 2The Japan Snake Institute, Yabuzuka
3318, Ota, Gunma 379-2301, Japan. 3Department of Emergency Medicine,
Graduate School of Medicine, University of the Ryukyus, 207, Uehara,
Nishihara, Okinawa 903-0215, Japan. 4Department of Bacteriology II, National
Institute of Infectious Disease, Gakuen 4-7-1, Musashimurayama, Tokyo
208-0011, Japan. 5Okinawa Prefectural Institute of Health and Environment,
2085 Ozato, Ozato, Nanjo, Okinawa 901-1202, Japan. 6Department of
Immunology, National Institute of Infectious Disease, Toyama 1-23-1,
Shinjuku, Tokyo 162-8640, Japan. 7Department of Emergency and Critical
Care Medicine, Tokai University School of Medicine, 143 Shimokasuya,
Isehara, Kanagawa 259-1193, Japan. 8Division of Critical Care Medicine andTrauma, National Hospital Organization Disaster Medical Center, 3256
Midoricho, Tachikawa, Tokyo 190-0014, Japan. 9Division of Critical Care
Medicine and Trauma, Yamanashi Prefectural Central Hospital, 1-1-1
Fujimicho, Kofu, Yamanashi 400-8506, Japan.
Received: 7 January 2015 Accepted: 9 March 2015

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