Saori Kawamura1), Kazuya Kiyota1), Hirosi Inagawa1),Taizou Terada1), Masamichi Nishida1), Sou Suzuki1),Kazuyuki Ono1), Kazuhiko Maekawa1),Suguru Mato2), and Yoshio Sawai3)

1) Department of Traumatology and Critical Care, Faculty of Medicine, University of Tokyo, 7-3-1, Hongou, Bunkyo-ku, Tokyo 113, Japan
2) Emergency and Critical Care Center, Saitama Medical College, 1981 Tujidouchou, Kamoda, Kawagoe, Saitama , Japan
3) Japan Snake Institute, Yabuzuka-honmachi, Nittagun, Gunma 379-23, Japan

Key words:

Agkistrodon Blomhoffii brevicaudus, rhabdomyolysis, paralysis

Abstract in japanese

Since Agkistrodon Blomhoffii brevicaudus is not native to Japan, no case has been reported of an envenomation by this snake. An envenomation of Agkistrodon Blomhoffii, a native to Japan, is a common occurrence; its clinical course is generally benign, and muscle paralysis seldom occurs. A case is presented here in whom an envenomation from the bite of Agkistrodon Blomhoffii brevicaudus resulted in severe rhabdomyolysis, followed by acute renal failure, prolonged external ocular paralysis and respiratory muscle paralysis. Hemodialysis was required for 12 days, and mechanical ventilatory support for 60 days. The patient was discharged alive after the prolonged hospitalization.

Case Report

The patient was admitted to the University of Tokyo Hospital a few hours after the injury. He was first seen by a physician on duty, and his wound was cleansed.

The patient was kept in the emergency observation bed during the night.The snake carcass was identified as that of Agkistrodon Blomhoffii brevicaudus（Fig.1）.

He was admitted to ICU about 20 hours after the injury because of progressive swelling of his left upper extremity and dyspnea（Fig.2）. Upon admission to ICU, the patient was awake and alert, complaining of difficulty breathing, tingling sensation of his left upper extremity. The blood pressure was 210/140 mmHg. The pulse was 114/min. , and the respiration was shallow and 28/min. Body temperature was 36.6℃. Physical examinations revealed the markedly swollen left upper extremity. Swelling was extended to the shoulder. The chest wall movement was severely limited. The motor function of both his upper and lower extremities was normal. External ocular movement was totally paralyzed.

Laboratory data upon admission revealed that there was an marked elevation in the serum myoglobin concentration and creatine phosphokinase activity. Other abnormal findings included myoglobinuria, respiratory and metabolic acidosis, and elevated hematocrit. Results of the main laboratory test are shown in Table 1.

As dyspnea progressed with a concomitant fall in the arterial oxygen saturation, nasotracheal intubation was performed and mechanical ventilation was started. He developed a compartment syndrome of his upper extremity as evidenced by sustained intracompartment pressure >41 mmHg, requiring fasciotomy in ICU.

Seventy hours following fasciotomy, the antivenin therapy was initiated after confirming the negative skin test. The decrease in myogenic enzyme activities was less than expected. The levels of myogenic enzymes decreased slightly, and increased again despite fasciotomy and antivenin therapy. On the 4th hospital day, the serum myoglobin concentration was 666,000ng/ml and creatine phosphokinase activity was 522,500IU/l, both of which were at their peak（Fig.3）.

As nonoliguric renal failure developed, the continuous hemodiafiltration was initiated and continued for 14 days. Swelling was most severe on the 4-5th hospital day, involving the left upper extremity, head, neck, trunk and a part of right upper extremity. Weaning from the ventilator failed several times. Finally he was able to breath on his own for a whole day without ventilatory support on day 53（Fig.4）. The eye movement slowly recovered. The slight horizontal movement was noted on day 14. From day 24 on, the voluntary eye movement was almost restored to normal except for bilateral abductor muscle palsy and diplopia. His external ocular paralysis resolved at the time of his discharge from the hospital（Fig.5）. Electromyogram of ocular orbicular muscles demonstrated waxing provoked by high frequency repetitive stimulation, which indicates a possible involvement of presynaptic blockade by a toxin causing the paralysis（Fig.6）. He was treated in ICU for 29 hospital days and was discharged from the hospital on 54th hospital day without any significant sequellae.

Discussion

Agkistrodon Blomhoffii brevicaudus is considered to be one of subspecies of Agkistrodon Blomhoffii. Bites by Agkistrodon Blomhoffii brevicaudus (A.B. brevicaudus) are common in Korea and the central and northern China (Sawai and Lah, 1978; Szyndler, 1984; Sun, 1990). Common symptoms associated with A. B. brevicaudus bites are also of hemorrhagic nature. However, certain neurologic symptoms such as ptosis of eyelids, blurred vision and respiratory distress may occur in severe bites(Sun, 1990). The venom of A.B.brevicaudus contains a neurotoxin called β-Agkistrodotoxin which is responsible for respiratory paralysis and other neurologic symptoms. Agkistrodon.halys, which is a widely distributed species in China, possesses a less potent neurotoxin. Xu Ke reports that there are differences in the amount of β-Agkistrodotoxin of Agkistrodon halys found in different parts of China(Xu Ke., 1990). For example, Agkistrodon Blomhoffii brevicaudus Stejneger(A. halys in the Jiangsu and Zhejiang provinces）have a certain amount of neurotoxin, whereas no neurotoxic component was found in the venom of the snakes collected in the Snake Island of the Northwest China.(Xu, Ke., 1990). Zao, et al. suggested that A. halys distributed in China could be classified into several species or subspecies depending on the toxic substances of the venom(Zao, et al. 1981). This neurotoxin blocks the presynaptic neuromuscular transmission, resulting in various symptoms.

Both hemolytic and neurotoxic symptoms were quite severe in our patient. External ocular muscles were paralyzed and respiratory muscles were also involved. Ventilatory support was necessary for about 2 months as respiratory muscle paralysis was prolonged. However, both upper and lower extremity muscles were unaffected throughout his stay in ICU. Brain CT and MRI demonstrated no evident lesion the brain. External ocular paralysis in this case was accompanied by no such neurological symptoms as ptosis, mydriasis, facial paresthesia, and contraction of the visual field, which indicates subnuclear impairment of III, IV, VI cranial nerves. There seems to be a site specific difference in the sensitivity to the toxin.

Various types of toxins have been purified from the venom of Agkistrodon Blomhoffii brevicaudus. Some toxins are presynaptic blockers, b-type of snake toxins. In our patient, electromyogram demonstrated waxing phenomenon induced by high frequency repetitive stimulation to the ocular orbicular muscle. It is speculated that the cause of this waxing and the external ocular paralysis was due to presynaptic blocking.

The antivenin therapy was initiated 70 hours after injury. The initiation of this specific therapy was delayed for two reasons; firstly the only available antivenin was of Agkistrodon Blomhoffii , not of Agkistrodon Blomhoffii brevicaudus.; secondly, on his preceding snake bite incident, the skin test had been positive. Antivenin therapy by Agkistrodon Blomhoffii was initiated finally. The elevated levels of myogenic enzymes in serum, the degree of extremity and torso swelling, neurological symptoms, and acute renal failure were unaffected following the antivenin therapy. Clinical symptoms and the abnormal laboratory findings improved gradually after initiating the continuous hemodiafiltration. There is no knowing whether his recovery would have been facilitated if the antivenin of Agkistrodon Blomhoffii brevicaudus had been used early in his course.

References

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Ke, Xu. （1990）β-Agkistrodotoxin: A Presynaptic Neurotoxin From Venom of the Pit Viper（Agkistrodon Blomhoffii brevicaudus STEJNEGER）Chin. sci. bull, 15: 1145-1155.

Mori, K. and Imaizumi, H （1994） Severe Bothrop Bite with Ocular Signs -Evaluation of the Mechanism of Ocular Signs. JJAAM 5; 699-705. （in Japanese with English summary）

Sawai, Y.（1992）Venomous Snakes and Snake bite Treatment In Asia. The SNAKE: 24, 129-141

Sawai, Y. and K, -Y. Lah（1978）Snakebites in the South Korea. Snake, 9: 39-47

Sun, X. -S. （1990）Experience in 3045 cases of treatment of snake bite by pit viper. Toxin Rev., 9: 134

Tateno, I., Y. Sawai and M. Makino （1963） Current status of mamusi snake（Agkistrodon halys） bite in Japan with special reference to severe and fatal cases. Japan. J. Exp. Med., 33: 331-346

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　今回我々は、中国産マムシに咬まれ、高度の横紋筋融解とそれによる急性腎不全、2カ月にわたる呼吸管理を必要とする程の呼吸筋麻痺、外眼筋麻痺を呈した症例を経験した。Agkistrodon Blomhoffiiの抗毒素血清の投与にて症状は改善せず、持続血液濾過透析使用により徐々に改善を見た。