Chapter 6 - Strikes and Bites

6. Strikes and Bites

 When a snake bites a man the effects are extremely variable and unpredictable. They range from transient and local discomfort…to collapse and death within a few minutes.

Sherman and Madge Minton, 1980

                Fascination with rattlesnakes led me to keep as many species as I could collect or buy in the late 1960’s. The first Mojave Rattlesnake (Crotalus scutulatus) I kept in captivity taught me that venom can act astonishingly fast and that scutulatus is exceptionally dangerous. Observations made during feeding many species rattlesnakes did not prepare me for the rapid and deadly nature of Mojave Rattlesnake venom. Within 15 seconds of introducing a white mouse to the cage housing the 80 cm scutulatus, the snake struck the mouse and released it. The mouse instantly started to bleed from its eyes, mouth, ears, anus, tail, and died. The combination of highly toxic venom and an efficient venom delivery system makes scutulatus one of the most dangerous snakes in North America. Hands-on-learning is not always safe, but it tends to create vivid memories not easily forgotten.

The unpredictable nature of venomous snakebite referred to by the Mintons is poorly understood by the general public. Many physicians are unfamiliar with the stochastic nature of envenomation unless they work in an area with venomous snakes. The unpredictability is at the heart of much of the snakebite mystique. Yet it has been long known to herpetologists; the literature is full of stories of people suffering no symptoms from a venomous snakebite while others experience a quick death. Oddly, others bitten by harmless snakes may show signs of envenomation. Consider the following stories from India.

                A boy cutting grass close to a bungalow was bitten on the foot by a krait. He continued to work, but eventually stopped because of increasing pain. When his family discovered the situation, they held a candle in front of him and asked him how many flames he saw; he replied five. This was considered a symptom of poisoning so the boy was brought to a local medicine man, or Mantri, who used incantations. Unconscious before he arrived, his teeth were firmly clenched and oral medicine could not be administered. The family believed the case hopeless, however, the Mantri soon brought the boy back to a conscious state and he recovered completely.

                In a second instance an 18-year-old male was bitten while lying down. He began vomiting and went into a stupefied state of consciousness. A Mantri had given the patient powdered root while repeating an incantation. An observer retrieved the dead snake and found it to be a young Dhaman, a large, harmless, colubrid snake. The boy was assured he was in no danger, but he fainted again and his feet and hands became very cold. Eventually, the boy recovered.

                What explains these stories? In the first case, it seems likely that if the snake was actually a krait (Bungarus) and not a similarly colored and patterned wolf snake (Lycodon), or other harmless species, little or no venom was injected during the bite. This is not uncommon. The literature suggests that 30–50% of defensive bites by venomous snakes are dry bites. In a dry bite no venom is injected. If venom is injected, there is a good chance it will be a sub-lethal dose. However, kraits are nocturnal and the boy was most certainly cutting grass during the day. Krait venom does not produce pain at the site of the bite, but cobra venom would. Using a candle may reveal double vision (diplopia), a common symptom of neurotoxic envenomation, and the clenched jaw demonstrates flaccid paralysis had not occurred. The presence of some symptoms and the absence of others suggest the boy was suffering from self-induced fear.

                The second instance is likely due to the power of suggestion. If the human brain is expecting something to happen, it may, in fact make the expected results appear within the body. This phenomenon is well known and commonly demonstrated in hypnotism, and the placebo effectseen in medical trials. Both are based upon the power of suggestion. The human mind is easily deceived because the imagination is a powerful tool and mind and body are not separate entities. Dwelling on the consequences of snakebite may induce anxiety, hyperventilation, faintness, a slowed heartbeat, and a variety of other symptoms that mislead physicians trying to diagnosis the situation.

At a hospital in southeastern Brazil, over the course of 34 consecutive months, 40 cases of snakebite with confirmed species identification involved either a tropical rattlesnake (Crotalus sp.) or a lancehead (Bothrops sp.). Of 33 bites from the lanceheads, 10 (33.3%) showed no signs of envenomation. Of the seven rattlesnake bites, three (42.9%) showed no signs of envenomation. A similar situation was reported by herpetologist Van Wallach who was bitten on the hand by a Variable Mole Viper (Atractaspis irregularis). He described swelling, which lasted about three days, extensive pain in muscles, nerves and lymph nodes from head to toe, and discoloration at the bite site. Even more interestingly, Wallach wrote that he had been bitten six times by venomous snakes and in two of these bites (33%) there were no symptoms of venom being injected. Venomous snakes do bite without injecting any venom. However, lethal doses of venom are sometimes delivered and death may be rapid or be delayed.

                Consider the case of Joe Slowinski, a 38-year-old herpetologist at the California Academy of Sciences studying the snakes of Myanmar. While working at a remote field site on the morning of September 11, 2001 his field assistant brought him a snake in a bag. The assistant believed it to be a harmless white-banded wolf snake in the genus Lycodon.  Tired, Slowinski reached into the bag to remove the snake and was bit at the base of his middle finger. The snake was a Multi-banded Krait (Bungarus multicinctus), a fact Slowinski immediately noted upon being bitten. Wolf snakes often mimic kraits very closely in color and pattern, and the assumption that the snake in the bag was indeed a wolf snake proved fatal. Slowinski died 30 hours later despite the best efforts of his colleagues to keep him alive using rescue breathing. Ironically, Slowinski had written a popular article for the California Academy’s magazine ending it with the following sentence, “The best way to avoid being bitten by a venomous snake is simply to leave it alone.”

                Avoiding venomous snakes is an excellent way to stay healthy, but avoidance is difficult if you make a living collecting venomous snakes. It was not practical for Slowinski, nor was it practical for William Oliver. In 18th century England venomous snakes were in great demand for their medicinal value, and a few people made a living collecting and selling snakes to apothecaries. William Oliver was a viper collector in southwest England, near Bath. On June 1, 1735 Oliver was bitten at the base of his right thumb and, even before the snake had released its bite, a burning pain shot up his right arm. Oliver’s eyes became bloodshot and watery. Within the hour he had chest pain, faintness, shortness of breath, and cold sweats. He was soon vomiting, the arm had swolled significantly, and he suffered temporary blindness. Oliver, however, had a remedy ― olive oil, a snakebite remedy he had saved for just such an occasion. About 75 minutes after being bitten, a dish of glowing charcoal was brought to him. He held his naked arm over the glowing embers while his wife rubbed the limb with the oil. The arm was rotated over the coals as if it was being roasted. It was Oliver’s opinion that the pain from the venom had ceased, but the swelling remained. His pulse was weak, but he started to drink the olive oil. He was put in bed and his arm was again treated with heat and bathed in salad oil. Oliver fell into a sound, nine-hour asleep, and when he awoke in the morning he was feeling healthy. But, the symptoms returned in the afternoon after he became intoxicated from drinking rum and beer. The heat treatment was used a third time and then his arm was wrapped in paper soaked in olive oil. Presumably, Oliver survived the bite. However, the account reported by his doctor makes no mention of the long-term effects of the venom or the heat treatment on his arm.

Oliver was bitten by the European Adder (Vipera berus), a small viper and the only native venomous snake known to inhabit the United Kingdom. Even in the 21st century, about 100 people sustain Adder bites each year. Roughly 70% of the victims have no symptoms, or suffer only from local pain and swelling at the bite site. The other 30% may have more severe symptoms including nausea, vomiting, diarrhea, sweating, fever, tachycardia, loss of consciousness, swelling of the face, severe lowering of blood pressure, bleeding, kidney failure, coma, and seizures. Deaths from Adder bites are rare but 14 deaths have been documented since 1875, the most recent was a 5-year old child in 1975

                Gourmet chef Le Hung Cuong, 22, died en route to a hospital in Haiphong, Vietnam on the 20th of August 2002. He was preparing a specialty dish, snake blood soup, when he lifted a half-meter long sea snake out of an aquarium. The snake thrashed around and bit his left arm. The restaurant owner believed that Cuong did not follow the rule of wearing gloves when handling the snake. After the bite, Cuong dropped the snake back into the tank where another chef picked it up and served it to a customer. Cuong’s death was quick and probably resulted from respiratory paralysis.

Envenomation Strategies

                In the mid 19th century, Philadelphia physician, novelist, and venom researcher, Silas Weir Mitchell described the strike of a rattlesnake and some of the events that can influence the success or failure of envenomation.

He does not pursue, he waits…Then his head and neck are thrown far back, his mouth is opened very wide, the fang held firmly erect, and with an abrupt swiftness, for which his ordinary motions prepare one but little, he strikes once and is back on guard again, vigilant and brave. The blow is a stab, and is given by throwing the head forward while the half-coils below it are straightened out to lengthen the neck and give power to the motions which drive the fangs into the opponent’s flesh; as they enter, the temporal muscle closes the lower jaw on and forces the sharp fangs deeper in. It is a thrust aided by a bite. At this moment the poison duct is opened by the relaxation of the muscle which surrounds it, and the same muscle which shuts the jaw squeezes the gland, and drives its venom through the duct and hollow fang into the bitten part.

                In so complicated a series of acts there is often failure. The tooth strikes on tough skin and doubles back or fails to enter, or the serpent misjudges distance and falls short and may squirt the venom four or five feet in the air doing no harm.

                Different clades of snakes show different strategies in hunting, striking, and envenomation. The fixed front-fanged elapids tend to have slender bodies and narrow heads. They actively forage for food, seeking prey in burrows, crevices, or in the open. Once the prey is located, the typical elapid will seize and hold the prey with its mouth. Some species also use coils of the body to prevent the prey from escaping. There are exceptions. The death adders of Australia have wide heads, thick heavy bodies and wait in ambush for prey, and are convergent with vipers in many aspects of their morphology and behavior. Taipans also differ from most elapids because they actively forage for mammals, strike from a longer distance, sometimes repeatedly, and then release. This behavior may then require trailing the prey until it is dead.

                Vipers have a different strategy. Like the death adders, vipers are ambush predators and don’t normally forage for prey by active searching. Instead, they sit and wait along trails used by prey. These may be a grass-lined runway used by rodents, the base of fallen logs where small animals will encounter the barrier and move along the edge, or on a branch of a tree full of fruit waiting for birds or mammals to approach. After the strike and bite, vipers frequently release the prey and then trail the bitten prey until it is immobilized by the venom. As always, there are exceptions. The Cottonmouth (Agkistrodon piscivorus) will actively forage for food by searching shorelines, though it too, will sometimes hunt from ambush. Additionally, some of the arboreal species will hold on to the prey when it is bitten so it won’t be lost.

                In an experiment using 20 Palestinian Vipers (Vipera palaestinae), Elazar Kochva investigated the volume of venom injected during a bite. Kochva allowed snakes to bite dead mice that were pre-weighed. Then, after the mouse was bitten, it was weighed again. He found the snakes injected only a small portion of their venom when biting the mouse, and if the snake was presented with a second mouse, about the same amount of venom was injected. It was only after one snake had bitten nine mice that the amount of venom injected declined, and was completely expended after 23 bites. In 20% of the bites, Kochva’s snakes injected no venom. It is this study and similar ones that suggest snakes may meter their venom.

                David Cundall used videotape to study the viper’s strike; slowing down the motion of a striking snake make the more subtle and rapid changes visible. He found snakes did not open their mouths to the maximum extent during the strike. Instead, maximum gape was obtained only when the snake released the prey. The wide, elongated head, narrow anterior body, and the enlarged posterior body are typical morphology for vipers. The head and body shape allows vipers to feed on prey large in both circumference and mass. Because of this shape, most of the viper’s mass is located toward the rear of the body, and Cundall suggested this is needed to anchor the rear body, allowing the snake to accelerate its head and forebody during the strike. Head acceleration may be fast enough during the strike that the snake is unable to stop exactly when the prey is reached; therefore the snake may carry or knock the prey a short distance past its original position. Vipers may maximize body mass by retaining waste material in their large intestine to increase inertia so the rear body stays in-place during the strike and to reduce the momentum of the accelerating head.

                In a review of factors that influence venom expenditure, William Hayes and colleagues explored whether the amount of venom used during a bite is selected by both intrinsic and extrinsic factors. They suggested that the amount of venom needed to subdue or kill prey, alter the odor of the prey so that it can be trailed after being released, start digestion, and repel predators is controlled by the snake. With every strike, the venom volume is selected by the snake for the situation at hand. The proposal suggested the amount of venom needed to obtain prey may be more than the amount of venom needed for defense, and that factors such as hunger, size, and species of prey all contributed to the decision the snake makes about how much venom to release during a bite. According to the authors, the volume of venom expended by a single predatory bite on an adult mouse by elapid snakes ranged from zero to 109 milligrams (mg). The Death Adder injected the most (3–109 mg) venom and the Australian Brown Snake injected the least (0–10 mg). Eight species of vipers were tested and the Palestinian Viper injected the most (1–188 mg), and the Russell’s Viper injected the least (1.2–2.4 mg). The amount of venom injected is always a fraction of the venom available, and varies from about 12% in the Russell’s Viper to 50% in the death adder. Elapids tend to inject more of their venom than vipers, and Hayes and colleagues suggest this was related to elapids biting and holding their prey. Vipers usually employ the bite-and-release strategy.

Fang Behavior

                Another window to understanding the nature of snakebites is the behavior of the fangs before and during contact with the prey.  Keeping in mind that viper fangs [Figure 6–1] are long, mobile, function independently of one another, and that the snake is attempting to sink at least one of the fangs into a live, moving animal makes for a complex problem for both the snake and the scientist trying to understand the events.

INSERT FIGURE 6-1.

Figure 6–1. A: A Terciopelo (Bothrops asper) having its venom extracted. The fang sheath is visible. B: An Indo-Chinese Spitting Cobra (Naja siamensis) and venom.

                In a more extensive study than his previous one, David Cundall videotaped more than 750 strikes from 285 vipers of 86 different species. Viper strikes are relatively fast. According to the results of the study, mean time for the snake to gape its mouth was 80 milliseconds (ms). Cundall found vipers usually contact the prey first with the lower jaw and then close the mouth to drive the fangs into the prey’s tissues. As the fang penetrates the prey, the sheath slides up the fang. Bites that did not involve fang repositioning had an average duration of 140 ms. Repositioning fangs after they had made contact with the prey occurred in 39% of the strikes, and the bite time increased to an average of 185 ms. Fangs for the species Cundall examined were 3–35% of the mandible length. The distance from the upper edge of the venom discharge opening to the tip of the fang ranged between 12–51% of the fang’s total length. Interestingly, species with shorter fangs had longer discharge openings. Cundall, and previous researchers, suggested viper fangs are long as an adaptation to feeding on vertebrates. A fang sinking into a vertebrate may encounter bone or solid connective tissue which would prevent the fang’s discharge orifice from extending below the skin, keeping the venom from being delivered into the prey. However, venom expulsion from a fang not embedded in prey is not common, suggesting the snake has some feedback about the position of the tooth. A likely source for this feedback is the position of the fang’s sheath, something already found to play a role in venom flow.  A better position for the fang’s discharge orifice might be at the tip of the fang, just as the discharge opening for a hypodermic needle is at the tip of the needle. This condition has not evolved in vipers or other front-fanged snakes, and the reason may lie in the way the fang develops or the mechanical properties of dentine and enamel. It may also be that soft tissue would plug the opening more readily and not let venom escape the fang into the prey. All of the evidence Cundall found suggested snakes have incredibly fine neural control over the strike and bite. Snakes are not working from sets of pre-programmed instructions but are adjusting their movements for the situation by the millisecond.

                Cundall’s study examined viper fangs capable of folding back into the roof of the mouth on a rotating maxillary bone, making it possible for the snake to reposition the fangs during the strike. The elapid maxillary bone and fangs are far less adjustable and, therefore, the fangs and the maxillary are better adapted to holding prey in the snake’s mouth.

Venom Metering

                The unpredictable nature of snakebites, the substantial number of dry bites, the fact that empty venom glands may take days to weeks to refill, the idea that venom may be expensive for the snake to produce, and the studies showing the volume of venom injected during a bite was highly variable all lead herpetologists to speculate that snakes are making decisions on how much venom needs to be injected in a given situation. Sherman and Madge Minton wrote,

Our observations on the feeding of captive venomous snakes of many kinds over a period of more than thirty years have convinced us that snakes can size up their prey and gauge their attack accordingly; moreover, there is a difference between a defensive strike and one intended to kill.

The idea that snakes meter their venom and have control over the volume of venom they inject has become well accepted. Considering the strike of a viper is often 50 to 200 ms in duration and there is no obvious way to observe venom flow, it is difficult to find evidence for or against this hypothesis, but not impossible.

                Measuring the volume of venom injected during a strike can be achieved by ELISA (enzyme-linked immunosorbent assays), a biochemical tool developed in the 1960's to detect the presence of an antibody or an antigen in a tissue sample. ELISA is useful in medicine and other research that involves antigen-antibody reactions. ELISA has been adapted for detecting venom in potential snakebite victims. The test is particularly useful when a person has been bitten by a snake but was not aware of the bite or is not capable of communicating with a physician, as is often the case with young children or unconscious adults. Antigen protein molecules are attached to a surface (usually a plastic microliter plate), and then washed with a specific antibody so the antigen can bind to its surface. An enzyme is linked to the antigen, followed by the addition of a signal substance that attaches to the enzyme and can be detected. The signal can be a molecule that is radioactive, fluoresces, or changes color when light of a specific wavelength illuminates the plate. The strength of the signal allows the volume of venom to be determined.

                The first use of an early ELISA-type test used to detect venom was in 2-year-old Belinda Smith of Jandacot, Western Australia. Belinda was seen playing with a piece of orange rope and soon after complained of having been bitten. Four puncture marks were present on her arm and her mother cleaned the wounds. Within minutes Belinda began to vomit; her father searched for the rope but did not find it, and she was taken to the hospital. She was kept for two hours and released after she showed no signs of envenomation. Her mother put her to bed and monitored her throughout the night. At 7:30 AM the next morning she was comatose, and at 8 AM she was pronounced dead at the hospital. Blood and tissues were sent to the Commonwealth Serum Lab in Melbourne, Australia where the tissues were examined with a radioisotope test. The cause of Belinda’s death was Tiger Snake (Notechis scutatus) venom.

                William Hayes and colleagues used ELISA to measure the quantity of venom injected into mice by the Northern Pacific Rattlesnake (Crotalus oreganus) in order to study venom metering. Medium and large-sized snakes injected similar quantities of venom, but they found the snakes injected more venom into larger prey. In addition to measuring the venom volume, they videotaped the snakes’ strike and found no behavioral differences that corresponded to the quantity of venom injected. Their conclusion was that the venom expended was the result of intrinsic control of venom flow.

                In a critique of the venom metering hypothesis, Bruce Young and colleagues note that the venom doses injected are often several times the lethal dose, and the snake’s ability to assess the nature of the target during the strike is questionable given the short duration. Additionally, they point out that hypothesis relies on the snake’s abililty to control the venom apparatus, something they suggest may not be possible. Fine control of muscles on the gland’s compartments, and the control of venom flow through the venom duct and associated structures, would be necessary. If the venom apparatus exerts a variable influence on venom expulsion then the metering hypothesis seems unlikely.

                Young and colleagues pointed to the dry bite phenomena as evidence of this. Dry bites could occur because the snake decided not to inject venom, or because the activation of the venom apparatus failed for a number of different reasons. Alternatively, they proposed the pressure-balance hypothesis to account for the variation in venom doses delivered during a bite. This idea depends on three factors: (1) the pressure placed on the venom gland by the attached muscles, (2) the pressure in the chambers near the fang (the duct, venom vestibule, venom chamber, and the entrance opening to the fang) and (3) the resistance of venom leaving the fang tip once it has sunk into the prey.

                Pressurized venom leaves the gland, flows through the duct and enters the venom vestibule, the venom chamber, and the opening of the fang canal where venom runs through the fang’s canal to the exit opening near the fang’s tip. Once the fang’s tip is embedded in the prey, the tissue of the prey surrounds the fang’s opening and offers resistance to the venom attempting to flow out. However, the amount of resistance depends on the kind of tissue. For instance, if the fang penetrates a muscle the resistance will be greater than if it hits the center of a blood vessel. If the resistance in the prey’s tissue is greater, then more venom can be expected to be found on the prey’s skin because the venom will leak out of the soft sheath tissue surrounding the fang, and some venom may actually flow backward into the gland, an event that has been experimentally documented.

                In order to test the pressure-balance hypothesis, Young and Kenneth Kardong examined the flow of venom in live Western Diamondback Rattlesnakes (Crotalus atrox). The snakes were outfitted with devices to contract the venom gland muscles and measure venom pressure at various points along the front end of the venom tract. Results showed the contraction of the compressor gland muscle accounted for only 30% of the variation in venom flow. However, when the fang sheath was lifted, as occurs during a normal strike, the venom flow increased more than 10 times the rate produced by the compressor gland muscle alone. Sliding the sheath back to expose the fang appears to tighten the tissue, possibly decreasing the size of the venom vestibule (the expansion of the venom duct near the fang) and creates a more direct and open route for the venom to flow from the venom gland to the opening on the fang’s tip.

                William Hayes argues that evidence for venom metering is compelling with the strongest evidence coming from studies that measure the volume of venom expended during bites of prey of different sizes. In other words, snakes tend to inject more venom into larger prey. Also, snakes biting mouse models that lacked a mouse odor tend have mechanically flawed strikes, probably because the snake did not detect the chemical signature of the mouse. Mouse models with mouse odor elicited more mechanically precise strikes.

                A recent study using the Black-necked Spitting Cobra (Naja nigricollis) suggests that snakes do, in fact, meter their venom. Hayes and co-workers videotaped defensive bites of this cobra during venom extraction. The snakes bit a piece of parafilm covering a glass funnel, no pressure was applied to the glands, the bites were voluntary, and the pulses of venom were timed. The venom was then collected and weighed. Mean venom flow lasted 0.35 seconds and the mean mass of venom expended per pulse was 14.2 mg for juveniles and 188 mg for adults. The video was reviewed and each venom pulse was found to be a discrete event with jaw contractions followed by a venom pulse. They found this cobra expended four times more venom when biting than when spitting.

                It seems likely snakes genuinely may be metering venom and that the factors described in the pressure balance hypothesis certainly play a role in venom delivery. The two hypotheses are not mutually exclusive and, as more work is done, more snakes will be shown to have some level of control, possibly a very fine level of control, over venom expulsion.

The Global Snakebite Problem

                Snakebites are a relatively rare medical hazard for the developed world; but in much of the rural tropical and subtropical regions, snakebites remains an important public health problem. A recent study of the global snakebite burden, funded by the World Health Organization (WHO) and authored by Anuradhani Kasturiratne and colleagues, estimated the number of envenomations per year between 0.4–1.8 million, with deaths estimated between 20,000 and 94,000. To put this in perspective, the WHO’s low estimate of snakebite envenomations works out to 1150 people per day, while their high estimate would mean that more than 5000 people per day are envenomated, and 54–275 people die each day from snake envenomation.

                The WHO’s numbers have come under considerable criticism in part because their numbers for snakebites in India and Pakistan were so much lower than those of the previous estimates by Jean-Philippe Chippaux. Chippaux suggested 5.4 million snakebites annually, with 2.6 million envenomations (or 7100 envenomations per day), and 125,000 deaths per annum (or 342 people per day die from snake venom).

                There are 227 countries. The WHO study found 58 of these countries do not have any incidence of venomous snakebite. These countries include Greenland, Iceland, Ireland, New Zealand, Madagascar, Cuba, and most of the island nations of the Caribbean and remote Pacific. These are countries that have no native front-fanged venomous snakes. The WHO found data for 77 countries with incidents of snakebite and was able to generate estimates for 92 countries. But snakebites, as well as other public health issues, remain poorly reported in many nations.

                A summary of snakebites by country follows. Not all countries are discussed, but the statistics are based on a review of Chippaux’s book and the recent WHO paper, as well as other documents. Additional discussion comes from a variety of sources that can be found in the References and Notes section for this chapter.

                Snakebites resulting in envenomation on the African continent are estimated to be 100,000, and there are about 20,000–30,000 deaths annually. Delayed treatment is a serious problem, with some victims not receiving treatment for one to two weeks after the bite. In North Africa, the snakebite problem is low, with 15 envenomations per 100,000 inhabitants. Sub-Saharan Africa has many more venomous snakes, and evidence suggests the snakebite problem is severely under reported. Many of the envenomations are from the Puff Adder (Bitis arietans) and two cobras (Naja nigricollis and N. mossambica). Surveys of households in Nigeria and Kenya report that only 8.5% and 27% of snakebites, respectively, received hospital treatment, but 70% of the reported bites are likely from harmless snakes.  Several locations in Sub-Saharan Africa are notable for snakebites.  The southern Ivory Coast has 200–400 envenomations per 100,000 inhabitants; however, among industrial agricultural workers, bites are 3,000 per 100,000 inhabitants. In north Benin, there are 210–650 cases per 100,000 inhabitants and among sugarcane workers, the incident of snakebite is 1,300 per 100,000, deaths are low at 1.5% of envenomations. However, the largest number of deaths seems to occur in the Benue Valley of Nigeria where snakebite cases are 600 per 100,000, and death occurs in about 15% of the cases. Most of the victims are males engaged in agriculture or hunting.

Two species of saw-scaled vipers (Echis ocellatus and E. leucogaster) are probably responsible for 90% of the bites in Nigeria. Symptoms include localized swelling, blistering, non-clotting blood, spontaneous systemic bleeding, and necrosis. And, while the bites may causes death, particularly from excessive bleeding, they more often result in long-term or permanent disabilities.

In North America there are about 4,735 envenomations annually; the total number of deaths is about 28 per year. Of the bites, 98% were from vipers and 2% from elapids. About 77% of victims were male, 70% were adults 20 years old, or older, and 12% were less than 10 years old.  There were 65 cases involving pregnant women bitten by rattlesnakes, and 70% of them resulted in moderate-to-severe effects. Rattlesnakes and copperheads produced the most severe results in children less than six years of age.

A survey of 142 snakebite fatalities that occurred between 1979 and 2005 found 90% of the bites were from native pitvipers, 2% from native coral snakes, and 8% from exotic species (mostly tropical American pitvipers of the genus Bothrops, African vipers of the genus Bitis and Asian cobras of the genus Naja).  Fatal bites were sustained mostly by males (80%) who were Caucasians (94%), between the ages of 25–54 (52%) and many were intoxicated while handling the snake. Geographically, 55% of the fatalities were in the states of Texas, Georgia, Florida, Arizona, and California. In a sub-sample of 26 fatal cases with details, 70% of the bites were from rattlesnakes, 19% were from exotic snakes, and 7 of the 26 (27%) were bites sustained during religious ceremonies in Appalachia.

                Coral snake bites are relatively rare in the USA and 50–70% of them occur while the snake is being handled; in some instances the snakes were misidentified, the handler believing they were harmless mimics. Robert Norris and colleagues report the first documented death from a coral snake bite in the USA in 40 years. The circumstances of the bite are of interest because they are representative what happens in many North American envenomations.

                On the June 10, 2006, victim A was drinking alcohol in a wooded area of Lee County, Florida with friends. An unlucky coral snake crawled into the midst of the men, and victim B grabbed the snake and was bitten. Victim A tried to stab and cut the snake with a broken beer bottle and was bitten at least once. The snake was killed and placed in a milk carton by victim B who rode a bicycle to a fire station for help. Victim B was taken to a hospital while victim A continued to drink alcohol. Two hours later, victim A stopped breathing and was pronounced dead when emergency personnel arrived. Victim B recovered completely. Victim A’s blood serum was later tested using ELISA and was confirmed to contain Eastern Coral Snake (Micrurus fulvius) venom. (Here, it is very difficult to resist making a comment about the Darwin Awards.)

                Only four West Indian islands have venomous snakes (St. Lucia, Martinique, Trinidad and Aruba) and the WHO study estimated between 1,098 and 8,039 envenomations per year for the Caribbean. Each of these islands has one or two species of endemic pitvipers, and Trinidad has two species of coral snakes.

                In Central and South America snakebite frequency is much higher, in part due to the greater diversity of pitvipers. Total bites in Latin America are estimated at 300,000 and there are about 5,000 deaths per year. Mexico is estimated to have 28,000 envenomations per year with about 1000 deaths. Snakebites may be severely under reported in Mexico considering the high numbers of rural poor who do not use hospitals.  The rich diversity of pitvipers and coral snakes in Mexico were a problem for the anacient Maya as they are for the present-day citizens. The lanceheads of the genus Bothrops have venom with hemorrhagic action, properties that the Maya were well aware of.  R. L. Roys translated a Maya passage that stated, “…when it bites a person, it causes him to exude blood from every pore like a bloody sweat, and if no remedy is applied, he will die in a day…”

                Costa Rica has about 1,000 envenomations each year, with 30 to 40 deaths. Most deaths are young males between 10 and 19 years old. Fatalities have declined from 5 per 100,000 in 1952 to 0.15 per 100,000 in 1996. By the 1990’s, Costa Rica’s population had increased and the annual number of snakebites increased to an average of 504 envenomations per year. However, the incidence per 100,000 people declined. Agricultural workers are most susceptible, and the snake of most concern is the Terciopelo (Bothrops asper).

                Brazil has an estimated 25,000 envenomations, (roughly 200 per 100,000) and the death rate is low at about 0.4 to 5 per 100,000 residents, but the state of Amazonas has 350–450 bites per 100,000 residents. In the dry, northeastern part of the country, lanceheads (Bothrops) are responsible for most (56%) of the bites; 32% were from rattlesnakes (Crotalus) and 1% from the bushmaster (Lachesis). In the Mato Grosso, 99% of 307 cases documented between 1993–95 were from lanceheads. A survey of households in Amazonas suggested snakebites were six times more common than official reports would suggest, however, many of these may be from non-venomous, or mildly venomous species.

                In Columbia, about 2,700 snakebites were reported annually during the 1990’s and the frequency was 23–26 bites per 100,000 residents. Lanceheads (Bothrops) were responsible for 95% of the bites and the fatality rate was about 5%.

                In Ecuador, about 4,000 people are hospitalized for snakebites, about 200 (5%) die. Among indigenous peoples living in forest, however, the bite frequency may reach 1,000 per 100,000 annually.

                In French Guyana, 110–120 people are hospitalized with envenomation and deaths number two or three per year. However, some locations may have bite frequencies that reach 590 per 100,000 residents.

                Asia has the highest incidence of snakebites, as a result of its dense population and diverse venomous snake fauna. An estimated 2 million envenomations and 100,000 deaths occur per year (about 274 deaths per day).

                Information on snakebites in China is scant, despite a fauna that contains numerous elapids and vipers. A 1990 report mentions 1,427 bites from the Short-tailed Mamushi (Gloydius brevicaudus) with one fatality. And, 120 cases of Chinese Moccasin (Deinagkistrodon acutus) bites with two fatalities, 31 disabilities, and 87 complete recoveries were reported in one paper. The reason for China’s poor snakebite data is discussed below. However, a recent paper by Wong Oi-Fung and colleagues surveyed four Hong Kong snake shops to identify species that may be involved in snakebite incidents. Expecting to find the four local species (the White-lipped Pitviper, the Chinese Cobra, and two species of local kraits), the team was surprised to find that local species were in short supply and that shops were importing snakes from Thailand. Snakes that were found in Hong Kong’s shops included the Monocellate Cobra (Naja kaouthia) and the Hamadryad (Ophiophagus hannah). The Hamadryad is known from Hong Kong, but they are considered rare on the island. Their presence in the snake shops suggests they were also imported, probably from Thailand. Another likely Thai import, the Red-necked Keelback (Rabdophis subminiatus), was also being sold in the snake shops, and it, too, could pose a significant health hazard.

                Japan has a relatively low overall incidence of snakebites (1 per 100,000 inhabitants). But, the southern archipelagos are tropical, and some islands have an incidence of snakebite that approach 600 per 100,000. The Amami Islands of Japan were covered with forests until they were colonized by humans who cleared the trees for agricultural crops like sugar cane and hay. People living here were at great risk of being bitten by a large (1.8 meter) venomous snake, the Habu (Protobothrops flavoviridis). The death rate from the bite of this pitviper was 10–15% of the envenomations prior to the start of the 20th century. However, the first antivenin was developed for Habu bites by 1905, and the death rate declined. Unfortunately, the bites still did major damage to the victims via necrosis. Necrosis occurs as venom enzymes digest their way through the tissue, turning body parts to liquid that will not regenerate. Necrosis from Habu venom has left many Amami farmers crippled and disfigured.

                By the 1960’s, the Habu became the subject of intense study by Japanese scientists. During this decade, an average of 250 people were bitten each year, and the maximum number of bites in a single year could be as high as 600 per 100,000 people in the areas of highest risk. The studies revealed that the larger the area under cultivation, and the greater the number farmers, the higher the incidence of snakebites. Most of the bites took place when farmers were working in their fields, harvesting sugar cane or weeding, though some bites occurred around houses and along roadsides. Most bites occurred during the day even though the Habu is nocturnal, presumably because farmers disturbed the snakes in their daytime hiding places.      

                Science’s war on reducing the number of Habu bites took many paths. The use of antivenin was helpful, but could only be used after the bite occurred. People still suffered the effects until they could get the serum. The production of a vaccine or toxoid was an attempt to be proactive, making the farmers resistant to the venom. Habu venom was treated with acid to deactivate its enzymes. Farmers were then inoculated with the toxoid, allowing their bodies to build resistance to necrosis. The vaccine was somewhat successful. The third step was to remove as many Habu from the farm fields as possible, reducing human contact with the snake. This was accomplished with electrified fences that kept snakes out of fields, as well as collecting snakes with baited traps. The added steps of keeping fields and yards free of rats, training dogs to find snakes, and hiring people to catch Habu, met with mixed results. Today Habu are still a threat to the farmers of the Amami Islands, although the risk may be less than it was 50 years ago.

                South Asia (Bangladesh, Myanmar, Nepal, Pakistan, Burma, India, Sri Lanka) has the most snake envenomations of any region in the world, at 121,000 per year, and the highest number of deaths due to snakebite, estimated at 14,000 annually. This works out to more than 331 people per day who are envenomated by snakes, and 38 deaths per day.

                Snakebites in Bangladesh are poorly known. A 1988–89 survey of 10% of the country suggested there were 764 bites reported in a single year, with 168 deaths (22%). Cobras were responsible for 34% of bites and these had a 40% fatality rate.

                India has the highest incidence of snakebites. Reports have estimated as many as 200,000 bites and 50,000 deaths annually. But these numbers are likely inflated. Chippaux suggested it is 65–165 per 100,000 inhabitants using data from areas with the highest snakebite numbers, with about 70 envenomations per 100,000 residents. The WHO estimated that envenomations exceed 100,000 per year, and deaths exceed 11,000 per year. While the number of bites is low per 100,000 individuals, the actual number of people envenomated by snakes in India is higher than any other country, with an estimated 81,000 envenomations yearly. People treated in a hospital have a 1.5–20% death rate. Most bites occur between June and November, and bites from vipers are twice as common as bites from elapids. But the death rate from vipers is about 6% and death from elapids is 25%. The WHO numbers for Indian snakebites are much lower than those reported by earlier studies. Four species of cobras (Naja), at least four species of kraits (Bungarus), Russell’s Viper (Daboia russelii), two species of saw-scaled vipers (Echis), and the Humped-nosed Viper (Hypnale hypnale) are the species responsible for envenomations. All of these snakes seem to thrive in human-modified habitats, feeding on rodents, and using microhabitats created by agriculture and urbanization.

                Myanmar (Burma) has between 35 and 200 bites per 100,000 residents, not a particularly high incidence, but it has the highest death rate at 35 deaths per 100,000 envenomations.  The Russell’s Viper (Daboia russelii) is thought to be responsible for 90% of the cases. The numbers reported are probably low; in 1991 there were an estimated 14,000 envenomations or bites with 1,000 fatalities, and there were more than 8000 bites with 500 fatalities in 1997. Bites peak in May and June in urban areas and during the rice harvest from October to December in rural areas.

                Nepal is estimated to have 20,000 bites per year and more than 1,000 reported deaths with most of the bites occurring during the monsoon season. Nepal may rank fourth in the world for the most envenomations. About half of the bites are from snakes not identified, but 30% are from cobras (Naja and Ophiophagus), 16.7% from kraits (Bungarus), and 3.3% from the green pitvipers (Trimeresurus complex). Many victims show signs of neurotoxins with drooping eyelids, slurred speech, and respiratory distress. Of 290 cases reported by hospitals between 1989 and 1995, there were 175 fatalities (60%).

                Envenomations in Pakistan are estimated at 12,000 per year with deaths estimated at 1200 per year, most of which occur in the agricultural areas of Sindh. The common Indian Cobra (Naja naja), Russell’s Viper (Daboia russelii), and the Indian Krait (Bungarus caeruleus) are responsible for some of the bites, but the Northern Saw-scaled Viper (Echis sochureki) is the species responsible for most of the bites and deaths.

                The densely populated island nation of Sri Lanka has about 250 bites per 100,000 inhabitants. The Indian Cobra (Naja naja) and Russell’s Viper are responsible for 35% and 40% of the bites, respectively. Total annual envenomations in Sri Lanka are estimated at 33,000 in the WHO study, but some of the same authors published a study in 2004 stating envenomations in Sri Lanka numbered 14,000 per annum. Sri Lanka is second in the list of countries with the most envenomations.

                Southeast Asia is right behind South Asia with 111,000 envenomations per year, or an average of 304 envenomations per day. However, many countries with large populations such as Cambodia, Laos, and Indonesia numerous venomous snakes lack snakebite statistics.

                In peninsular Malaysia snakebite data is not collected, but bites are thought to be common, particularly in the north near its border with Thailand. Malaysia and other countries may not collect snakebite data because of the cultural beliefs of the population. H. Alistair Reid, a physician at Penang’s General Hospital, made more than 50 visits to 17 villages in the northwest peninsula to determine the incidents of sea snakes bites, discover how the victims were bitten, and determine the survival rate. Carrying a bag of dead sea snakes and accompanied by a health worker known to the local fishermen he visited coffee shops. Reid started the conversation by opening the bag. The snakes attracted much interest until the subject of bites was brought up. People became less talkative, wandered off, and denied all knowledge of bites. All deaths must be reported to the police, and a snakebite death is considered sudden. This requires a doctor viewing the body and increases the probability that the body will be removed, the burial delayed, and a postmortem performed. The Malay and Chinese are offended by these procedures and snakebite deaths were often attributed to a "fever," or some other problem that would be accepted by local officials.

                Reid’s investigation found 144 cases, 25 (17%) of which were fatal. Of the 144 cases, only 18 sought hospital or dispensary care, and six of these were fatal. Reid considered these cases to be a gross underestimate of the actual number of bites that occur. The diagnosis was not always certain, and it was known that some died who did not go to the hospital; the mortality rate was somewhere between 3% and 25% for sea snake bites untreated by specific therapy. Reid investigated 120 cases of sea snake bites, and found 41% happened while fishers untangled nets with trapped snakes. Other bites occurred while sorting fish or wading in water. Reid sampled 600 sea snakes (alive and dead) during the study. Of these, 158 of these were the Beaked Sea Snake (Enhydrina schistosa), 178 were the Curtus’ Sea Snake (Lapemis curtus), and 101 were the Annulated Sea Snake (Hydrophis cyanocinctus), and all were species most likely responsible for the bites.

                From 1958 to 1980, there were 55,000 snakebites reported in Malaysian hospitals. Based upon these numbers, the mortality rate is only 0.3 per 100,000 individuals, but the local necrotic effects of some venoms can cause prolonged morbidity and crippling deformities. Although the Malayan Pitviper (Calloselasma rhodostoma) was responsible for most of the bites, the numbers may be severely under reported for the reasons suggested by Reid.

                Thailand has more than 10,000 envenomations each year with the Malayan Pitviper responsible for 35–40% of the bites. In 1989, there were 6,038 bites reported with 19 deaths. About 2% of the bites were fatal. The green pitvipers (Trimeresurus complex) accounted for another 25–30% of the bites and while fatalities are known, they are rare. Russell’s Viper accounts for another 15% of bites; this snake is particularly common in Thailand’s Central Plain and has a very low mouse LD50 (about 1.6 micrograms). A lethal human dose ranges from about 20–25 milligrams. In 46 fatal cases, Malayan Kraits (Bungarus candidus) and the Malayan Pitviper were each responsible for 13, the Monocellate Cobra (Naja kaouthia) was responsible for 12, and Russell’s Viper for seven deaths. Snakebite deaths in Thailand have been greatly reduced with the availability and use of antivenom. In 2004, I visited a snakebite clinic in southern Thailand that continued to use traditional herbal remedies for snakebites. Rubber plantations were common in the area, and rubber tappers are susceptible to snakebites as they often walk barefoot from tree to tree.

                Vietnam has 30,000 envenomations per year, placing it third on the list of countries with the most envenomations where it is tied with Brazil.  Again, the snake responsible for most bites is the Malayan Pitviper but cobras and sea snakes are also likely to be involved.

                Rice farmers in the Philippines have exceptionally high snakebite mortality, but the numbers are rough estimates. George Watt and colleagues from the U.S. Naval Medical Research Unit No. 2 suggested deaths from cobra bites may be as high as 107 per 100,000 residents and confirmed a death rate of 53.8 per 100,000 residents. They found only 8% of the victims studied survived to reach the hospital. An estimated 200 to 300 deaths per year from cobras (Naja sp.) are suspected.

                The island nation of Taiwan has about 15,000 to 20,000 bites per year and about 500 deaths per year from snakebite. The snakes most often responsible include Stejneger’s Green Pitviper (Trimeresurus stejnegeri), Russell’s Viper (Daboia russelii), cobras (Naja), and the Taiwan Habu (Protobothrops mucrosquamatus).

                Australia is well known for its highly venomous snake fauna, with most snake species belonging to the front fanged Elapidae. The island continent has 1,000–3,000 snakebites per year with the number of bites decreasing in the temperate regions. This has been attributed to urbanization and lifestyle changes with more people living in cities. But, the introduction of the poisonous Marine Toad (AKA the cane toad) has also been implicated in reducing the number of frog-eating snakes. Additionally, the increased use of fertilizers and pesticides in agricultural regions has reduced the food supply for snakes, and these chemicals may play a role in poisoning or disrupting their physiology.

                In 1940, Hugo Fleckner discovered tropical Queensland had more snakebites than southeastern subtropical areas of the state, even though the tropical region of the state had only one-third of the population found in subtropical regions. Children in subtropical southeast Queensland had a snakebite frequency of 7.1 per 100,000 in the early 1970’s. Bart Currie found the annual rate in the 1990’s of snakebite in children was 18.3 per 100,000 in the Northern Territory, but notes that it decreased to 4.0 per 100,000 by 1998. Deaths from snakebite are now rare in Australia. No deaths from snakebite in the Northern Territory occurred in the 1990’s despite the state having the highest rate of snakebite incidents in Australia. With the discovery and availability of antivenom at the start of the 20th century, the mortality dropped from 13 per year in 1900 to less than four per year by the late 1970’s.

                Snakes responsible for bites in the Northern Territory are, in decreasing order of importance, the Western Brown Snake (Pseudonaja nuchalis), the Mulga (Pseudechis australis), the Death Adder (Acanthophis antarcticus), and the Coastal Taipan (Oxyuranus scutellatus). In tropical Queensland the Eastern Brown Snake (Pseudonaja textilis), the Coastal Taipan, Western Brown Snake, the Mulga, Death Adder, Rough-scaled Snake (Tropidechis carinatus), and Eastern Small-eyed Snake (Cryptophis nigrescens) delivered the most bites. Recent estimates for the number of deaths across Australia from venomous snakes are six per year, and anecdotal reports suggest death from snakebite was more common in 19th century Queensland. Garde, writing about Queensland snakebites, reported that a Mr. Jonstone from northern Queensland had seen four out of seven people bitten by death adders recover, but he had attended funerals of all 12 people who had been bitten by the "brown snake" or taipan. Prior to the availability of antivenom, only two people were known to have survived taipan bites.

                Snakebites in New Guinea are a different story. The coastal Kairuku area just north of Port Moresby (Papua) had a snakebite incidence of 526 bites per 100,000; a frequency close to the highest reported in the world. Papua is tropical, so snakes are active and biting year-round. The snakes responsible for these bites are the Papuan Taipan (Oxyuranus scutellatus canni), death adder (Acanthophis sp.), Papuan Black Snake (Pseudechis papuanus), the New Guinea Small-eyed Snake (Micropechis ikaheka), and the Brown Snake (Pseudonaja sp.). The estimated number of deaths per year for the entire island of New Guinea is estimated to be 22 per 100,000. In the mid 20th century, snakebites were thought to be responsible for 155 hospital admission per year, 6.3 per 1,000 admissions in Papuan hospitals. Overall Australasia is estimated to have 1460–5895 envenomings per year, with annual deaths estimated at 229–520. Since the number of deaths in Australia is less than 10 per year, it is clear most bites occur in New Guinea.

Effects of Venom

                Venoms have traditionally been classified as neurotoxic or hemorrhagic, with elapid venoms having mostly neurotoxic symptoms and viper venoms damaging blood vessels and altering blood clotting mechanisms.  Terrestrial elapid venom (African cobras, coral snakes, mambas, and kraits) is often described as doing little damage at the bite site. Instead, these venoms have a systemic impact the nervous system. However, the exceptions are quite numerous. The African Black-necked Cobra (Naja nigricollis) and the Mozambique Spitting Cobra (N. mossambica) cause significant swelling and local damage from necrosis at the site of the bite and produce virtually no neurotoxic symptoms. The cobra that may damage tissue to the greatest extent is the South African spitting Rinkhal (Hemachatus heamachatus). This snake has low viscosity venom, making it easier to spray; while its venom has relatively low toxicity it causes considerable tissue damage. Tissue is liquefied as the enzymes break cell membranes and digest the adhesive that cements cells together. These cobras rarely cause damage to nerves. On the other hand, some rattlesnakes have been shown to have potent neurotoxic venom (see Chapter 5).

                Neurotoxic envenomation first impacts muscles well supplied with nerves like the upper eyelid, eye ball muscles, and muscles on the lens of the eye. Twenty minutes to several hours after being bitten, the victim will likely have dropping eyelids, blurred vision, headache, and excessive drooling. Paralysis sets in and eventually moving the jaw, talking and breathing become impossible. Once breathing stops, death can only be postponed with the use of artificial respiration devices or rescue breathing. The krait -suffered by Slowinski demonstrated these kinds of symptoms. Toxins in these snakes interfere with the ability of nerve cells to pass their message to the muscle cells.

                Neurotoxic venoms, like those found in cobras, may act post-synaptically by blocking the receptors of acetylcholine; or they may act before the synapse (pre-synaptically) by destroying the vesicle at the end of the neuron that produces the acetylcholine, as found in kraits. Pre-synaptic venoms are more serious because the neurons have to rebuild the vesicles, and this may require the victim to be on a ventilator for days or weeks while their body repairs the damage. The pre-synaptic venoms cause massive paralysis and may give the impression that the patient has died when they are in-fact, completely conscious and aware of what is going on around them but unable to respond because of the paralysis. Post-synaptic venoms can be cleared from the receptors relatively easily within hours or a day or two, given the help of antivenom.

                Australian elapid venoms produce many different symptoms depending upon the species. Brown snakes (Pseudonaja) alter the clotting ability of blood. Tiger snakes (Notechis) and taipans (Oxyuranus) cause swelling, lower blood pressure, damage muscles, produce convulsions, and damage kidneys.  Death adders (Acanthophis) have severe neurotoxic symptoms that appear rapidly.

                Sea snakes do bite humans, but frequently deliver dry bites at a rate that may be as high as 80%. Sea snake venom is painless at the site of the bite, but if envenomated, muscles stiffen and ache, and spasms begin to occur within minutes to hours. Headaches, thirst, and vomiting soon follow and three to six hours after the bite the victim’s urine may start to turn dark from the breakdown of myoglobin. Sea snake venom is mostly myotoxic, attaching to muscle and damaging the membranes and neuromuscular junctions. Death may occur more rapidly with a large dose of venom. The widespread Beaked Sea Snake (Enhydrina schistosa) has a mouse LD50 of 0.04 mg/kg, suggesting the venom is exceptionally toxic.

                Viper venom often results in swelling, but some species such as the Russell’s Viper (Daboia russelii), and saw-scaled vipers (Echis) may not cause any swelling whatsoever [Figure 6–2]. Viper venoms also tend to liquefy tissue, and this may rapidly spread from the site of the bite and continue for days after the bite, requiring amputation of a limb. Continuous bleeding from the fang punctures, eyes, nose, mouth, and anus may occur, while blood may be clotting in other parts of the body at the same time. The continuous bleeding results from consumption coagulopathy where the haemorrhagins disrupt the blood’s ability to clot. Some vipers and rattlesnakes may also induce neurotoxic symptoms, and viper venoms often have a combination of toxin and enzymes that work in the blood stream to damage nerve cells and tissues.

INSERT FIGURE 6-2.

Figure 6–2. Necrosis from the bite of a saw-scaled viper (Echis). Photo by Ian Simpson.

The African and Middle Eastern stiletto snakes’ venom cause swelling and work on the blood vessels and heart. They also liquefy tissues, induce vomiting, and make breathing difficult. Death can occur in less than 60 minutes. Stiletto snakes produce a unique group of toxins with neurotoxic, renal, pulmonary, and cardiovascular effects. A researcher bitten while extracting venom from an Israeli Stiletto Snake (Atractaspis engaddensis) sustained a puncture from one fang.  Swelling, discoloration, and numbness occurred within minutes of the bite. Systemic effects soon followed: weakness, sweating, vomiting, diarrhea, fluctuations in consciousness, and blood pressure increased to 180/110. The victim survived but discoloration, tenderness, and pain around the site of the bite remained for 10 months.

                A snakebite qualifies as a medical emergency, one that has caused medical professionals to take desperate measures. While antivenom has gone a long way toward reducing the need for radical measures, they are still sometimes necessary. Prior to the option of antivenom, William Theobald writing in 1876 commented on Joseph Fayrer's recommended treatments for snakebite.

...Dr. Fayrer treats this subject exhaustively in his elegant and valuable work on the Thantophidia, and recommends such heroic treatment not only as actual cautery with live coals or gunpowder, or the free use of mineral acids after excision of the bite, but even amputation of a limb to save a life. Doubtless in the hands of intelligent medical men such remedies are not altogether condemned, but to recommend such treatment in general, seems to me to risk subjecting the unhappy sufferer to fruitless agony at the hands of anxious but wholly ignorant friends, without the smallest possible chance of any good resulting from such a course.

By the end of the 19th century a much more efficient, effective, and humane treatment for envenomation was being developed―antivenom sometimes called antivenin.

Antivenom

                The observation that people infected with a disease did not become re-infected is ancient and dates to at least 2430 YBP. It was not until the 19th century that experimentation with snake venom was applied to the concept of immunity. Henry Sewall, working at the University of Michigan in 1886–1887, used Pigeons and venom from the Eastern Massasaugua (Sistrusus c. catenatus) to demonstrate that organisms could be made resistant to rattlesnake venom. Sewall injected small doses that were gradually increased until the birds could withstand 10 times the lethal dosage. Sewall’s experiments were the stimulus for developing other antitoxins.

                Within a year, Pierre Roux and Alexander Yersin demonstrated animals could be immunized to the Diphtheria toxin using the blood from animals exposed to the toxin. And, in 1890, Emil von Behring and Shibasaburo Kitasato showed passive immunity for Diphtheria and tetanus, and initiated antiserum therapy. Soon afterwards these techniques were applied to the snakebite problem.

                In 1894, Maurice Kaufmann duplicated Sewall’s results using viper venom. A series of 1894 experiments done by Césaire-Aguste Phisalix and Gabriel Bertrand at the Natural History Museum in Paris took the work a step further. They inactivated the venom by heating it to 68ºC for five minutes and immunized Guinea Pigs against the venom. Furthermore, they took blood serum from resistant Guinea Pigs, mixed it with snake venom and gave it to untreated rodents. Resistance to venom was transferred with the serum. However, their work only produced neutralization of venom in glassware, not immunization in a living animal.

                The French Colonial Health Service established a daughter organization to Paris’ Pasteur Institute in Saigon, French Indonesia (now Ho Chi Min City, Vietnam) to produce vaccines for Small Pox and Rabies in 1891. Albert Calmette was appointed director of the Saigon Institute, and soon after he arrived an exceptionally heavy monsoon resulted in cobras invading the village of Bac-Lieu. Forty people had been bitten and at least four deaths occurred immediately. One of the villagers captured 19 snakes and shipped them to the Pasteur Institute in a barrel. The snakes were euthanized and their venom glands removed and stored. Calmette knew of Roux and Yersin’s work with diphtheria toxins, and that they had produced an antiserum to the toxins that would cure the sick. However, Calmette’s first attempts to produce a cobra venom cure took a different path. He experimented with a gold chloride solution which failed to work after two years of research in Saigon. Ill with dysentery, he returned to Paris and continued the search for an antiserum. In 1894, he succeeded by diluting cobra venom with sodium or calcium hypochlorite and subcutaneously injected rabbits every 8–10 days with an increasing dose. He was eventually able to inoculate the rabbits with 35 mg of cobra venom with no signs of envenomation.  Calmette experimented further and found that rabbits inoculated with cobra venom that showed signs of envenomation could be cured with the antiserum.

                Calmette’s success led to a dispute with Phisalix and Bertrand over the priority of the discovery of antivenom serum, a dispute that fueled a long standing rivalry between the Paris Museum and the Pasteur Institute. Today, Calmette is credited as the discoverer of snake antiserum because Phisalix and Bertrand’s reaction only involved the formation of immunoglobin M, which allowed for the neutralization of venom. Calmette’s work produced hyperimmunized animals that produced specific immunoglobin G (IgG) that would protect against envenomation in a live animal. By the end of 1894, Calmette was using donkeys to produced anti-cobra serum that could be used to treat humans. In 1896, Calmette became the Director of the Pasteur Institute in Lille, France, where he produced cobra antivenom using horses venom supplied from Saigon.

                Thomas Fraser confirmed Calmette’s work and exhibited a rabbit vaccinated against a dose of cobra venom 50 times the lethal level before the Medico-Chirurgical Society of Edinburgh. He also used Timber Rattlesnake and Australian Tiger Snake venoms to produce animals that were immune to each of these species’ venoms. However, Calmette believed all snakes produced the same venom and claimed his cobra antivenom effective against a wide range of species, including the European Adder, the Australian Tiger Snake, and the Australian Black Snake. His thinking changed by 1904 when he suggested venom came in two forms, neurotoxic and hemorrhagic.

                Vital Brazil, a Brazilian physician, had worked for a state’s Sanitary Department as well as maintained a private practice. He had dealt with outbreaks of cholera and yellow fever, and had the opportunity to work with snakebite victims. Observations and experiments revealed venom from lanceheads and tropical rattlesnakes produced different symptoms. In 1896 he read Calmette’s work, closed his practice, and returned to São Paulo to work with Aldolpho Lutz at the Institute of Bacteriology. In addition to his normal workload, he began injecting dogs and goats with small doses of untreated venom from the Tropical Rattlesnake (Crotalus terrificus) and the Jararaca (Bothrops jararaca). By 1898, Brazil had evidence that venom was species- specific. Rattlesnake antiserum did not provide immunity for the lancehead venom and vice versa. He also tested Calmette’s cobra antiserum against the neurotoxic rattlesnake venom and found it ineffective. The Institute of Butantan opened in 1901 and Brazil was named Director. The Institute produced vaccines for the plague, and used horses and mules to produce snake antivenoms. Some were injected only with tropical rattlesnake venom, others with a mixture of lancehead venoms (Bothrops atrox, B. alternatus, and B. jararaca).  By immunizing horses against multiple snake venoms, he was able to produce the first polyvalent antiserum, a valuable tool for dealing with a snakebite when the snake could not be identified to species. Brazil distributed antiserum, syringes, a tool for catching snakes, and wooden boxes for shipping snakes to the larger plantations and ranches. This gave local people access to medical treatment and allowed the Institute to obtain more than 5,000 snakes per year, including many new species. During a visit to New York in 1915, Brazil was asked to help treat a Bronx Zoo employee bitten by a Western Diamondback Rattlesnake. The man showed symptoms of severe envenomation and Brazil successfully treated him with a dose of his anti-tropical rattlesnake serum, demonstrating that antivenom could sometimes be used effectively for treating envenomation from different species.

                Using crude venom to inoculate animals (often horses) will produce effective antiserum, but it can be hard on the animals. In 1924, Gaston Ramon detoxified venom by combining it with an aldehyde, such as formalin. Detoxified venom or raw venom used for immunization could be combined with another chemical such as aluminum hydroxide or sodium alginate to act as an adjuvant. Adjuvants slow the release of venom and stimulate the immune response. The number of injections needed to hyperimmunize an animal varies from 10 to 50 injections over a period of 3 to 15 months. Blood samples are tested for the antibodies and, once an acceptable level is reached, the animal’s blood can be collected, mixed with an anticoagulant (often sodium citrate), purified, and prepared for distribution as a liquid or a freeze-dried product [Figure 6–3]. The antivenom is usually said to have a shelf-life of two years in the liquid form or 5 years in the freeze-dried form. Dried antivenom, however, has a shelf-life of 15-20 years and can remain effective much longer.  However, in a business move, and in order to move stocks of antivenin, one company began shortening the shelf life to 5 years to encourage cash flow.  Many others followed suit.  Antivenom is the only effective treatment for snake envenomation. Unfortunately, its capacity to induce severe allergic reactions in some patients concerned physicians.

INSERT FIGURE 6-3.

Figure 6–3. Antivenom products for snakebite. Photo by Ian Simpson.

                Patients receiving the antibodies may suffer from several types of reactions that include an anaphylactoid reaction that is rapid and systemic and involves swelling in the face and throat that can result in death. Such reactions need to be treated quickly with epinephrine. Other reactions to antivenom are less dangerous. Pyrogenic reactions induce a fever and need to be treated with pyretics. Serum sickness may also occur and may be delayed up to two weeks after exposure to the antibodies. Serum sickness is characterized by rashes, swollen lymph nodes, hypotension, and other symptoms associated with allergic reactions. These responses are often treated with corticosteroids and antihistamines. Reactions to antivenom were reported to exceed 20% in patients and this resulted in physicians delaying treatment and administering a dose of antivenom that was too low to be effective.

                Despite this, a study done by Steve Offerman and colleagues in 2001 found the use of polyvalent Crotalid antivenom was safe and should be used in treating patients with moderate to severe envenomation from rattlesnakes. They used hospital records from 65 patients who had received antivenom between 1988 and 1998.  Allergen related side effects in those receiving the antivenom were seen in 12 patients (18%) and in 11 of these the reaction was limited to a rash. Only one patient (2%) required epinephrine.

                 It was discovered that by digesting the IgG with an enzyme like pepsin or papain that the part of the antibody that neutralizes venom can be separated from the rest of the molecule. This has become known as fragment antibody binding or Fab. This process presumably reduces the probability of adverse reactions to the antivenom. In October of 2000, the United States Food and Drug Administration approved a Fab antivenom product as treatment for mild to moderate crotalid snake envenomation after trials had been conducted from 1993 to 1996. CroFabTM was manufactured by Protherics in Nashville, TN.  Protherics began using sheep instead of horses for antibody production. However, it has not yet been demonstrated that humans have a lowered reaction to ovine antibodies or antivenom produced by the Fab process. FabAV (fragmented antibody binding antivenom) is a second generation antivenom. Unfortunately, CroFabTM  currently costs US$1200 per vial, making it a financially irresponsible alternative when one considers that anaphylactoid reactions can be treated with a US$1 injection of epinephrine. This situation is complicated by the facts that anaphylactoid reactions can occur very rapidly, and CroFab has yet to be show to produce fewer unwanted side effects.

                Purification of crude serum by removing cellular particles and unnecessary proteins is done with a centrifuge and precipitation of the antibodies is achieved with ammonium sulphate or caprylic acid. The number of antibodies collected is twice as great using caprylic acid and makes production more efficient and less costly. Currently, India produces one million vials of antivenom using ammonium sulphate precipitation. By changing to caprylic acid methodology, antivenom manufacturers could double their output.

                A BBC report on August 31, 2000 reported a global shortage of antivenom due to manufactures closing down their antivenom operations for economic reasons. However, the loss of production was due to ‘snakebite experts’ close to the manufacturers who called for more quality control with no real evidence that it was needed. The manufacturers were using inefficient methods of production and would not acknowledge the more efficient methods of production using caprylic acid.

                During the first decade of the 21st century, the availability of antivenom in the USA and other countries has been in short supply. In 2000 Federal inspectors found "quality control" problems at the Wyeth Pharmaceutical plant in Pennsylvania. Wyeth was the only producer of whole IgG rattlesnake antivenom for US species. Production was halted until 2001, and the manufacturer was forced to ration its remaining inventory, leaving some hospitals with very limited supplies. In 2000, a Washington Post story cited a survey of Arizona hospitals that had only 1,000 vials of antivenom on the shelves, when they usually require twice that number. The litigious nature of medicine in the USA has placed pressure on physicians to administer antivenom for any symptoms of envenomation, including swelling and necrosis which are not controlled by antivenom. This has resulted in the need for more antivenom on hospital shelves even though it may not be necessary.

                The halt in production of the polyvalent pitviper antivenom was soon followed by Wyeth’s announcement that it would cease production of antivenom in 2001. Note that the Offerman study cited above showed that using polyvalent Crotalidae antivenin was safe, but Wyeth had stopped production.

                By 2002 it was apparent there was a shortage of antivenom in the USA. A University of California Davis Medical Center press release that said that both horse and sheep derived antivenom for rattlesnake bites were in short supply. Protherics reported a problem with the product being “out of specification” as the result of a short-term problem with the production process. But, by 2004 CroFabTM was again readily available in the USA.

                By 2009 there was no available whole IgG antivenom available in the USA. A study by Eric Lavonas and colleagues at the Rocky Mountain Poison and Drug Center examined the medical records of patients who had been given FabAV between 1996 and 2008 in an attempt to determine its effectiveness for patients with severe envenomation. Their conclusion was FabAV therapy was well tolerated and is appropriate for managing severe envenomations.

                The six Indian manufacturers of snake antivenom combined produce more than 1 million vials of polyvalent venom per year. The average treatment per snakebite envenomation is 15 vials of antivenom. There are about 80,000 envenomations in India and therefore a need for 1.2 million vials. Indian manufacturers currently produce enough antivenom so there is probably no shortage in that country. A trial of effective protocols in West Bengal reduced the use of antivenom by 20,000 vials per year at one District hospital.  Ian Simpson and Robert Norris reviewed the instructions accompanying the antivenom and found that reliance on those instructions would waste antivenom. But of greater concern, following the instructions would actually cause more harm to the victim. The instructions included recommendations for using rubber ligatures, making deep incisions at the bite site, and applying suction by mouth or mechanical device. Furthermore, the instructions suggested the use of magnesium sulfate to “eliminate tissue fluid containing the venom” and they advocated strychnine for the treatment of shock. All of these treatments have been applied in the past; they often are described in the older snakebite literature, and they have not been considered effective or safe since the early to mid-20th century. Simpson and Norris also found problems with the brochures’ lists of anticipated symptoms and the instructions for dosing and the timing of dosing. They made recommendations at the Indian National Snakebite Protocol Consultation Meeting in 2007 with the hope that all manufacturers would adopt their suggestions for modernizing their instructions. Both Indian and Pakistan now have a national treatment protocol.

                Bites from the Martinique Fer-de-lance (Bothrops lanceolatus) between 1993 and 2001 were treated effectively with antivenom, but three of 10 patients treated with the antivenom between 2003 and 2004 developed cerebral infarctions. When the antivenom was tested on mice it was found to be less effective than specified by the manufacturer. Some of the antivenom was more than 15 years old. In 2007 the Health and Social Development Administration on the Caribbean island of Martinique was making special requests for people to collect the Fer-de-lance so that they could replenish antivenom stocks.

                An Australian study found antivenom to be ineffective in controlling coagulopathy (excessive bleeding) from elapid bites and reported the administration of fresh frozen plasma was needed to restore coagulation factors in the blood, which takes the liver about six hours. A study of expired antivenoms looked at the activity of expired taipan, brown snake, and polyvalent antivenoms. While all of the antivenom batches remained partially active they showed some deterioration in activity and binding over time. All tested taipan antivenom, including one 15 years expired, still prevented blood clotting. Brown snake antivenoms also prevented clotting, except for two vials that were 10 years old.  Thus, antivenom remains effective long past the expiration date. 

                The WHO snakebite study discussed above clearly considers snakebite a neglected issue, They point out that antivenom for snakebites is not widely available in many countries, and that its availability is not sustainable. Simpson and Norris took exception and note that the lack of physician training, poor advice from experts, and a lack of economic analysis are part of the problem. In Africa one antivenom producer made a product called ‘Bitis’ for viper bites from the Puff Adder (Bitis arietans) and the Rhinoceros Viper (B. nasicornis). Another product called ‘Naja’ provided treatment for envenomation by the Black-necked Cobra (Naja melanoleuca) and the Mozambique Spitting Cobra (Naja mossambica). Both antivenoms are recommended for use in Mozambique. However, Puff Adder and Mozambique Spitting Cobra envenomation produce similar symptoms (swelling) and doctors are often unsure as to which antivenom to use. An Indian manufacturer of antivenom wanted to market its product in Africa so it obtained the product insert of an African antivenom producer and copied its species list, selling Indian antivenom in Africa. Yet a third supplier who attended the WHO meeting supplied ineffective antivenom to Africa, and another entrepreneur provided outdated advice on how the product was to be used. The concept of species specific proteins may be missing here. Simpson and Norris pointed out that the global snakebite problem has not been neglected so much as misunderstood. Newer techniques for antivenom production as well as physician training are critical to improving the treatment for snakebite.

                Considering that the fundamentals of antivenom production have been known for a century, the current problems seem unnecessary and unconscionable. Simpson and Norris have laid out a marketing mix that can make antivenom both sustainable and available and would allow manufacturers to produce a vial of IgG antivenom for a reasonable cost (US$8 to $42 per vial) depending upon volume. So, why is reasonably priced whole IgG antivenom not available in the USA? This is a question that needs investigation, considering the fact that Fab produced antivenom has not been demonstrated to have reduced side effects or be more effective at reducing the symptoms of envenomation.