Venom comprises a complex mixture of enzymes, metalloproteinases and other compounds that are designed to immobilize, kill and begin digestion of prey. Swelling and ecchymosis result from hemorrhagic toxins that increase the permeability of capillary endothelial cells, allowing extravasation of blood and fluid into surrounding tissues. Coagulopathy is multi-factorial but is at least partially related to the depletion of fibrinogen and the inhibition of clotting factors.
Thrombocytopenia is also common, although the mechanism remains unclear. Crotaline antivenoms are polyvalent antibodies whole or Fab fragments that bind and inactivate venom parts. Depending on the make-up of the particular venom, along with the binding affinity of the antivenom to the venom components, the results of therapy may vary.
Whole IgG-derived antivenom, such as the older Wyeth product, are thought to be slowly deposited on endothelial cells after infusion and eventually eliminated by macrophages, resulting in prolonged elimination times in the body.
The smaller Fab fragments of CroFab are removed by the kidneys. Circulating Fab fragments of CroFab generally drop to low levels within about 24 hours of infusion. The volume of distribution throughout the body of the Fab fragments is greater than the larger whole IgG. Envenomated patients commonly present with pain at the site of the bite along with marked tissue edema and evidence of local tissue injury. Over time, the wound site may develop ecchymosis and signs of frank necrosis, especially if located on a digit.
In some cases, patients may exhibit hypotension secondary to hypovolemia, severe coagulopathy hypofibrinogenemia and prolongation of the prothrombin time and thrombocytopenia, however, cases of spontaneous hemorrhage are uncommon. Even more rarely, anaphylaxis from the bite, disseminated intravascular coagulation, or death may occur. Swelling is sometimes delayed and may be difficult to measure depending on the location.
In addition, swelling of the extremity may be so severe that increased compartment pressures have been documented.
Unless the bite occurs directly into the muscular compartment, the compartment pressure elevation seen proximally from the site of a rattlesnake bite does not usually lead to compartment syndrome. In a subset of pit viper bites, most notably from the Mojave rattlesnake, the venom appears to contain a neurotoxin that may present with parathesias and myokymia fasciculations at sites distal to the bite.
Individual presentations differ among patients because the composition of the venom varies greatly among different snakes and even among envenomations from the same snake. Recognition of these signs and symptoms should prompt the use of antivenom.
Human fatalities following a rattlesnake bite are very rare. It is estimated that fatal bites occur in California each year. Life-threatening spontaneous hemorrhage can be seen after a severe rattlesnake bite and include gastrointestinal and intracerebral bleeding. Some of these cases are likely the result of direct intravenous or intra-arterial envenomation, and in these cases, bleeding can occur rapidly following the bite. Anaphylactic and anaphylactoid reactions can also develop after rattlesnake bites and lead to airway compromise and severe hypotension that can be refractory to antivenom.
These hypersensitivity reactions can appear in patients without previous snake or snakebite exposures, and may require treatment with epinephrine and other vasopressors along with endotracheal intubation during resuscitation. Bites on or close to the face can produce rapid swelling of the mouth and throat necessitating early airway control. As the venom spreads through the lymphatic system, it may produce tender lymphadenopathy in the groin or axilla depending on the extremity affected. Systemic effects may manifest as nausea or vomiting, myokymia, perioral numbness and a metallic taste.
Severe envenomations may cause respiratory distress, hypotension, altered mental status and death. Rarely, compartment syndrome can be seen with a rattlesnake bite. In these rare cases, the bite is almost always deep into a muscular compartment. Since almost all rattlesnake bites can result in pain and swelling of an extremity irrespective of elevated compartment pressures, quantitative measurement of intracompartmental pressure is necessary when considering the diagnosis of compartment syndrome.
Aggressive treatment of a bite with antivenom and limb elevation can prevent compartment syndrome in the majority of cases. The mainstay of treatment is the administration of intravenous fluids with isotonic crystalloid to maintain fluid homeostasis. He then extracted blood from those horses and injected it into the snake-bitten victim. Today, although techniques have improved over the century, the process remains more or less the same.
In a typical antivenom institute, various species of snakes are bred, cared for, and constantly monitored to ensure they are in good health.
When the time is ripe, professionals introduce the snakes which can include some of the deadliest, like banded kraits or black mambas into a milking room. The snake is grabbed with the thumb and index finger at the very back of the head just behind the angle of the jaw where the venom glands reside. The quantity of venom even seasoned professionals can milk is very small, so the snakes have to be milked many, many times to produce a useful amount. For instance, it took a total of three years and 69, milkings to produce a single pint of coral snake venom.
This process also concentrates the venom by removing water. Then comes the immunization part. Goats and sheep are also used, as well as donkeys, rabbits, cats, chickens, camels, and rodents. Some institutes even experiment with sharks. Before injecting the animal, chemists carefully measure the venom and mix it with distilled water or some other buffer solution.
A veterinarian supervises the process at all times so that the horse or another animal of choice remains in a healthy condition. At this point, the horse is ready to have its blood harvested — typically 3 to 6 liters of blood is drained from the jugular vein. The next step in the antivenom fabrication process is purification. During this step, producers typically employ their own methods, many of which are kept a trade secret.
One of the last steps in antivenom preparation involves using an enzyme to break down the antibodies and isolate the active ingredients. It's usually a good idea to break up the shot into smaller doses in various locations to avoid causing an ulcer or sore on the skin and to maximize the surface area for an immune reaction.
This part of the process can vary depending upon the type of antivenom, the company involved, the snake used and the sort of antibodies desired. The specific details are hush-hush. It's vital to have a trained veterinarian on hand to monitor the horse's health. If it tolerates the injection, you'll probably give it several more doses days or weeks apart. Antibodies in the horse's bloodstream peak after about eight to 10 weeks. At that point the horse is ready to be bled, which involves drawing 3 to 6 liters of blood from the jugular vein, according to WHO guidelines.
Step 5: Purifying. Use a centrifuge to filter the plasma, the liquid portion of the blood not including blood cells. The WHO recommends injecting the blood cells back into the horse, although horses can usually stay alive and healthy without this. Now it's time to separate out the antivenom. Again, this multistep process varies by antivenom producer.
Generally, it begins by getting rid of unwanted proteins. You do this by causing them to precipitate, or fall out, often by adjusting the plasma's pH or adding salts to the solution. One of the last steps involves using an enzyme to break down the antibody into small parts and isolating its active ingredient. Alvin Bronstein, medical director of the Rocky Mountain Poison Center, says this creates a small antibody with a much lower likelihood of causing an allergic reaction compared to its predecessor.
Now that you've gone through all this effort, your antivenom still must be deemed safe and effective by the FDA, which can take another 10 years. Step 6: Human Use. Once approved, the purified antibody product is freeze-dried or concentrated into powder or liquid form and put into vials for shipment. The antivenom usually needs to be refrigerated or frozen, which further hinders availability in developing countries where electricity may be unreliable.
Once the product reaches an emergency room and a snakebite victim arrives, the vials are usually filled with saline solution and injected intravenously. If everything goes right, the antibodies then bind to and neutralize the venom, while the liver or kidneys clear out the excess chemicals.
All these steps certainly add up on the balance sheet. Touger recalls the case of a man bitten by a timber rattlesnake, whose venom disrupts blood's ability to form clots; the man bled for three weeks and went through 30 vials of CroFab. The patient survived, as has everyone treated for venomous snakebites at Jacobi since the treatment center opened in But the time and money required to make antivenom, combined with the fact that most deadly snakebites happen in developing countries, has decreased the financial incentive for drug companies to produce more antivenom, contributing to a worldwide shortage.
There's one other, quirkier way to make antivenom—one that physicians don't exactly recommend. For decades Bill Haast, who died this June at the age of , milked about snakes a day with his bare hands, and in began injecting himself with increasing doses of diluted cobra venom in order to develop his own immune resistance.
At the time of his death not caused by snakebite , he'd survived bites from many of the world's deadliest snakes, including a blue krait, a king cobra and a Pakistani pit viper.
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