Specific data on cottonmouth venom toxicokinetics in humans is extremely limited.  Pit vipers have curved hollow fangs that inject venom subcutaneously. In rats who had an intramuscular injection of Agkistrodon halys ussuriensis, the absorption half-life was 2.5 hours, distribution half-life of 4.8 hours and elimination half-life of 125 hours with an apparent volume of distribution of 19 L/kg.[11]

After initial assessment for acute life-threatening conditions, a thorough history and physical examination are necessary. The clinician should determine when the bite occurred, obtain a description of the snake if possible, and evaluate the site of envenomation. Common physical exam findings from a pit viper envenomation include one or more fang marks, pain, erythema, ecchymosis, and progressive edema. Nausea, vomiting, coagulopathy, and systemic signs of envenomation can occur as well. Patients will also occasionally bring in the snake, which can help to identify venomous versus non-venomous species. In general, it is not advised to go catch the snake to bring it to the hospital as this may risk further bites. Even dead snakes can still cause envenomation if not handled carefully.[12][13]

Prehospital considerations include immobilizing the extremity and transportation to a healthcare facility. There is no role for constrictive tourniquets in pit viper envenomation. Additionally, there is no role for any venom extraction device.[14] After arrival at the emergency department, airway, breathing, and circulation should undergo assessment. Acute, life-threatening signs or symptoms would be extremely uncommon but can occur from either an anaphylactic or anaphylactoid reaction to venom or if the envenomation injection was into a vein.[15][16] Unstable patients should undergo customary resuscitation as it relates to securing the airway, ensuring adequate oxygenation and ventilation and supporting hemodynamics.

Hematologic laboratory abnormalities are common after pit viper envenomation, especially with rattlesnakes. Significant abnormalities are less frequent and less severe with cottonmouth or copperhead envenomations.[17] Hematologic abnormalities of moderate to severe pit viper envenomation may include thrombocytopenia, elevated prothrombin and activated partial thromboplastin time, depressed fibrinogen concentration and elevated fibrin degradation products and d-dimer. This constellation of laboratory abnormalities can mimic disseminated intravascular coagulopathy (DIC). Pit viper envenomation, however, unlike DIC, rarely causes clinically significant bleeding or thrombosis.[18] There is very little data evaluating thromboelastography in the setting of pit viper envenomation and requires additional study.[19] Hematologic abnormalities can reoccur several days after treatment. Specific data on cottonmouths is limited. However, reports exist of recurrence of coagulopathy up to two weeks post-envenomation despite initial treatment with antivenom.[20]

Most patients with a confirmed or presumed envenomation require observation for eight hours. If there are no physical or laboratory signs of envenomation during this observation period, then the envenomation is presumed to be a “dry bite,” meaning that a bite occurred with little or no venom injected. In these cases, patients can be discharged from the emergency department with customary return precautions. During the observation, if there are signs of progressive soft tissue injury, then hospital observation would be reasonable. All patients receiving antivenom require admission. Reasonable laboratory studies for a cottonmouth envenomation can include a complete blood count, basic metabolic panel, fibrinogen, and prothrombin time.[8] The clinician should perform a serial examination of the envenomated extremity or site. There is no consensus on the exact method of evaluation, but a reasonable approach is the neurovascular status of the limb, the overall degree of limb edema as well as determining the proximal line of envenomation; this is the proximal edge where the patient reports pain. Measuring limb circumferences at the bite site and several proximal sites to compare to the contralateral side has some appeal due to its simplicity and objectivity. However, there is no clear indication of how much circumference asymmetry would prompt antivenom. Furthermore, there may be inaccuracies with repeated measures, especially from different operators.[21]

Compartment syndrome is a theoretical concern given many similarities between envenomation and compartment syndrome. The majority of pit viper envenomations occur in the subcutaneous space, and involvement of the muscle is very uncommon. If compartment syndrome does occur, it could be in the setting of a severe rattlesnake envenomation with myonecrosis.[15]

After a snakebite, patients should immobilize the limb and seek medical attention. There are many folklore treatments for venomous snakebites, including venom extraction, electric current, tourniquets, and applying ice packs. These therapies, including mechanical venom extraction devices, are not useful.[14] Local wound care and tetanus should be updated if needed. Elevation of the limb may be useful to reduce distal edema and reduce pain. Patients presenting after a cottonmouth bite should undergo observation for eight hours post-envenomation. If there are no physical or hematologic signs within eight hours, then the patient can be discharged home.[22] If the patient starts to show signs and symptoms of envenomation, then they should be admitted for observation. Patients who exhibit progressive proximal edema, hematologic toxicity, or systemic effects should receive antivenom.[22][15] There are two commercially available antivenom products available in the United States. Crotalidae polyvalent immune Fab (Fab) is processed from sheep immunoglobulins inoculated from four North American pit vipers: eastern and western diamondback (C. adamanteus and atrox), Mojave rattlesnake (C. scutulatus), and cottonmouth (Agkistrodon piscivorus).[15] Crotalidae Immune F(ab’)2  is a newer antivenom processed from horse immunoglobulin inoculated from the South American rattlesnake (C. durissus) and fer-de-lance (Bothrops asper) snakes.[15] It is worth noting that F(ab)2 antivenom has not been derived from an Agkistrodon species and its efficacy for cottonmouth envenomation is unknown.

The initial dose of Crotalidae polyvalent immune Fab antivenom is four to six vials given intravenously. Antivenom will not reverse the soft tissue effects of pit viper envenomation but should halt progression. Control of progression of soft tissue injury and/or hematologic toxicity is the goal of antivenom therapy. If initial control has not been achieved, then another loading dose of four to six vials should be given. More than six vials can be initially administered if there are signs of shock or severe bleeding.[22] Once control of progression has occurred, maintenance dosing includes giving two vials every six hours for three doses (six additional vials).[9] 

The dose of Crotalidae Immune F(ab’)2  is ten vials intravenously given once; this can be repeated in one hour if failing to achieve initial control. Since F(ab’)2 is a larger fragment with slower elimination kinetics, there is no maintenance dosing. Treatment of venom-induced hematologic toxicity is an additional antivenom. If clinically significant bleeding is occurring, treatment with blood products in addition to antivenom may be necessary.[15]

Despite being rare, if compartment syndrome develops, it should be treated with additional doses of antivenom. There is a very limited role for fasciotomy for North American pit viper envenomation, and it is a consideration for persistent concerns despite adequate antivenom, or for decompression of digits.[23][15]

Often patients will see the snake which leaves very few differential diagnoses to consider except for the identification of the snake species.  Patients occasionally will not see the actual snake when bitten so there may be questions about whether the wound is from a snake or due to another process. Two puncture wounds next to one another are suggestive of a pit viper envenomation. However, not all patients will have two puncture wounds. Punctures from other sharp objects or thorns could be considerations. Punctures from non-snake sources could result in cellulitis that may potentially mimic a pit viper envenomation; however, the temporal course and appearance will be different. As such the differential diagnosis can include:

• Arthropod envenomation
• Cellulitis
• Vascular trauma
• Wasp sting
• Deep vein thrombosis

Specific data on prognosis from cottonmouth envenomation are very limited. These envenomations are considered to be less serious on average than rattlesnake bites. Cottonmouth envenomation has a lower likelihood of being a severe systemic envenomation.[5] In 2017, there were 255 cottonmouth envenomations reported to the US poison center, but only ten serious outcomes and no deaths.[7] In a retrospective study of snakebites, cottonmouth envenomation, regardless if they received antivenom, did not require surgical intervention and only needed pain control and wound care.[10] Patients bitten by a cottonmouth snake will require observation, local wound care, the elevation of the affected limb, and potentially antivenom. Patients that have any signs of coagulopathy or worsening pain, edema, or ecchymosis should receive antivenom, and require admission. Prospective data from copperhead bites, a pit viper in the same family as cottonmouths, reported resolution of envenomation typically between 7 to 13 days.[11] It is essential to inform patients that they may experience symptoms for up to four weeks before they have full resolution of limb dysfunction.

Serious complications from cottonmouth envenomation are uncommon. Data are limited for cottonmouth snakes. The copperhead (Agkistrodon contortrix) is another North American pit viper of the same species with some clinical data available. Hematologic abnormalities occur in about 14% of copperhead envenomations; however, clinical bleeding is rare.[17] True coagulopathy and serious bleeding are rare, but reports do exist.[24] Less serious complications from cottonmouth envenomation include limb dysfunction, which can include pain and edema for up to 30 days post envenomation.[25] Antivenom can cause immediate hypersensitivity reactions and require prompt treatment. A meta-analysis from 1997 to 2010 reported that when Crotalidae polyvalent immune Fab antivenom is used the incidence of immediate hypersensitivity was eight percent, and serum sickness was 13%.[12]

• Medical toxicology consultation can be useful but may not be accessible at all hospitals
• Any US regional poison control center is available by calling (800) 222-1222. Medical toxicologists are available to discuss treatment 24 hours per day.

The following are summary recommendations in the management of pit viper envenomation. 

• Patients should avoid mechanical venom extraction
• Do not apply heat or ice to the wound
• Avoid tight and constrictive bandages
• Do not use a tourniquet 
• Elevate the affected limb to help with pain and edema
• Patients should be evaluated in an emergency department and observed for 8 hours

• Cottonmouth snakes are venomous pit vipers with a range throughout the Southeast United States.
• Their venom contains enzymes that cause local destruction of tissue through the metabolism of cellular membranes and causing an inflammatory response.
• Systemic effects and coagulopathy from cottonmouth envenomation are uncommon. The most common symptoms are pain, ecchymosis, and edema.
• Crotalidae polyvalent immune Fab antivenom should be administered for patients exhibiting progressive signs of proximal edema, significant hematologic abnormalities, or severe systemic symptoms.
• Patients with early signs of envenomation require admission for observation. Those that do not have symptoms after eight hours can be discharged.

When a patient presents with a cottonmouth envenomation, it requires the prompt evaluation and management of an interprofessional healthcare team. This team includes nursing, emergency provider, a toxicologist, or the regional poison center. The collaborative effort from these teams can properly triage patients and appropriately manage patients with snake bites envenomation. Patients in the emergency department should have the following:

• Vital signs recorded and monitored by the nurse with reporting of changes to the clinician 
• Assess the wound and provide local wound care
• Record the patient's last tetanus shot and update if needed
• Elevate the affected limb to help with pain and swelling 
• Avoid tourniquets, ice packs or manipulating the wound
• Observe all patients with suspected envenomation for at least 8 hours
• Administer antivenom if indicated

While most patients improve with local wound care, the patient requires monitoring for the development of compartment syndrome; this is where nursing can fill a vital role, informing the physician or contacting toxicology if they have any concerns. If there is any concern about blood flow compromise, the surgeon should be asked to perform a fasciotomy. If antivenom is necessary, it will be obtained from the pharmacy, and the pharmacists should be sure to familiarize themselves with the interaction and adverse event profile since it is an infrequently encountered agent; this will enable them to be a better asset to the care team. Today with prompt treatment, the outcomes following cottonmouth envenomation are good, but only if the interprofessional healthcare team, including physicians, toxicologists, pharmacists, and nursing work collaboratively to ensure patients receive the care they need in a timely fashion.[Level V]