#94111: Pit Viper Snakebite Assessment and Treatment

The bite from a pit viper usually causes some degree of swelling around the bite area within 5 to 10 minutes. Nearly all bites cause pain, and pain that is initially mild usually increases in severity as edema progresses. The bite of a non-venomous snake may also be painful, but the pain results simply from the trauma of the bite and is of limited severity and duration, in contrast to the dull, constant pain and tenderness caused by envenomation. As local tissue damage increases, there is progressive swelling and ecchymosis.

Local swelling resulting from a deposit of venom may be immediate, greatly delayed, or absent, depending on the venom load and the depth of the bite. Deeper bites that penetrate muscle are more likely than subcutaneous bites to swell less, especially early on, but the venom is likely to make a more rapid entry into the systemic circulation due to the greater vasculature of muscle. This increases the likelihood of rapid clinical deterioration and more severe clotting abnormalities.

Most bites penetrate subcutaneous tissue, and the early spread of venom is by lymphatic drainage rather than venous flow [10]. For this reason, swelling and tenderness of the regional lymph nodes is common, even if only a relatively minor degree of envenomation is present [15].

Local tissue reaction is the body's first line of defense, serving to contain and neutralize the venom to a greater or lesser degree. Depending on venom load, swelling can be very impressive, extending over a day or so in spite of what is thought to be reasonable doses of antivenom. Unfortunately, poor perfusion due to tissue dissolution accounts in large part for the difficulty getting intravenous (IV) antivenom into the injured region to bind effectively with the venom molecules. If early and adequate doses of properly administered antivenom are able to penetrate the local site of injury well, systemic envenomation is limited and any swelling generally resolves within 10 days.

Pit viper envenomation can rise to the level of a complex poisoning, affecting every organ system, resulting in coagulopathy and hemoconcentration (early) followed by a decrease in erythrocytes (anemia), thrombocytopenia, hematuria, proteinuria, hematemesis, melena, hemoptysis, epistaxis, and hypotension [19]. Hypofibrinogenemia and thrombocytopenia are common findings. Physiologic responses to envenomation, such as release of bradykinin, contribute to the severity of pain and, short of a shock state, may cause significant but transient hypotension [15]. Difficulty swallowing (dysphagia), blurred vision, and marked thirst may occur, and the patient may experience significant weakness after eastern and western diamondback envenomation [12]. The patient may feel faint, nauseated, and/or numb or tingly around the mouth, tongue, scalp, fingers, toes, or site of the bite [19]. Such paresthesias indicate that a significant envenomation exists. Fasciculations are very common in human victims, and when present after a bite by an unidentified snake should suggest the eastern diamondback, the Mojave, or the southern Pacific rattlesnake as the offending reptile. Fasciculations in severe cases may become generalized, especially with eastern diamondback rattlesnake bites [15]. Transient myosis is said to be a symptom of severe envenomation due to the bite of the eastern diamondback rattlesnake [15]. Convulsions are particularly common in children [12]. Prolongation of bleeding and clotting times may occur [19]. In addition to visible tissue destruction (including blebs, sloughing, and gangrene), changes in capillary permeability may occur, leading to great fluid loss and hypovolemic shock as well as pulmonary edema (both of which are frequent causes of death) and swelling of entire limbs. Anaphylaxis and Kounis syndrome are unlikely but possible results of snakebite and should be considered in the overall assessment of the patient.

According to Wingert, "large amounts of venom can result in…an immediate profound fall in systemic arterial pressure and a decrease in circulating blood volume believed due to pooling of blood in the major vessels and capillary beds in the lung. Hypovolemic shock and pulmonary edema appear to cause most fatalities. Hemoglobin decreases and bleeding occurs throughout the body, often as soon as six hours after envenomation" [37].

Russell describes the effects of serious envenomation as follows [11]:

In moderate or severe envenomations, the tingling or numbness may extend to the face and scalp within the first 30 minutes, with tingling of the fingertips and toes following later. Sometimes changes in taste and sensation occur even before swelling, so asking about them may help establish the diagnosis sooner. A metallic, rubbery, or minty taste in the mouth and tingling of the tongue and lips are virtually pathognomonic of rattlesnake envenomation, and may occur before or in the absence of swelling. Fasciculations may also appear very early in the course of some rattlesnake poisonings but are rarely seen after bites by copperheads. Fasciculations are most noticeable on the face and over the large muscles of the back and neck, as well as in the bitten extremity. Moderate-to-severe rattlesnake poisoning may also cause erythema and ecchymosis around the bite area within three to six hours. Ecchymosis may occur in any area whose skin rubs against itself, or may be precipitated by even slight trauma.

Pit viper venom has direct and indirect adverse effects on vital organs, including the kidneys and the lungs. When there is widespread tissue toxicity (to a large amount of venom), cellular debris, hemoglobin, and myoglobin released into the circulation may precipitate in the kidney tubules, resulting in renal shutdown [37]. This complication can be avoided if IV fluids are administered at a rate sufficient to provide a brisk urinary output and if antivenom administration is begun early and given in adequate amounts. Bush and Jansen advise that the risk of nephrotoxicity from rhabdomyolysis and myoglobinuria is increased at low urine pH and thus may be reduced by alkalinization [48].

While providing adequate hydration to support blood pressure and protect renal function is important, one should be mindful that venom-induced changes in capillary permeability within the pulmonary vascular system render the lung more susceptible to pulmonary edema in response to fluid challenges. Wingert comments that, "Pulmonary edema occurs in severe cases due to injury of the epithelial lining of the pulmonary vasculature, with loss of serum proteins and plasma into the alveoli" [37]. Prevention and amelioration of pulmonary toxicity depends on early and adequate amounts of antivenom as well as careful monitoring for signs of fluid overload. Lung sounds should be closely monitored for signs of pulmonary edema. IV fluid administration rates should be carefully adjusted to prevent renal toxicity and to prevent fluid overload.

The heart can be directly affected as well. Some pit viper venoms contain a direct cardiac muscle depressant [37]. A single case of cardiac arrest in an otherwise healthy young adult male patient has been noted to be a potential direct venom effect, as electrolytes were within normal limits, the patient was well-hydrated, and there was no reason to believe that antivenom would cause such an event. The patient recovered after a few moments of chest compressions. Antivenom administration was not stopped, and no further arrests occurred.

Snake venom is one of a number of environmental exposures known to trigger Kounis syndrome [96]. This should be considered along with the need of antihistamine administration, supplemental oxygen, and possibly other interventions for any patient with known or suspected snakebite who is experiencing chest pain or electrocardiographic changes.

Coagulopathy

Activation of the coagulation cascade and multiple defects in blood clotting (coagulopathy) are common following pit viper envenomation, putting the patient at risk of a serious bleeding diathesis. Platelet counts and fibrinogen levels are key to assessment and treatment. Consultation should be considered in any case with confusing features and promptly sought for any patient whose clotting factors fail to improve after two 6- or 10-vial doses of CroFab or two 10- or 20-vial doses of Anavip. The platelet count is usually a sensitive indicator of systemic venom activity and an early marker of antivenom effectiveness, providing a quick laboratory measurement that is used (hourly in severe envenomations, along with hemoglobin, hematocrit, and fibrinogen) to assess progress in reversing the coagulopathy. The cause of thrombocytopenia in pit viper envenomation is not yet fully understood. There is no evidence of a defect in production of platelets, and the treatment approach to thrombocytopenia is administration of antivenom, not platelet transfusion [4]. Platelet counts usually respond rapidly to antivenom administration alone. Reversal of thrombocytopenia may be seen within one hour following treatment with an adequate dose of antivenom.

As important as it is to monitor platelets, it is at least as important to monitor fibrinogen, as this is a more sensitive marker of envenomation in the early hours after snakebite. At times, even in the face of a heavy venom load, it is possible to have a normal platelet count but low fibrinogen. The platelet count in such cases could remain normal in spite of potent venom activity because there is no fibrinogen available to convert to fibrin, and thus no fibrin available to be snared by platelets, leaving the platelets free to be counted.

Close monitoring of clinical status and laboratory parameters and, when indicated, early intervention with adequate doses of antivenom are required to assure a safe outcome. Initial laboratory studies to evaluate coagulopathy include fibrinogen, platelets, PT, PTT, and FDP. The unstable patient requires serial assessment of the PT, hematocrit, platelets, and fibrinogen at regular intervals, perhaps every hour, until stable. Laboratory studies are generally performed every six hours after initial control is achieved and the patient is stable. More severe cases may require selective laboratory monitoring every four hours after the patient is stabilized. Laboratory monitoring for coagulopathy is also performed one hour after each dose of antivenom has infused, including maintenance doses in the case of CroFab administration, to assist in assessing whether initial control has been attained or maintained.

While local swelling in the region of the snakebite may be the most visible sign used to identify progression or lack of progression of envenomation, it is important to bear in mind that an occasional patient will have scant or even no swelling and yet a severe coagulopathy demonstrated by a plummeting fibrinogen level and likely plummeting platelet count as well. The impact of the venom on the blood coagulation cascade, coupled with the possibility of hypovolemic shock resulting from leakage of intravascular fluid into the tissues, constitutes the greatest threat to the victim. Incipient coagulopathy following envenomation is, in a sense, a "stealth attack," because coagulopathy cannot be felt by the patient or seen by the clinician unless overt bleeding is present. This, along with the fact that an occasional coagulopathy develops only after a surprising number of hours, is the reason that all pit viper snakebite victims who have and continue to have no swelling or other signs or symptoms should be evaluated for coagulopathy and monitored clinically by an informed staff in an urgent care setting with the ability to perform all required laboratory studies for 8 to 12 hours before being discharged home. Typical urgent care units are unlikely to be able to perform timely fibrinogen or FDP testing and thus would be an inappropriate setting for pit viper snakebite evaluation. As such, patients typically initially present to a hospital-connected emergency center, and those who begin to demonstrate any signs or symptoms of envenomation should be admitted to an ICU for a minimum of 24 hours.

Derangement of the coagulation cascade, when pronounced, often results in overt signs of bleeding. This may present as renewed bleeding at the bite wound site or at venipuncture sites. New-onset hematuria may be a more common and early sign of bleeding diathesis. Microscopic hematuria often develops before gross hematuria is evident. Microscopic hematuria can be detected rapidly by dipstick urinalysis, a simple bedside test that can easily be included in regular clinical monitoring along with vital signs and laboratory tests. Importantly, a dipstick that is positive for blood may also indicate myoglobinuria (indicative of rhabdomyolysis), which should be confirmed by further testing. During clinical observation, the performance of hourly dipstick urinalyses at the bedside may lead to a significantly earlier treatment intervention than if one were to wait for the results of the next serial blood tests. Recalling that early and adequate doses of antivenom are the mainstay of snakebite treatment, the importance of this simple, inexpensive bedside test cannot be overemphasized.

Pit viper venom, if in a dose that precludes neutralization by local tissue, may attack the blood and blood coagulation cascade, breaking up fibrin, preventing the conversion of fibrinogen to fibrin, and/or causing thrombocytopenia, any of which puts the patient at risk of serious bleeding. In other clinical contexts (e.g., cancer chemotherapy), transient thrombocytopenia and hypofibrinogenemia are common findings that do not usually lead to overt bleeding; however, clotting abnormalities produced by envenomation tend to be progressive, sustained, and life-threating unless controlled by early and adequate doses of antivenom. At the same time, however, it is important to be alert to the patient's baseline health and medical history (e.g., anemia, other hematologic disorder, anticoagulant drug use) in interpreting initial laboratory data. In addition to pit viper envenomation, the following conditions are associated with hematologic and coagulation factor abnormalities [9]:

If the patient arrives from the field wearing a band or tourniquet applied to sequester venom, do not release the pressure all at once, but gradually, so as to prevent a bolus of venom from being released into the systemic circulation. When antivenom is available, apply a less constricting band proximal to the tourniquet, and after the IV solution has been infusing for five minutes, slowly release the original tourniquet, and in another three minutes remove the secondary band as well[11]. Consideration should be given to administering antivenom before the tourniquet or constricting band is removed, as a large (and possibly fatal) bolus of venom could be released[38]. Elevate the extremity after an IV is established and antivenom is available. Do not apply ice, heat, or tourniquets. Cleanse the puncture wounds and administer tetanus prophylaxis, if indicated.

If possible, determine whether the offending snake is venomous, non-venomous, or unknown. Notify a snakebite specialist and report to poison control. If likely to administer CroFab, note on the snakebite triage sheet (Figure 3) any allergy to sheep protein, papain, chymopapain, other papaya extracts, the pineapple enzyme bromelain, dust mites, latex, and any additional allergies[4]. If likely to administer Avavip, note any allergy to horse protein as well.

PIT VIPER SNAKEBITE TRIAGE SHEET

Figure 3

Source: Compiled by Author

The patient should be kept NPO and on bed rest, with vital signs monitored every 15 minutes (including pulse oximetry). An IV lock should be placed in an unaffected extremity. Blood should be immediately collected and held for a possible type and crossmatch, followed by collection for a complete blood count (lavender top), coagulation studies (blue top), chemistry determinations (light green top), serology (red top), and FDP (another blue top or special top, depending on the laboratory) (Figure 4). A Foley catheter with urometer should be placed if the patient is unable to void every one to two hours or if menstruating.

LABORATORY FLOW SHEET

Figure 4

Source: Created by Author

A blood band should be applied, and the blood requisition is labeled "Snakebite: hold clot tube only." The signed blood sample and requisition are sent to the blood bank, but type and screen or crossmatch should be performed only if it becomes necessary. Differential, creatine kinase (CK), and ethanol (if indicated) tests should also be included in the initial laboratory assessment. The following tests should be performed immediately and every six hours thereafter:

All stools should be assessed for occult blood, and urine should be evaluated hourly for the presence of blood until the time of discharge from the hospital.

Patients with known or suspected snakebite having potential for envenomation should be observed every 15 minutes for:

Any progression of signs or symptoms of envenomation or any abnormal laboratory values, including if the laboratory or blood bank reports that the patient's blood will not clot, should be immediately reported to the treating physician. All asymptomatic patients with known or suspected viper bites should be studied closely in the emergency department for 8 to 12 hours from the time of the bite before considering discharge [13].

Any patient with signs, symptoms, or abnormal laboratory values consistent with envenomation should be admitted to an ICU for at least 24 hours. Otherwise, after a minimum of eight hours of observation and laboratory testing, patients who have had no paresthesias, fasciculations, erythema, ecchymosis, pain other than minor pain, swelling, or other signs or symptoms of envenomation, and no relevant laboratory abnormalities at baseline or six-hour follow-up, may be discharged to outpatient care[86]. Note: "Detection of fibrin split [degradation] products may be an early sign of a hematologic venom effect, and is a sensitive predictor of subsequent coagulopathy. In prospective studies, the presence of fibrin split products within the first 12 hours of observation or treatment predicted subsequent hypofibrinogenemia with 87% sensitivity and 69% specificity" [85]. At discharge, patient education should include information on reporting changes in signs/symptoms and avoiding anticoagulants until cleared by a physician (Figure 5). Patients with a prosthetic heart valve should have a plan (with their cardiologist) for restarting their anticoagulation regimen.

INFORMATION FOR PATIENT UPON DISCHARGE

Figure 5

Source : Compiled by Author

As part of the initial evaluation, steps should be taken to try to determine whether the offending snake is venomous or unknown. If the patient arrives wearing a band or tourniquet applied to diminish blood flow to and from the affected extremity, this should be managed/released in a step-wise fashion, as outlined previously, once antivenom is available. Consideration should be given to administering antivenom before the tourniquet or constricting band is removed entirely, as a large (and possibly fatal) bolus of venom could be released [38].

All jewelry should be removed. Bites to the face and neck are likely to produce a degree of soft tissue swelling that poses a threat to the patient's airway, and steps should be taken to assure that swift intubation can be performed if the need arises. If the bite is on an extremity, it should be elevated after an IV is established and antivenom is available. Do not apply ice, heat, electric shock, or tourniquets. Tetanus prophylaxis is administered at this point, if indicated. A snakebite specialist and poison control should be notified [4].

If CroFab is used, note any allergy to sheep protein, papain, chymopapain, other papaya extracts, the pineapple enzyme bromelain, dust mites, or latex. If Anavip is used, document allergy to horse protein. Any additional allergies should also be noted on the triage sheet [4].

All patients with any signs/symptoms of envenomation should be admitted to an ICU. These patients are kept NPO and on strict bed rest initially, with vital signs taken every 15 minutes (including pulse oximetry); automated blood pressure measurements should be avoided. Morphine sulfate may be administered as needed for pain if the patient has no history of allergy. Infection is rarely an issue in the early management of snakebite, and prophylactic antimicrobials are not indicated. If there is uncertainty about the diagnosis or if objective signs (e.g., purulent discharge, fever) develop as a late complication of tissue breakdown, antimicrobial therapy may be indicated, guided by cultures [12].

It is helpful to have two IV lines available, away from the affected extremity—one IV lock for serial blood draws and one large-bore line for IV fluid and medication administration. The same blood draws should be conducted as those outlined for asymptomatic patients. Any swelling or tenderness should be marked and monitored for progression every 15 minutes. Intake and output should be monitored along with the presence of blood in urine or stools; a Foley catheter with urometer is typically placed in patients who are significantly envenomed.

The affected extremity should be lightly immobilized in a position of function on a well-padded splint and elevated after antivenom is available. Any fang wounds should be cleaned daily with an antiseptic solution and covered with a dry, sterile dressing.

Blebs, vesicles, and superficial necrotic tissue should be aseptically debrided on the fourth or fifth day, per local protocol, if coagulation values are normal. Active and passive rehabilitation therapy should be initiated as soon as the patient is able to tolerate it to prevent contractures, and the patient with significant injury should be referred to rehabilitation therapy at discharge.

Serial electrocardiogram monitoring is recommended during the first 48 hours for all severe envenomations and for all patients older than 40 years of age or with a history of heart disease [40]. For patients with prosthetic heart valves, a cardiology specialist should be consulted.

A blood band should be applied, and the signed blood requisition is labeled "Snakebite: hold clot tube only." The blood and requisition are sent to the blood bank, but type and screen or cross should be ordered only if it becomes necessary. Differential, CK, and ethanol (if indicated) tests should be included in initial laboratory studies. CK may be repeated as necessary to assess muscle breakdown in the presence of generalized fasciculations. Hemoglobin/hematocrit with platelets and fibrinogen should be assessed every hour until the patient is stable. Urine dipstick for blood should be done every hour until discharge from the hospital. The following tests should be done as soon as possible and every six hours thereafter (or every four hours in severe cases) regardless of antivenom administration:

These tests should be coordinated with the following, which must be done one hour after each dose of antivenom has infused to track progression:

Patients with signs of envenomation should be observed every 15 minutes for:

Any progressive signs or symptoms of envenomation or any deteriorating laboratory values, including if the laboratory or blood bank reports that the patient's blood will not clot, should be immediately reported to the treating physician.

Envenomation of the finger or hand is treated more aggressively than most other areas of the body for the following reasons [3]:

Progression of circumferential or linear (leading edge) swelling measuring 1 cm/hour is considered to be significant, regardless of the site of the bite. Without early and adequate treatment, swelling and healing can take weeks to return to a level of maximum improvement. With early and adequate treatment, swelling can be expected to subside in approximately 10 days [4]. It is therefore important to not wait hours to see how far swelling progresses before beginning antivenom administration, because further and perhaps irreversible tissue destruction may well be occurring during that time. Swelling can occur haltingly as the venom dissolves different types and layers of tissue and can be thought to have stopped, only to become obvious again. One should not wait for multiple episodes of such a pattern to pass before beginning treatment.

The patient who has a hand or finger envenomation and whose life is not yet known to be in danger faces the decision of whether or not to accept early treatment. A clear, unhurried explanation to the patient by someone comfortable with the treatment of snakebite is essential if he or she is to make an appropriate decision. The basic conversation should include the following [4]:

Each vial of CroFab should be reconstituted with 18 mL of 0.9% saline drawn from an IV bag of normal saline containing the volume of fluid the patient is to receive over the next hour (minimum: 250 mL) [4]. The diluent should be instilled gently along the wall of each vial to avoid foaming. To hasten mixing, release pressure after all diluent is added. Each vial of CroFab should be mixed by continuous, gentle manual inversion at a rate no faster than two complete inversions per second, until no solid material is visible in the vial; to prevent foaming, it should not be shaken. The reconstituted antivenom is then returned to the IV bag.

Reconstitution of Anavip is similar to that of CroFab, except 10 mL of 0.9% saline drawn from the IV bag is added to each vial rather than 18 mL, and gentle swirling of each vial is employed rather than inversions.

With the physician at the bedside, pit viper antivenom should initially be infused slowly for 10 minutes (at a pump setting of 30 cc/hour with a limit of 5 cc), observing for frank anaphylactic shock, hypotension, urticaria, sneezing, dyspnea, apprehension, flushing, coughing, cyanosis, vomiting, wheals, pruritus, wheezing, and/or edema of the face, tongue, or throat.

Patients with more apparent signs and symptoms or more severe coagulopathy should receive antivenom over one hour if possible; others may benefit from a somewhat slower infusion, because the rate of infusion is directly linked to the likelihood of adverse reactions. Intravascular volume depletion, which can lead to hypotension and shock, is common in patients with a significant envenomation (especially children), and nearly all patients should receive generous resuscitation with warmed isotonic crystalloid fluids [89]. In volume-depleted children, the usual fluid bolus is 20 mL/kg (isotonic crystalloid), which can be repeated two times for a total of 60 mL/kg [90,91]. A 250 mL bolus of CroFab or Anavip, although not exclusively crystalloid, would be expected to be tolerated by most pediatric patients [4].

There are no studies examining the use of antivenom in volumes less than 250 mL. Because the rate of administration is tied to allergic responses, a more concentrated solution of antivenom should be run at a slower rate [4]. If the patient has known myocardial dysfunction or other reason for fluid restriction, the decision to reduce the total administration volume of antivenom should be left up to the treating physician [92]. After the test dose, regardless of dosage to be administered and in the absence of hypersensitivity symptoms, the rate of infusion should be doubled every three minutes to an end point that allows the total volume to infuse over one hour.

Severe Envenomation

Severe envenomation is characterized by swelling, erythema, or ecchymosis possibly involving the entire extremity and spreading rapidly; systemic manifestations are pronounced and may include nausea and vomiting, changes in mental status, severe tachycardia or bradycardia, tachypnea, respiratory distress, and hypotension. Coagulation defects are usually present; serious or spontaneous bleeding may occur. Platelet counts are often less than 20,000/mcL, and other laboratory values are abnormal [12]. Fasciculations, strong taste changes, weakness or faintness, transient myosis, and/or shock may be present. Generally (with the possible exception of bites by the copperhead), the less time between the bite and the onset of severe symptoms, the greater the venom load [31].

Fluid balance is a critical element in the treatment of severe envenomation. Andrews summarizes, "A severe snakebite should be treated and followed closely with fluid balance as in a very severe 50% third-degree burn, with careful attention to blood pressure, pulse, respiration, urine output, and hematocrit" [49].

Regardless of patient age, in severe envenomation CroFab is initially administered approximately each hour in increments of 10 vial doses to gain control (rather than the routine 6 vial doses discussed later) until initial control is achieved. Consultation should be sought early with severe envenomation, particularly if initial control is not achieved by the administration of two 10-vial doses of CroFab.

Rather than the routine CroFab maintenance dose of two vials every six hours for three doses, consider administering two- to four-vial doses every four to six hours for more than 24 hours [6]. Keep in mind this is a titration of antivenom to laboratory values and to signs and symptoms of envenomation, and it is safer to slightly overtreat with antivenom than to undertreat.

In severe envenomation, Anavip is administered approximately each hour in increments of 20 vials rather than the routine 10 until initial control is achieved. This dosage is used for all patients, regardless of age. After initial control is achieved, four to eight vials are given as needed. Consultation should be sought if initial control is not achieved by the administration of two 20-vial doses of Anavip.

For the patient with signs/symptoms of shock, infuse warmed normal saline (at least 20 mL/kg), and administer 10 vials of CroFab or 20 vials of Anavip. Consider intubation/oxygenation and patient positioning. Immediate consultation should be sought. Be prepared to administer additional doses (10 vials with Crofab or 20 vials with Anavip) before initial control is achieved. A vasopressor may be added, but not in lieu of an adequate amount of saline. Packed red cells may be added, if needed.

If the patient is hypotensive and fails to respond to resuscitative efforts, immediate consultation should be sought. Do not administer albumin or plasma expanders, as these can confuse the coagulation abnormality by creating one of their own [6].

Lesser Envenomation

The recommended initial antivenom dose for apparently lesser envenomations is 6 vials of CroFab or 10 vials of Anavip [1,97]. If initial control is not achieved by the first dose (approximately one-half of all cases), additional doses of 6 vials CroFab or 10 vials Anavip should be repeated approximately hourly until initial control of the envenomation syndrome has been achieved [87]. Consultation should be sought if initial control is not achieved by the administration of two 6-vial doses of CroFab or two 10-vial doses of Anavip [86]. Based on clinical trial data, after initial control has been established, additional two-vial doses of CroFab should be administered every 6 hours for 18 hours (three doses) to lessen the incidence of local and coagulopathy recurrence [9]. The manufacturer of Anavip does not recommend routine maintenance dosing but recommends administering four additional vials as needed to halt progression.

"Initial control" may be defined as complete arrest of local manifestations and return of coagulation tests and systemic signs toward normal in non-bleeding patients [6]. In general, one can judge achievement of initial control and adequacy of dosing on the basis of a combination of clinical and laboratory parameters, including a halt to progression of swelling; improvement in systemic symptoms, such as nausea, paresthesias, and fasciculations; restoration and stability of vital signs (e.g., blood pressure, pulse); and degree of reversal of coagulopathy. Laboratory studies performed one hour after infusion of each dose of antivenom are required and will help to define whether initial control has been achieved.

Further treatment following antivenom administration depends on the clinical course of the patient. Generally, two- to four-vial doses of CroFab or fourto eight-vial doses of Anavip are administered as deemed necessary based on laboratory values and symptomatology [9]. It is important to remember that the effective half-life of the antivenom is likely to be much less than that of the venom, which can be many days. The half-life of CroFab is 12 to 23 hours, and the half-life of Anavip is 133 hours, due to its larger molecular mass.

After swelling appears to have ceased and coagulation studies have normalized or are trending substantially toward normal, one should continue to measure and mark the zone of local swelling every 30 minutes to 2 hours for the next 48 hours. Importantly, recurrence or delayed-onset of one or more venom effects occurs in up to approximately half of patients treated with CroFab antivenom [87]. Recurrence can also occur after treatment with Anavip. Local tissue recurrence typically develops within 6 to 36 hours of initial control. The onset of recurrent or delayed-onset hematologic venom effects typically occurs 2 to 7 days after initial control, with some cases up to 10 days after initial control [88].

It is important to monitor all symptoms and signs on the same schedule as for the monitoring of swelling. The Foley catheter and regular urine dipstick testing for blood should continue until the patient is close to being discharged. It is important not to discontinue the catheter and dipsticks prematurely, as they are important visual monitoring tools that warn of recurrent coagulopathy (hematuria) and/or myoglobinuria. Serial laboratory studies every 6 to 12 hours should be continued until the patient is discharged, with close observation for downward trends.

Serum Sickness

Patients who receive antivenom therapy should be followed expectantly for serum sickness, a reaction that can occur 4 to 20 days after initial exposure to antivenom. If serum sickness develops in an adult patient, it can be treated with 10 mg of oral prednisone every six hours at the onset of pruritus and urticaria [18]. In children, prednisone may be administered at a dosage of 2 mg/kg/day in two divided doses [18,28]. For prophylaxis against serum sickness, consider prescribing a two-week supply of methylprednisolone at the time of discharge [29]. In children, the use of hydroxyzine 1 mg/kg every four to six hours, as needed, is helpful for sedation and control of pruritus [28].

Epinephrine is the drug of choice for anaphylaxis and should be administered as first-line therapy. Epinephrine may rarely be used prophylactically in patients known to be acutely sensitive to antivenom or its components and who have a life-threatening envenomation.

The actions of this agent address the pathophysiologic changes that occur in anaphylaxis better than any other single drug. Failure to administer epinephrine in the course of treatment has been repeatedly implicated in anaphylaxis fatalities [58,59,60,61,62,63,64]. The use of antihistamines is the most common reason reported for not using epinephrine [65]. The therapeutic actions of epinephrine include the following [66]:

Epinephrine has a narrow toxic-therapeutic index (risk-to-benefit ratio). In therapeutic doses and by any route, epinephrine frequently causes mild transient adverse effects in individuals of all ages. These include anxiety, fear, restlessness, headache, dizziness, palpitations, pallor, and tremor. Rarely, epinephrine may lead to ventricular arrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and intracranial hemorrhage [66]. These severe adverse effects are more likely to occur when a dilution error has occurred in preparation of the dose to be administered, as for example, after an IV bolus injection of a 1:1,000 epinephrine solution instead of the proper 1:10,000 epinephrine solution [67].

Epinephrine has an onset of action within minutes, but it is rapidly metabolized. Therefore, the effect is often short-lived and repeated doses may be necessary [65,68,69]. Repeat doses should be administered within 5 to 15 minutes, if required.

Epinephrine can be delivered through a variety of routes, including intramuscular (IM), IV, and endotracheal or intraosseous routes [70]. IM epinephrine is recommended over subcutaneous injection because it provides a more rapid increase in plasma and tissue concentrations of epinephrine [70,71,72]. The IM dose should be given in the anterolateral thigh, in the vastus lateralis muscle. The needle used should be of adequate length to reach the muscle beneath the subcutaneous adipose tissue. IM injection into the thigh may be impossible in overweight or obese individuals, especially those with thicker subcutaneous fat tissue in this area [73,74].

Most patients suffering from anaphylaxis respond to IM epinephrine (possibly repeated doses) if promptly administered and if the injection site is well massaged. However, consideration should be given to the possibility of poor perfusion affecting the ability to absorb epinephrine administered intramuscularly.

IV epinephrine may be used for anaphylaxis, but this route should be reserved for severe, refractory cases characterized by imminent or actual airway obstruction or hypotension that is unresponsive to IM epinephrine (including repeated doses) and vigorous fluid resuscitation. The data regarding IV epinephrine for anaphylaxis are anecdotal, but poor outcomes from excessively vigorous IV epinephrine dosages have led to cautious recommendations. When epinephrine is infused slowly, beta-receptor effects predominate, while alpha effects predominate with rapid rates of infusion. In addition, beta-receptors respond to lower doses of epinephrine than alpha-receptors. Therefore, a low, slow dose of epinephrine favors beta effects while minimizing undesirable increases in systolic blood pressure. For patients with anaphylaxis who are in extremis, some experts recommend infusing 1 cc of 1:10,000 epinephrine (i.e., 1 cc of the "crash cart" 10-cc vial) further diluted in 10 cc of normal saline slowly over 5 to 10 minutes. An epinephrine drip can be administered as well, titrated to effect [34].

Although epinephrine is the first-line agent for anaphylaxis, there are relative contraindications to its use. When administered intravenously, epinephrine should be given with extreme caution to patients older than 35 years of age, those with underlying cardiovascular disease, pregnant women, and patients using beta-blockers. Malignant hypertension, myocardial infarction, and fetal demise have all been reported [34,35].

Generally speaking, pediatric patients tolerate IV epinephrine better than adults. In elderly patients or those with cardiovascular disease, consider a test dose of epinephrine of 0.10–0.15 cc of 1:1000 administered subcutaneously [36].

For airway symptoms (e.g., cough, wheezing, stridor), cardiovascular compromise or collapse, or severe skin reactions in adults, administer epinephrine 1:1,000 0.3–0.5 mL IM in the vastus lateralis immediately and massage the injection site well. This may be repeated at 5- to 10-minute intervals up to three to five doses. If a patient has poor perfusion (i.e., systolic blood pressure <30–40 mm Hg) that precludes absorption of IM doses, proceed to IV administration when access is available. The maximum IM dose for elderly patients is 0.3 mL [54].

If the response to IM doses is inadequate and IV access is delayed, keep giving the age-appropriate maximum IM dose and massage the injection site [54]. If the patient does not respond, epinephrine 1:10,000 3–5 mL IV should be administered (over five minutes) immediately when IV access becomes available (maximum dose for the elderly: 3 mL) [54]. Further dilution in 10 cc normal saline for IV use is recommended [36]. This may be repeated at five-minute intervals if there is no improvement, or every three minutes in severe reactions.

The approach to treating antivenom-related anaphylaxis in children is similar. IM epinephrine 1:1,000 is administered immediately in the thigh at a dose of 0.01 mL/kg (maximum: 0.3 mL), and the injection site is massaged well. If the calculated dose is not helpful, the maximum dose should be given [54]. The dose may be repeated every 5 to 10 minutes for three to five doses. Doses should be given IM unless the patient has signs of poor perfusion (e.g., systolic blood pressure less than 30–40 mm Hg), regardless of existing IV or endotracheal access. If hemodynamic improvement is not achieved after three to five IM doses, or if circulatory perfusion remains poor, a 0.1 mL/kg dose of IV epinephrine 1:10,000 should be given immediately over five minutes. This is repeated at five-minute intervals if no improvement is noted, or every three minutes in severe reactions. Further dilution in 10 cc normal saline is recommended [36].

The patient being treated for anaphylaxis should be placed in a recumbent position (when tolerated), with the lower extremities elevated to maximize perfusion of vital organs. This also helps prevent empty ventricle syndrome, in which severe hypotension leads to inadequate cardiac filling and electrical cardiac activity without a pulse [83].

Massive fluid shifts can occur rapidly in anaphylaxis due to increased vascular permeability, with transfer of up to 35% of the intravascular volume into the extravascular space within minutes [82]. Any patient who does not respond promptly and completely to injected epinephrine should be assumed to have intravascular volume depletion causing persistent hypotension despite maximum vasoconstriction. Large-volume warmed fluid resuscitation should be initiated immediately in patients who present with orthostasis, hypotension, or incomplete response to IM epinephrine [81]. Adults may require 1–2 L normal saline administered at a rate of 5–10 mL/kg in the first five minutes. Children should receive up to 30 mL/kg in the first hour [98].

Oxygen should be administered initially to all patients experiencing anaphylaxis, especially those with evidence of hypoxia or respiratory distress. Supplemental oxygen helps not only with optimization of oxygen delivery and organ perfusion, but also with bronchodilation [81]. Delivery of oxygen should be by a non-rebreather mask or simple cannula. (Simple masks without a reservoir bag attached can suffocate patients.)

Steroids do not relieve stridor, shortness of breath, wheezing, GI symptoms, or shock; therefore, they should be considered adjunctive therapy and should not be substituted for epinephrine [54,58,59,63,75,76,77,78]. Corticosteroids are not helpful in the treatment of acute anaphylaxis due to their slow onset of action (four to six hours). These agents are often given because of their anti-inflammatory properties, which counter allergic and inflammatory reactions, and also because they may help prevent biphasic or protracted reactions, which occur in up to 20% of individuals [60,79]. If used, methylprednisolone is the recommended agent.

For adults, the recommended dose of methylprednisolone in conjunction with epinephrine is 60–80 mg IV over at least one minute [54]. This may be repeated every 2 to 6 hours until stable, but it usually should not be continued beyond 48 to 72 hours [55]. In life-threatening shock, massive IV doses of methylprednisolone as the sodium succinate (e.g., 30 mg/kg initially and repeated every four to six hours if needed, or 100–250 mg initially and repeated at 2- to 6-hour intervals as required) have been recommended [55].

In children 12 years of age and younger, the recommended methylprednisolone dose is 30 mg IV over at least one minute. In children older than 12 years of age, adult dosing should be used. In either case, treatment may be repeated every 2 to 6 hours until stable, but usually should not be continued beyond 48 to 72 hours [55].

Albuterol administration via nebulizer is recommended for bronchospasm, as opposed to metered-dose inhalers with spacers. Albuterol does not relieve airway edema (e.g., laryngeal edema) and should not be substituted for IM epinephrine dosing in the treatment of anaphylaxis [67].

According to Russell, "IV diphenhydramine can be given before antivenom is administered to manage itching and urticaria and may be of particular value when the patient requires large amounts of antivenom in a short time" [12]. Cimetidine should be considered as well. Diphenhydramine (an H1-receptor antagonist) works synergistically with cimetidine (an H2-receptor antagonist). Therefore, if diphenhydramine is required, consideration should be given to also administering cimetidine to maximally protect from itching and urticaria.

Adults may be administered IV diphenhydramine every 6 hours at a dose of 50–100 mg and as needed during antivenom administration, up to a maximum of 400 mg in 24 hours. It should be administered undiluted at a rate not to exceed 25 mg/minute [101].

For pediatric patients, IV diphenhydramine is given at a dose of 1 mg/kg every 4 to 6 hours and as needed, up to a maximum of 300 mg in 24 hours. It is given undiluted at a rate not to exceed 25 mg/minute [7,101].

Adults may be administered IV cimetidine 300 mg every six hours during antivenom administration. It is diluted in 20 mL normal saline and administered over at least five minutes to avoid negative cardiac effects. Consideration should be given to using greater dilution and administering over a longer period, if appropriate.

For children younger than 2 years of age, IV cimetidine is given at a dose of 5–7 mg/kg, diluted with normal saline to a total volume of 20 mL and injected over at least five minutes. Neonates require cimetidine to be preservative-free. For children 2 through 16 years of age, IV cimetidine is given at a dose of 300 mg diluted in 50 mL D5W administered over 15 minutes. Those 17 years of age and older receive the same dose as adults [7].

In all patients, consideration should be given to extending administration of diphenhydramine and cimetidine for two to three days after resolution of the untoward reaction.

Consider intravenously administered atropine for patients with bradycardia [67].

No published prospective studies exist on the optimal management of refractory anaphylactic shock. Repeated use of epinephrine, as well as IV fluids, corticosteroids, and vasopressor agents, may be needed [81]. Patients who have persistent hypotension despite the administration of epinephrine and IV fluids should receive vasopressor medications titrated to the desired effect of restoring blood pressure [67,80]. No compelling evidence exists to support one vasopressor over another in this clinical scenario [67].

Glucagon should be considered in patients who do not respond to epinephrine. Adults are administered an initial dose of 50 mcg/kg IV over one to two minutes. Higher doses (up to 10 mg) may be needed if the initial dose is ineffective. This may be followed by an infusion of 2–5 mg/hour (to a maximum 10 mg/hour) [100].

In pediatric patients weighing less than 20 kg, glucagon is administered at an initial dose of 20–30 mcg/kg IV (maximum: 1 mg) given over five minutes and followed by an infusion of 5–15 mcg/minute, titrated to clinical response [98,99].

Glucagon is known to cause nausea and emesis and increases the risk of aspiration. Placement of the patient in the lateral recumbent position will assist in protecting the airway in those who are not intubated [98].

Epinephrine is the first-line drug for treatment of anaphylaxis for all patients, regardless of whether pregnancy exists. A risk of its use in pregnancy is uterine hypoxia. In spite of its lower efficacy, Entman and Moise suggest that "ephedrine (25–50 mg IV bolus) should be the first-line therapy of anaphylaxis during pregnancy to bypass the uterine hypoxia that may result from epinephrine use" [10]. However, by using ephedrine rather than epinephrine, and thus not as quickly reversing maternal hypotension (which causes fetal hypotension and hypoxia), one risks missing the roughly 5- to 10-minute window to most effectively reverse the maternal hypotension that quickly endangers both the mother and the fetus.

The American Society of Hospital Pharmacists states that it is not known whether ephedrine can cause harm to the fetus [2]. The question is whether with anaphylaxis in pregnancy one has the luxury of time to see if a less-efficacious drug will reverse the life-threatening effects of maternal, and fetal, hypotension. Because anaphylaxis places both the patient and fetus at risk, one must weigh the risk of epinephrine-induced uterine hypoxia against the risk of not using epinephrine as the first-line drug in anaphylaxis. The severity and rate of progression of a reaction helps delineate this conundrum.

One path to successful treatment of the pregnant patient with anaphylaxis may be to use a lower dose of epinephrine as a bridge to the use of ephedrine by administering epinephrine 1:1,000 0.15–0.2 mg IM while staff is readying IV ephedrine. One could administer a second dose of epinephrine 1:1,000 0.2–0.5 mg IM as needed, while steadily considering the degree of hypotension, the lower efficacy of ephedrine, the timing of ephedrine availability, and the point at which ephedrine rather than epinephrine might be administered, if at all. If the reaction is more prolonged but is controllable with ephedrine, then IV ephedrine could be titrated as required while antivenom is slowly administered. This method provides timely initial treatment of anaphylaxis (within 5 to 10 minutes of onset) that is important to maternal and fetal survival and may lessen the overall threat to the fetus [54].

Patients who are on beta-blockers are particularly susceptible to extreme blood pressure responses, as the alpha-receptor remains the only site available for epinephrine binding[36]. This class of drugs may cause patients to be resistant to treatment with epinephrine, and they can develop refractory hypotension and bradycardia. Glucagon should be administered in this setting, because it has inotropic and chronotropic effects that are not mediated throughβ-receptors[56].

Re-starting antivenom should wait until after the reaction has subsided. In acutely sensitive patients, it may be necessary to reduce the concentration of the antivenom to half that of the original solution. Re-treatment should be started at the initial test rate of 30 cc/hour. If there are no signs of another untoward reaction after 10 minutes, the rate of administration should be increased at a slower pace than before to no faster than the original rate less about 25%. Frequently repeated doses of diphenhydramine may be needed. In rare cases, a titration of epinephrine may be required.

The value of the rate of administration of the antivenom cannot be overstated. According to the Arizona Poison and Drug Information Center, slowing the rate of administration (without any further dilution of the original solution) will solve the problem in some cases [3]. Malone adds [54]:

At the slower rate, perhaps in combination with the single dose of diphenhydramine and cimetidine, many patients do well and need no further treatment as antivenom is continued [3].

Boyer et al. recommend that patients who have received antivenom should be re-evaluated at least once within five days after treatment [5]. If the results of laboratory testing remain normal, recurrence is unlikely. However, patients at risk for recurrence (i.e., with abnormal coagulation during the first 36 hours) should be reassessed every 48 hours after the last antivenom dose, until coagulation values are clearly stable or improving for several days [5].

If coagulation values become significantly abnormal on follow-up, or if there is a definite downward trend, then laboratory test results should be monitored daily and consideration should be given to re-treatment with antivenom. Until more data are available, re-treatment with FabAV should be considered in patients with any of the following [5]:

Frank bleeding should be treated with additional antivenom, regardless of whether the laboratory criteria have been exceeded. Antivenom therapy is recommended when asymptomatic patients develop multicomponent coagulopathy that reaches critical values (e.g., INR greater than 3.0, a PTT greater than 50 seconds, fibrinogen concentration less than 75 mg/dL, platelet count less than 50,000/mcL) [20].

Besides the often-overlooked consideration of the need to re-evaluate clotting ability following discharge from the ICU, until recently there were no specific techniques recommended by which to measure actual or patient-perceived improvement following snakebite treatment. In 2015, Lavonas and Gerardo published a study examining methods for measuring outcome following envenomation by a copperhead [95]. They suggest three techniques for re-evaluating discharged patients who were envenomed by any type of pit viper: grip strength, ability to walk 25 feet (7.62 meters) unassisted, and global function. In this study, global function was assessed with the Patient-Specific Functional Scale. On the initial assessment, the patient is asked to identify up to three important activities that he/she is unable to do or is having difficulty with as a result of the snakebite. The patient then provides a rating for each item, on an 11-point ordinal scale ranging from 0 ("unable to perform activity") to 10 ("able to perform activity at the same level as before the injury or problem"). During reassessments, the subject is prompted to re-rate the same three activities [95].