Current Management of Copperhead Snakebites in Missouri

Abstract

The past two decades have seen changes to the management of copperhead snakebites. We review the current use of antivenom, analgesics, and laboratory testing as well as the declining role of surgical management.

Introduction

Snakebites are common in Missouri.^1,2 The Missouri Poison Center reported an average of 190 snakebites per 100,000 residents between 2001–2005.¹ Of the total 952 snakebites reported in Missouri in this period, 50% were copperhead bites. An additional 40% were unknown venomous snakes, which were also likely copperheads, given their extremely high prevalence in Missouri. This is consistent with national data suggesting that copperheads are responsible for approximately half of reported snakebites.³

The optimal management of copperhead snakebite is far from settled. There are several areas of active controversy, including indications for the use of antivenom, need for laboratory assessment of coagulopathy, expected degree of coagulopathy, and appropriate analgesic therapy. In this piece, we will review historical developments in copperhead bite management since the publication of Missouri Medicine’s last review on this topic and then move to a discussion of current trends in management

Historical Developments

Much has changed in the two decades since Missouri Medicine published a review of copperhead snakebites. In 1976, Krochmal and Anderson reviewed the management of copperhead snakebites.⁴ In 1998, Anderson updated this review.⁵ At the time of both prior reviews, the only available FDA-approved antivenom for pit vipers was an equine-derived, whole IgG antibody product, Antivenin (Crotalidae) Polyvalent® (Wyeth Pharmaceuticals) with a high risk of serum sickness and anaphylactoid reactions.⁶ Both reviews recommended against using antivenom and reflected the prevailing opinion of the time that the risks of the Wyeth antivenom outweighed the benefits for copperhead snakebite victims.^4–6

Since the 1998 review, there have been several exciting advancements in the management of copperhead envenomation. The most important has undoubtedly been the development and FDA approval of ovine Fab antivenom (FabAV® BTG International, Conshohocken, PA; hereafter FabAV) in 2000. FabAV is an ovine-derived, affinity purified, polyvalent Fab fragment that is derived from the serum of animals injected with venom from eastern diamondback, western diamondback, Mojave rattlesnake, and cottonmouth species.⁷ During FabAV production, the enzyme papain removes the highly immunogenic Fc domain from the collected antibodies, which makes FabAV less likely than equine derived Wyeth antivenom to cause anaphylactoid reactions and serum sickness.⁸ The Wyeth AV is no longer available as production ended in 2001, and all stocks available in the U.S. expired over a decade ago.

A prospective, multi-center trial by Dart and colleagues demonstrated that FabAV effectively terminated venom effects in patients with mild or moderate rattlesnake envenomations.⁹ This trial excluded patients bitten by copperheads and most patients were enrolled in the Southwest, where copperhead snakes are not native.

Fab Antivenom for Copperheads?

The use of FabAV in copperhead bites remains controversial. Historically, many authors advocated avoidance of antivenin in copperhead bites, which are frequently considered mild and unlikely to cause significant morbidity.¹⁰ Lavonas and colleagues noted beneficial effects of FabAV use in copperhead snake envenomations in a case series.¹¹ However, as Caravati noted in his editorial on the cases series, only a properly controlled prospective trial could produce high-quality evidence of benefit of FabAV in copperhead envenomations.¹²

Gale et al. retrospectively reviewed charts of copperhead snakebite patients in East Texas from 2002 to 2013.¹³ Only 13.8% of their patients received FabAV, but those treated with FabAV had more swelling, more pain, and higher snakebite severity scores. Compared to patients who did not receive antivenom, the FabAV treated patients were twice as likely to be transferred from outlying hospitals, four times as likely to be admitted to the hospital, and twice as likely to have an upper extremity bite.

In an uncontrolled, prospective, open-label pilot study, Lavonas et al. saw similar outcomes between patients receiving FabAV and those not receiving it. However, the patients who received FabAV had more severe envenomations than the patients who did not receive FabAV. These studies likely reflected the preference in the early 2000s to reserve FabAV for more severe cases, and highlighted practice pattern variations in copperhead bite management. The goals of this study were to determine the typical duration of recovery following a copperhead snakebite and to test the outcome assessment procedures for the next study.¹⁴

Gerardo and colleagues recently conducted a multicenter, randomized double-blind placebo controlled trial to evaluate the efficacy of FabAV for the treatment of copperhead bites.¹⁵ They enrolled patients from August 2013 through November 2015. Seventy-four patients received a study drug; forty-five received FabAV, and twenty-fine received placebo. The primary outcome studied was function of the affected limb at 14 days post-envenomation, as measured by a validated functional scale.^16–18 Patients receiving FabAV had superior 14-day limb function scores than patients receiving placebo (8.6 versus 7.4, difference 1.2, 95% CI 0.1–2.3, p=0.04),¹⁷ and also required significantly less opioid pain medication.¹⁹

In a secondary analysis of data from this trial,²⁰ the authors also found that patients who received antivenom early (less than 5.5 hours after envenomation) experienced faster return to baseline limb function than those who received antivenom late. This effect was substantial—median time to full recovery in the “early” group was 17 days, while median time to full recovery in the “late” group was 28 days (p=0.025). In an earlier retrospective review,²¹ the same group established that early administration of antivenom did not significantly increase the total amount of antivenom required in a copperhead-predominant snakebite population. They also noted that 80% of “minimal” envenomations progressed to moderate grade envenomations. Taken together, these results suggest that it would be prudent to administer antivenin as soon as possible, instead of observing patients for progression of symptoms prior to administering antivenom. This may benefit patients by promoting faster recovery without substantially increasing the amount of antivenom they receive.

Many physicians are concerned that aggressive use of FabAV in copperhead envenomations may unnecessarily expose patients to the risk of adverse effects of FabAV.^5,13 Fortunately, available data suggest that this risk is relatively low. Schaeffer et al. performed a meta-analysis of safety data from multiple trials of FabAV in rattlesnakes.²² They conservatively attributed all adverse events to the antivenom and none to the envenomation itself. They estimated that allergic reactions and delayed serum sickness might occur in up to 13% and 8%, respectively, of patients receiving Fab AV. All patients in their analysis received FabAV with no placebo group for comparison, and all patients had rattlesnake bites in the southwestern U.S.

The randomized, placebo-controlled trial of FabAV in copperhead snakebites provided the opportunity to study the events attributable to the antivenom.¹⁵ The secondary safety analysis found that 16 patients treated with FabAV developed at least one treatment-emergent adverse effect related to study treatment, as compared to three patients treated with placebo.²³ There were no deaths, and few serious or severe adverse effects occurred in either the treatment or placebo groups. Most adverse effects were mild skin reactions such as pruritus or urticaria. There were no cases of serum sickness. These findings are consistent with three other independent studies showing low incidence of adverse events following Fab AV use.^24–26

A newer F(ab′)₂ antivenom (Anavip ® Rare Disease Therapeutics, Nashville, TN) recently received FDA approval in 2015. Originally developed in Mexico by Instituto Bioclon, it includes two monospecific antibody strains for pit vipers native to South America, Central America, and Mexico, Crotalus durissus and Bothrops asper.²⁷ A prospective, multicenter trial in the US demonstrated effectiveness of F(ab′)₂ AV for some North American pit vipers; notably, F(ab′)₂ is not currently FDA approved for copperhead envenomations.²⁸ Among rattlesnake envenomations, which often produce coagulopathy and thrombocytopenia, F(ab′)₂ compared favorably with Fab AV with better control of coagulopathy in the F(ab′)₂ AV group. Aside from this, the two antivenoms appear to have similar effectiveness.

Among the 114 patients studied by Bush et al., only 21 had copperhead snakebites evenly distributed among the three treatment groups.²⁸ There was no subset analysis of these patients. Although these preliminary data suggest that F(ab′)₂ is as safe and effective as Fab AV, we await further clinical experience with F(ab′)₂ AV in copperhead envenomations.

One may wonder whether the F(ab′)₂ antivenom raised against two Central and South American vipers will cross react with copperheads. However, the obsolete equine-derived Wyeth antivenom also included antibodies to four pit vipers representing North and South America (three Crotalus species and one Bothrops species). A murine study of the Wyeth antivenom for experimental copperhead envenomations.²⁹ Mice received an LD90 dose of copperhead venom following pretreatment with either Wyeth polyvalent AV or normal saline. All control animals died, but 14 of 15 AV-treated animals survived to 24 hours. Based upon this study, the published experience with Fab AV, and the preliminary experience with F(ab′)₂ AV, is reasonable to conclude that F(ab′)₂ AV will be as effective as Fab AV for copperhead envenomations in clinical practice. Both Fab AV and F(ab′)₂ AV are similarly expensive, but perhaps some competition in price will make one or both treatments less expensive and more accessible.

The Bleeding Edge?

Laboratory evaluation of patients with North American pit viper bites includes coagulation testing, regardless of geographic location or snake species. These typically include complete blood count (CBC), prothrombin time/international normalized ratio (PT/INR), partial thromboplastin time (PTT), and fibrinogen. Several sources recommend these routine tests initially and repeated 6 to 12 hours later for all snake bites within the United States.^30–34 Coagulopathy and thrombocytopenia indicate the need for antivenom therapy in any snake envenomation, particularly in rattlesnake bites.

Copperhead snakebites differ from rattlesnake bites and generally do not cause coagulopathy or thrombocytopenia. Ali et al. performed retrospective chart review of identified copperhead snakebite cases in Missouri over 14 years and evaluated most extreme values of coagulation studies including INR, PT, PTT, INR, and fibrinogen.³⁵ They concluded that these laboratory values consistently remained within normal limits with rare, small, and clinically insignificant excursions just beyond the normal ranges. No patients developed bleeding complications. Other reports corroborate this observation.^5,32,36–41

We advise that copperhead envenomations likely do not require repeated testing if the initial laboratory results are normal and if there is no clinically apparent bleeding.

Snakebites Are Such a Pain

Previous guidelines for the management of pit viper envenomations recommend against using nonsteroidal anti-inflammatory drugs (NSAIDs) to treat pain and inflammation due to concern for platelet dysfunction.^33,34 These arise from expert opinion and are based on the frequency of coagulopathy and thrombocytopenia commonly seen in rattlesnake bite victims but seldom in copperhead snakebites.

We regard NSAIDs as acceptable and safe pain management treatment for copperhead snakebite patients. Copperhead venom is less hemotoxic than rattlesnake venom. In our experience, copperhead snakebites rarely cause clinical bleeding or coagulopathy. Although it may seem intuitive to avoid NSAIDs that might interfere with coagulation, there is little evidence to support this practice. Epidemiologic data on snake bites demonstrate lower rates of thrombocytopenia, hyperfibrinogenemia and coagulopathy in copperhead snake bite patients compared to rattlesnake bite patients.⁴⁰ Pham et al. reviewed 147 Missouri copperhead bites treated at Barnes-Jewish Hospital and St. Louis Children’s Hospital. Slightly more than half of these patients received NSAIDs in their acute treatment (usually ketorolac and/or ibuprofen).⁴² There were no significant differences in laboratory studies between patients who received NSAIDs and those who did not. Two patients had self-limited epistaxis before receiving NSAIDs, and one had microhematuria. All three had no bleeding observed after receiving NSAIDs.⁴²

Lavonas and Gerardo jointly endorsed the findings by Pham and Mullins with the caveat that the data only pertain to copperhead snakebites.⁴³ They also pointed out that NSAID use was common in both the RCT of Fab AV for copperhead bites¹⁵ and among copperhead bites in the comparative trial of F(ab′)₂ AV and Fab AV²⁸ without adverse effects.

Do Copperhead Bites Need Surgery?

Snakebite often perceived as a surgical emergency, however data do not support this belief. Toschlog et al. pointed out that although North American crotalid snakebite may produce signs and symptoms that mimic compartment syndrome, it rarely produces true compartment syndrome.⁴⁴ A systematic review of copperhead snakebites indicated that fasciotomy and routine surgical consultation are usually unnecessary.⁴⁵ Mazer-Amirhshani successfully treated elevated compartment pressures in a 17-month-old child with antivenom therapy without fasciotomy and had no neurovascular compromise.⁴⁶ A retrospective review of adult and pediatric patients in the Journal of Surgical Orthopaedic Advances noted that supportive care and antivenom alone were sufficient in the management of snakebites.⁴⁷ Current surgical and toxicology literature indicated antivenom is more useful than surgery.^{30,37,38,44,46–48} In some facilities, the physician with most experience treating snakebites may be a surgeon; we encourage clinicians to consult early with available local experts in addition to discussing cases by phone with a poison center and/or medical toxicologist.

Conclusion

Copperhead snakebites are the most common envenomation in Missouri. Fab antivenom is safe and effective. Although F(ab′)₂ is not FDA approved for copperhead envenomation, evidence suggests that it is likely safe and effective also. Coagulopathy is rare with copperhead snakebites, and repeat laboratory testing is unnecessary if initial results are normal. NSAIDS are acceptable and safe analgesics when the clinician is confident that the culprit snake is a copperhead and not a rattlesnake. Surgical intervention is seldom necessary.

Figure 1.

When a Copperhead Comes Calling

Pre-Hospital

• Prioritize scene safety
• Obtain pictures of the culprit snake if possible
• Remove tight clothing or jewelry proximal to the bite
• Do not apply a tourniquet or ice
• Do not use a suction device

Emergency Department

• Obtain intravenous access
• Obtain plain radiographs of the affected part to rule out underlying fracture or retained radiopaque foreign body
• Consider drawing basic laboratory tests: complete blood count, coagulation studies, and fibrinogen.
• Control pain with non-steroidal anti-inflammatory drugs, with the addition of opioids if required
• Obtain expert consultation (with a medical toxicologist or local poison control center) to discuss administration of FabAV and potential transfer to a tertiary care center