Case Report

Shock, respiratory failure, and coagulopathy after an intravenous copperhead envenomation

Abstract

We report the first documented case of rapid onset shock, respiratory failure, and coagulopathy after an intravenous copperhead envenomation. The 47-year-old victim, bitten over his left greater saphenous vein, responded to Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV, Savage Laboratories, Melville, NY) fragment therapy and recovered completely, leaving the hospital 3 days later.

The copperhead or Agkistrodon contortrix is a common Venomous snake in North America and accounts for the largest number of envenomations in central Texas. The venom does not normally induce many systemic effects, and symptoms are generally limited to local tissue swelling and ecchymosis. Some authors have argued against administe- ring antivenom for its relatively benign course [1-6] and even those authors who support use of antivenom justify their approach based on reversing local effects [7-10].

The patient was walking outside his house with a gun to check on barking dogs. He stepped on a snake, which struck him on his left lower leg. He shot and killed it and then fell backward striking his head on the ground. His son called emergency medical services, which found him unresponsive, vomiting, and hypotensive with agonal respirations. He was intubated, a 2-L bolus of normal saline was started, and he was taken by helicopter to the University Medical Center at Brackenridge (Austin, Tex) emergency department.

On arrival, which was approximately 30 minutes after the 911 call, the patient continued in severe distress with unstable vital signs as follows: blood pressure of 68/40 mm Hg; heart rate of 83/min; assisted respirations; O₂ saturation of 97%; and temperature of 98.6?F. On examination, he had left parietal scalp swelling with no active bleeding. heart sounds were normal to auscultation without murmur or gallop. Lungs were clear to auscultation. A Foley catheter was inserted producing an output of 30 mL of clear yellow urine. Examination of the extremities showed some linear abrasions on the left upper arm; a 2 x 2 cm area of erythema and abrasion on the left inner knee region; a 5 x 6 cm area of

contusion on the anterior left lower leg; and Hemorrhagic bullae and contusion on the left medial malleolar area.

Electrocardiogram showed ST depression in leads V₄ to V₆ and T-wave inversion in leads I and aVL (see Fig. 1). Head and neck computed tomographic scan was normal except for mild soft tissue swelling overlying the left parietal bone. Initial chest x-ray showed endotracheal tube in good position and no infiltrates. Initial and follow-up blood work is shown in Table 1.

The patient received 6 vials of CroFab and 8 U of fresh frozen plasma in the emergency department. He received an additional 12 vials of CroFab after he was transferred to the intensive care unit. The coagulation tests returned to normal range within 18 hours (see Table 1). He was extubated the next day and transferred to the floor. On the third day, the EKG normalized (see Fig. 2), and an echocardiogram showed left ventricular ejection fraction of 60%, mild mitral insufficiency, trace tricuspid insufficiency, and no Wall motion abnormality. The patient was feeling better, and with continued wound care, his Left lower extremity edema and swelling decreased. The patient was discharged on the fourth day. He was still feeling some pain in his left lower extremity, although it was healing well.

According to the American Association of Poison control centers, 2939 crotaline Snake bites were reported in 2006, with 1065 (36%) being identified as copperhead snakes [11]. Many cases of snake bites are unreported, and the estimated true number of bites in the United States may exceed 8000 annually [11]. Copperheads are easily identifiable by their triangular orange to rust-colored heads, and this patient was familiar with the species and had no doubt about its identification. Later, the patient also produced a photograph of the carcass, which was reviewed by an emergency physician who identified the snake as a copperhead. Copperhead venom rarely causes systemic effects, and its local effects are general less severe than other crotalines.

This has led several authors to argue against the use of antivenom for copperhead bites [1-6], though these opinions were published before the use of CroFab that appears to cause fewer Allergic reactions (though the danger still exists [12]) than the older Wyeth (Madison, NJ) (horse- serum based) antivenom. Although death has been reported

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from copperhead envenomation [13], severe symptoms are extremely rare. The largest case series examining the use of CroFab in 32 copperhead envenomation victims found no instance of hypotension or respiratory failure and rare (3 patients), mild protime elevation (maximum International Normalized Ratio, 1.5) [9]. Other antivenom proponents also focus on the local effects [8,10].

It is likely, based on the bite to the medial ankle near the greater saphenous vein, that this patient became extremely ill because of a direct intravenous envenomation. Anaphylaxis or anaphylactoid reaction is a possible, though less likely, alternative explanation, especially given the patient had no rash or clinically evident bronchospasm, and he improved without treatment for that condition, such as epinephrine.

The patient had EKG changes and positive cardiac markers indicating myocardial insult. Crotaline venom has the capacity to impair heart function using several different mechanisms, including direct cardiotoxicity, venom-induced Coronary vasospasm or thrombosis, and myocardial hemor- rhage. This tissue injury and hemodynamic instability, and subsequent deterioration of cardiac performance, may be attributed partially to tumor necrosis factor, which is converted to the active form by venom metalloproteinases. After envenomation in rat models, there is a systemic

increase in serum levels of tumor necrosis factor, accom- panied by a substantial drop in blood pressure [14].

This patient had the typical local venom effects but also surprisingly severe systemic effects. Crotaline venom contains a complex mixture of enzymes, amino acids, lipids, and metals such as zinc, copper, and magnesium [15,16]. The exact composition varies depending on several factors such as species, age of snake, diet, season, and geographic location [14,15,17-20]. The enzymes possess mainly cyto- toxic, hemorrhagic, and neurotoxic properties. The proteo- lytic enzymes, collagenase and hyaluronidase, produce the marked swelling and local tissue destruction at the site of envenomation [15]. Lysis of red blood cells, platelets, and mitochondria may be the direct result of phospholipase activation in the presence of lecithin and divalent metal ions [15], though thrombocytopenia is much less common in copperhead, vs rattlesnake, envenomation, as illustrated in this case. Several different types of hemorrhagins have also been identified. Direct lytic factor, phospholipases, and proteases may act synergistically with the hemorrhagins, resulting in extravasation of blood, ecchymosis at the bite site, and possibly systemic hemorrhage [14].

Crotaline venom exerts “thrombinlike” effects on fibrinogen molecules. Normally, thrombin forms fibrin by

Fig. 1 Electrocardiogram at presentation.

	range		2	7	18	35	56
pH Art	7.35-7.45	7.226	7.297	-	-	-	-
pCO2, mm Hg	35-45	51.1	48.7	-	-	-	-
pO2, mm Hg	80-100	425.6	280.3	-	-	-	-
HCO3 Art	23-27	20.7	23.3	-	-	-	-
WBC, thousand/mm3	4.5-11	22.4	-	17.8	10.5	10.1	7.4
RBC, million/mm3	4.6-6.2	5.52	-	4.17	3.83	3.88	4.24
Hgb level, g/dL	14.0-18.0	17.8	-	13.0	11.9	12.1	13.0
Hct, %	40.0-54.0	48.7	-	35.7	33.4	33.9	36.7
Platelets, thousand/mm3	150-450	301	-	236	235	242	226
INR	-	4.23	2.62	1.53	1.11	1.03	0.93
PT, s	11.8-14.3	29.6	22.4	16.4	13.6	13	12.3
PTT, s	22.9-36.5	80.6	54.8	37.6	30.6	29.3	28.2
Fibrinogen, mg/dL	209-440	34	-	154	303	-	-
Na, mmol/L	136-145	142	141	142	142	140	137
K a, mmol/L	3.6-5.0	3.4	4	3.5	3.4	4	3.3
Cl, mmol/L	101-111	113	110	113	109	110	107
BUN, mg/dL	6-20	17	18	19	13	8	10
Creatinine, mg/dL	0.5-1.2	1.1	1.1	0.8	0.3	0.8	0.9
Glucose, mg/dL	70-100	131	225	120	98	100	110
Calcium, mg/dL	8.5-10.5	7.3	7.7	7.2	7.3	7.8	8.4
Albumin level, g/dL	3.2-5.5	-	-	3.0	3.0	3.0	-
Total protein, g/dL	6.7-8.2	-	-	5.1	5.1	5.3	-
Alk phos, IU/L	42-121	-	-	50	54	47	-
AST, IU/L	10-42	-	-	49	46	33	-
ALT, IU/L	10-60	-	-	33	31	27	-
Bili total, mg/dL	0.2-12	-	-	2.2	1.7	2.2	-
Magnesium, mg/dL	1.7-2.8	-	-	1.6	-	-	-
Total CK, IU/L	38-174	1020	-	992	1177	856	-
CK-MB, ng/mL	0.6-6.3	13.3	-	11.9	8.1	-	-
Troponin I, ng/mL	b0.04	1.04	-	2.10	0.60	0.19	-

removal of the low-molecular-weight peptides, fibrinopep- tide A and fibrinopeptide B, from each molecule of fibrinogen. Thrombin then stimulates fibrin-stabilizing factor, adding strength to the fibrin meshwork forming a clot. Crotaline venom catalyzes the hydrolysis of an arginine sequence of the ? chain of fibrinogen, thereby splitting off fibrinopeptide A but not fibrinopeptide B [21,22]. The resulting monomers aggregate normally, but form unstable, end-to-end linking instead of normal cross- linking fibrin polymers. These fibrin polymers are suscep- tible to normal fibrinolysis and phagocytosis by the reticuloendothelial system, and their presence is represented clinically by falling Fibrinogen levels and elevated fibrin- fibrinogen degradation products. It has been shown that the rapid infusion of crotaline venom, as seen after a direct intravenous envenomation, mimics true thrombin activity leading to widespread intravascular coagulation [23,24]. However, true disseminated intravascular coagulation is rarely seen after crotaline envenomation, probably owing

Table 1 Changes in Laboratory test results after snakebite

Parameters Reference Arrival

Hours after arrival

WBC indicates white blood cell; RBC, red blood cell; Hgb, hemoglobin; Hct, hematocrit; BUN, blood urea nitrogen; Alk phos, alkaline phosphatase; AST, aspartate transaminase; ALT, alanine transaminase; Bili, bilirubin; CK-creatine kinase; CK-MB, creatine kinase myocardial band; PT, prothrombin time; PTT, partial thromboplastin time; Art, arterial, INR, international normalized ratio.

^a Final K level before discharge was 3.7 mmol/dL.

to the low incidence of direct intravenous envenomations. Disseminated intravascular coagulation is characterized by a platelet count of less than 100 000/mm³ at presentation, or a rapid decline in the platelet count, prolongation of prothrombin time and partial thromboplastin time times, presence of Fibrin degradation products in the plasma, and low plasma levels of coagulation inhibitors, such as antithrombin III [25]. This patient maintained normal Platelet levels and therefore did not exhibit true DIC, though he did have a severe coagulopathy with an initial international normalized ratio above 4.

Previous reports show severe envenomation and DIC only in cases with rattlesnake bites, and there are no reports of DIC after a copperhead bite. There is a documented case of DIC after envenomation by a pit viper from the same genus, Agkistrodon blomhoffu, in which the patient developed ischemic colitis with stricture and acute renal failure [26]. Although the incidence of bites from copper- heads is high, their venom has weak effects on the

Fig. 2 Electrocardiogram on third hospital day.

coagulation cascade, resulting in lower morbidity after envenomation [27].

This is the only reported case of shock, respiratory failure, and coagulopathy after copperhead envenomation. Although a rare presentation, it appears to argue against the characterization that copperhead envenomation is a largely local and benign process, particularly when the bite is on or near a vein.

The copperhead snake, or Agkistrodon contortrix, is a common species to central Texas and is responsible for a large percentage of bites in this area. Its venom is relatively benign and does not normally produce a gross systemic response, though this patient had severe, life-threatening sequela, probably from direct intravenous infusion via his left greater saphenous vein. He responded to CroFab antivenom and recovered completely.

Omid Zad MD

University Medical Center at Brackenridge

Austin, TX 78731, USA

Hassie Cooper BA

University Medical Center at Brackenridge

Austin, TX 78731, USA

Patrick Crocker DO

Dell Children’s Medical Center of Central Texas

Austin, TX 78731, USA

Truman Milling MD

University Medical Center at Brackenridge

Austin, TX 78731, USA

E-mail address: [email protected] doi:10.1016/j.ajem.2008.08.013

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