Crotaline Fab Antivenom for Treatment of Children With Rattlesnake Envenomation
Martin O. Behm, MDGregory L. Kearns, PharmD, PhD
Division of Pediatric Clinical Pharmacology and Medical Toxicology
Department of Pediatrics
Children’s Mercy Hospitals and Clinics
Kansas City, MO 64108, USA
To the Editor.—
Offerman et al1 have recently demonstrated the efficacy and safety of Crotaline polyvalent immune Fab (ovine) antivenom (CroFab, Protherics Inc, Nashville, TN) over the previously used horse-derived antivenoms in pediatric patients. The 12 children (14 months–13 years of age) reported by these investigators received doses of CroFab approximately equal to those recommended for adults.2 Although the authors admittedly caution against weight-based dosing of Fab antivenom (FabAV) in pediatric patients, they do not delineate the rationale for their recommendation. Hence, more discussion and clarification is required to more fully inform pediatricians about this important antidote.
Although Crotalinae envenomation in infants and children does results in a higher "mg/kg" venom dose as compared with adults, the molar "dose" of venom delivered by the snake is independent of the size of the victim. Rather, it primarily depends on snake-specific factors (eg, size of the snake, the temporal proximity of the last envenomation, depth of fang penetration, and duration of envenomation).3
In determining the FabAV dose, the snake venom proteins, FabAV and the venom-antivenom (V-A) complex, should be considered as distinct "compounds," each with unique and measurable pharmacokinetic properties.4 This relationship is illustrated by Fig 1. Venom- and patient-specific physiochemical factors such as the heterogeneous nature of venom proteins (eg, 6–100 kDa),5 the volume of venom injected and the area of envenomation result in erratic and potentially protracted diffusion from the interstitial to the vascular space. The local inflammatory reaction (eg, inflammation, edema, and disruption of vascular integrity) produced by venom constituents may also contribute to variable rates of venom absorption. Collectively, these factors would appear to determine both the time course of toxicity after envenomation and, as suggested by Gold et al,2 the duration of FabAV treatment.
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As the mechanism for FabAV to neutralize the venom is one based primarily on principles of stoichiometry, the effective dose for an adult or child is directly determined by the molar dose of venom protein, not the "mg/kg" dose. Accordingly, uniform recommendations for FabAV dose not based on age1,2 appear both prudent and appropriate. As well, similarity in the half-life of the V-A complex between children and adults provides additional support for the same dosing frequency and duration of FabAV therapy.2
Given the relatively high cost and potential limited institutional availability of FabAV, our concern is that practitioners may be tempted to "scale" the recommended adult FabAV dose down for pediatric patients using an allometric approach based on body weight or surface area. Such an approach to FabAV dosing has the potential to severely compromise the efficacy of this antidote. The importance of proper FabAV dosing in pediatric patients cannot be understated, given that previous reports of recurrent/latent symptoms after treatment6,7 were likely associated with the administration of subantidotal doses2 with regard to either amount and/or duration of treatment. These adverse effects have been prevented by the use of a recently published FabAV treatment algorithm,2 which in our view should be adopted for pediatric patients until data supporting a superior (ie, safer and/or more efficacious) approach are available.
REFERENCES
- Offerman SR, Bush SP, Moynihan JA, Clark RF. Crotaline Fab antivenom for the treatment of children with rattlesnake envenomation.
Pediatrics.2002; 110
:968
–971
[Abstract/Free Full Text] - Gold B, Dart R, Barish R. Current concepts: bites of venomous snakes.
N Engl J Med.2002; 347
:347
–356
[Free Full Text] - Moss S, Bogdan G, Dart R, Nordt S, Williams S, Clark R. Association of rattlesnake bite location with severity of clinical manifestations. Ann Emerg Med.1997; 30 :1997
- Hawgood B. Physiological and pharmacological effects of rattlesnake venoms. In: Tu A, ed. Rattlesnake Venoms. New York, NY: Marcel Dekker; 1982:121–153
- Stocker K. Composition of snake venoms. In: Stocker K, ed. Medical Use of Snake Venom Proteins. Boca Raton, FL: CRC Press; 1990:33–56
- Dart R, Seifert S, Carroll L, et al. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. Ann Emerg Med.1997; 30 :33 –39[CrossRef][Web of Science][Medline]
- Dart R, Seifert S, Boyer L, et al. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States.
Arch Intern Med.2001; 161
:2030
–2036
[Abstract/Free Full Text]
Steve Offerman, MD
Sean P. Bush, MD
Richard F. Clark, MD
Division of Medical Toxicology
Department of Emergency Medicine
University of California, San Diego Medical Center
San Diego, CA 92103-8676, USA
In Reply.—
We appreciate Drs Behm and Kearns’ extensive discussion of venom and crotaline Fab pharmacokinetics. A thorough understanding of these principles does shed light on the rationale for current pediatric dosing recommendations. We agree that antivenom dosing should be based on the potential venom load and not on patient size. Although we are not aware of practitioners modifying the recommended adult Fab antivenom (FabAV) dose for children, we agree that attempts to scale down antivenom doses based on patient weight may result in underneutralization of toxic venom components and less than optimal outcomes. We also point out that venom load is extremely variable, and the exact amount of venom delivered after any given snakebite is not known.
The treatment algorithm and dosing recommendations outlined in the article by Gold et al1 are based on the initial adult human trials using crotaline FabAV.2,3 Although we agree that, based on the currently available information, this algorithm appears to be safe and effective, we remind readers that this approach has not yet been extensively studied, and no controlled pediatric trials have been performed. Debate regarding the optimal antivenom dosing regimen exists. Although scheduled dosing may reduce local recurrence, it does not seem to completely prevent it.4,5 Future research is necessary and may yield substantial modifications to the current recommendations.
REFERENCES
- Gold BS, Dart RC, Barish RA. Current concepts: bites of venomous snakes. N Engl J Med.2002; 347 :347 –356
- Dart RC, Seifert SA, Carroll L, et al. Affinity purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid venom poisoning. Ann Emerg Med.1997; 30 :33 –39
- Dart RC, Seifert SA, Boyer LV, et al. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med.2001; 161 :2030 –2036
- Bush SP, Green SM, Moynihan JA, et al. Crotalidae polyvalent immune Fab (ovine) antivenom is efficacious for envenomations by Southern Pacific rattlesnakes (Crotalus helleri). Ann Emerg Med.2002; 40 :610 –624
- Ruha AM, Beuhler M, Brooks D, et al. Crofab for the treatment of rattlesnake envenomation. J Toxicol Clin Toxicol.2001; 39 :546
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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