Abstract
Introduction
Compartment syndrome (CS) is a rare but serious complication after crotalid envenomation in the United States. Few data are available regarding the epidemiology and management of these cases. Significant controversy and misunderstanding over best practices, including measurement of compartment pressures and use of fasciotomy, exist for this syndrome. This study aims to describe presentation and management of suspected CS cases after native snakebite reported to the North American Snakebite Registry (NASBR).
Methods
This is an analysis of snakebite cases reported to the Toxicology Investigators Consortium NASBR between January 1, 2013 and December 31, 2021. Cases of native snakebite with documented concern for CS were included.
Results
Over an 8-y period, 22 cases of suspected CS were identified, representing 1% of all cases reported to the NASBR. Fasciotomies were performed in 41% (n=9) of these cases, most commonly to the upper extremity (67%, n=6). In cases of suspected CS, intracompartmental pressures (ICPs) were rarely measured (23%, n=5) and fasciotomies were performed without measurement of ICPs frequently (56%, n=5). In 1 case, ICPs were measured and found to be low (8 mm Hg) and fasciotomy was avoided.
Conclusions
Measurement of compartment pressures in cases of suspected CS was uncommon in cases reported to the NASBR. Fasciotomy was commonly performed without measurement of compartment pressures.
Introduction
In the United States, the Crotalinae subfamily of the Viperidae family are responsible for most clinically significant snake envenomations 1 and include the genera Crotalus (rattlesnakes), Sistrurus (rattlesnakes), and Agkistrodon (copperheads and cottonmouths). The degree and type of toxicity can vary significantly by snake species, geographical region, season, and from year to year. Comparatively, rattlesnake envenomations are generally more severe than Agkistrodon envenomations. 1 Antivenom is the first-line treatment for crotalid-induced hematologic or tissue toxicity as well as for systemic reactions. 2 Although deaths are rare, morbidity after crotalid envenomation is common and complications can occur. 3
One such serious complication is compartment syndrome (CS). 4 Sequela of CS can range from impaired function of a digit or extremity to amputation of a limb, particularly when diagnosis is delayed. Fortunately, true CS should be rare after crotalid envenomation. Fangs do not commonly penetrate fascial compartments, and studies show increased, not impaired, distal blood flow after crotalid envenomation. 5 Despite this, typical tissue toxicity after crotalid envenomation mimics clinical features of CS. Swelling can be severe and tense. Affected limbs are often exquisitely painful to minimal physical manipulation. Pulses may not be palpable, and distal sensation can be diminished due to extreme swelling. Because of this mimicry, making the diagnosis of CS in these cases is challenging on physical examination alone. When CS is suspected after crotalid envenomation, antivenom should be given as first-line therapy and measurement of intracompartmental pressures (ICPs) should be obtained for confirmation of CS. 2 These practices, however, are not always followed, and patients may be instead taken to the operating room for unnecessary fasciotomies, greatly increasing ultimate morbidity from the envenomation.6,7
The literature on CS after US crotalid envenomation is limited. The incidence, demographics, and contributing risk factors for development of CS after crotalid envenomation are not well understood. Furthermore, although the medical toxicology community has a consensus on best practice guidelines for management of suspected CS,2,8 other specialties involved in the management of these cases have conflicting practices. 9 How often ICPs are obtained and if they are commonly elevated, and how often fasciotomy is performed and subsequent outcomes are not well described. This study aims to better characterize CS after crotalid envenomation in cases reported to the North American Snakebite Registry (NASBR).
Methods
This is an analysis of snakebite cases reported to the Toxicology Investigators Consortium (ToxIC) NASBR between January 1, 2013 and December 31, 2021. The ToxIC Core Registry was established in 2010 by the American College of Medical Toxicology as a prospective multicenter toxicosurveillance and research tool. This deidentified patient registry records consecutive cases evaluated and treated by medical toxicologists at over 50 contributing sites across the United States and internationally. The methods and scope of the ToxIC Core Registry have been previously reported. 10
ToxIC NASBR is a subregistry established in 2013 that collects more detailed information on snakebite cases reported to the Core Registry. Deidentified information collected includes patient demographics, past medical history, snake species, circumstances surrounding the envenomation event, clinical effects of envenomation, and response to treatment for patients who receive bedside or telemedicine care from medical toxicologists at participating sites. Follow-up information is collected for patients when applicable. Individual site follow-up visit number and timing variations exist based on practice patterns and resources.
In this study, inclusion criteria were cases occurring in the United States in which the envenomation was from a native snake and there was a documented concern for CS. Data reviewed include demographics, clinical envenomation features, management, and outcome. Thrombocytopenia was defined as platelet count <120 K/mm3, and hypofibrinogenemia was defined as fibrinogen level <170 mg/dL. Systemic toxicity was defined as the presence of hypotension, angioedema, vomiting, or diarrhea.
ToxIC has been reviewed by the WIRB‒Copernicus Group (WCG) institutional review board and operates pursuant to the approval of the participating site institutional review boards. All data collected by ToxIC are deidentified and compliant with the Health Insurance Portability and Accountability Act.
Results
Twenty-two cases of suspected CS after envenomation by native US snakes were identified in the NASBR between 2013 and 2021. This represents 1% of NASBR native envenomation cases (n=1604) reported over the 9-y period. Cases occurred most commonly in Arizona (41%; n=9), followed by California (14%; n=3), Texas (9%; n=2), and Missouri (9%; n=2). One case was reported in each of the following states: Connecticut, Georgia, North Carolina, Pennsylvania, Utah, and Colorado. Sixty-eight percent (n=15) were rattlesnake envenomations. Men represented 82% (n=18) of cases, and median age was 34 y (interquartile range [IQR], 16–50). Two cases reported a history of previous snakebite.
The majority (68%; n=15) of cases of suspected CS occurred after envenomation to the upper extremities, most commonly to the hand (47%; n=7). Lower-extremity bites occurred in the remaining 32% (n=7) of cases. The lower leg was the most common lower-extremity bite location (71%; n=5). All but 1 case (95%, n=21) presented with swelling beyond the local bite site. Systemic symptoms on presentation occurred in 8 patients (36%). Hemotoxicity during initial hospitalization was present in 50% (n=11) cases. See Table 1 for case envenomation details.
Baseline envenomation details of suspected cases of compartment syndrome
Percentage of lower-extremity bites.
Percentage of upper-extremity bites.
Percentage of systemic toxicity.
Hemotoxicity during initial hospitalization.
Percentage of hemotoxicity cases.
Table 2 describes management and hospital course details. Nonrecommended field treatment was reported in 2 cases. In 1 case, a tourniquet was applied, and in 1 case, an attempt was made to suck the venom out of the wound. Initial elevation of the extremity was reported in 91% of cases (n=20). Antivenom was given in all cases, most commonly Crotalidae immune polyvalent Fab (ovine) (Fab) alone (86%, n=19). Median time to healthcare was 1 h (IQR, 0.65–1), and median time to antivenom was 2 h (IQR, 1.4–4.3). Peak creatine phosphokinase (CPK) was reported in 15 cases (68%); it was elevated (CPK > 1000 units/L) in 47% of those cases (n=7).
Management and hospital course details of suspected cases of compartment syndrome
CPK: creatine phosphokinase; Fab: Crotalidae immune polyvalent Fab (ovine); Fab2: Crotalidae immune F(ab)′2 (equine); ICP: intracompartmental pressure.
ICPs were obtained in 5 cases (23%). Eighty percent (n=4) of ICPs were measured in the lower extremities. ICP values ranged from 8 to 80 mm Hg. Two cases measured ICPs in only 1 compartment, 2 cases measured ICPs in 2 compartments, and 1 case measured ICPs in 3 compartments. Eighty percent (n=4) of cases in which it was measured reported elevated ICPs (ICP > 20 mm Hg); 3 (75%) were in the lower extremities, and all 4 received fasciotomies. When ICPs were measured in more than 1 compartment, all ICPs were elevated. In 1 case of a lower leg envenomation in a 2-y-old, the single ICP reported was low (8 mm Hg) and a fasciotomy was not performed. Of the 4 cases in which ICPs were elevated, CPK was reported in 3 cases and was greater than 1000 units/L in 67% (n=2) of the cases. In the case with a low ICP of 8 mm Hg, peak CPK was reported at 5915 units/L. One case had a single ICP measurement of 71 mm Hg, and peak CPK reported was 784 unit/L.
Hospital length of stay was >72 h in most (59%; n=13) cases; median length of stay in the >72 h group was 8 d (IQR, 5–13.5). In the cases with length of stay >72 h, 69% (n=9) received fasciotomies.
Fasciotomy Cases
Fasciotomies were performed in 9 (41%) suspected CS cases (0.6% of NASBR native US envenomation cases). One fasciotomy case (11%) involved a copperhead envenomation; the remainder (89%; n=8) occurred after rattlesnake envenomation. In the copperhead case, there was a significant delay in treatment. The patient presented initially with minimal swelling of the foot and was discharged. He returned 2 d later with significant swelling and an ICP of 71 mm Hg and ultimately underwent fasciotomy after receiving 6 vials of Fab antivenom. Forty-four percent (n=4) of cases in which fasciotomies were performed presented with signs of systemic envenomation, including gastrointestinal symptoms (vomiting, n=4; diarrhea, n=2; and hypotension, n=2). Sixty-seven percent (n=6) were upper-extremity fasciotomies. Compartment pressures were measured in 44% (n=4) of fasciotomy cases. In fasciotomy cases, median time to presentation was 1 h (IQR, 0.9–2) and time to antivenom was 3 h (IQR, 1.6–4.5). Median number of vials of antivenom was 20 (IQR, 14–32). See Table 3 for details of fasciotomy cases. One fasciotomy case was treated with Crotalidae immune F(ab)′2 (equine) (Fab2) antivenom alone and 1 with both Fab and Fab2. The remainder received only Fab. In 1 case, a tourniquet was applied in the field. One case required a surgical graft for loss of tissue. Three cases required multiple surgical interventions. All cases in which fasciotomies were performed had a length of stay >72 h.
Fasciotomy case details
AV: antivenom; C: copperhead; CPK: creatine phosphokinase; Fab: Crotalidae immune polyvalent Fab (ovine); Fab2: Crotalidae immune F(ab)′2 (equine); LE: lower extremity; M: male; NR: not reported; R: rattlesnake; UE: upper extremity.
Discussion
Suspected CS after native US snake envenomation was rare in the 9-y period of data collection from the NASBR. Overall, basic demographic and envenomation details in this series were similar to those of previous publications of the larger NASBR data set, with some exceptions. 4 Though most cases of suspected CS occurred in Arizona, consistent with previous NASBR publications (41% vs 36%, respectively), 4 very few cases were reported from Texas. In this series, only 9% of suspected CS cases were from Texas, compared with 35% of total cases in prior NASBR reports. 4 Although small numbers and chance may play a role, other theoretical explanations include regional variation in snake species, venom content, differences in clinician awareness of CS in snakebite, and potential variations in details reported by sites to the NASBR.
The percentage of copperhead cases in this study of suspected CS was similar (27% vs 29%) to that reported in a larger study inclusive of all snakebite cases cared for by NASBR sites. 4 This finding was unexpected because, as a group, copperhead envenomations are considered less severe than rattlesnake envenomations, inclusive of both hematologic and tissue toxicity. 1 We did not expect copperhead envenomations to result in tissue toxicity severe enough to raise concern for CS, as most do not require treatment with antivenom. 11 Again, small numbers, differences in clinician awareness of CS, or registry reporting may explain this finding. Importantly, the single case of copperhead fasciotomy involved a missed diagnosis and a significant delay in antivenom administration.
Small numbers prevent any conclusions regarding the difference in location (upper extremity 68% vs lower extremity 32%) of cases of suspected CS in this report. Previous publications report a higher risk of necrosis, CS, and fasciotomy in the upper extremities.6,12 This increased risk may be explained by the more superficial fascial layer in upper extremities, which allows fang penetration of fascial compartments, combined with the relatively small compartments in the fingers.6,13
Although rhabdomyolysis is used as a clinical marker for CS, in this small sample, it did not appear to correlate as an indicator of CS. High ICPs were documented in cases with low CPKs, and high CPKs were documented in cases with low ICPs. Time to healthcare and antivenom did not appear to be delayed compared with the results from previous reports (2.75 h vs 3.0 h, respectively) and is unlikely to have contributed to the severity of the presentation in these cases. Most cases of suspected CS were treated with Fab antivenom, as this was the only commercially available antivenom until 2019. No conclusions on protective effects of specific antivenoms against CS can be made from this study.
Most notable from this series is the rarity in which ICPs were obtained. Only 23% of cases reported ICP measurements, and fasciotomies were performed without ICPs in over half of surgical cases. Details surrounding the decision to proceed with fasciotomy without pressure measurements were unfortunately not collected in this subregistry. Despite this, the practice of performing fasciotomies without pressure measurements should raise serious concern. Crotalid envenomations are well known to present as CS mimics. Moreover, existing data document poor outcomes after fasciotomy for rattlesnake envenomation. 7 Adding to this, improvement in perfusion pressures in animal models and resolution of ICP elevation in human cases have been demonstrated with antivenom alone.14,15 Considering these factors, fasciotomies should rarely, if ever, be performed after crotalid envenomation without documented elevation of ICPs and trial of antivenom when available. 8 Fasciotomies may indeed be necessary in the exceptional case after antivenom failure, but a true CS should be diagnosed on objective measurements. Enhanced education on snakebite presentation and management for healthcare providers may improve compliance with this standard of care.
Limitations of this study include those inherent to registry data and reporting compliance, including information bias and selection bias. Data are collected or entered by physicians caring directly for patients, and inclusion of consecutive cases is a registry requirement, both of which serve to limit these biases in the ToxIC NASBR subregistry. New fields were added to the NASBR midway through this data collection period, limiting the cases in which full data were available. Prior to 2017, rigorous criteria were not yet established for confirmation of snake species; thus, misidentification was possible prior to this time. Additionally, ToxIC data are composed of cases cared for by medical toxicologists, contributing to possible selection bias skewed toward more ill presentations. With regard to snakebite patients in ToxIC NASBR, however, medical toxicologists typically care for all snakebites and do not select for the more severe envenomations. Given their specialized understanding of snakebite pathophysiology and management, medical toxicologists are more likely to obtain ICPs and avoid fasciotomies. Thus, these data likely underrepresent the rate of fasciotomies being performed without compartment pressure measurements after crotalid envenomation in the United States, so generalizability of results may be limited.
Conclusions
Concern for CS after crotalid envenomation was uncommon in the NASBR. Fasciotomy was commonly reported as performed without measurement of compartment pressures in cases of suspected CS.
Footnotes
Acknowledgements
Previous Presentation: This work has not previously been submitted to any journal in any form. It was presented as an abstract at the North American Congress of Clinical Toxicology 2021 (virtual).
Acknowledgments
The authors thank Peter Akpunonu, Hassan Albalushi, Timothy Albertson, Kim Aldy, Adam Algren, Suad Alsulaimani, Alexandra Amaducci, Connie Aubin, Regan Baum, Kevin T. Baumgartner, Gillian Beauchamp, Michael Beuhler, Caitlin Bonney, Nick Brandehoff, Jeffrey Brent, Dazhe Cao, Joseph Carpenter, Jorge Castaneda, Rachel Castelli, Edward Cetaruk, James Chenoweth, Kiesha Cleark, Joseph Clemons, Daniel Colby, Grant Comstock, Matthew Cook, Matt Correia, Lee Crawley, Jonathan De Olano, Jason M. Devgun, Christopher Dion, William H. Dribben, Lindsey Epperson, Rita Farah, Hank Farrar, Sing-Yi Feng, Derek Fikse, Ari Filip, Erik Fisher, Jonathan Ford, Carolyn Fox, Jakub Furmaga, Deborah Garcia, Melissa Gittinger, Spencer Greene, Matthew Griswold, Stacy Hail, Thao-Phuong Christy Hallett, Ben Hatten, Rob Hendrickson, Michelle Hieger, Ruby Hoang, Zane Horowitz, Christopher Hoyte, Adrienne Hughes, Zachary Illg, Nicholas Imperato, Laura James, Lilyanne Jewett, Sasha Kaiser, Kenneth Katz, Ziad Kazzi, Emily Kiernan, Kurt Kleinschmidt, Andrew Koons, Anita Kurt, Shana Kusin, Dayne Laskey, Rebecca Latch, Brian Lewis, Erica Liebelt, David B. Liss, Chin-Yu (Jean) Lo, Kadera Lymon, Stacy Marshall, Kelsey Martin, Nikolaus Matsler, Charles McElyea, Drew Micciche, Brent Morgan, Michael E. Mullins, HoanVu Nguyen, Matt Noble, Daniel Nogee, Nancy Onisko, Jenna Otter, Kelly Owen, Angela Padilla-Jones, Lesley Pepin, Tammy Phan, Todd Phillips, Christopher Pittotti, Andrea Ramirez, Tony Rianprakaisang, Shannon Rickner-Schmidt, Daniel Rivera, Brett Roth, Pieter Scheerlinck, Joanna Schwab, Evan S. Schwarz, Steven Seifert, Michael Semple, Kerollos Shaker, Kapil Sharma, Sophia Sheikh, Susan Smolinske, Andres Guzman Sotto, Alaina Steck, Jennifer Stephani, Molly Stott, Kyle Suen, Ryan Surmaitis, Courtney Temple, John Thompson, Michelle Thompson, Stephen Thornton, Nicholas Titelbaum, Chiemela Ubani, George Wang, George Warpinski, Brandon Warrick, and Amy Young.
Author Contributions: study design (MS, GM, MR); data analysis (MS, GM, KA); manuscript editing (MS, GM, KA, BW, KEM, MC, MR); case contribution to registry (BW, KEM, MC); manuscript authorship (MS, MR). The final manuscript was approved by all authors.
Financial/Material Support: The North American Snakebite Registry is supported with a grant from BTG International; BTG was not involved in any aspect of this study.
Disclosures: None.