Bedside Whole-Blood Clotting Times: Validity after Snakebites

Bedside Whole-Blood Clotting Times: Validity after Snakebites

The Journal of Emergency Medicine, Vol. 44, No. 3, pp. 663–667, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/...

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The Journal of Emergency Medicine, Vol. 44, No. 3, pp. 663–667, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2012.07.073

Clinical Laboratory in Emergency Medicine

BEDSIDE WHOLE-BLOOD CLOTTING TIMES: VALIDITY AFTER SNAKEBITES Damien Punguyire, MBCHB,* Kenneth V. Iserson, MD, MBA, FACEP, FAAEM, FIFEM,† Uwe Stolz, PHD, MPH,† and Stephen Apanga, MBCHB, MSC*‡ *Kintampo Municipal Hospital, Kintampo, Ghana, West Africa, †Department of Emergency Medicine, The University of Arizona, Tucson, Arizona, and ‡Kintampo Health Research Centre, Kintampo, Ghana, West Africa Reprint Address: Kenneth V. Iserson, MD, MBA, FACEP, FAAEM, FIFEM, Department of Emergency Medicine, The University of Arizona, 4930 N. Calle Faja, Tucson, AZ 85724

, Keywords—snakebite; envenomation; clotting time; coagulopathy; bedside laboratory testing

, Abstract—Background: Venomous snakebites contribute to morbidity and mortality throughout the world, most commonly in resource-poor areas, with about 2.5 million humans sustaining snakebites annually. Coagulopathy is a significant cause of both morbidity and mortality in these patients. In the absence of more sophisticated hematological studies or obvious physical findings, many clinicians must rely on whole-blood clotting times to assess whether their patients are coagulopathic. Alternative (bedside) methods to assess clotting times are often officially recommended and used, but have not been validated. Objective: We assessed two bedside methods for measuring whole-blood clotting time after snakebites for their congruence with results from a hospital laboratory. Methods: Over a 5-month period, 46 sequential patients presenting with a possible snakebite had blood drawn for bedside (using syringe and ceftriaxone bottle as containers) and laboratory wholeblood clotting tests. All three tests used 5 mL whole blood and looked for any clot formation within 20 min. Results: Compared to the laboratory, the syringe method correctly classified the patients 84.7% of the time (sensitivity 88.9%; specificity 82.4%). The bottle method correctly classified the patients 86.8% of the time (sensitivity 83.3%; specificity 90.0%). Comparing the area under the Receiver Operator Characteristics curves shows that both the syringe and bottle methods do not differ in their discrimination for identifying clotting. Conclusions: Both the syringe and ceftriaxone bottle bedside clotting test methods appear to be accurate enough to help guide therapy after potential snake envenomations when formal laboratory testing is unavailable. Ó 2013 Elsevier Inc.

INTRODUCTION Venomous snakebites are a well-known occupational hazard among farmers, other outdoor workers, and those in wilderness settings, and contribute to morbidity and mortality throughout the world. Although it is thought that around 2.5 million humans sustain snakebites annually, resulting in more than 100,000 deaths, accurate statistics do not exist (1). However, from what is known, West Sub-Saharan Africa seems to have the highest global incidence, with about 93 envenomations/100,000 people/year (2). Coagulopathy is a significant cause of both morbidity and mortality in these patients (3). In many areas where venomous snakes are common, antivenin is scarce, and there are usually limited government funds to pay for this expensive medication. Therefore, it becomes vital to quickly ascertain which patients require this medication. In the absence of significant edema, pain, ecchymosis, or systemic symptoms, hematological studies are often what helps decide which patients require antivenin (1,4). In medically developed areas of the world (often including large cities in developing countries), sophisticated hematological tests are used to assess patients’

RECEIVED: 1 February 2012; FINAL SUBMISSION RECEIVED: 22 May 2012; ACCEPTED: 30 July 2012 663

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clotting status. Both in resource-poor settings and in outof-hospital environments, these common laboratory coagulation studies are generally unavailable. In the absence of more sophisticated hematological studies, many clinicians must rely on whole-blood clotting times to assess whether their patients are coagulopathic. In many cases, whether because the laboratory is closed or no laboratory is available to perform the test, alternative (bedside) methods are often officially recommended and used to assess clotting times (5). We assessed how often two bedside methods for measuring whole-blood clotting time after snakebites produced findings congruently positive (coagulopathy) or negative (normal clotting) compared with those from a hospital laboratory. MATERIALS AND METHODS Between May and October 2011, 46 sequential patients presenting to the District Hospital Emergency Department with a complaint of possible snakebite had blood drawn, per protocol, for bedside and laboratory (if available) whole-blood clotting tests. The local Institutional Review Board approved this study and gave it a waiver for needing signed consents. Laboratory method: The laboratory’s protocol for whole-blood clotting time is to put 2–5 mL whole blood in a clean (preferably new) dry test tube at room temperature. At 20 min, they tip the tube upside down once. If no clot is seen, the test is positive, indicating abnormal coagulation. As with all these tests, if any clot (even very small) is seen, the test is negative, indicating that the patient has approximately normal coagulation. With the syringe method, clinicians leave about 5 mL of blood in the syringe (plastic) with which the blood was drawn. The syringe is laid on a desk or taped to the wall. In the bottle method, 5 mL of blood is injected into a used ceftriaxone bottle; there is often a small amount of the drug remaining in the bottle. The bottle is set on a flat surface. The test time is when any clot forms. Failure to clot after 20 min is positive. Patients showing physical signs of envenomation, such as local edema and ecchymosis or hypotension,

received the ASV (anti-snake venom) immediately, without awaiting clotting time results. Sensitivity and specificity, along with 95% confidence intervals (CIs), were calculated for the syringe and bottle methods of detecting failure to clot. The areas under the receiver operator characteristics curves (AUC) were compared between the two methods to assess discrimination, using laboratory results as the comparison standard. We did not conduct a formal a priori power analysis. All statistical analysis was done using Stata v.12 (StataCorp, College Station, TX). RESULTS Forty-six patients had blood samples drawn. More than 39% (18/46) of the patients were <18 years old. Nearly all patients had been walking through agricultural fields when bitten. Although the results from a whole-blood clotting time are dichotomous (either positive or negative), the times for negative results ranged from 2 to 20 min (laboratory) and 5 to 20 min (syringe and ceftriaxone bottle). All times >20 min were considered positive. Nine patients had only the syringe and ceftriaxone bottle (bedside) results, because the laboratory was unavailable, and thus they were not used in the AUC analysis. Among these 9 patients, none had discordant study results compared to each other. Two patients had positive tests for both the syringe and bottle method, and 7 patients had negative tests for each. One patient, despite initially negative results for both methods, later developed symptoms and received ASV. Of the 37 patients with laboratory results available, one patient had two bottle samples tested, and 3 patients had only the laboratory test and bottle method. For the syringe method, the sensitivity is 88.9% (95% CI 65.3–98.6; 16/18) and specificity, 82.4% (95% CI 56.5–96.2; 14/17). The bottle method has a sensitivity of 83.3% (95% CI 58.6–96.4; 15/18) and a specificity of 90.0% (95% CI 68.3–98.8; 18/20). Statistical analysis comparing results from each of the two methods to those from the laboratory produced the results in Table 1. Although the bottle method has a higher specificity than the syringe method, it has a lower sensitivity (Table 1). However, comparing the AUC for the

Table 1. Comparison of the Syringe and Bottle vs. the Laboratory Methods

Syringe method (n = 35) Bottle method (n = 38)

Correctly Classified (95% CI)

Sensitivity (95% CI)

Specificity (95% CI)

AUC* (95% CI)

85.7% (69.7–95.2) 86.8% (71.9–95.6)

88.9% (65.3–98.6) 83.3% (58.6–96.4)

82.4% (56.5–96.2) 90.0% (68.3–98.8)

0.856 (0.737–0.976) 0.858 (0.739–0.976)

CI = confidence interval; AUC = area under the receiver operator characteristics curve. * p = 0.98.

Whole-Blood Clotting after Snakebite

syringe and the bottle methods showed that the two methods do not differ (p = 0.98) in their overall discrimination for identifying clotting, using the laboratory results as the comparison standard (Table 1). DISCUSSION Fortunately, the experience globally is that 50% of venomous snake bites are ‘‘dry bites’’ that result in negligible envenomations, although this varies from 10–80% depending on the species (6). In this series, 39% of the patients exhibited coagulopathy by laboratory findings: a positive laboratory test or two positive bedside tests in the absence of a laboratory result. This result, however, reflects only those patients coming to the hospital. For cultural reasons, as well as the time and distance to medical care, many patients rely on local traditional healers, seeking medical treatment only if their situation worsens. Ideally, clinicians generally provide antivenin and other treatments, when available, to envenomated patients with significant coagulopathy. (In this setting, antivenin was often not available.) Many sophisticated hematological tests are used to assess whether patients presenting after a presumed venomous snakebite are coagulopathic and require antivenin. These tests are also used to assess the return of clotting function after snakebite-venom-induced consumptive coagulopathy (7). In most areas of the world where the populace frequently encounters venomous snakes, however, these tests are unavailable. An alternative that is often used is the whole-blood clotting time. This test relies on the clot produced by whole blood when it is removed from the vascular system and exposed to a foreign surface. In 1913, Lee and White first described this test as a replacement for more than 31 other less-than-optimal clotting tests then in existence (8). Also called coagulation time, this test was used to diagnose various serious coagulation disorders and to monitor anticoagulant therapy during much of the 20th century. Although it is rarely used today in developed countries, clotting times are commonly used throughout most of the world to assess coagulopathy, especially after potential snake envenomations. Limitations The method this hospital laboratory uses (described above) for assessing whole-blood clotting times varies somewhat from methods used in other laboratories, where tubes are often immersed in a 37 C water bath, tilted, and inspected frequently for clot formation. With that protocol, no clot formation within 15 min is considered positive (non-coagulating) (9,10). The technique

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that this laboratory uses is standard throughout the country and has been shown to be both accurate and less labor-intensive than other methods. Of the two bedside methods evaluated in this study, the syringe method most closely parallels the method commonly employed globally—generally using a test tube. However, in resource-poor areas, leaving the blood in the syringe conserves test tubes, which may be sufficiently scarce so that even the laboratory encounters problems with reusing them (11). The use of empty ceftriaxone bottles (commonly available, because it is a frequently administered parenteral antibiotic in much of the developing world) was a locally developed method for doing bedside clotting times that also has seemed to be reasonably reliable and can be done in most resourcepoor regions of the world, although it may not be applicable to providers in austere wilderness settings. When using this method, the bottle’s interior must be dry. This study found that both the syringe and ceftriaxone bottle methods for assessing clotting time after potential snake envenomation produce results very similar to those obtained in the clinical laboratory and that the two methods were similar to each other. A major limitation of this study is that our sample size was relatively low and the confidence intervals for sensitivity and specificities were wide ( 6 15%). However our point estimates suggest that both methods are sufficiently sensitive and specific to provide valuable information that, along with clinical findings, can help medical providers make treatment decisions in resource-poor settings where laboratory testing is unavailable. CONCLUSION Both the syringe and ceftriaxone bottle bedside clotting test methods seem accurate enough to help guide therapy after potential snake envenomations in resource-poor areas where laboratory testing is unavailable. A clotting test with one of these methods plus clinical findings can be used to guide therapy.

REFERENCES 1. Ahmed SM, Ahmed M, Nadeem A, et al. Emergency treatment of a snake bite: pearls from literature. J Emerg Trauma Shock 2008; 1:97–105. 2. Kasturiratne A, Wickremasinghe AR, de Silva N, et al. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med 2008;5:e218. 3. White J. Snake venoms and coagulopathy. Toxicon 2005;45:951–67. 4. O’Neil ME, Mack KA, Gilchrist J, Wozniak EJ. Snakebite injuries treated in United States emergency departments, 2001–2004. Wilderness Environ Med 2007;18:281–7. 5. Ghana Ministry of Health. Standard Treatment Guidelines – Ghana. Accra, Ghana, West Africa: Ghana National Drugs Programme, Ministry of Health; 2004.

666 6. Theakston RD, Warrell DA, Griffiths E. Report of a WHO workshop on the standardization and control of antivenoms. Toxicon 2003;41:541–57. 7. Isbister GK, Williams V, Brown SG, et al. Clinically applicable laboratory end-points for treating snakebite coagulopathy. Pathology 2006;38:568–72. 8. Lee RI, White PD. A clinical study of the coagulation time of blood. Am J Med 1913;145:495–503.

D. Punguyire et al. 9. Davidsohn I, Henry JB. Todd-Sanford clinical diagnosis by laboratory methods. 14th edn. Philadelphia, PA: WB Saunders; 1969. 10. Ochei J, Kolhatkar A. Medical laboratory science: theory and practice. New York: McGraw-Hill; 2000. 11. Valenzuela R, Iserson KV, Punguyire D. False-positive urine pregnancy tests—clinicians as detectives. Pan Afr Med J 2011;8:41. Available at: www.panafrican-med-journal.com/conten/article/8/ 41/pdf/41.pdf. Accessed September 18, 2012.

Whole-Blood Clotting after Snakebite

ARTICLE SUMMARY 1. Why is this topic important? This is, to the best of our knowledge, the first study assessing two commonly used methods to assess coagulopathy after snakebites. 2. What does this study attempt to show? Whether two common methods for measuring wholeblood clotting time after snakebites give findings consistent with those from a hospital laboratory. 3. What are the key findings? Both the syringe and ceftriaxone bottle bedside clotting test methods are excellent alternatives for guiding therapy in resource-poor areas where laboratory testing is unavailable. 4. How is patient care impacted? This study validates two bedside methods for performing whole-blood clotting times, both of which can be used in resource-poor settings. In settings where alternative testing is not available, these methods can help clinicians make decisions about which patients to treat/evacuate after possible envenomations.

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