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Utility of Sodium Thiosulfate in Acute Cyanide Toxicity
Correspondence absence of pulmonary embolism in symptomatic emergency department patients: results of a prospective, multicenter study. Ann Emerg Med. 2010;55:305-315. 5. Stein PD, Henry JW. Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest. 1997;112:974-979.
In reply: In response to the rebuttal by Kline et al,1 we agree that a case report provides limited insight and, as previously stated, does not suggest “a failure of a validated decision rules such as the PERC [pulmonary embolism rule-out criteria].”2 In our discussion, we questioned the relationship between falsenegative PERC status, clot burden, and outcomes. Kline et al1 attempt to offer a more “scientifically valid” look at this question than our case report but go on to reference a study in which PERC was retrospectively applied to a cohort of patients “that lack[ed] a reliable assessment of gestalt suspicion of [pulmonary embolism]” and in whom clot burden was not measured.1,3 Instead of the actual variable of clot burden, Kline et al1 assume that the complaint of pleuritic chest pain (a finding more common in false-negative PERC patients per this study) is likely to represent a pulmonary infarction, which is more often associated with small distal clots.1 This assumption is drawn from an article by Stein and Henry,4 in which patients with pleuritic chest pain (which the authors label the “pulmonary infarction” syndrome) were more likely to manifest higher PaO2 and trended toward lower pulmonary artery pressure than the “isolated dyspnea” group. Care must be used about terminology because Stein and Henry4 used “pulmonary infarction syndrome” to describe patients with either pleuritic chest or hemoptysis. Overall, it is unclear that the pleuritic chest pain patients in the study by Pollack et al3 are truly similar to the “pulmonary infarction” group analyzed by Stein and Henry,4 particularly because the latter also included patients with hemoptysis. Outcomes are not addressed here because our patient case caused us to consider the ramifications of not identifying emboli-positive patients by the PERC who are therefore unlikely to receive anticoagulation and are consequently sent home. We look forward to these questions being answered in future prospective studies. Adam Hennessey, DO Wayne B. Lau, MD Jason M. Fields, MD Thomas Jefferson University Hospital Department of Emergency Medicine Philadelphia, PA http://dx.doi.org/10.1016/j.annemergmed.2012.07.115
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 124 Annals of Emergency Medicine
1. Kline JA, Sattery D, O’Neil BJ, et al. Clinical features of patients with pulmonary embolism and a negative PERC rule. Ann Emerg Med. 2013;61:122-124. 2. Hennessey A, Setyono DA, Lau WB, et al. A patient with a large pulmonary saddle embolus eluding both clinical gestalt and validated decision rules. Ann Emerg Med. 2012;59:521-523. 3. Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll Cardiol. 2011;57:700-706. 4. Stein PD, Henry JW. Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest. 1997;112:974-979.
Utility of Sodium Thiosulfate in Acute Cyanide Toxicity To the Editor: In the June 2012 issue of Annals, Bebarta et al1 conducted an elegant animal study examining the efficacy of sodium thiosulfate in the treatment of cyanide toxicity versus hydroxocobalamin, or a combination of the 2 drugs; we commend the authors on their work. However, the study left us contemplating the clinical effects and outcomes on subjects excluded from the data analysis. Given the complexity and toxicity of cyanide, we understand the safety and ethical issues that must be taken into consideration (laboratory personnel, animal subjects) when designing such a study. Nonetheless, it is important to appreciate the definitions used by the researchers in order to assimilate a complete clinical picture. In this study, each arm defined death as a mean arterial pressure of less than 20 mm Hg for 5 minutes. Although all subjects randomized to the sodium thiosulfate– only group died before completion of the study, it is unclear whether the animals succumbed to the toxin, experienced an adverse effect of the antidote,2,3 or met the objective definition of death, raising the question of whether the animals would have shown improvement if only allotted more time for enzyme reactivation. In addition, the variability of enzyme activity between species and chronologic age could also play a role in the efficacy of the antidote.4 We hope that further studies will elucidate the effectiveness of sodium thiosulfate in the human population. Mae De La Calzada-Jeanlouie, DO Department of Emergency Medicine North Shore University Hospital Manhasset, NY Jaron Coombs, DO Department of Emergency Medicine San Antonio Uniformed Service Health Education Consortium San Antonio, TX Volume , . : January
Correspondence Nadia Shaukat, MD Department of Emergency Medicine St. Luke’s–Roosevelt Hospital New York, NY Dean Olsen, DO Department of Emergency Medicine St. Barnabas Hospital Bronx, NY http://dx.doi.org/10.1016/j.annemergmed.2012.07.125
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 1. Bebarta VS, Pitotti RL, Dixon P, et al. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59:532-539. 2. http://reference.medscape.com/drug/sodium-thiosulfate-343750#0. Accessed July 13, 2012. 3. Howland MAAntidotes in depth (A39): sodium thiosulfate. In: Goldfrank LR, ed. Goldfrank’s Toxicologic Emergencies.9th ed. New York, NY: McGraw-Hill, Medical Publishing Division; 2011:16921694. 4. Aminlari M, Li A, Kunanithy V, et al. Rhodanese distribution in porcine (Sus scrofa) tissues. Comp Biochem Physiol B Biochem Mol Biol. 2002;132:309-313.
In reply: We thank Dr. Calzada-Jeanlouie et al for their comments about our study of cyanide-induced toxicity.1 Sodium thiosulfate is used as an antidote for cyanide toxicity. It has been used most commonly with other pharmacologic treatments, and it is purported to be effective alone. Sodium thiosulfate may have a delayed effect partly because it must move across the mitochondrial membrane and then convert cyanide to thiocyanate catalyzed by rhodanese.2 This delayed effect has not been reported in a human study, to our knowledge. In our study, all animals received intravenous cyanide until severe toxicity and hypotension, defined as 50% below the baseline mean arterial pressure. Then the animal received treatment. Death was defined was a mean arterial pressure less than 20 mm Hg for more than 5 minutes.3 In addition, per our laboratory animal protocol and previous studies, all animals were observed for 20 minutes after death while ventilated and receiving supplemental oxygen to detect a late effect of any treatment. At the end of that period, the animal was killed. We determined that if the animal did not recover after an observation period of 20 minutes after death, it was nonrecoverable. For all animals in this study, once an animal died (mean arterial pressure ⬍20 mm Hg for ⬎5 minutes), it did not recover within the 20minute observation period in any arm. Because all 3 arms were similar in design and baseline values, we attribute the outcome to the ineffectiveness of sodium thiosulfate. Volume , . : January
Rhodanese is found in swine at levels similar to that in humans and is also found in the liver in greater levels than other organs, as in humans.4,5 Age, comorbidities, and individual susceptibility affect rhodanese levels in swine as they do in humans. We agree that human clinical trials are important and better delineate the effectiveness of the chemical toxin antidotes; however, these trials are difficult to conduct because of trial and drug costs, exposure rarity, outcome severity, and range in exposure dose. The “animal rule” is accepted by the Food and Drug Administration as evidence to support countermeasure effectiveness with these uncommon exposures.6 Finally, given the overwhelming findings in our study, it would difficult to recommend sodium thiosulfate alone. Lt. Col. Vikhyat S. Bebarta, MD, USAF, MC San Antonio Military Medical Center San Antonio, TX Rebecca Pitotti, RN, MSN Maj. Julio Lairet, DO, USAF, MC Department of Emergency Medicine San Antonio Military Medical Center San Antonio, TX Patricia Dixon, MS Anneke Bush, ScD, MSH Clinical Research Division Wilford Hall Medical Center San Antonio, TX CAPT David A. Tanen, MD, USN, MC Department of Emergency Medicine Naval Medical Center San Diego, CA http://dx.doi.org/10.1016/j.annemergmed.2012.08.008
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. The US Air Force Office of the Surgeon General funded this study. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the US Air Force, Department of Defense, or the US government. 1. Bebarta VS, Pitotti RL, Dixon P, et al. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59:532-539. 2. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol. 2009;39:541-552. 3. Bebarta VS, Tanen DA, Lairet J, et al. Hydroxocobalamin and sodium thiosulfate versus sodium nitrite and sodium thiosulfate in the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2010;55:345-351.
Annals of Emergency Medicine 125
In reply: In response to the rebuttal by Kline et al,1 we agree that a case report provides limited insight and, as previously stated, does not suggest “a failure of a validated decision rules such as the PERC [pulmonary embolism rule-out criteria].”2 In our discussion, we questioned the relationship between falsenegative PERC status, clot burden, and outcomes. Kline et al1 attempt to offer a more “scientifically valid” look at this question than our case report but go on to reference a study in which PERC was retrospectively applied to a cohort of patients “that lack[ed] a reliable assessment of gestalt suspicion of [pulmonary embolism]” and in whom clot burden was not measured.1,3 Instead of the actual variable of clot burden, Kline et al1 assume that the complaint of pleuritic chest pain (a finding more common in false-negative PERC patients per this study) is likely to represent a pulmonary infarction, which is more often associated with small distal clots.1 This assumption is drawn from an article by Stein and Henry,4 in which patients with pleuritic chest pain (which the authors label the “pulmonary infarction” syndrome) were more likely to manifest higher PaO2 and trended toward lower pulmonary artery pressure than the “isolated dyspnea” group. Care must be used about terminology because Stein and Henry4 used “pulmonary infarction syndrome” to describe patients with either pleuritic chest or hemoptysis. Overall, it is unclear that the pleuritic chest pain patients in the study by Pollack et al3 are truly similar to the “pulmonary infarction” group analyzed by Stein and Henry,4 particularly because the latter also included patients with hemoptysis. Outcomes are not addressed here because our patient case caused us to consider the ramifications of not identifying emboli-positive patients by the PERC who are therefore unlikely to receive anticoagulation and are consequently sent home. We look forward to these questions being answered in future prospective studies. Adam Hennessey, DO Wayne B. Lau, MD Jason M. Fields, MD Thomas Jefferson University Hospital Department of Emergency Medicine Philadelphia, PA http://dx.doi.org/10.1016/j.annemergmed.2012.07.115
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 124 Annals of Emergency Medicine
1. Kline JA, Sattery D, O’Neil BJ, et al. Clinical features of patients with pulmonary embolism and a negative PERC rule. Ann Emerg Med. 2013;61:122-124. 2. Hennessey A, Setyono DA, Lau WB, et al. A patient with a large pulmonary saddle embolus eluding both clinical gestalt and validated decision rules. Ann Emerg Med. 2012;59:521-523. 3. Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll Cardiol. 2011;57:700-706. 4. Stein PD, Henry JW. Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest. 1997;112:974-979.
Utility of Sodium Thiosulfate in Acute Cyanide Toxicity To the Editor: In the June 2012 issue of Annals, Bebarta et al1 conducted an elegant animal study examining the efficacy of sodium thiosulfate in the treatment of cyanide toxicity versus hydroxocobalamin, or a combination of the 2 drugs; we commend the authors on their work. However, the study left us contemplating the clinical effects and outcomes on subjects excluded from the data analysis. Given the complexity and toxicity of cyanide, we understand the safety and ethical issues that must be taken into consideration (laboratory personnel, animal subjects) when designing such a study. Nonetheless, it is important to appreciate the definitions used by the researchers in order to assimilate a complete clinical picture. In this study, each arm defined death as a mean arterial pressure of less than 20 mm Hg for 5 minutes. Although all subjects randomized to the sodium thiosulfate– only group died before completion of the study, it is unclear whether the animals succumbed to the toxin, experienced an adverse effect of the antidote,2,3 or met the objective definition of death, raising the question of whether the animals would have shown improvement if only allotted more time for enzyme reactivation. In addition, the variability of enzyme activity between species and chronologic age could also play a role in the efficacy of the antidote.4 We hope that further studies will elucidate the effectiveness of sodium thiosulfate in the human population. Mae De La Calzada-Jeanlouie, DO Department of Emergency Medicine North Shore University Hospital Manhasset, NY Jaron Coombs, DO Department of Emergency Medicine San Antonio Uniformed Service Health Education Consortium San Antonio, TX Volume , . : January
Correspondence Nadia Shaukat, MD Department of Emergency Medicine St. Luke’s–Roosevelt Hospital New York, NY Dean Olsen, DO Department of Emergency Medicine St. Barnabas Hospital Bronx, NY http://dx.doi.org/10.1016/j.annemergmed.2012.07.125
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 1. Bebarta VS, Pitotti RL, Dixon P, et al. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59:532-539. 2. http://reference.medscape.com/drug/sodium-thiosulfate-343750#0. Accessed July 13, 2012. 3. Howland MAAntidotes in depth (A39): sodium thiosulfate. In: Goldfrank LR, ed. Goldfrank’s Toxicologic Emergencies.9th ed. New York, NY: McGraw-Hill, Medical Publishing Division; 2011:16921694. 4. Aminlari M, Li A, Kunanithy V, et al. Rhodanese distribution in porcine (Sus scrofa) tissues. Comp Biochem Physiol B Biochem Mol Biol. 2002;132:309-313.
In reply: We thank Dr. Calzada-Jeanlouie et al for their comments about our study of cyanide-induced toxicity.1 Sodium thiosulfate is used as an antidote for cyanide toxicity. It has been used most commonly with other pharmacologic treatments, and it is purported to be effective alone. Sodium thiosulfate may have a delayed effect partly because it must move across the mitochondrial membrane and then convert cyanide to thiocyanate catalyzed by rhodanese.2 This delayed effect has not been reported in a human study, to our knowledge. In our study, all animals received intravenous cyanide until severe toxicity and hypotension, defined as 50% below the baseline mean arterial pressure. Then the animal received treatment. Death was defined was a mean arterial pressure less than 20 mm Hg for more than 5 minutes.3 In addition, per our laboratory animal protocol and previous studies, all animals were observed for 20 minutes after death while ventilated and receiving supplemental oxygen to detect a late effect of any treatment. At the end of that period, the animal was killed. We determined that if the animal did not recover after an observation period of 20 minutes after death, it was nonrecoverable. For all animals in this study, once an animal died (mean arterial pressure ⬍20 mm Hg for ⬎5 minutes), it did not recover within the 20minute observation period in any arm. Because all 3 arms were similar in design and baseline values, we attribute the outcome to the ineffectiveness of sodium thiosulfate. Volume , . : January
Rhodanese is found in swine at levels similar to that in humans and is also found in the liver in greater levels than other organs, as in humans.4,5 Age, comorbidities, and individual susceptibility affect rhodanese levels in swine as they do in humans. We agree that human clinical trials are important and better delineate the effectiveness of the chemical toxin antidotes; however, these trials are difficult to conduct because of trial and drug costs, exposure rarity, outcome severity, and range in exposure dose. The “animal rule” is accepted by the Food and Drug Administration as evidence to support countermeasure effectiveness with these uncommon exposures.6 Finally, given the overwhelming findings in our study, it would difficult to recommend sodium thiosulfate alone. Lt. Col. Vikhyat S. Bebarta, MD, USAF, MC San Antonio Military Medical Center San Antonio, TX Rebecca Pitotti, RN, MSN Maj. Julio Lairet, DO, USAF, MC Department of Emergency Medicine San Antonio Military Medical Center San Antonio, TX Patricia Dixon, MS Anneke Bush, ScD, MSH Clinical Research Division Wilford Hall Medical Center San Antonio, TX CAPT David A. Tanen, MD, USN, MC Department of Emergency Medicine Naval Medical Center San Diego, CA http://dx.doi.org/10.1016/j.annemergmed.2012.08.008
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. The US Air Force Office of the Surgeon General funded this study. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the US Air Force, Department of Defense, or the US government. 1. Bebarta VS, Pitotti RL, Dixon P, et al. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59:532-539. 2. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol. 2009;39:541-552. 3. Bebarta VS, Tanen DA, Lairet J, et al. Hydroxocobalamin and sodium thiosulfate versus sodium nitrite and sodium thiosulfate in the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2010;55:345-351.
Annals of Emergency Medicine 125