- Email: [email protected]
The Tipping Point
TOXICOLOGY/EDITORIAL
The Tipping Point Cynthia K. Aaron, MD* *Corresponding Author. E-mail: [email protected]. 0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2015.06.008
A podcast for this article is available at www.annemergmed.com.
SEE RELATED ARTICLE, P. 165. [Ann Emerg Med. 2015;66:182-184.] Salicylate poisoning remains a significant toxicologic issue. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup article represents a major scientific review on the use of extracorporeal treatment for salicylate poisoning.1 Clinicians who regularly manage salicylate poisoning respect the effort involved in this Herculean review. Because physicians have treated salicylate toxicity for almost 80 years, there is a pervasive belief that most physicians “know how to treat this overdose.” Regrettably, this is a case in which familiarity has led to errors in management, and despite improved patient recognition, supportive care, and safety initiatives, patients continue to experience significant morbidity and mortality. Salicylate toxicity is a multifactorial condition with complex pathophysiology. Many of the signs, symptoms, and subsequent management decisions are predicated on this knowledge. Salicylate is a potent mitochondrial poison, leading to central hyperventilation and metabolic acidosis. Between the increased minute ventilation and uncoupled oxidative phosphorylation, there is a large free water loss, leading to a frequently unrecognized state of systemic hypovolemia even in the face of apparent pulmonary edema. Acidemia has multiple causes, including uncoupling of oxidative phosphorylation (lactic acidosis), altered gluconeogenesis (ketogenesis), and the contribution of acidic salicylate metabolites (nonlactic acidosis). As cells lose their ability to maintain normal transmembrane gradients, end-organ toxicity develops, with cerebral edema becoming the most lethal component. Unfortunately, salicylate toxicity is a continuum and there is no magic number that identifies individuals who will become grievously ill. It is critically important to concomitantly evaluate patient status and the laboratory abnormalities, recognizing that these patients may look “good” until they don’t and then they cross over to their tipping point. 182 Annals of Emergency Medicine
Although the EXTRIP authors mention cardinal errors, medical and clinical toxicologists and poison centers have seen these same mistakes repeat themselves.1 The following aspects deserve greater emphasis when the new recommendations are interpreted: EXTRIP recommends supportive measures as initial treatment, with urinary alkalinization as the predominant method for noninvasive enhanced elimination. Enhanced elimination by urine alkalinization is a potassium-dependent process and alkaluria cannot be achieved in the setting of hypokalemia. Between urinary losses and ongoing bicarbonate-induced potassium shifts, patients may become profoundly hypokalemic and require huge amounts of potassium replacement to achieve potassium concentrations approaching 4.0 mEq/L. Because of safety concerns associated with high-dose intravenous administration, oral replacement is the preferred method. We frequently encounter patients with serum pH greater than 7.5 but acidic urine. Because the kidneys rely on a hydrogen-potassium exchanger, this situation best responds to the addition of potassium rather than a decrease in bicarbonate. Patients receiving aggressive supportive care with serum and urine alkalinization sometimes develop evidence of pulmonary dysfunction. Regrettably, this is most frequently attributed to fluid overload but may actually represent drug-induced pulmonary capillary leak. Patients with unrecognized noncardiogenic pulmonary edema will do badly with diuresis and fluid restriction. EXTRIP clearly makes the distinction that pulmonary capillary leak and increasing oxygen demands represents an indication for extracorporeal treatment. Unfortunately, even when other evidence of fluid overload may be lacking, many clinicians remain unaware that salicylate intoxication is the cause of the pulmonary edema and there is a need for hemodialysis. Although EXTRIP recommends hemodialysis when supportive measures fail, determining this point is open to discussion. In the face of a decreasing blood pH, the patient whose salicylate level is less than the Volume 66, no. 2 : August 2015
Aaron
recommended hemodialysis level of 80 to 90 mg/dL may not be recognized as being in imminent danger of tipping the balance. The absolute value of the salicylate concentration has little meaning without knowing the acid-base status of the patient. Because salicylate is an acid with a pKa of 3.4, the more acidemic the patient, the more the drug shifts toward an unionized form, increases its apparent volume of distribution, and crosses into the brain. Normally, a pH decrease from 7.4 to 7.2 is considered clinically acceptable (eg, permissive hypercapnia). In salicylate toxicity, it can be lethal. This has been elegantly demonstrated in animal models in which an equivalent pH change led to doubling of soft tissue salicylate content.2,3 As a result, even patients with salicylate levels of 50 mg/dL may require extracorporeal treatment in the appropriate setting. Patients with decreasing salicylate levels are not always improving, and the level must be interpreted with both physical and biochemical parameters. Minimally decreasing levels may actually represent ongoing absorption in the face of drug elimination and changes in drug distribution. In our practice, we would like to see a decrease of 10% every 2 to 3 hours with improving clinical status, keeping in mind that even though the salicylate level may be decreasing, as long as drug is present, it continues to back-diffuse into the central nervous system. Finally, intubation is another tipping point. Patients die immediately after intubation. This demonstrates how pathophysiology should direct deviation from usual practice. Salicylate-intoxicated patients manifest an enormous minute ventilation that is frequently represented by hyperpnea rather than tachypnea. Unfortunately, normal “lung sparing” ventilator settings don’t account for this change and patients rapidly develop respiratory acidosis once they’ve begun ventilator treatment. This causes salicylate to rapidly shift into the central nervous system. To avoid this, respirator settings must provide minute ventilation to mimic the patient’s respiratory status. Although we usually titrate ventilator settings by pulse oximetry, salicylate-intoxicated patients need adjustments in ventilation rather than oxygenation. Rather than pulse oximetry, these patients need an assessment of ventilatory sufficiency with an arterial blood gas obtained within minutes of their beginning to receive assisted ventilation. Beyond these situations, EXTRIP makes specific recommendations for initiating extracorporeal treatment based on salicylate levels without evidence of failing physiochemical parameters. Their recommendations were determined from limited outcome data, which reflects the Volume 66, no. 2 : August 2015
The Tipping Point
poor state of the literature. We do know that as salicylate levels increase, patients do worse and the elderly do even poorer, with the tipping point averaging 80 to 90 mg/dL. Averages, however, exhibit a bell-shaped distribution, with some doing better and some doing worse, supporting the use of an individualized approach to determine how the risk-benefit ratio favors intervening with extracorporeal treatment. Because no data exist in regard to early intervention, patients may actually do better when hemodialyzed at lower salicylate levels. Another consideration when using these suggested extracorporeal treatment values is that in most cases the resulting critical value already reflects a point between 1 and 6 hours in the past when the level was actually measured. Adding the time required for the clinician to be notified of the critical level by ancillary staff; the nephrologists’ involvement; the logistic considerations in arranging staff, bed, and equipment; placement of the dialysis catheter; and finally initiation of hemodialysis, the salicylate level may have incrementally increased, allowing the intoxication to progress. This is another reason to consider starting the process at a lower salicylate value. In practice, once the patient shows evidence of end-organ toxicity with hypotension, fever, and cerebral edema regardless of level, it is increasingly difficult to reverse the process. Finally, once the decision is made to proceed with hemodialysis, there are concepts that the EXTRIP authors assume are commonly understood but we have found to be somewhat less accepted.1 Nephrologists in clinical practice normally dialyze hyperkalemic, fluid-overloaded, chronically uremic patients over a set time period and on a repeating schedule. Salicylate-intoxicated patients are quite different and, although usually healthy at baseline, may be hypotensive, underresuscitated, hypokalemic, and fluid depleted. Many nephrologists are unfamiliar with salicylate-induced pathophysiology changes and the particular needs of these patients. Salicylatepoisoned patients require only 1 or 2 extracorporeal treatment sessions but have specific requirements for their hemodialysis parameters, such as requiring a bicarbonate or citrate bath with high potassium content and undergoing dialysis without ultrafiltration and continued for a period greater than the standard 3 hours. Once treated, these patients frequently improve rapidly and are discharged within 24 to 48 hours. Salicylates remain a lethal and under-appreciated intoxication. The EXTRIP guidelines should help guide invasive therapy to rapidly enhance drug elimination and reduce morbidity and mortality. However, although Annals of Emergency Medicine 183
Aaron
The Tipping Point
authoritative and based on best evidence, they remain guidelines and should be adapted to each patient’s situation to meet the best interests of the patient. Clinicians can obtain expert assistance from medical and clinical toxicologists and poison centers, with the final medical decision determined by the treating clinicians. Supervising editor: Matthew D. Sztajnkrycer, MD, PhD Author affiliations: From the Departments of Emergency Medicine and Pediatrics, Wayne State University School of Medicine and the Michigan Regional Poison Control Center at Children’s Hospital of Michigan, Detroit, MI.
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 author has stated that no such relationships exist.
REFERENCES 1. Juurlink DN, Gosselin S, Kielstein JT, et al. Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. Ann Emerg Med. 2015;66:165-181. 2. Hill JB. Current concepts: salicylate intoxications. N Engl J Med. 1973;21:1110-1113. 3. Goldberg MA, Barlow CF, Roth LJ. The effects of carbon dioxide on the entry and accumulation of drugs in the central nervous system. J Pharmacol Exp Ther. 1961;131:308-318.
Annals’ Toxicology Resource Center now has four content topics: Snakebite Digoxin Acetaminophen Cyanide The Resource Center gives you the best information on selecting and administering appropriate antidotes.
www.annemergmed.com.
184 Annals of Emergency Medicine
Volume 66, no. 2 : August 2015
The Tipping Point Cynthia K. Aaron, MD* *Corresponding Author. E-mail: [email protected]. 0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2015.06.008
A podcast for this article is available at www.annemergmed.com.
SEE RELATED ARTICLE, P. 165. [Ann Emerg Med. 2015;66:182-184.] Salicylate poisoning remains a significant toxicologic issue. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup article represents a major scientific review on the use of extracorporeal treatment for salicylate poisoning.1 Clinicians who regularly manage salicylate poisoning respect the effort involved in this Herculean review. Because physicians have treated salicylate toxicity for almost 80 years, there is a pervasive belief that most physicians “know how to treat this overdose.” Regrettably, this is a case in which familiarity has led to errors in management, and despite improved patient recognition, supportive care, and safety initiatives, patients continue to experience significant morbidity and mortality. Salicylate toxicity is a multifactorial condition with complex pathophysiology. Many of the signs, symptoms, and subsequent management decisions are predicated on this knowledge. Salicylate is a potent mitochondrial poison, leading to central hyperventilation and metabolic acidosis. Between the increased minute ventilation and uncoupled oxidative phosphorylation, there is a large free water loss, leading to a frequently unrecognized state of systemic hypovolemia even in the face of apparent pulmonary edema. Acidemia has multiple causes, including uncoupling of oxidative phosphorylation (lactic acidosis), altered gluconeogenesis (ketogenesis), and the contribution of acidic salicylate metabolites (nonlactic acidosis). As cells lose their ability to maintain normal transmembrane gradients, end-organ toxicity develops, with cerebral edema becoming the most lethal component. Unfortunately, salicylate toxicity is a continuum and there is no magic number that identifies individuals who will become grievously ill. It is critically important to concomitantly evaluate patient status and the laboratory abnormalities, recognizing that these patients may look “good” until they don’t and then they cross over to their tipping point. 182 Annals of Emergency Medicine
Although the EXTRIP authors mention cardinal errors, medical and clinical toxicologists and poison centers have seen these same mistakes repeat themselves.1 The following aspects deserve greater emphasis when the new recommendations are interpreted: EXTRIP recommends supportive measures as initial treatment, with urinary alkalinization as the predominant method for noninvasive enhanced elimination. Enhanced elimination by urine alkalinization is a potassium-dependent process and alkaluria cannot be achieved in the setting of hypokalemia. Between urinary losses and ongoing bicarbonate-induced potassium shifts, patients may become profoundly hypokalemic and require huge amounts of potassium replacement to achieve potassium concentrations approaching 4.0 mEq/L. Because of safety concerns associated with high-dose intravenous administration, oral replacement is the preferred method. We frequently encounter patients with serum pH greater than 7.5 but acidic urine. Because the kidneys rely on a hydrogen-potassium exchanger, this situation best responds to the addition of potassium rather than a decrease in bicarbonate. Patients receiving aggressive supportive care with serum and urine alkalinization sometimes develop evidence of pulmonary dysfunction. Regrettably, this is most frequently attributed to fluid overload but may actually represent drug-induced pulmonary capillary leak. Patients with unrecognized noncardiogenic pulmonary edema will do badly with diuresis and fluid restriction. EXTRIP clearly makes the distinction that pulmonary capillary leak and increasing oxygen demands represents an indication for extracorporeal treatment. Unfortunately, even when other evidence of fluid overload may be lacking, many clinicians remain unaware that salicylate intoxication is the cause of the pulmonary edema and there is a need for hemodialysis. Although EXTRIP recommends hemodialysis when supportive measures fail, determining this point is open to discussion. In the face of a decreasing blood pH, the patient whose salicylate level is less than the Volume 66, no. 2 : August 2015
Aaron
recommended hemodialysis level of 80 to 90 mg/dL may not be recognized as being in imminent danger of tipping the balance. The absolute value of the salicylate concentration has little meaning without knowing the acid-base status of the patient. Because salicylate is an acid with a pKa of 3.4, the more acidemic the patient, the more the drug shifts toward an unionized form, increases its apparent volume of distribution, and crosses into the brain. Normally, a pH decrease from 7.4 to 7.2 is considered clinically acceptable (eg, permissive hypercapnia). In salicylate toxicity, it can be lethal. This has been elegantly demonstrated in animal models in which an equivalent pH change led to doubling of soft tissue salicylate content.2,3 As a result, even patients with salicylate levels of 50 mg/dL may require extracorporeal treatment in the appropriate setting. Patients with decreasing salicylate levels are not always improving, and the level must be interpreted with both physical and biochemical parameters. Minimally decreasing levels may actually represent ongoing absorption in the face of drug elimination and changes in drug distribution. In our practice, we would like to see a decrease of 10% every 2 to 3 hours with improving clinical status, keeping in mind that even though the salicylate level may be decreasing, as long as drug is present, it continues to back-diffuse into the central nervous system. Finally, intubation is another tipping point. Patients die immediately after intubation. This demonstrates how pathophysiology should direct deviation from usual practice. Salicylate-intoxicated patients manifest an enormous minute ventilation that is frequently represented by hyperpnea rather than tachypnea. Unfortunately, normal “lung sparing” ventilator settings don’t account for this change and patients rapidly develop respiratory acidosis once they’ve begun ventilator treatment. This causes salicylate to rapidly shift into the central nervous system. To avoid this, respirator settings must provide minute ventilation to mimic the patient’s respiratory status. Although we usually titrate ventilator settings by pulse oximetry, salicylate-intoxicated patients need adjustments in ventilation rather than oxygenation. Rather than pulse oximetry, these patients need an assessment of ventilatory sufficiency with an arterial blood gas obtained within minutes of their beginning to receive assisted ventilation. Beyond these situations, EXTRIP makes specific recommendations for initiating extracorporeal treatment based on salicylate levels without evidence of failing physiochemical parameters. Their recommendations were determined from limited outcome data, which reflects the Volume 66, no. 2 : August 2015
The Tipping Point
poor state of the literature. We do know that as salicylate levels increase, patients do worse and the elderly do even poorer, with the tipping point averaging 80 to 90 mg/dL. Averages, however, exhibit a bell-shaped distribution, with some doing better and some doing worse, supporting the use of an individualized approach to determine how the risk-benefit ratio favors intervening with extracorporeal treatment. Because no data exist in regard to early intervention, patients may actually do better when hemodialyzed at lower salicylate levels. Another consideration when using these suggested extracorporeal treatment values is that in most cases the resulting critical value already reflects a point between 1 and 6 hours in the past when the level was actually measured. Adding the time required for the clinician to be notified of the critical level by ancillary staff; the nephrologists’ involvement; the logistic considerations in arranging staff, bed, and equipment; placement of the dialysis catheter; and finally initiation of hemodialysis, the salicylate level may have incrementally increased, allowing the intoxication to progress. This is another reason to consider starting the process at a lower salicylate value. In practice, once the patient shows evidence of end-organ toxicity with hypotension, fever, and cerebral edema regardless of level, it is increasingly difficult to reverse the process. Finally, once the decision is made to proceed with hemodialysis, there are concepts that the EXTRIP authors assume are commonly understood but we have found to be somewhat less accepted.1 Nephrologists in clinical practice normally dialyze hyperkalemic, fluid-overloaded, chronically uremic patients over a set time period and on a repeating schedule. Salicylate-intoxicated patients are quite different and, although usually healthy at baseline, may be hypotensive, underresuscitated, hypokalemic, and fluid depleted. Many nephrologists are unfamiliar with salicylate-induced pathophysiology changes and the particular needs of these patients. Salicylatepoisoned patients require only 1 or 2 extracorporeal treatment sessions but have specific requirements for their hemodialysis parameters, such as requiring a bicarbonate or citrate bath with high potassium content and undergoing dialysis without ultrafiltration and continued for a period greater than the standard 3 hours. Once treated, these patients frequently improve rapidly and are discharged within 24 to 48 hours. Salicylates remain a lethal and under-appreciated intoxication. The EXTRIP guidelines should help guide invasive therapy to rapidly enhance drug elimination and reduce morbidity and mortality. However, although Annals of Emergency Medicine 183
Aaron
The Tipping Point
authoritative and based on best evidence, they remain guidelines and should be adapted to each patient’s situation to meet the best interests of the patient. Clinicians can obtain expert assistance from medical and clinical toxicologists and poison centers, with the final medical decision determined by the treating clinicians. Supervising editor: Matthew D. Sztajnkrycer, MD, PhD Author affiliations: From the Departments of Emergency Medicine and Pediatrics, Wayne State University School of Medicine and the Michigan Regional Poison Control Center at Children’s Hospital of Michigan, Detroit, MI.
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 author has stated that no such relationships exist.
REFERENCES 1. Juurlink DN, Gosselin S, Kielstein JT, et al. Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. Ann Emerg Med. 2015;66:165-181. 2. Hill JB. Current concepts: salicylate intoxications. N Engl J Med. 1973;21:1110-1113. 3. Goldberg MA, Barlow CF, Roth LJ. The effects of carbon dioxide on the entry and accumulation of drugs in the central nervous system. J Pharmacol Exp Ther. 1961;131:308-318.
Annals’ Toxicology Resource Center now has four content topics: Snakebite Digoxin Acetaminophen Cyanide The Resource Center gives you the best information on selecting and administering appropriate antidotes.
www.annemergmed.com.
184 Annals of Emergency Medicine
Volume 66, no. 2 : August 2015