Now That’s What I Call Tox!

EMRA’s Toxicology Committee summarizes noteworthy toxicology papers. These were some of our favorites from 2024!

Article: Love J, Levine M, Aldy K, et al. Opioid Overdoses Involving Xylazine in Emergency Department Patients: A Multicenter Study. Clin Toxicol (Phila). 2022;61:173-180.

Review by: Brittany Garza, DO, MPH (Central Michigan University)

• Background: Synthetic opioids and adulterants are becoming the leading cause of overdose fatalities in the United States. These opioids are being laced with substances such as xylazine, which is thought to create a potentially more deadly ingestion. Xylazine is an alpha-2 agonist and is used as a veterinary tranquilizer. Previous to the publication of this article, the clinical outcome of patients with opioid overdose with and without xylazine exposure had not been analyzed. 
• Research question: This study aims to evaluate the outcomes of opioid overdoses with and without xylazine exposure. The authors hypothesize that xylazine would be associated with worse clinical outcomes, most important, cardiac arrest and coma. 
• Methods: This was a multicenter, prospective cohort study of adults with opioid overdoses who presented to 9 U.S. emergency departments between September 2020 and August 2021. Patients were screened for opioids and xylazine by a qualitative assay (liquid chromatography quadrupole time-of-flight mass spectroscopy). The measures of severity includes cardiac arrest requiring CPR, coma within 4 days of arrival in the hospital, discharge from the ED, ED length of stay, hospital admission rate, and mortality rate. Results were analyzed with a multivariable regression analysis. 
• Results: Of 321 patients included in the study, 90 tested positive for xylazine and 231 did not. Of those testing positive for opioids and xylazine, there was a lowered risk of cardiac arrest and coma. There was no statistically significant difference in proportion of patients discharged from ED, ED length of stay, hospital admission rate, or mortality rates. 
• Conclusion: This study identified that opioid overdoses with xylazine exposures were less severe than isolated opioid exposures.

CRITIQUE

• Pros: This was the largest study of xylazine overdose and its severity. Prescription opioids were excluded which is clinically appropriate. Further, the study was controlled for age group, sex, race, prior psychiatric history, initial blood pressure, and naloxone administration.
• Cons: Only qualitative studies were performed on opioids and xylazine; therefore, there could be a drastically different concentration of both substances in an ingestion. If there was more opioid concentration in an ingestion, there may have been more respiratory depression and subsequent worse clinical outcomes. The study also does not account for the timing of ingestion. Theoretically, xylazine could have been ingested in a previous use and the patient would have still tested positive for it. Further, pre-hospital fatalities were not included in the results, which could skew results. Finally, the data collection was in large cities and the data may not be application to rural settings where drug adulterants may be different.

IMPLICATION FOR TOXICOLOGISTS/EM 

Both groups had large naloxone requirements. It is hypothesized that this is due to the CNS depression associated with xylazine that masquerades as opioid overdose. This could also be due to respiratory depression associated with drug ingestions that have a higher proportion of opioid to xylazine. 

Article: Keenan M, Rice S, Frawley E, et al. Rate of Adverse Outcomes During 6-Hour Observation for Asymptomatic Patients with Select Ingestions. J Med Toxicol. 2023;19(3):288–292.  

Review by: E. Mason Jackson, MD (Prisma Health Upstate)

• Background: The origin and etiology of the 6-hour observation window frequently recommended by certified specialists in poison information (C-SPIs) is shrouded in mystery. It is thought that it may have originated from some of the tricyclic antidepressant and antihypertensive data from the 1980s and 1990s. Others believe it may be a best practice to guard against unreported coingestions. Many SPIs indicated that they would recommend a 6-hour window of observation even for benign ingestions.
• Research question: Do patients with asymptomatic ingestions on presentation have any adverse outcomes during the recommended 6-hour observation period?
• Methods: This was a retrospective cohort study conducted on a convenience sample of patient cases called into the regional poison center over a one-year period. Patient met inclusion criteria if they were over the age of 13 years old and had a 6-hour observation time recommended in addition to normal labs (basic metabolic panel and coingestion labs), vital signs, EKG and were reported as being otherwise asymptomatic. Patient suffering from ingestion of anti-hypertensive agents, digoxin, tricyclic antidepressants, toxic alcohol, caustics, extended-release products, venlafaxine, lithium, aspirin, acetaminophen, sulfonylureas, metformin, or bupropion were excluded. Additionally, patients were excluded if the poison center recommended repeat labs during their ED visit. Once criteria were met, the case was analyzed to assess for adverse events including mechanical ventilation, seizure, vasopressors use, prolonged observation, hospital admission (excluding psychiatric) or death.
• Results: 107 cases met inclusion/exclusion criteria with 73.8% of cases being female and 71% of cases involving a single xenobiotic. The most common xenobiotic class was analgesics (16.8%) and over 88% of cases were of suicidal intent. 4 patients (3.7%) experienced an adverse event, with two patients being admitted and two requiring longer observation time. Several confounders exist with several of these four patients, including iatrogenic benzodiazepine use for agitation leading to prolonged observation time and admission for non-toxicologic cause of a patient’s ED visit.
• Conclusion: There was a low rate of adverse outcomes experienced by patients with asymptomatic ingestions during the 6-hour observation window recommended by the regional poison center.  Further research regarding the utility of a 6-hour observation period is needed.

CRITIQUE

This study is limited by its single center, retrospective nature centered around a convenience sample of patients.  It also relies on subjective data entry and review by the SPIs and research team. It should also be noted that poison center recommendations may slightly vary from center to center and the frequency of this recommendation by not be generalizable to other regions.

IMPLICATION FOR TOXICOLOGISTS/EM 

This study attempts to shed light on the recommendation by poison centers for 6-hour observation period for asymptomatic patients. Certainly, in the absence of a medical toxicologist consult service, C-SPIs serve as the expert in management of the acutely poisoned patient. If a provider consults them for recommendations, adherence is important as any adverse outcome experienced because of deviation from their recommendations can lead to poor patient care and medicolegal risk. A shorter period of observation may be appropriate for select patients and the risk of adverse outcomes in asymptomatic patients is low. However, more data is needed before any official recommendation changes.

Article:​​ Stolbach AI, Mazer-Amirshahi ME, Nelson LS, Cole JB. American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time. J Med Toxicol. 2024;20(1):64-67.

Review by: Katherine M. Markin, MD (George Washington University)

• Background: In the age of the ongoing opioid crisis in the United States, researchers have been investigating alternative approaches for opioid reversal. The United States Food and Drug Administration approved intranasal nalmefene in May 2023 for this purpose, and to be used as an alternative emergency treatment for opioid overdose. Nalmefene was previously approved as an intramuscular formulation, but was taken off the market due to commercial reasons, and therefore only required the Abbreviated New Drug Application pathway for renewed approval. Nalmefene is now marketed as having high affinity for opioid receptors while having a longer duration of action compared to naloxone, though data supporting its clinical effectiveness and safety are limited.
• Research question: This paper seeks to assess the potential of nalmefene as an opioid overdose reversal agent as compared to naloxone (the current standard of care).
• Methods: Review of clinical trial data, pharmacokinetics, and pharmacodynamics of nalmefene as compared to naloxone.
• Results: Nalmefene has a 5x higher fold binding affinity of opioid receptors than naloxone. However, it  is  not clear that an antagonist with a higher affinity for the opioid receptor is  desirable or  would result in better outcomes, even in patients with synthetic opioid overdose. Increased affinity may contribute to more severe and intractable withdrawal. It was also reported that nalmefene has a longer duration of action than naloxone (half-life 7.1 hours vs 2.08 hours when administered intranasally). The primary adverse reaction was acute withdrawal in patients with opioid dependence.
• Conclusion: The longer duration of action of nalmefene does not eliminate the need for medical observation after administration. Nalmefene may require longer monitoring times and result in increased patient ED length of stay and resource utilization. In  the case of naloxone, which has a relatively short duration of  action, severe withdrawal usually lasts less than an hour. A  longer acting antagonist may cause longer lasting precipitated withdrawal and may lead to  worse patient outcomes. Therefore, it was the opinion of  the American College of  Medical Toxicology and the American Academy of Clinical Toxicology that nalmefene should not replace naloxone as the primary opioid antidote.

CRITIQUE

• Pros: This paper considered several studies that were included in FDA reviews for the nalmefene over time, starting from its initial approval in the 1990s. It considered both clinical data from FDA investigations with pharmacologic understanding of the medications to compare it to naloxone.
• Cons: The paper acknowledges that the clinical data on nalmefene for safely reversing opioid poisoning is sparse. They also report that some of the studies that were conducted occurred before fentanyl became a common cause of opioid overdose in the United States, and thus may have limited application to the current opioid crisis.

IMPLICATION FOR TOXICOLOGISTS/EM 

This paper highlights the importance of continued efforts to challenge the standard of care to promote improved patient care. While nalmefene has limited data supporting its use in current practice, reviewing its limitations allows physicians and medical professionals to acknowledge the risks and benefits of naloxone in treating acute opioid overdose in the ED.

Article: Van Oyen A, Barney N, Grabinski Z, et al. Urine Toxicology Test for Children With Altered Mental Status. Pediatrics. 2023;152(5):e2022060861. 

Review by: John Michael Sherman (Carolinas Medical Center)

• Background: Cannabis use is increasing worldwide, and with the increased prevalence and availability of various THC products, there has been over 1000% increase in unintentional edible cannabis ingestions presenting to pediatric emergency departments since 2017. Cannabinoid toxicity can have a variable presentation in pediatric patients, including altered mental status (AMS), ataxia, tachycardia, mydriasis, seizures, hypotonia, and respiratory depression. While intoxication is often considered as a cause of AMS for adult patients, this may not be the case for pediatric patients. Urine toxicology screening may be ordered less frequently in a pediatric population, leading to delays in diagnosis and unnecessary testing.
• Research question: Can obtaining urine toxicology screen reduce diagnostic testing or hospital admission in pediatric patients presenting with altered mental status? 
• Methods: This is a case series of five patients under 6 years of age who presented to the ED for altered mental status and were found to have cannabinoid toxicity diagnosed on urine toxicology immunoassay. 
• Results: All 5 patients presented with altered mental status and decreased level of responsiveness, ranging from arousable to verbal stimuli to unresponsive; 3 of the 5 initially presented to community EDs, and the urine toxicology screen was not performed until after they were transferred to a pediatric ED. Additional testing included CBC, CMP, EKG, acetaminophen and salicylate levels, ethanol level, and VBG. 4 of the 5 received a head CT, and one additionally had CTs of the cervical spine and chest. Of note, this patient was noted to be dizzy and vomited after being struck in the head by his sibling with a metal water bottle. Two patients were discharged from the ED after observation, one was admitted to the pediatric floor, and two were admitted to the PICU.
• Conclusions: For each of these patients who presented with altered mental status, the diagnosis was made via the urine toxicology screen. Had this test been ordered earlier in the patients’ ED course, additional testing, admission, or transfer may have been avoided.

CRITIQUE

• Pros: The delay in obtaining urine toxicology screen in 3 of the 5 patients discussed may have led to delay in diagnosis and possibly to unnecessary testing and admission. The authors discuss that for one of the patients (#5), the urine toxicology screen was obtained immediately on arrival and obviated the need for some additional testing.
• Cons: This was a case series and not a randomized controlled trial or observational trial. Three of the 5 patients were ultimately admitted to the hospital, including two to the PICU. Although the urine toxicology screen may have spared one of the patients (#5) from a head CT, they were still admitted to the PICU, a resource-heavy and costly disposition.

IMPLICATION FOR TOXICOLOGISTS/EM

The urine toxicology immunoassay is a much-maligned test by toxicologists, and is often criticized for seldom changing management in the ED, introducing bias to patient care, and increasing ED costs. This study suggests that ED physicians should have a high index of suspicion for THC toxicity for pediatric patients with altered mental status, given the rapid and profound increase in pediatric exposures to THC, and should consider utilizing this diagnostic tool. It is still not a diagnostic panacea, and physicians should not anchor on THC toxicity at the expense of considering other etiologies of AMS including trauma, metabolic derangements, or infection.

Article: Freund, Y, Viglino D, Cachanado M, et al. Effect of Noninvasive Airway Management of Comatose Patients with Acute Poisoning: A Randomized Clinical Trial. JAMA. 2023; 330(23):2267-2274. 

Review by: Laura Szczesniak, MD, PhD (Medical College of Wisconsin Affiliated Hospitals) 

• Background: One reason we intubate acutely ill patients is to prevent aspiration pneumonia from gastric contents when a patient is not able to protect their own airway, but intubation itself can also cause pneumonia. Other risks of intubation include hemodynamic instability, and any unanticipated difficulties from intubation may lead to hypoxia or damage to teeth or the oropharynx. The authors of this paper argue that there may be a clinical benefit to withholding intubation specifically in acutely poisoned patients to decrease overall hospitalization and reduce adverse events from intubation. 
• Research question: Does withholding intubation in comatose patients suspected of acute poisoning improve patient  outcomes when compared to routine intubation practice?
• Methods: This was a multicenter, unblinded, randomized, parallel-group trial on a convenience sample of comatose patients (defined as GCS < 9) with suspected acute poisoning over a 2-year period. Patients were randomly assigned to control or intervention group and each hospital site, which included 20 EDs and 1 ICU. The intervention group intubation strategy was to withhold intubation unless emergency criteria were met, defined as seizure, respiratory distress (pulse oximetry <90% persisting after nasal cannula), vomiting, and shock (systolic BP < 90 mm Hg refractory to 1 L crystalloid fluid resuscitation). The control group intubation strategy was based on the treating physician’s discretion. The intervention lasted 4 hours total, after which patients were managed according to routine practice. Primary outcomes included length of hospitalization, length of intensive care unit (ICU) admission, and/or mortality rates. Numerous secondary outcomes were measured, including patients developing rapid-onset pneumonia or patients that experienced adverse events from intubation. Patient outcomes were measured for a total of 28 days.
• Results: There were 116 patients in the intervention group and 109 in the control group who underwent primary analysis. The mean age was 33 years and 35% of patients were female. 19 patients were intubated in the intervention group (16.4%) compared to 63 patients in the control group (57.8%). Patients in the intervention group had a shorter median ICU stay when compared to the control group (0 vs 24 hours), as well as a shorter medial length of hospital stay (21.5 vs 37 hours). No patients died in either group. Patients in the intervention group had 8.6% less adverse events from intubation and 7.8% less instances of rapid-onset pneumonia. When comparing all intubated patients, the authors found that there was no significant difference in adverse events, first pass failure, or length of ICU stay between the intervention and control groups.
• Conclusion: There appears to be some clinical benefit and no significant risk to avoiding or delaying intubation in acutely poisoned patients. It should make you think twice before intubating an acutely poisoned patient, but overall, more studies should be done before any major practice changes are implemented. 

CRITIQUE

• Pros: This study examined outcomes about one month out from the intervention, which provided more long-term effects of each group. They also examined whether patients with delayed intubation in the intervention group had any differences in outcomes, which provides an additional reassurance that avoiding or at least delaying intubation will not worsen outcomes.
• Cons: Most ingestions in this study were attributed to alcohol or benzodiazepines, which is difficult to generalize to all acute poisonings. Many patients were excluded from this study, including patients that took cardiotropic drugs such as beta blockers, calcium channel blockers, and ACE inhibitors. The intervention duration was limited to 4 hours. Using physician discretion for intubation in the control group also likely caused significant variation in intubation based simply on different practice patterns.

IMPLICATION FOR TOXICOLOGISTS/EM

This was an interesting study despite its significant limitations. As we face surges in ED visits and increased ED boarding, a more conservative strategy for intubation may allow for more flexibility in staff and resource allocation in the ED and hospital.