Article

Ketamine exposure demographics and outcomes over 16 years as reported to US poison centers

Journal logoUnlabelled imageAmerican Journal of Emergency Medicine 36 (2018) 1459-1462

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Ketamine exposure demographics and outcomes over 16 years as reported to US poison centers?

Andrew Ni, F. Lee Cantrell, Richard F. Clark ?

The Division of Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, San Diego, CA, United States

a r t i c l e i n f o

Article history:

Received 6 April 2018

Received in revised form 28 April 2018

Accepted 30 April 2018

Keywords: Ketamine Toxicity Poison centers Demographics Outcomes

a b s t r a c t

Background: This study sought to examine ketamine exposures reported to US poison centers over the past 16 years and identify trends in exposures and outcomes.

Methods: A retrospective review was performed of all cases involving ketamine exposures reported to US poison centers and entered into the National Poison Data System from 2000 to 2015. Cases were divided into those in- volving ketamine alone and those involving ketamine and other agents. Data collected included: age, sex, form of ketamine used, reason for exposure, and outcome.

Results: A total of 3109 cases were evaluated. 1595 (51%) reported ketamine to be the only substance exposure, while 1514 (49%) involved multiple substances with ketamine. For single agent exposures, more involved males (67%) between the ages of 16-25 years (49%). Single agent ketamine exposures peaked between 2000 and 2002, fell consistently until 2008; then rebounded to previous peak levels through 2015. Intentional exposures (65% of all cases) were the most common reason for single agent ketamine exposures. 53% of ketamine-only cases re- sulted in minor effects, with two deaths. In contrast, ketamine exposures with multiple agents resulted in out- comes judged as moderate or worse in 62% of cases, including 20 deaths.

Conclusion: Single-agent ketamine exposures reported to US poison centers have rebounded to historical peaks in recent years. More deaths and serious outcomes were reported IN ketamine exposures involving multiple substances.

(C) 2018

Introduction

Ketamine is a dissociative anesthetic that was first introduced into clinical practice in 1965 with utilization in the fields of the Vietnam War [1]. Since then, its use has become widely established in the medi- cal community and it is currently listed as an injectable anesthetic on the World Health Organization (WHO) Model List of Essential Medi- cines [2]. The main mechanism of action of ketamine is via N-methyl-

D-aspartate (NMDA) receptor antagonism, though there is significant opioid receptor activity as well [3]. Cholinergic and sympathomimetic receptors may also be affected. The most common complaints with ke- tamine intoxication involve impaired consciousness, ranging from mild agitation to dissociation with hallucinations. However, due to a rela- tively short half-life, significant first-pass metabolism, and lack of car- diorespiratory depression, ketamine toxicity cases have classically required minimal intervention with no lasting effects [4].

? Presented at the 2017 North American Congress of Clinical Toxicology Scientific meet- ing in Vancouver, BC.

* Corresponding author at: 200 West Arbor Dr., San Diego, CA 92103-8676, United States.

E-mail address: [email protected] (R.F. Clark).

Ketamine is well-known as a staple anesthetic in pediatric emer- gency departments, likely owing to the rarity of circulatory and respira- tory system depression [5,6]. Due to its psychotropic nature and relative safety, in recent years there has been research into the use of ketamine for novel indications. For example, ketamine may have some efficacy in some refractory pain conditions, such as with complex regional pain syndrome [7]. Ketamine has also been shown effective for depression and bipolar disorder, with rapid onset and good tolerability [8]. Combin- ing ketamine during sedation with other agents such as propofol or using subdissociative Ketamine doses may lower adverse effects while maintaining efficacy [9-11].

The emergence of recreational use ketamine (also known as K, Special K, vitamin K, and Kit Kat) began largely due to its purported hallucinogenic properties. Individuals in our emergency depart- ment have also reported the use of illicit ketamine to mitigate the Withdrawal symptoms associated with discontinuing heroin. Dur- ing recreational use, unlike with medical administration, ketamine is typically insufflated through the nose as a liquid or powder, or taken orally in liquid form [12]. The side effects of ketamine use are rare through these routes of administration when compared to injection, with even lower rates of respiratory depression, laryngospasm, and excessive salivation [12].

https://doi.org/10.1016/j.ajem.2018.04.066

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As ketamine becomes accepted for wider medical indications, illicit usage may also increase. We therefore undertook this retrospective re- view of ketamine exposures reported to US poison centers to character- ize trends in exposures.

Methods

This study was exempted from review by our institution’s Human Research Protection Program by using retrospective and de-identified records. The data used in this study included all cases of ketamine expo- sures reported to US poison centers from January 1, 2000 to December 31, 2015 as compiled in the National Poison Data System (NPDS). This included exposures from homes and health care facilities. Only human calls were included. The NPDS contains cases from poison centers

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throughout the US, and data can be accessed by contributors. Exclusion criteria for our study included: cases where more than one data point of our analysis was missing from the record, and those where ketamine was mistakenly coded in the poison center chart as being involved in the exposure. The information abstracted from each case included: year, number of substances involved, age, gender (sex), reason for expo- sure, and medical outcome. Exposure site and exposure route were not included in the evaluation since this information was missing from many charts. The formulation of ketamine (such as liquid or powder) involved in the exposure was also recorded. Cases were organized and plotted using simple descriptive statistical methods to observe trends in Ketamine usage.

Regarding reason for the exposure, cases comprising the “inten- tional” group included those reported to poison centers and coded as “intentional abuse”, “intentional misuse”, and “suspected suicide at- tempt”. Cases included in the “non-intentional” group included those reported and coded as “adverse reaction”, “unintentional — therapeu- tic”, “unintentional — occupational” and “unintentional — general”. Medical outcomes were divided into four coded categories: minor, moderate, major, and death. The “minor” group included all outcomes reported as “no effect”, “not followed, judged as nontoxic exposure (clinical effects not expected)”, “not followed, minimal clinical effects possible (no more than minor effect possible)”, “unable to follow, judged as a potentially toxic exposure”, and “minor”. The “moderate”, “major”, and “death” groups were reported as such. Since some cases were missing only one data point to be evaluated, these cases were in- cluded but the resulting categorical totals differ slightly and reflect the available data. A chi-squared analysis was conducted to assess and to compare outcomes between intentional and non-intentional use.

Results

A total of 6233 cases were available for review, but 3124 were ex- cluded due to incomplete records or miscoding, leaving 3109 cases studied. Cases were divided into those where the ketamine exposure was as a single agent (1595, 51%) and those where the ketamine expo- sure reportedly occurred with multiple substances (1514, 49%).

The demographics (age and gender) of ketamine exposures (single agent) are plotted in Fig. 1. Males aged 16 to 25 years accounted for a large portion of all reported cases during our study period (35%). Includ- ing the cases of multiple agent exposures does not largely affect the age distribution of the cases, with 16 to 25 year-old males still accounting for 36%.

Ketamine exposures as reported in calls to US poison centers over our study period showed a “U-shaped” distribution (Fig. 2). It is unclear whether the early 2000s witnessed a peak in reported ketamine expo- sures without data from earlier years, but 2003 marked the beginning of a decline in reported exposures, dipping to 46 in 2008. However, re- ported exposures began trending upward again in 2011, reaching a peak of 146 in 2013. Including cases with multiple substance exposures did not affect the general distribution of reported cases.

Fig. 1. The demographics (age and gender) of ketamine exposures (single substance) over the study period.

The most common formulation of ketamine used as reported to US poison centers was liquid, accounting for 45% of all cases (Fig. 3). The next two most used formulations included capsule and powder, at 21% and 16%, respectively.

Intentional exposures were by far the most common reason for reporting a case of ketamine exposure, accounting for 65% of all cases (Fig. 4). Non-intentional exposures represented 25% of all cases.

Outcomes analysis showed 53% of ketamine-only cases resulted in only minor effects, with only two deaths. Ketamine exposures associated with multiple substances showed 62% of outcomes as moderate or worse, including 20 deaths (Figs. 5). A chi-squared anal- ysis comparing the total number of exposures over the study period with moderate or worse outcomes (including death) in each group obtained a statistically significant p-value of b0.00001, suggesting worse outcomes in reported exposures when multiple substances were involved with ketamine. Although Outcome severity classifica- tions for exposures as coded by poison centers did not change throughout the study period, we do not know if subjective outcome coding may have changed among different contributing poison centers over time.

Discussion

Ketamine has been accepted as a form of anesthesia for decades. Since it was considered less titratable and more psychotropic than other forms of anesthesia, use was limited and data sparse regarding

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Fig. 2. Ketamine exposures reported to US Poison Centers from 2000 to 2015.

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Fig. 3. Formulations (does not distinguish between intravenous [IV], intramuscular [IM], rectal or oral) of ketamine used in exposures reported to US Poison Centers during the study period where ketamine was the single substance.

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Fig. 5. Reported outcomes of ketamine (single drug vs multiple drug) exposures to US Poison Centers during the study period.

ketamine toxicity. However, with the increase in novel and recreational use of ketamine, characterizing trends in ketamine toxicity presentation and outcomes is more important than ever.

The change in ketamine exposures reported to US poison cen- ters over the 16-year study period had a U-shaped distribution. It seems that reported exposures have risen again despite a decline in the mid-2000s. The internet contains extensive discussions of recreational use of ketamine and may have stimulated recent interest. Ketamine’s revitalized roles as a psychoactive agent and anesthetic continue to stimulate research and increase medicinal indications.

Even though about two-thirds of reported solo ketamine expo- sures in our study were intentional (including 71 suspected suicide attempts), outcomes were rather mild, with only two deaths. Multi- ple substance exposures with ketamine showed worse outcomes, with most cases reporting “moderate” or more Severe outcomes. Though the total cases were about evenly split between solo keta- mine exposures and multiple substance exposures (51% and 49% respectively), multiple substance exposures accounted for 20 of 22 deaths.

Limitations

Retrospective review of poison center data always suffers from limitations. First, reporting of cases is voluntary and will miss

unreported exposures. Information in cases is limited to that pro- vided by callers and recorded by poison center specialists. It is unclear whether the trends noted by poison center data are consis- tent with general use patterns in society. It is also impossible to determine whether the ketamine exposures occurred from illicit sources or were hospital acquired. Another limitation is potential incorrect coding of substances as ketamine in poison center data bases. The National Poison Data System does not collect the sub- stance text field, so there is no way to evaluate the accuracy of the substance coding.

Some of the data we collected involves ketamine exposures with other agents. Our collected data did not specify the other agents in- volved. It is possible that the other agents used with ketamine were solely responsible for the higher numbers of more severe outcomes and death. Finally, a significant number of cases were excluded due to missing variables. Including these cases could have affected numbers and comparisons.

Summary

As ketamine use increases in medicine, it is likely that hospital ad- ministration and recreational use will increase. Reports to US poison centers from 2000 to 2015 have mostly been the result of intentional abuse, but our data suggested isolated use of ketamine rarely led to major side effects. Despite the relative safe toxicity profile of ketamine, physicians should be aware of its abuse potential.

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