Critical Illness Secondary to Synthetic Cannabinoid Ingestion

Key Points Question What are the clinical manifestations of synthetic cannabinoid intoxication, and are they life threatening? Findings This case series of 30 adult patients describes the acute neurologic and cardiopulmonary complications of synthetic cannabinoid intoxication, including severe toxic encephalopathy, acute respiratory failure, and death. Meaning These findings suggest that synthetic cannabinoids are a continued public health threat, with potential for morbidity and mortality from acute intoxication.


Introduction
Synthetic cannabinoids (SCs), also known as K2, spice, and fake weed, are cheap, artificially manufactured recreational drugs that have emerged as a major public health threat in various regions of the world. Data from European, Australian, and American toxicology centers show a steady increase in SC use since 2012. 1,2 On the basis of a preliminary report by the American Association of Poison Control Centers, 3 at least 2695 exposures were confirmed in 2016 alone.
Our current knowledge of the physiologic effects of SC comes from case reports, toxicology case series, and forensic literature. [4][5][6][7] More recent studies [8][9][10] have shown that some synthetic cannabinoids are at least as potent as Δ9-tetrahydrocannabinol, whereas others can be as much as 100-fold more potent. There is no known antidote for SC intoxication. 11 Clinical manifestations are unpredictable and vary by the type and the amount of SC used. 5,7 Synthetic cannabinoids have neuropsychological effects due to the nonstandardized ingredients during production, and the toxic effects can vary widely. 12 Producing SCs involves spraying different chemical compounds on various inert plant materials that are consumed with smoking. 10 Furthermore, the Centers for Disease Control and Prevention reported the potential for addiction along with signs of withdrawal in regular users. 13,14 The long-term effects of SC use are largely unknown. 6,15 New York, New York, is a major trafficking center for SC, with episodes of mass intoxication occurring in 2015 and 2016. 16 The increase in acute SC poisonings, notably with the substance K2, is the focus of our case series. We describe 30 patients with acute life-threatening neurologic and respiratory complications who required intensive care unit (ICU) admission within a 2-year period. To our knowledge, this is the largest reported series of critically ill patients with SC intoxication.

Methods
This case series received exempt approval from the institutional review board of Mount Sinai Morningside and Mount Sinai West Hospitals. A waiver of documented consent was granted by the institutional review board committees because this research presented no more than minimal risk of harm to participants. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We retrospectively reviewed records of 42 adult patients (aged Ն18 years) with reported SC intoxication who were admitted to the ICU at Mount Sinai Morningside and Mount Sinai West Hospitals during a 2-year period (2014-2016). Data were extracted from the medical record and prehospital records. All data were deidentified.
Patients were identified through ICU census records. The inclusion criterion was use of SC, as confirmed by either oral report from the patients or reported by bystanders or paramedics and documented in the medical record. Patients who denied use of SC, had high serum alcohol levels, or had urine toxicology studies that were positive for phencyclidine, amphetaminoids, or cocaine were excluded unless they reported such use more than 3 days before admission. patients were admitted to the ICU, whereas 7 patients received critical care services in the emergency department (ED). Twenty-five patients had a history of polysubstance abuse, psychiatric illness, or known personality disorder. Twenty patients admitted to smoking K2, and for 10 additional patients, K2 use was witnessed and recorded by friends, bystanders, or paramedics. Seven patients reported that they obtained K2 at main train stations in New York or after they were released from jail. Figure 1 summarizes the demographic characteristics, resource utilization, and clinical outcomes of the patients.
The ICU admissions were all for neurologic toxic effects and/or associated respiratory failure.
Eight patients (26%) presented with acute kidney failure. Table 1 summarizes the clinical findings of the critically ill patients.
One young woman with history of asthma died of complications from ARDS shortly after presentation to the ED (patient 26 in Table 2). A man in his 30s presented with hemoptysis after smoking K2 and was found to have radiographically unilateral pulmonary edema (Figure 2).
Bronchoscopy was performed before his discharge, and the findings were consistent with diffuse alveolar hemorrhage (patient 30 in Table 2). A man in his 50s was admitted with unresponsiveness and moderate ARDS after admitted K2 use. The ARDS resolved after 7 days of mechanical ventilation (patient 9 in Table 2). A man in his 20s with history of end-stage renal disease (ESRD) and pulmonary hypertension, as well as bipolar disorder and long-term marijuana use, was admitted with respiratory distress and was found to have anterolateral wall ST-segment-elevation myocardial infarction after  smoking K2 for the first time. His care was complicated by elopement twice (patient 15 in Table 2).
Our cohort included another patient with ESRD and coronary artery disease who presented with pulmonary edema shortly after K2 use (patient 29 in Table 2).
Computed tomography scan of the head was performed for 26 patients (86%), and 6 patients (20%) underwent electroencephalogram monitoring (Table 1). One patient was found unresponsive, hypothermic, and hypoxemic on the street. He had absent brain stem reflexes and decerebrate Readmission associated with K2 5 (16) posturing (patient 16 in Table 2). Computed tomography of the head showed global cerebral edema with loss of gray-white differentiation (Figure 3), consistent with anoxic brain injury; however, he improved and was extubated 40 hours later after treatment with mannitol and hypertonic saline.
Lumbar puncture needed to be performed for a woman who presented unresponsive and with nuchal rigidity (patient 12 in Table 2). Two patients underwent diagnostic cardiac catheterization for chest pain with associated electrocardiographic abnormalities (patients 15 and 28 in Table 2).
All patients underwent routine serum and urine toxicology testing, which was negative in 16 cases; however, testing revealed at least 1 coingestion (cocaine, marijuana, alcohol, or methadone) in the other 14 cases. We included in our cohort 2 patients who admitted to long-term cocaine use but who reported their last use days before their presentation in the ED (patients 13, 18 Table 2), and a patient whose urine toxicology findings indicated phenylcyclidine; he denied using phenylcyclidine but admitted to K2 use (patient 28, Table 2). Five patients in our cohort were known K2 users with K2-related ED visits in our hospital system noted days before their admission that required critical care attention (patients 1, 5, 9, 10, and 19 in Table 2).
Rhabdomyolysis was noted in 8 patients (26%) (Figure 1). QT prolongation, which has been reported in the literature 17 in association with SC use, was noted in 10 patients (33%). Sixteen  Table 2).

mm
Computed tomography of head was obtained without intravenous contrast agent. Note the diffuse cerebral edema and loss of gray-white differentiation. The patient self-extubated within 3 days after his presentation (patient 16 in Table 2). patients (53%) left the hospital against medical advice, and 4 were admitted in the psychiatric unit after the resolution of the acute effects of intoxication for persistence of the behavioral alteration and the unsafety of community disposition (patients 9, 10, 16, and 23 in Table 2).

Discussion
Synthetic cannabinoids were developed in research in the 1970s to study the cannabinoid system. 6,18 It was not until 2008 that SCs reemerged in the US as a cheap recreational drug. 1,19 The harmful effects of exposure to SC were first reported in the US in 2009. 3 Cannabinoid CB1 receptors are among the most abundant receptors expressed in the brain and play a significant role in the modulation of GABA and glutamate neurotransmission, 10,20 affecting the neuronal functioning of the prefrontal cortex 21 and, thus, emotional processing, sensory perception, and elaboration of incoming sensory information. 12 Other serious adverse effects, particularly sympathomimetic and hallucinogenic effects related to new compounds, may be due to indirect activation of other receptors via excess activation of cannabinoids receptors, direct receptor activations due to mixed receptor effects of new cannabinoids, or possibly adulterants, including plant material effects 7 .
Synthetic cannabinoids are often smoked. 11 When inhaled, effects begin within minutes, with a shorter duration of action and quicker time to peak onset compared with nonsynthetic cannabinoids. 22 Intoxication with SCs may manifest as violent behavior, 6 psychosis, 23 paranoia, 10,23 delirium, 23 and withdrawal. 10,13 Patients may develop severe neurologic toxic effects, including generalized tonic-clonic seizures, 10,24 cardiovascular events, including myocardial infarction, 25,26 transient cerebral edema mimicking anoxic brain injury, 27 intracranial hemorrhage, and cerebral ischemic events. 28 Pulmonary manifestations include diffuse alveolar hemorrhage, 29 respiratory failure, with radiographs showing diffuse pulmonary infiltrates and tree-in-bud morphologic features, and computed tomography findings mimicking organizing pneumonia in young users. 30 Severe rhabdomyolysis, acute kidney injury with acute tubular necrosis, 6,31,32 and death are also manifestations of SC intoxication. 10,11,19 In our series, all 30 patients required critical care interventions, with 23 requiring ICU level of care. Most of the patients were young men with a history of either psychiatric disorders or substance abuse. Most presented with mental status changes ranging from coma (10 patients), to agitation (10 patients), to seizures (6 patients). Bizarre behavior was documented in some patients without further characterization. Twenty-one patients required invasive mechanical ventilation, including 40% who presented with hypercarbia. Patients also presented with acute kidney injury (26%) and cardiac toxic effects, including myocardial infarction, bradycardia, and QT prolongation. Although they were critically ill at admission, rapid improvement was the usual course, and most (53%) left the hospital against medical advice.
In our experience, catastrophic presentations of K2 intoxication, such as cerebral edema and ARDS, have the potential for rapid reversal. We have previously described 1 patient who was found unresponsive, hypothermic, and hypoxemic on the street. 27 He had absent brain stem reflexes and decerebrate posturing (patient 16 in Table 2). Computed tomography of the head showed global cerebral edema with loss of gray-white differentiation (Figure 3), consistent with anoxic brain injury; however, he improved and was extubated 40 hours later after treatment with mannitol and hypertonic saline. A man in his 50s was admitted with unresponsiveness and moderate ARDS after admitted K2 use. The ARDS resolved after 7 days of mechanical ventilation (patient 9 in Table 2). A woman in her 20s with a history of asthma and anxiety, presented with respiratory distress, altered sensorium, and generalized tonic-clonic seizures after K2 inhalation. She was profoundly hypoxemic upon presentation and had repeated cardiac arrests (patient 26 in Table 2). She eventually died despite aggressive resuscitative efforts.
What remains unclear is whether these manifestations of K2 intoxication are due to the toxicity of the chemicals or due to excessive dosages. 5,7 The amount of K2 smoked could not be quantified, but a few patients reported that they smoked only 1 cigarette. We are reluctant to comment on the

JAMA Network Open | Substance Use and Addiction
Critical Illness Secondary to Synthetic Cannabinoid Ingestion extent of effect when patients are found with coingestions, but for those with opioid coingestion, we observed that some patients had no response to naloxone. On the basis of our experience, we have a high index of suspicion for SC intoxication in cases of severe and uncontrolled agitation in the setting of negative or inconsistent toxicology studies. Similarly, we suspect SC use in cases of unresponsiveness with no response to naloxone, or with an atypical presentation of known intoxication. Our cohort included 2 patients with significant comorbidity, including 1 with ESRD and pulmonary hypertension (patient 15 in Table 2) and 1 with ESRD and coronary artery disease (patient 29 in Table 2). We do not conclude that the SC was an isolated causative factor for their decompensation. Yet, because of the observed temporal association between SC smoking and when they sought and received medical attention, we speculate that the acute cardiovascular effects of SC use led to their decompensation.
Understanding the limitations of toxicology screening is important. Although detection of some SCs is possible with means of liquid chromatography or mass spectrometry in specialized laboratories, 33 conventional drug test panels available in most hospitals do not detect the broad range of SCs. Metabolites of SC can be detected by specialized forensic toxicology laboratories. 5,7 Efforts to identify other ever-emerging SC metabolites continue. During an outbreak in Brooklyn, New York, in 2016, 16

Limitations
This study has several limitations, including the retrospective nature of the analysis. Our cases were confirmed by history and emergency medical services report and not by chemical analysis, which was not available at our institution. Because signs of SC intoxication usually abate over time, it is possible that cases were missed. The toxicology studies sent from our ED and ICU reflected the presence of other coingestions. We excluded cases where phenylcyclidine, cocaine, amphetamines, or high alcohol levels were isolated in the urine or serum studies. We included in our cohort 2 patients who admitted to long-term cocaine use, but who reported last use days before their presentation in the ED (patients 13 and 18 in Table 2), and a patient whose urine toxicology findings indicated phenylcyclidine; he denied its use but admitted to K2 use (patient 28 in Table 2). Given the difficulty in identifying SC as an intoxicant, it is inevitable that SC use is both underreported and underdiagnosed. 11,34 Most patients who admitted to SC use did so only when they were specifically asked; hence, this series could be an underestimate of the true prevalence of critically ill patients with SC intoxication. Five patients in our cohort were known K2 users with K2-related ED visits in our hospital system noted days before their admission that required critical care attention (patients 1, 5, 9, 10, and 19 in Table 2).

Conclusions
Health care practitioners should be familiar with the potential adverse effects of SC and suspect its use in the at-risk population. Despite the toxicity of SC and the legal acts to stop its distribution, abuse is expected to increase, in part because of the ease of acquisition though online retailers and a false perception among users that SCs are safe, affordable alternatives to cannabis. Management of SC intoxication in the critically ill patient remains supportive, targeting hemodynamic stabilization, electrolyte balance, seizure control, hydration with intravenous fluids, and observation until the