• D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

      Kato, Risako; Zhang, Edlyn R.; Mallari, Olivia G.; Moody, Olivia A.; Vincent, Kathleen F.; Melonakos, Eric D.; Siegmann, Morgan J.; Nehs, Christa J.; Houle, Timothy T.; Akeju, Oluwaseun; et al. (2021-05-18)
      D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an alpha2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 +/- 37.2 min; d-amphetamine:1.8 +/- 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 +/- 18.0 min; d-amphetamine:20.3 +/- 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies < 25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.
    • Outcomes of Prehospital Chemical Sedation With Ketamine Versus Haloperidol and Benzodiazepine or Physical Restraint Only

      O'Connor, Laurel; Rebesco, Matthew; Robinson, Conor; Gross, Karen; Castellana, Andrew; O'Connor, Mark J.; Restuccia, Marc C. (2018-08-27)
      OBJECTIVE: The goal of this study is to describe complications and outcomes of prehospital ketamine use for agitation as compared to other methods of physical or chemical restraint such as haloperidol plus benzodiazepine or physical restraint only. METHODS: We conducted a single-center retrospective review of patient encounters in which restraint was administered in the prehospital setting. At the beginning of our study window, only physical restraint was available to paramedics managing agitated patients but subsequently, haloperidol and benzodiazepines were introduced, followed by ketamine 2 years later. By comparing patients before and after each transition, we divided subjects into 3 cohorts based on restraint type: physical restraint, haloperidol plus benzodiazepine, and ketamine. Demographic data were collected, and outcome measures included intubation rate, need for additional physical or chemical restraint, emergency department (ED) length of stay, need for hospital admission, and employee injury. RESULTS: Of 214 subjects included in the study, 95 patients were administered ketamine, 68 received haloperidol and benzodiazepine, and 51 were physically restrained. Eleven of the patients (11.6%) who received ketamine were intubated. Compared to patients who received haloperidol plus benzodiazepine, patients who received ketamine were more likely to be intubated (odds ratio [OR] = 8.77, 95% confidence interval [CI], 1.10-69.68) and were more likely to require additional chemical restraint when compared to haloperidol/benzodiazepine or physical restraint only (OR =2.94, 95% CI, 1.49-5.80, and OR =2.15, 95% CI, 1.07-4.31, respectively). There were no differences between the 2 chemical sedation groups in terms of ED length of stay or hospital admission rate. CONCLUSIONS: This study demonstrates a lower intubation rate in patients administered ketamine than prior literature in association with a lower weight-based dosing regimen. Ketamine use was correlated with a higher frequency of intubation and a greater need for additional chemical restraint when compared with other restraint modalities, though exogenous factors such as provider preference may have impacted this result. There was no difference in ED length of stay or admission rate between the ketamine and haloperidol plus benzodiazepine groups. Further prospective study is needed to determine whether there is a subset of patients for whom ketamine would be beneficial compared to other therapies.
    • Patient Outcomes Following Ketamine Administration for Acute Agitation with a Decreased Dosing Protocol in the Prehospital Setting

      Cunningham, Cassidy; Gross, Karen; Broach, John P.; O'Connor, Laurel (2021-06-01)
      BACKGROUND: Agitated behaviors are frequently encountered in the prehospital setting and require emergent treatment to prevent harm to patients and prehospital personnel. Chemical sedation with ketamine works faster than traditional pharmacologic agents, though it has a higher incidence of adverse events, including intubation. Outcomes following varying initial doses of prehospital intramuscular (IM) ketamine use have been incompletely described. OBJECTIVE: To determine whether using a lower dose IM ketamine protocol for agitation is associated with more favorable outcomes. METHODS: This study was a pre-/post-intervention retrospective chart review of prehospital care reports (PCRs). Adult patients who received chemical sedation in the form of IM ketamine for agitated behaviors were included. Patients were divided into two cohorts based on the standard IM ketamine dose of 4mg/kg and the lower IM dose of 3mg/kg with the option for an additional 1mg/kg if required. Primary outcomes included intubation and hospital admission. Secondary outcomes included emergency department (ED) length of stay, additional chemical or physical restraints, assaults on prehospital or ED employees, and documented adverse events. RESULTS: The standard dose cohort consisted of 211 patients. The lower dose cohort consisted of 81 patients, 17 of whom received supplemental ketamine administration. Demographics did not significantly differ between the cohorts (mean age 35.14 versus 35.65 years; P = .484; and 67.8% versus 65.4% male; P = .89). Lower dose subjects were administered a lower ketamine dose (mean 3.24mg/kg) compared to the standard dose cohort (mean 3.51mg/kg). There was no statistically significant difference between the cohorts in intubation rate (14.2% versus 18.5%; P = .455), ED length of stay (14.31 versus 14.88 hours; P = .118), need for additional restraint and sedation (P = .787), or admission rate (26.1% versus 25.9%; P = .677). In the lower dose cohort, 41.2% (7/17) of patients who received supplemental ketamine doses were intubated, a higher rate than the patients in this cohort who did not receive supplemental ketamine (8/64, 12.5%; P < .01). CONCLUSION: Access to effective, fast-acting chemical sedation is paramount for prehospital providers. No significant outcomes differences existed when a lower dose IM ketamine protocol was implemented for prehospital chemical sedation. Patients who received a second dose of ketamine had a significant increase in intubation rate. A lower dose protocol may be considered for an agitation protocol to limit the amount of medication administered to a population of high-risk patients.