Ketamine Potpourri
/In our most recent journal club, we took a look at 3 articles focused on the use of ketamine in the Emergency Department. When treating pain with ketamine, does a rapid administration of ketamine result in more dysphoria? When used for RSI, is ketamine more hemodynamically stable than etomidate? When using ketamine for procedural sedation in adult patients, does pre-treatment with versed or haldol decrease clinically significant emergence agitation?
Motov, S., Mai, M., Pushkar, I., Likourezos, A., Drapkin, J., Yasavolian, M., Brady, J., Homel, P., Fromm, C. (2017). A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain in the ED The American Journal of Emergency Medicine 35(8), 1095-1100. https://dx.doi.org/10.1016/j.ajem.2017.03.004
Background
Ketamine has become an increasingly popular medication in the ED for many purposes, including its use as an analgesic agent. Ketamine can be given in a “pain-dose” at 0.15-0.3 mg/kg and there have been several RCTs showing its effectiveness. Commonly quoted benefits of pain-dose ketamine include it’s opioid sparing effect and relative hemodynamic stability. You can see why this is an attractive option. However, pain-dose ketamine is not without its own side effects - feelings of unreality (aka the “k-hole), over-sedation, nausea/vomiting and dizziness. The authors of the original studies observed that side effects were more likely to be present shortly after ketamine administration and the side effects seemed less severe when ketamine was given over a longer period of time. ED providers confirmed these findings anecdotally in their own practice, however no studies existed to specifically answer this question – which leads to this article…
Methods
This was a prospective, randomized, double-blind, and double-dummy trial that attempted to evaluate the rates of adverse effects and analgesic efficacy of IV push pain-dose ketamine compared to a slow infusion of IV ketamine. This was a single center trial that enrolled adult patients age 18-65 that presented to the ED with acute painful conditions with an intensity of 5 or greater. Many different exclusion criteria were present, most notably for patients with unstable vital signs, head injuries, alcohol or drug abuse, psychiatric illness or other analgesic use in the prior 4 hours. They obtained a convenience sample of patients and randomized them to either receive IV push ketamine (0.3 mg/kg) given by slow push over 5 minutes or mixed in a 100cc NS bag and infused over 15 minutes. This was a double-dummy trial so each patient also received a placebo administration of the other intervention. The authors had two primary outcomes – (1) rate/severity of nine adverse effects on the SERSDA scale and (2) severity of agitation/sedation on the RASS scale. These were assessed at regular intervals from 5 min to 120 min. Secondary outcomes included pain severity, changes in vitals, and need for rescue analgesia.
Results
They enrolled a total of 48 patients (24 in each intervention arm). The groups were similar in terms of demographic characteristics and 21 patients per group made it until the end of the 120 min observation period (subjects were either discharged or transferred from the ED). Patients were more likely to experience a feeling of unreality at any time in the IV push group compared to the slow infusion group (91.7% vs 54.2%, p=0.008). At 5 minutes, the median SERSDSA score for the feeling of unreality was 3.0 in the IV push group compared to 0 in the slow infusion group. The SERSDA score was higher in the IV push group up to 30 minutes. There was no difference in the other 8 side effects that were assessed. Additionally, patient’s in the IV push group had a higher degree of sedation compared to the slow infusion group at 5 minutes (RASS -2 versus RASS 0, p=0.01). No patients in the slow infusion group had a RASS score less than or equal to -2. There were no differences in any secondary outcomes.
Discussion
This was a well-designed RCT that asked a clinically relevant question, but was limited by a small sample size and exclusion criteria that may limit its external validity. The methods/design of this study represent the “top tier” of medical literature as a randomized, double blind and placebo controlled trial. However, they only enrolled patients on weekdays from 8am-8pm (matching their ED pharmacist schedule) and may have missed the population of patients that typically present overnight or on weekends. Additionally, this study was limited by strict exclusion criteria that eliminated a significant number of patients that, in my experience, are more likely to receive pain-dose ketamine. For example, they excluded patients with unstable vital signs and oftentimes when I am reaching for pain-dose ketamine, it is in trauma patients with unstable vitals who I am hesitant to give opioids. In addition, our institution’s protocol actually lists failure of other analgesics as a prerequisite to receive pain-dose ketamine, while this study excluded any patient that received analgesia in the prior 4 hours.
The authors discussed resource utilization as a possible limitation to their findings, as not all EDs may have enough IV pumps to provide the slow infusion of pain-dose ketamine. Interestingly at our institution, the protocol for pain-dose ketamine lists an administration time of 1 minute for IV push ketamine, which is quicker than the “fast” administration time in this study. I would be interested to know if we have even higher side effect rates because of this and should consider altering our protocol to at least slow down our IV push to 3-5 minutes. All of these policy-type changes require nursing buy-in, and I would be interested to learn what is more cumbersome from a nursing perspective – standing at the bedside to push a small volume of ketamine over 3-5 minutes or mixing up a bag/setting up an IV pump to infuse the ketamine over 15 minutes, but then being able to walk away?
April, M., Arana, A., Schauer, S., Davis, W., Oliver, J., Fantegrossi, A., Summers, S., Maddry, J., Walls, R., Brown, C., Investigators, t. (2020). Ketamine Versus Etomidate and Peri‐intubation Hypotension: A National Emergency Airway Registry Study Academic Emergency Medicine https://dx.doi.org/10.1111/acem.14063
Why we chose this article
Ketamine and etomidate are two medications frequently used by emergency physicians when there is concern for peri-intubation hypotension.
Ketamine offsets hypotension via catecholamine release but is associated with myocardial depression.
Etomidate is regarded as hemodynamically neutral but is associated with 24 hour adrenal suppression (though clinical relevance is unclear).
Why it’s important
Etomidate is the most widely used medication for emergent intubation
Ketamine is becoming increasingly popular given evidence for catecholamine release
Ketamine catecholamine release is likely blunted by catecholamine depletion in a shock state
Few large comparisons of these medications exist
Study Details
Retrospective review of National Emergency Airway Registry (NEAR) intubations at 25 emergency departments over 2 years.
Inclusion Criteria:
Patients greater than 14 years old
Requiring intubation for ANY reason
Normotensive (SBP 100-139)
Exclusion criteria:
Hypotension or hypertension
Pretreatment with vasopressors
Preceding cardiac arrest
Data obtained included: inducation medication use and dose, pre/post-intubation blood pressure, mortality, patient demographics (age, gender, BMI), presence of difficult airway characteristics, difficulty of intubation, intubation method, use of post-intubation pressors or fluids
Data analysis:
Chi-square test of hypotension in ketamine vs. etomidate group
Logistic regression analysis to control for: body habitus, device used, estimated airway difficulty, presence of difficult airway characteristics, paralytic used, pretreatment (i.e. lidocaine)
Multi-variable logistic regression modelling of low dose ketamine (< 1 mg/kg) , high dose ketamine ( >1 mg/kg), low dose etomidate (< 0.3 mg/kg), high dose etomidate (> 0.3mg/kg)
Results
738 patients received ketamine
6068 patients received etomidate
Higher instance of hypotension with ketamine (18.3%) than etomidate (12.4%)
Higher instance of hypotension requiring treatment with ketamine (15.4%) than etomidate (8.9%)
Ketamine patients were more likely to have trauma, assessed airway difficulty, difficulty airway characteristics, video intubation, sepsis
Logistic regression modelling to control for device used, body habits, estimated difficulty, presence of difficult airway characteristics, pretreatment, paralytic agent supported increased hypotension with ketamine
First pass success, Cormack-Lehane grade, mortality similar between agents
Larger proportion of hypotension after ketamine in subgroup of medical patients
No difference in hypotension between agents in trauma patients
No difference in incidence of hypotension when evaluated for low vs. high dose of both agents
Limitations
Relatively few patients in the ketamine group
Retrospective review that lacks randomization, control
NEAR registry data limited and may not represent entire clinical picture
Increased proportion of ketamine patients with trauma, sepsis, difficult airway may skew results
Excluded hypotensive patients who are more likely to be catecholamine depleted at baseline
Prior studies show dose dependence of hypotension in ketamine that was not demonstrated here (possibly due to chosen dose cut-points)
Strengths
Rigorous methods to ensure that data was accurate with frequent reporting and adherence to STROBE guidelines
Large sample size that would be difficult to achieve in RCT (particularly as these drugs are generic)
Take-homes
Ketamine is not necessarily superior to etomidate to prevent peri-intubation hypotension
Large incidence of ketamine-related hypotension in medical patients (more likely to be catecholamine depleted) fits with prior data demonstrating benefit of catecholamine release
Not practice changing, but provides counterpoint to recent trend toward increasing ketamine use in patients expected to become hypotensive
Akhlaghi, N., Payandemehr, P., Yaseri, M., Akhlaghi, A., Abdolrazaghnejad, A. (2019). Premedication With Midazolam or Haloperidol to Prevent Recovery Agitation in Adults Undergoing Procedural Sedation With Ketamine: A Randomized Double-Blind Clinical Trial Annals of Emergency Medicine 73(5), 462-469. https://dx.doi.org/10.1016/j.annemergmed.2018.11.016
Why we chose this article
Ketamine is frequently used for conscious sedation in our department.
Some physicians have trepidation about using ketamine for conscious sedation for fear of agitation as the patient recovers from full sedation.
Why is it important
Potential to reduce problematic sedation agitation in patient's undergoing ketamine conscious sedations
Study details
Three arm, Double blind, single center, randomized control trial
Included 185 patients over the age of 18 years of age, who presented to the ED when one of the researchers was present and needed conscious sedation.
Subjects were randomized to receive either placebo (distilled water), 0.05 mg IV midazolam, or 5mg IV haloperiodl 5 minutes before the administration of 1 mg/kg IV ketamine.
After allocation, a package prepared by someone not involved in the study was provided to the treatment team. Within this package were two syringes containing the following combinations of medications: placebo and placebo, placebo and ketamine, or placebo and midazolam.
The primary outcome of the study was sedation agitation, assessed by the Richmond Agitation-Sedation Scale score at 5, 15, and 30 minutes after ketamine administration, and the maximum Pittsburgh Agitation Scale (PAS) Score during the entirety of the sedation.
Secondary outcomes included clinician satisfaction, based on the Clinician Satisfaction With Sedation Instrument, and recovery duration, defined as the time from ketamine administration to the time the patient is arousable with minimal stimulation.
Results
Ketamine-induced agitation, defined as a PAS score > 0, had an incidence of 63.9% in the placebo group, 25% in the midazolam group, and 19.7% in the haloperidol group.
The incidence of clinically important disruptive behaviors, defined as a PAS >3, occurred 26.2% in the placebo group, 5.0 % in the midazolam group, and 1.6% in the haloperidol group.
The RASS score at all time points trended lower in the midazolam and haloperidol groups, but the difference was not found to be statistically significant when compared to placebo.
Overall Clinician satisfaction did not differ significantly between the three groups
Average length of recovery time was 18 minutes in the placebo group, 35 minutes in the midazolam group, and 50 minutes in the haloperidol group.
Limitations
Small Sample size
The study population, although well balanced between the groups, was 90% male.
Convenience sample rather than consecutive sampling
Large Excluded population (intoxication, history of alcohol abuse, psychiatric illness, long QT...)
Majority of patients were undergoing sedation for orthopedic injuries obtained from accidents or fights, which may represent a population with a greater incidence of sedation-agitation.
Take home point
Premedication with midazolam or haloperiodol prior to a ketamine sedation reduces the incidence of sedation-agitation. However, agitation scores and the incidence of clinically significant agitation seems to be low even when ketamine is used without premedication. Additionally, premedication with haloperidol and midazolam can significantly increase the duration of the sedation.
References
Motov, S., Mai, M., Pushkar, I., Likourezos, A., Drapkin, J., Yasavolian, M., Brady, J., Homel, P., Fromm, C. (2017). A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain in the ED The American Journal of Emergency Medicine 35(8), 1095-1100. https://dx.doi.org/10.1016/j.ajem.2017.03.004
April, M., Arana, A., Schauer, S., Davis, W., Oliver, J., Fantegrossi, A., Summers, S., Maddry, J., Walls, R., Brown, C., Investigators, t. (2020). Ketamine Versus Etomidate and Peri‐intubation Hypotension: A National Emergency Airway Registry Study Academic Emergency Medicine https://dx.doi.org/10.1111/acem.14063
Akhlaghi, N., Payandemehr, P., Yaseri, M., Akhlaghi, A., Abdolrazaghnejad, A. (2019). Premedication With Midazolam or Haloperidol to Prevent Recovery Agitation in Adults Undergoing Procedural Sedation With Ketamine: A Randomized Double-Blind Clinical Trial Annals of Emergency Medicine 73(5), 462-469. https://dx.doi.org/10.1016/j.annemergmed.2018.11.016
Authorship
Motov et al - Danny Gawron, MD, PGY-3 University of Cincinnati Department of Emergency Medicine
April et al - Logan Walsh, MD PGY-3 University of Cincinnati Department of Emergency Medicine
Akhlaghi et al - Meaghan Frederick, MD PGY-3 University of Cincinnati Department of Emergency Medicine
Editing, Posting - Jeffery Hill, MD MEd
