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InFocus: No Proven Efficacy for Ketofol over Propofol Alone

Roberts, James R. MD

doi: 10.1097/01.EEM.0000473167.39486.17
InFocus

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, CEN, athttp://bit.ly/ProceduralPause, and read his past columns athttp://bit.ly/RobertsInFocus.

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Ten to 15 years ago, one would have to look long and hard to find an emergency clinician who had used ketamine in the ED. The drug conjured up grave warnings from our anesthesia colleagues who considered ketamine strictly an anesthesia drug. There were many voiced but no totally verified concerns of increased intracranial pressure, excessive salivation, and dreaded post-ketamine effects. To listen to the opponents of ketamine, one would think that the drug made everyone have nightmares for weeks and that massive salivation would wreak havoc with emergency intubation.

How things have changed. One of the most fascinating changes is that emergency clinicians are now doing ketamine research. Even pediatricians have rallied around ketamine as a sedation agent for a variety of pediatric procedures over the past five to 10 years, some as simple as laceration repair and joint reduction. Importantly, concerns about increased intracranial pressure have been debunked. Simply stated, the drug is not associated with cerebral edema or worsening of intracranial pressures. The saliva issue is nowhere near as dire as predicted, but a few patients do exhibit elevation for a short period.

These days many clinicians, even residents, have used ketamine for a variety of procedures and to quell the acutely agitated and violent patient whose diagnosis is still obscure. I have written in the past about ketamine as a general sedative and its role as an excellent drug to aid in the intubation of a hypoxic and unstable asthmatic. (“Yet Another Ketamine Myth Debunked,” EMN 2014;36[10]:7; http://bit.ly/1rvJuaO.) Now the drug has almost revolutionized sedation in the ED for pediatric patients, from CT scans, laceration repairs, and burn debridement to joint dislocations and cardioversion. Unraveling the vagaries of ketamine outside the OR marches on.

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Randomized, Double-Blinded, Clinical Trial of Propofol, 1:1 Propofol/Ketamine and 4:1 Propofol/Ketamine for Deep Procedural Sedation in the Emergency Department

Miner JR, Moore JC, et al.

Ann Emerg Med

2015;65(5):479.

This study compared the frequency of adverse airway events and respiratory issues leading to an intervention when two concentrations of propofol and ketamine were used for patients undergoing deep sedation in the ED. It included 71 subjects who received one of three therapies: propofol alone, a 1:1 propofol/ketamine concentration mixture, or a 4:1 propofol/ketamine combination. The authors begin their report by noting that propofol is a popular ED procedural agent, but warn it can produce respiratory depression and hypotension. The cardiopulmonary stability of ketamine makes it a much different agent from propofol. The combination of propofol and ketamine, sometimes termed ketofol, has been used for a few years to reduce respiratory depression, hypotension, and emesis by combining the known beneficial effects of both medications.

Evidence before this study did not indicate a reduction in adverse airway and respiratory events of propofol mixed with ketamine, but the topic has received minimal investigation. In fact, the optimal formulation of propofol/ketamine is not known.

These authors set out to determine whether adding ketamine resulted in a decrease in adverse respiratory events compared with propofol alone. They also compared sedation efficacy, recovery duration, and patient-reported pain and recall. In essence, the authors tried to establish why previous studies have not shown a marked benefit of ketofol over propofol alone.

All subjects were over 18, and were ED patients chosen to receive deep procedural sedation by emergency clinicians. Pregnant patients and those showing signs of alcohol intoxication were excluded. Patients were extensively monitored on cardiac and respiratory parameters. Patients received a standard analgesic dose of IV morphine (0.1 mg/kg) or IV hydromorphone (0.015 mg/kg) before the procedural sedation. Most patients had supplemental oxygen at 8-10 liters supplied by face mask during the procedure. The drugs were administered under the guidance of a respiratory therapist, a nurse, and two clinicians, one for the procedure and one for administering the medication. All were blinded to the specific medication. The two concentrations contained 5 mg propofol/ml and 5 mg ketamine/ml (1:1) or 8 mg propofol/ml and 2 mg ketamine/ml (4:1). Syringes containing 20 mls of the study solution were used.

Subjects were given a 0.1 ml/kg intravenous bolus of the study medication following the opioid. The first dose for a 70 kg patient would include 35 mg propofol and 35 mg ketamine in the 1:1 concentration. A 70 kg patients getting the 4:1 concentration received 56 mg/propofol and 14 mg/ketamine in the first bolus. Half that dose was administered every three to five minutes as needed to achieve and maintain adequate sedation. If more than the 20 mls of study medication were required, all patients received only propofol in addition.

Potential adverse respiratory and airway events and the clinical interventions required are noted in Table 1. A research assistant asked the sedating physician to rate the success of the procedure and to judge his perception of the presence or absence of adverse effects following the procedure. The assistant also asked whether the patient felt any pain, if he recalled any of the procedure, and if he found the treatment satisfactory. The sedation was termed efficacious if the patient had absence of recall, lack of an adverse event resulting in abandoning the procedure, a permanent complication, an unplanned admission to the hospital, or prolonged ED observation.

Table 1

Table 1

Procedures included abscess I&D, fracture/dislocation treatment, cardioversion, and chest tube placement. No patients had episodes of arrhythmia or aspiration, required intubation, or had unexpected admissions. Likewise, no cases of airway obstruction, laryngospasm, or aspiration were reported. Some support with bag-valve-mask was used in about 10 percent of each group. The frequency of airway or respiratory adverse events, whether or not intervention was required, and interventions regardless of an adverse event were similar in all groups. Also similar were the total sedation recovery time, proportion of the time spent at each sedation level, and multiple other study outcomes.

Two adverse events were reported in the 1:1 group. One patient developed dystonia that resolved with diphenhydramine, and one patient suffered hypoxia (83%) and a prolonged period of observation after the procedure. The authors concluded that they could not detect a difference in the frequency of adverse airway or respiratory events leading to intervention with any of the combinations or with propofol alone. All mixtures were deemed to be similarly safe and effective.

Recovery agitation was more common in the 1:1 group. The patients reported similar rates of pain, recall, and satisfaction with the sedation.

An accompanying editorial written by Green et al. appeared in the same publication, and noted that ketamine and propofol are core emergency department sedatives. (Ann Emerg Med 2015;65[5]:489.) The theoretical benefit of this study was that the sympathomimetic effects of ketamine could mitigate propofol-associated respiratory depression and hypotension, and propofol could ameliorate ketamine-associated recovery agitation and emesis. The analgesic effect of ketamine was also thought to be beneficial.

Previous trials have demonstrated similar results concerning airway and respiratory adverse events with these two sedating agents. The combination of ketamine and propofol does not significantly reduce airway or respiratory adverse events related to propofol nor do the medical effects of ketamine have any marked benefits on the slight hypotension associated with propofol. Recovery times are slightly longer with the combination, but patient satisfaction is similar. Pro-con arguments for this drug combination appear in Table 2.

Table 2

Table 2

Overall, it was concluded that ketofol demonstrated no compelling advantage over propofol or ketamine alone, did not provide superior sedation to either drug used alone, and did not reduce clinically important adverse events. A major argument against a combination is that using two drugs instead of one introduces ketamine-specific adverse events. The overall conclusion is that ketamine and propofol provide similar clinical benefit, but no compelling reasons exist to combine the two.

Comment: Reasonable evidence supports using ketamine alone, propofol alone, or a combination the two. No marked benefit is seen from combining the two drugs, but the analgesic effect of ketamine is probably helpful. All patients in this study had 8-10 liters per minute of oxygen delivered via mask. It seems prudent to provide supplemental oxygenation to all patients undergoing deep sedation in the ED. These patients also received opioids in relatively standard doses at least 20 minutes before sedation. Arguments can be made for and against the pre-sedation use of intravenous opioids, but certainly patients can receive a small dose of morphine or hydromorphone while they are being evaluated, x-rayed, or otherwise prepared for an elective procedure.

One must remember, however, that opioids and propofol do have a synergistic effect and can cause hypotension or respiratory depression in the elderly, trauma or hypovolemic patients, and those who are intoxicated or have respiratory diseases. I personally support giving a relatively modest dose of opioids while preparing for the procedure while being well aware that the combination can result in increased side effects.

It is also important to note that two physicians provided deep sedation in this study. One cannot walk into the room alone with the thought of administering IV sedation and then turn total attention to the procedure. It is always prudent to have at least two people in the room: one to do the procedure and one to administer the medications and monitor the patient. A trained ED nurse would fit the bill as the second person if the clinician is working alone. I usually grab a resident to join the team, asking him whether he would rather give the sedation or perform the procedure. Sometimes, this is a difficult decision.

I tend to agree with the concern of using two drugs over one. It does raise the potential for dosing errors, does not seem to have a marked difference in outcome, and may just confuse the overworked clinician. Propofol alone and ketamine alone provide appropriate deep sedation for the vast majority of ED procedures. I would prefer ketamine as an intubation adjunct and propofol for a short procedure, such as a joint dislocation. No matter the agents used, deep sedation in the ED demands your greatest attention and respect. If you have not had a scary moment from providing such sedation in the ED yet, you are inexperienced or failed to recognize significant complications. Bottom line: Don't give deep sedation in the back room at 3 a.m. by yourself.

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Rapid Administration Technique of Ketamine for Pediatric Forearm Fracture Reduction: A Dose-Finding Study

Chinta SS, Schrock CR, et al.

Ann Emerg Med

2015;65(6):640

These authors extol the benefits of ketamine, calling it one of the most common drugs to sedate children for procedures in the ED. The generally advised dosing guideline is an intravenous dose of 1.5 to 2 mg/kg administered over 30-60 seconds. This regimen usually achieves great sedation for five to 10 minutes, but it is associated with a variety of recovery issues. It has been postulated that giving the drug slowly results in prolonged recovery times. These authors were interested in determining whether a more rapid infusion of the drug would provide a sufficient period of effective sedation but result in a more rapid recovery. The theory is that the rapid infusion of a smaller dose provides the clinical effectiveness because of rapid ketamine concentrations on the brain.

The researchers enrolled 20 children from three age groups: 2-5, 6-11, and 12-17. Treatment was only for the reduction of forearm fractures. Most patients were pretreated with an opioid. No benzodiazepine or other sedatives were administered. A video was taken of the procedure, and three blinded investigators independently graded sedation effectiveness.

No supplemental oxygen was routinely administered, but patients were closely monitored by a variety of methods. The investigators queried the parents at discharge to see if the children had experienced any adverse effects or post-recovery complications, including any unpleasant recall of the procedure. The family was contacted again at two weeks and asked about any adverse events that occurred after discharge.

The ketamine was administered intravenously over five seconds followed by a saline bolus. The dosage was 0.7 to 0.8 mg/kg. This was effective in 95 percent of patients 2-17. They compared this technique with the 1.5 to 2 mg/kg dose generally advocated to be given intravenously over 30-60 seconds. The mean total sedation time for all age groups was about 25 minutes when only one dose of ketamine was administered. An additional dose of ketamine was required in about half to two-thirds of patients. Overall, 40 of 60 patients received an additional dose of ketamine.

Patients had a higher incidence of emesis — about 35 percent in the ED or after discharge. This is higher than has been reported in previous ketamine studies. No attempt at mitigation of the emesis was attempted, although ondansetron given with ketamine can be somewhat effective but in only about one of about 10 patients. The high frequency of emesis after discharge was noted mostly in the 2- to 5-year-old group.

The authors conclude that the rapid administration of a small dose of IV ketamine achieves brief effective sedation for fracture reduction, and patients fully recover within 30 minutes. The dose and time for recovery were less than the high-dose regimens standardly used. No patients had serious cardiopulmonary adverse events or unpleasantly recalled procedures.

These authors concluded that rapidly infused ketamine will provide three to five minutes of effective sedation for children undergoing fracture reduction. This is based on the initial 0.8 mg/kg dose. Additional ketamine is often required.

Comment: It is suggested that IV ketamine should be given over 30-60 seconds, but I doubt that most clinicians know that or take that long to administer an IV dose. The increased incidence of emesis is difficult to explain, and some of it may be from pretreatment with opioids. Fracture reduction only took three to five minutes to complete, so adequate sedation is probably satisfactory for patients with this pathology. I see no direct benefit of using a smaller dose that often requires repeated doses in patients having procedures that take longer to perform. A laceration of the face, for example, would generally not be effectively sedated with this method. The small number of patients makes an evaluation of this study somewhat difficult, but it is certainly another scientific investigation that proves the efficacy and safety of ketamine in children.

An accompanying editorial by Pershad discusses a number of issues with this study, and emphasizes the method for evaluating the effectiveness of sedation by viewing the video. The study had no control group, somewhat limiting the evaluation of dose and recovery time. The time of anesthesia for the first dose is likely not enough for repeat attempts after radiographic confirmation or for pain-free casting or molding a splint.

This is an interesting study, but I see no great clinical knowledge forthcoming. Less recovery time would be helpful, but deciding when to discharge a patient is a rather subjective decision. I see no downside in holding a patient in the ED for an additional 60 minutes following a fracture reduction, abscess drainage, or a complex laceration repair. Patients who receive ketamine in the ED should be warned that vomiting is a common side effect. Whether one gives ondansetron or another antiemetic is a matter of personal choice. It is not totally effective.

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