Resident and Fellow Corner
Ketofol for Pediatric Procedural Sedation
By Shobhit Jain, MD
There are many agents available for procedural sedation and analgesia; in recent years drugs such as ketamine and propofol have become widely used outside the operating room (OR). An ideal agent would have reliable effectiveness, rapid onset and recovery combined with minimal adverse effects. This article will review the features of two leading agents – ketamine and propofol, used separately and in combination – termed “ketofol”.
Ketamine is a phencyclidine derivative and works as a dissociative anesthetic agent. It works as an NMDA receptor antagonist, but also involves opioid and monoamine receptors. Ketamine has become one of the leading agents for use outside of the OR over the past two decades. Ketamine has an excellent safety profile, preservation of airway reflexes and spontaneous respirations. Ketamine has a sympathomimetic effect resulting in increased heart rate, blood pressure and coronary perfusion, which is beneficial for the majority of patients.1
Typical initial dosing includes 1 to 2 mg/kg IV until dissociation is observed, or 4 to 5 mg/kg IM. The resultant depth of anesthesia is not dose-dependent once dissociation has been achieved, however additional dosing contributes to the duration of sedation and recovery. In their recent study, Chinta et al observed that rapid infusion of a small ketamine dose achieved brief effective sedation with rapid recovery.2
The major adverse effects of ketamine are respiratory, namely airway obstruction, laryngospasm, hypoxia and apnea, with a combined reported incidence of up to 3.9%. Laryngospasm is an idiosyncratic event that occurs in less than 1%, and has been associated with rapid administration.3 Most patients with ketamine-related respiratory issues can be managed by simple maneuvers such as repositioning the airway, providing supplemental oxygen, and occasionally brief assisted ventilation. Severe laryngospasm necessitating neuromuscular paralysis (i.e. succinylcholine) is very rare. Vomiting, a more common adverse effect, occurs with an incidence of 7% to 26%.4 It has highest incidence in early adolescence, and is not dose-related.4,5 Emergence phenomena involving hallucinations and agitation may be seen during recovery from the dissociated state. These phenomena prolong the monitoring/recovery period, and are more common in older children and adolescents.
Ketamine is a preferred agent for many brief painful procedures in the emergency department such as laceration repair and fracture reduction. It is not ideal for enabling radiologic studies since random movements are extremely common. Because ketamine causes exaggerated airway reflexes, it is relatively contraindicated with procedures which may stimulate the larynx – such as otolaryngologic and dental procedures.6 Historically, ketamine was considered contraindicated in patients with suspected or known increased intracranial pressure. However, newer evidence has challenged this dogma, and there is accumulating evidence that ketamine may actually be neuroprotective.7,8
Propofol (2,6-diisopropylphenol) is an ultra-short acting hypnotic agent. It produces rapid sedation by potentiating γ-aminobutyric acid effect (GABA) on neuronal lipid membranes.9 It has a very short onset of action (10-50 seconds) and a short half-life of less than 10 minutes. Propofol is a potent sedative and amnestic agent, and has potent anti-emetic properties. It is a useful sole agent for short non-painful procedures; however since it has no analgesic effects an additional agent such as an opiate analgesic is usually added for painful procedures. Since propofol burns on administration, pre-treatment with lidocaine is often administered.
Usual initial doses range from 1-2 mg/kg followed either by 0.5 mg/kg boluses every 1-2 minutes or continuous infusion of about 0.1mg/kg/min. The major adverse effect of propofol is respiratory depression. Since the respiratory depression is dose-dependent, it is seen especially with repeated boluses and in combination with other agents such as opioids. Transient hypotension frequently develops with initial dosing, especially in patients with depleted intravascular volume.10
Even though its use has been documented in the emergency departments since 1996, controversy has existed about its use outside the OR.10 A large study by the Pediatric Sedation Research Consortium (PSRC) published in 2009 evaluated the use of propofol in over 49000 patients outside the OR, demonstrating safe use by practitioners skilled in airway management.11 This study also clarified the types of adverse events seen with propofol, helping define the skills set needed to rescue patients undergoing propofol sedation.
The combined use of ketamine and propofol was initially described in 1991 in adults.12 Combining these agents tends to provide a smoother sedation than either agent alone for brief painful procedures. Ketamine provides analgesia, cardiovascular stability and airway reflex preservation, while propofol adds sedative and antiemetic benefits.
The drugs may be mixed in one syringe prior to administration, typically in a 1:1 ratio. Alternatively, the drugs can be titrated separately—ketamine given first in a sub-dissociative dose (e.g., 0.5 mg/kg), followed by propofol (e.g., 1 mg/kg initial dose, then 0.5-1mg/kg every 2-4 min as needed). Administration of ketamine prior to propofol minimizes injection-related pain, making pre-treatment with lidocaine unnecessary.
The combination of ketamine and propofol appears to have significantly fewer adverse effects than either agent used alone. Ketamine appears to reduce the incidence of airway compromise associated with propofol. The addition of ketamine provides cardiovascular stability as compared to propofol alone. The combination also reduces the total amount of propofol required.13
The antiemetic effect of propofol reduces the incidence of nausea/vomiting as compared to ketamine alone. One study noted only a 2% incidence of vomiting with ketofol compared to 12% with ketamine alone.14 In addition, recovery is generally smoother with ketofol, with significant emergence phenomena less likely.15
As summarized in Table 1, Ketofol provides a beneficial combination of two agents with an improved safety profile. The brief and smooth recovery makes it a desirable regimen for use in rapid turnover settings such as day surgery and emergency departments.
Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann. Emerg. Med. 2011;57:449-461. doi:10.1016/j.annemergmed.2010.11.030.
Chinta SS, Schrock CR, McAllister JD, Jaffe DM, Liu J, Kennedy RM. Rapid Administration Technique of Ketamine for Pediatric Forearm Fracture Reduction: A Dose-Finding Study. Ann. Emerg. Med. 2015. doi:10.1016/j.annemergmed.2014.12.011.
Green SM, Roback MG, Krauss B, et al. Predictors of Airway and Respiratory Adverse Events With Ketamine Sedation in the Emergency Department: An Individual-Patient Data Meta-analysis of 8,282 Children. Ann. Emerg. Med. 2009;54. doi:10.1016/j.annemergmed.2008.12.011.
Thorp AW, Brown L, Green SM. Ketamine-associated vomiting: is it dose-related? Pediatr. Emerg. Care 2009;25(1):15-8. doi:10.1097/PEC.0b013e318191db68.
Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann. Emerg. Med. 2009;54(2):171-80.e1-4. doi:10.1016/j.annemergmed.2009.04.004.
Green SM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation in children. Ann. Emerg. Med. 2004;44(5):460-71. doi:10.1016/S0196064404006365.
Bhutta AT, Schmitz ML, Swearingen C, et al. Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: a pilot randomized, double-blind, placebo-controlled trial. Pediatr. Crit. Care Med. 2012;13:328-337.
Sakowitz OW, Kiening KL, Krajewski KL, et al. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke. 2009;40(8):e519-22. doi:10.1161/STROKEAHA.109.549303.
Barnett P. Propofol for pediatric sedation. Pediatr. Emerg. Care 2005;21(2):111-4; quiz 115-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15699822. Accessed March 10, 2015.
Miner JR, Burton JH. Clinical practice advisory: Emergency department procedural sedation with propofol. Ann. Emerg. Med. 2007;50(2):182-7, 187.e1. doi:10.1016/j.annemergmed.2006.12.017.
Cravero JP, Beach ML, Blike GT, Gallagher SM, Hertzog JH. The incidence and nature of adverse events during pediatric sedation/anesthesia with propofol for procedures outside the operating room: a report from the Pediatric Sedation Research Consortium. Anesth. Analg. 2009;108(3):795-804. doi:10.1213/ane.0b013e31818fc334.
Guit JB, Koning HM, Coster ML, Niemeijer RP, Mackie DP. Ketamine as analgesic for total intravenous anaesthesia with propofol. Anaesthesia 1991;46(1):24-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1996747. Accessed March 10, 2015.
Aouad MT, Moussa AR, Dagher CM, et al. Addition of ketamine to propofol for initiation of procedural anesthesia in children reduces propofol consumption and preserves hemodynamic stability. Acta Anaesthesiol. Scand. 2008;52(4):561-5. doi:10.1111/j.1399-6576.2008.01584.x.
Shah A, Mosdossy G, McLeod S, Lehnhardt K, Peddle M, Rieder M. A blinded, randomized controlled trial to evaluate ketamine/propofol versus ketamine alone for procedural sedation in children. Ann. Emerg. Med. 2011;57(5):425-33.e2. doi:10.1016/j.annemergmed.2010.08.032.
Andolfatto G, Willman E. A prospective case series of pediatric procedural sedation and analgesia in the emergency department using single-syringe ketamine-propofol combination (ketofol). Acad. Emerg. Med. 2010;17(2):194-201. doi:10.1111/j.1553-2712.2009.00646.x.