Study to Find the Dose of Rapidly Administered Ketamine for Brief Painful Procedures in Children

During fracture reduction in children, the investigators found less distress using ketamine+midazolam (K/M) sedation (P<0.0001) and less hypoxia (5% vs. 25%) compared to sedation with fentanyl+midazolam (F/M)(1). Others also found less hypoxia with K/M (4%) compared to propofol+fentanyl (P/F) (18-31%)(2,4). Because of the greater safety and efficacy determined in these and similar studies, ketamine is now the most common drug administered for procedural sedation of children undergoing painful procedures in the ED.(7) For the past 15 years, the investigators have sedated about 2,500 children each year with ketamine in the St. Louis Children's Emergency Department for setting broken bones, debriding burns, draining abscesses, and other very painful procedures. Midazolam was co-administered with ketamine in early studies to reduce dysphoria during recovery, but this practice has since been shown not to be beneficial. For the past 5-10 years the investigators have used ketamine without midazolam and have seen no change in how children wake up from ketamine sedation.(6,11)

Ketamine administration in the investigators previous studies (1,3) was similar to recent recommendations (1.5-2 mg/kg I.V. infused over 30-60 sec)(7). Problematically, while most of these ED procedures such as fracture reduction, burn debridement, or abscess incision and drainage, require only 5-10 minutes of deep sedation, this standard ketamine technique results in recovery periods of 60-120 minutes(1,3,6). During recovery, patients remain in treatment rooms to be monitored one-on-one by nurses for respiratory depression, airway obstruction, vomiting and other potentially life-threatening adverse events, thus tying up these limited resources(10). This long recovery has led to increased use of propofol based techniques which have more rapid recovery (20-30 minutes) but cause increased respiratory depression and hypotension and less effective sedation(2-6,9). Because of ketamine's greater safety and efficacy profile, the investigators have been interested in developing alternative ketamine administration regimens that result in more rapid recovery, similar to propofol. If successful in hastening recovery, the investigators believe that the relative lack of respiratory depression and greater analgesia with ketamine will improve patient safety by encouraging continued use of ketamine as the preferred technique for procedural sedation in children undergoing painful procedures in the ED.

To explore new techniques for hastening recovery from sedation, the investigators took advantage of the uniqueness of ketamine. Rapid administration of opioid and gabaergic drugs such as fentanyl and propofol significantly augments the drugs' beneficial effects, but it also markedly increases respiratory depression, apnea and hypotension.(13) Cautions that rapid infusion of ketamine may cause brief respiratory depression stem from early anesthesia trials using doses larger than those typically used for sedation.(7) Although not formally studied, for the past 5 years the investigators have observed no adverse effects with rapid administration of 0.5-1.5 mg/kg ketamine doses for brief painful procedures like fracture reduction and abscess incision \& drainage in children in the Emergency Unit of St. Louis Children's Hospital.

Lipophilic drugs used for procedural sedation-analgesia, such as ketamine, fentanyl, and propofol rapidly diffuse from the bloodstream into the brain. A disproportionately high percentage of the cardiac output goes to the brain, thus a large portion of a drug injected intravenously initially goes into the brain's circulation on first pass through the heart and exerts clinical effects within a single circulation time, usually < 60 seconds. The drug remaining in the bloodstream circulates throughout the body and diffuses into muscle, bone and fat, causing the blood concentration to fall. The blood-brain concentration gradient then favors drug diffusion out of the brain and the patient awakens.

Rapid infusion of sedative drugs increases central nervous system clinical effects by directing a larger portion of the drug into the brain. A rapidly injected dose of drug travels as a more concentrated bolus into the brain circulation than a slowly injected dose that is diluted by the passing blood. With rapid injection, therefore, the initial blood-brain concentration gradient is greater and a larger portion of the dose initially enters the brain, causing deeper sedation. Smaller doses, rapidly injected, therefore can be used to achieve deep sedation similar to that of larger doses injected more slowly. With the smaller dose, the blood-brain concentration gradient subsequently reverses more rapidly and "wake up time" is shorter. Because rapid increases in brain concentration of ketamine does not cause respiratory depression, unlike that seen with fentanyl or propofol, this rapid infusion technique can be used with ketamine.

The purpose of this research project is to determine formally the minimum dose of ketamine that, when rapidly infused, achieves 5 minutes of deep sedation in 95% of patients (ED95). The investigators will use the up and down method (15) which is a standard method in anesthesiology to find the mean effective dose. Five minutes is typically enough time to perform these brief painful procedures. The investigators anticipate the ED95 will be smaller than the standard recommended ketamine dose and thus patients will wake up faster.

Of special note, determination of the "standard dose and rate of administration of ketamine"(7) has been based upon our and others' studies in which the dose and rate of infusion of ketamine were not carefully controlled and, in fact, varied widely(1,3,4,7). Thus, the "standard recommendation for administration of ketamine" is somewhat anecdotal and has not been precisely determined. Our proposed study will be the first to precisely determine a minimum effective ketamine dose.