Study to Find the Dose of Rapidly Administered Ketamine for Brief Painful Procedures in Children
Condition: Abscess; Fracture
MeSH terms: Abscess
Study type: Interventional

Summary: 
      The purpose of the study is to find the dose of rapidly administered ketamine in 3 different
      pediatric age groups (2-5, 6-11 and 12-17) for abscess drainage and fracture reduction.

      Ketamine is the most common drug administered to children to facilitate painful procedures in
      the emergency setting because it achieves potent sedation, pain relief and amnesia with
      minimal adverse cardiopulmonary effects.(1-5) However, the 1-2 hour recovery period (1,6)
      associated with standard ketamine administration guidelines(7) strains work flow because it
      requires bedside one-on-one nurse monitoring in a treatment room, tying up these limited and
      valuable resources. Consequently, a combination of two other drugs, propofol + fentanyl
      (P/F), with recovery of 20-30 minutes, is rapidly gaining popularity for procedural sedation
      despite more frequent respiratory depression, apnea and hypotension caused by this
      technique.(2,4,8,9)

      The investigators believe recovery associated with our novel method for administering
      ketamine is significantly shorter than with the standard larger dose more slowly administered
      ketamine technique(7). Through the investigators clinical experience, the investigators have
      found rapid infusion of smaller than standard doses of ketamine safely achieves the drug's
      sedative effect, with the benefit of more rapid recovery due to the use of a smaller dose.
      However, this novel technique challenges published beliefs that time of recovery from
      ketamine sedation does not differ significantly with the dose administered, within the usual
      dose ranges, and that rapid infusion may cause respiratory depression, similar to that seen
      with other classes of sedative-analgesic drugs.(7,10) the investigators believe the slow
      infusion recommended by standard guidelines(7) requires a larger ketamine dose necessary to
      achieve effective sedation, and, consequently, prolongs recovery. It is the prolonged
      recovery that has prompted increased use of other less safe but briefer sedatives, such as
      propofol/fentanyl. By demonstrating patients recover rapidly with new ketamine technique,
      without increased adverse cardiopulmonary effects, the investigators will provide clinicians
      with an important new method for ketamine procedural sedation. The investigators believe
      clinicians will prefer more rapid recovery ketamine technique because it is safer and reduces
      pain and distress better than the propofol/fentanyl combination for sedation.

      The investigators complete proposal requires two steps. In Step One, this proposal, the
      investigators will determine the minimum effective dose of rapidly infused ketamine that
      achieves deep sedation for at least 5 minutes in 95% of children (ED95). Two groups of
      patients will be studied: one group is patients undergoing abscess incision and drainage and
      the other group is patients undergoing fracture reduction in our Emergency Department. The
      investigators believe that the ED95 is different for both the groups as the severity of pain
      is different. The investigators will compare the safety and recovery times to published
      standard ketamine techniques. In the following study, Step Two, the investigators will
      compare this novel technique, in a blinded randomized trial using the ED95 ketamine dose
      determined in Step One to the standard ketamine technique to determine if the novel technique
      results in significantly shorter recovery without an increase in the frequency of adverse
      effects. The study the investigators are proposing in this submission is Step One only.
    

Detailed description: 
      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.
    

Intervention name(s): Ketamine
Intervention type(s): Drug
Intervention description(s): participants who need ketamine sedation for abscess drainage or fracture reduction will be approached for enrollment. there is no comparison group. A predetermined dose of Ketamine will be administered over 5 seconds or less intravenously. Sedation provider will assess for effectiveness of sedation at one minute.
Other intervention name(s): Ketalar
Intervention MeSH terms: Ketamine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: ketamine sedation; pediatric; abscess drainage; fracture reduction