Sedation Clinical Trial
Official title:
Phase I Trial to Determine Steady State Pharmacokinetics and Sedative Effects of Low Dose Ketamine Infusion
Opioids, such as fentanyl, are commonly used in PICU patients to provide comfort and pain
control. Opioid tolerance, the need to increase the dose of medication to achieve the same
effect,is seen in PICU children who require opioid infusions. Animals and human studies have
shown that activation of the N-methyl-D-aspartate (NMDA) receptor is involved in the
development of opioid tolerance and that deactivation of this receptor can slow the
development of tolerance. Ketamine, an NMDA receptor antagonists, turns off the NMDA
receptor. Ketamine is used to provide sedation and anesthesia in children. Its use in
inhibiting the development of opioid tolerance has not been tested in children. We aim to
determine ketamine's effectiveness in the treatment of tolerance in PICU patients who
require fentanyl infusions to treat pain and discomfort .
Some physicians have reported using ketamine doses of 0.04mg/kg/hr to 0.5mg/kg/hr to inhibit
opioid tolerance. We propose to study the sedative effect, and the metabolism of, three
doses of ketamine, 0.1mg/kg/hr, 0.3mg/kg/hr, and 0.5mg/kg/hr.
Patients admitted to the PICU, requiring a breathing machine and fentanyl infusion for
discomfort or pain control will be enrolled. Patients' age three to eighteen years will be
enrolled. Patients will receive a ketamine infusion once their COMFORT scores indicate an
adequate sedation/comfort level on their current sedation regimen. The COMFORT score is a
validated scale that measures distress in PICU patients. The COMFORT score will be continued
for the twelve hours the patient receives the ketamine to test whether the ketamine adds to
the level of sedation. Blood samples during and following the ketamine infusion will be
taken to determine how ketamine and norketamine (one of ketamine's metabolites) are used in
the body.
To determine the effect of ketamine on tolerance it must be a ketamine dose that does not
cause additional sedation. The goal of this study is to define a non-sedating dose of
ketamine and define how it is used by the body. A non-sedating ketamine dose could be added
to current sedation regimens allowing us to monitor the development of tolerance without the
confusion of added sedation. The data obtained in this study will be used to design a study
to further investigate the effect of ketamine on opioid tolerance.
Background:
There has been an increasing awareness of the need for adequate sedation and analgesia in
critically ill pediatric patients. The choices of treatment for pain are numerous, but in
the Pediatric ICU parenteral opioids are most commonly used. At equipotent doses, all mu
agonist opioids (morphine, fentanyl, meperidine and codeine) produce similar physiologic
effects and side effects. Opioids can cause hypoventilation, hypotension, constipation, and
may cause urinary retention. Patients receiving continuous opioid infusions experience not
only these physiologic side effects, but also the side effects of dependence, tolerance and
withdrawal. These lastly named side effects often complicate medical issues and contribute
to longer ICU admissions.
There are numerous articles addressing the problem of opioid tolerance, dependence, and
withdrawal . Despite repeated efforts, the mechanism of tolerance remains unclear. Current
in-vitro and in-vivo investigations focus on five theories of opioid tolerance: receptor
down-regulation, desensitization, internalization, alternative coupling, and functional
antagonism. Recent studies suggest that receptor down-regulation is not the main mechanism
in-vivo. Desensitization by receptor decoupling, receptor internalization and increased
alternative coupling to stimulatory G-proteins have been demonstrated to be clinically
insignificant. However, functional antagonism of the opioid effects seems to be clinically
most important. This functional antagonism is mediated by the activation of
N-methyl-D-aspartate (NMDA) receptors, up-regulation of adenylyl cyclase and nitric oxide
synthase . Drugs blocking these mechanisms are promising in the treatment of opioid
tolerance. Numerous in-vivo studies have focused on blocking the NMDA receptor. Studies in
animals have shown a decrease in the development of opioid tolerance when NMDA antagonists
are used . This effect has been escalated to the next level of investigation as several
adult case reports and randomized controlled trials demonstrate patients receiving small,
sub-anesthetic doses of ketamine respond with a subsequent dramatic decrease in opioid
requirement. The doses of ketamine used in these case reports vary, from 1mg/kg/24 hours
(0.04mg/kg/hr), to 0.1mg/kg/hr . Bell recently reviewed four randomized controlled trials in
cancer patients receiving ketamine as an adjuvant to opioids for pain. Dosing and route of
ketamine varied between trials. He cautiously concluded that there is promise in the
potential efficacy of ketamine as an adjuvant to opioids for cancer pain . Another review
reported that coadministration of ketamine reduced pain, analgesic consumption, and in some
studies both . Suresh and Anand anecdotally report using 0.2mg/kg/hr-0.5mg/kg/hr in children
with a resultant decreased need to escalate morphine infusion rates.
Part of the difficulty in determining an appropriate pediatric dose is the lack of clinical
studies evaluating ketamine as adjuvant to opioids in children. There have been numerous
attempts in adults to evaluate the effect of adding ketamine to opioids to improve pain
management. Many of these studies were reviewed by Subraminiam. Of the fifty-seven studies
reviewed, only seven used continuous infusion IV ketamine in addition to opioids. Of these
seven studies, four reported significantly improved analgesia with the addition of ketamine.
Of the fifty-seven studies, only four evaluated ketamine as an adjuvant to opioids in
children. All of these studies were evaluating postoperative pain control and only one used
continuous infusion ketamine. Of the four only one, evaluating preoperative ketamine
administration, showed improvement in pain control .
In the future, we anticipate conducting a randomized, blinded, placebo controlled trial to
evaluate the effect of low dose ketamine on the development of opioid tolerance. However,
there is no standardized dose of ketamine for this role. The goal of this phase I trial to
is to establish a dose of continuous infusion ketamine to be used in future studies, and to
further the pharmacokinetic details of ketamine as a continuous infusion at this dose. There
is currently no data describing the pharmacokinetics of low dose ketamine in children. These
details would include plasma concentration, elimination rate, and half-life of ketamine and
its primary metabolite norketamine. In addition to expanding the available data on ketamine
this information could be useful in future studies. It has been reported that ketamine
causes sedation in children at serum levels of 1 to 1.5 ug/ml, and that at levels less than
0.5ug/ml there are no sedative effects . The assumption can be made that at levels less than
1ug/ml ketamine is non-sedating, but this has not been tested.
While opioids are considered an analgesic, they also have sedative properties and are often
the first-line drug for sedation in Pediatric ICU's even when true analgesia is not required
. Fentanyl is frequently used in the Pediatric ICU at Children's Medical Center Dallas for
the sedation/analgesia of patients requiring mechanical ventilation. A future study would
use percent increase in fentanyl dose as a measure of tolerance. Patients would receive
ketamine or placebo, in addition to the fentanyl infusion that is the standard of care for
sedation in the Pediatric ICU. The fentanyl infusion would be titrated as per standard of
care, with the addition of midazolam at the discretion of the primary team, to maintain
adequate sedation. As tolerance develops there should be an increase in the fentanyl dose to
maintain the same clinical effect. If ketamine does inhibit the development of tolerance
then the ketamine group should remain adequately sedated with a smaller percent increase in
fentanyl. For sedation to be a valid measure in this circumstance it would have to be known
that the ketamine dose used was itself non-sedating.
The purpose of this study is to determine the sedative properties, and pharmacokinetics, of
several low dose ketamine regimens. By determining the sedative profile of ketamine at these
doses, we will be able to accurately define low dose ketamine as a dose that is nonsedating.
Hypothesis:
In PICU patients, age 3 years to 18 years receiving continuous fentanyl infusions and/or
benzodiazepine infusions for mechanical ventilation, low dose ketamine will not cause an
increase in sedation from baseline.
Study Design:
This will be a phase I trial evaluating ketamine at various doses for pharmacokinetics and
the effect of over-sedation (sedation increased significantly from baseline defined as a six
point change) according to the COMFORT score. The COMFORT score is an objective scale
developed to measure distress in pediatric critical care patients . Its use in predicting
optimal sedation for mechanically ventilated patients has been validated .
We will enroll patients admitted to the Pediatric Intensive Care Unit at Children's Medical
Center Dallas for respiratory failure requiring intubation and mechanical ventilation. The
PICU at Children's Medical Center is a 44 bed ICU that admits patients with a wide range of
medical problems. In 2005 there were 118 patients admitted with the primary diagnoses of
respiratory failure. Another 147 patients had secondary diagnoses of respiratory failure. We
anticipate enrolling 15 patients over the course of one year.
Once patients are enrolled, the COMFORT score will be administered by nursing staff every
four hours. When the patient has had scores of seventeen to twenty-six on two successive
occasions, with no need for alteration of sedation regimen, they will be considered
optimally sedated. At this time a ketamine infusion will be initiated per standard infusion
pump. Ketamine will be administered as an infusion for twelve hours. The ketamine doses to
be administered are within the dosage range of ketamine used in prior literature. It is felt
that these doses are non-sedating. The first five patients enrolled in will receive ketamine
at 0.01mg/kg/hr. The COMFORT score will continue to be administered every four hours for the
twelve hours while the patient receives the ketamine infusion. If the COMFORT score is less
than seventeen, the patient is considered over-sedated, and medication adjustments will be
made by the primary team. The ketamine infusion will continue but the fentanyl and/or
midazolam dose will be adjusted according to the primary care team. If the COMFORT score is
more than twenty-six, the patient is considered under-sedated and will require medication
adjustments. The ketamine infusion will not be changed but the fentanyl and or midazolam
will be adjusted according to the primary care team. The COMFORT score will be repeated one
hour after all medication changes.
If the COMFORT score is consistent with optimal sedation no medication changes will be made.
If, in the opinion of the primary team, the patients requires a level of sedation resulting
in a COMFORT score lower than 17 that patient will be removed from the study. Any patient
who requires a change in the fentanyl or midazolam infusion will be removed from the study.
If possible the ketamine infusion will be completed and serum levels drawn but the patient
will not be included in the sedation portion of the study.
Prior to enrolling patients at the next dose, we will ensure that all serum levels are less
than 1ug/ml. If levels are satisfactory, enrollment will begin at the next dose. The doses
to be studied are 0.01mg/kg/hr, 0.1mg/kg/hr, and 0.5mg/kg/hr.
By enrolling five patients at each dose, we will be able to accurately define the
pharmacokinetics as well as the sedation profile for each. In order to determine the
pharmacokinetics of ketamine, blood samples to determine the serum concentration of ketamine
and its primary metabolite, norketamine will be obtained. Whole blood samples of 400ul will
be obtained via available venous or arterial catheter. If no catheter is available then the
blood may be obtained via heel stick per current PICU standards. Serum samples will be
obtained just prior to starting the ketamine infusion, six hours after starting the
infusion, and at twelve hours after starting the infusion. Three additional samples will be
obtained at two, four, and six hours after discontinuing the infusion. Assuming a one
compartment open model and first order elimination the following parameters will be
estimated: Plasma concentration, volume of distribution, elimination rate, half-life, dose
and steady state concentration. The elimination half-life will be determined from the slope
of the best-fit concentration versus time plot following discontinuation of the ketamine
infusion. Ketamine and norketamine will be analyzed using a qualified LC-MS/MS method .
Throughout the study, patients will be monitored for adverse events. Should the patient
develop any adverse events not related to their current medical condition including but not
limited to nausea, vomiting, hypotension, hypertension, tachycardia, tremulousness,
increased tone in extremities, seizures, cardiac arrhythmias, and/or hallucinations that can
not be otherwise explained by the current medical condition, the ketamine infusion will be
discontinued. Serum samples for elimination half-life will be obtained at two, four and six
hours after discontinuing the infusion.
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Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label
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