Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00286052 |
| Other study ID # |
IRB File: 1002-605 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
January 31, 2006 |
| Last updated |
January 31, 2006 |
| Start date |
December 2002 |
| Est. completion date |
August 2004 |
Study information
| Verified date |
September 2005 |
| Source |
University of Texas Southwestern Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
Recently there has been an increased awareness in the need for adequate sedation and pain
control for Pediatric Intensive Care Unit (ICU) patients. Fentanyl is an opioid commonly
used in Pediatric ICU patients to decrease pain and increase sedation. Although opioids
(e.g. morphine and fentanyl) provide excellent pain relief, they have many side effects
including dependence, tolerance and withdrawal. These side effects lead to increased doses
in order to maintain pain control and/or sedation. There have been a few adult studies
pointing to some possible treatments. For example, giving low dose naloxone along with
opioids. Adult studies show that this combination not only decreases the frequency of opioid
side effects, but also improves pain control and prevents the development of tolerance. We
propose that children who receive low dose naloxone infusions along with fentanyl infusions
will demonstrate: 1) decreased total daily doses of Fentanyl, 2) decreased frequency of
withdrawal and 3) increased pain and sedation control. In this randomized, blinded
prospective trial we will enroll 168 Pediatric ICU patients. Patients will receive either
low dose naloxone or placebo simultaneously with their fentanyl infusion. Pain and sedation
will be assessed using the Modified Motor Activity Assessment Scale (MMAAS). The fentanyl
infusion will be increased to provide adequate pain control and/or sedation. Naloxone
infusion will not be adjusted. Approximately 48 hours prior to removal from the ventilator,
patients will have their fentanyl infusions decreased while being monitored for withdrawal.
Patients showing signs of withdrawal will receive methadone, an opioid taken by mouth. Once
off fentanyl, naloxone will be stopped. Patients will continue to be monitored for
withdrawal for 4 days or until ICU discharge. If this study works, patients who receive low
dose naloxone along with opioid infusions will have less tolerance and dependence and
demonstrate less withdrawal. This may cause shorter Intensive Care Unit stays.
Description:
Objective:
To determine if Naloxone administration to pediatric ICU patients on Fentanyl infusions
require less Fentanyl compared to control patients.
Background:
During recent years there has been an increased awareness of the need for adequate sedation
and analgesia of critically ill pediatric patients. The choices of the treatment of 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 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 last side effects complicate medical issues and contribute
to longer ICU admissions.
Anand wrote a review article addressing the problems of drug dependence and withdrawal in
the PICU. In his article he discussed the mechanisms, pharmacology and presentation of
opioid withdrawal. He also discussed prevention of opioid withdrawal including such
therapies as the concomitant infusion of opioid agonists and low dose Naloxone. Tobias also
wrote a review article describing the consequences of the prolonged use of sedative and
analgesic agents in the Pediatric ICU. Among the problems of note are tolerance, dependence
and withdrawal in the Pediatric ICU. He discussed several possible therapies for the
treatment and prevention of opioid withdrawal. Among these was the concomitant infusion of
opioid agonist and low dose Naloxone, an opioid agonist. Naloxone selectively blocks those
opioid receptors that are coupled with stimulatory G proteins, thus blocking mechanisms for
super-activation of the cAMP pathway. This improves the efficacy of analgesia and prevents
the development of acute tolerance.
Recent preclinical and clinical studies (Crain, Gan, Levine, Joshi) have shown that
co-treatments with extremely low doses of opioid receptor antagonists can markedly enhance
the efficacy specific to Morphine and related analgesics. Crain did studies using Naloxone,
in-vitro and in-vivo, that show direct competitive antagonism of Gs coupled excitatory
opioid receptor functions. This markedly enhances Morphine’s antinociceptive potency and
simultaneously attenuates opioid tolerance and dependence.
Studies by Gan and Levine with adult post-op hysterectomy patients in one study and adult
patients following tooth extraction in a separate study show that low dose Naloxone could
enhance the analgesic potency of opioid agonists. The striking consistency of these studies
provides evidence that clinical treatment of pain can be improved by administering opioid
analgesics together with low doses of excitatory opioid receptor antagonists. The
possibility of these same effects occurring in Pediatric ICU patients has not been explored.
Hypothesis:
Children admitted to the Pediatric ICU requiring continuous infusions of opioids who receive
low dose Naloxone infusions will have a 30% decrease in the maximum total daily dose of
Fentanyl and a decreased need for escalating doses of continuous infusions during ICU
admission.
Study Design:
This will be a prospective double-blinded randomized placebo-controlled study. Patients
admitted to the ICU and consented for the study will be started on either Naloxone
continuous infusion of 0.25micrograms/kilogram/hour (mcg/kg/hr) or normal saline continuous
infusion at equal rate and volume to be determined by the pharmacy. The dose or rate of
Naloxone infusion will not be manipulated throughout the study.
During the first four hours of ICU admission the patients will be assessed hourly via the
Modified Motor Activity Assessment Scale (MMAAS, see appendix 1). Adjustments will be made
to Fentanyl and Midazolam infusions according to protocol for patients not achieving a
sedation score of –1 to +1 (see figure 1). Patients with score of greater than +1 and
associated tachycardia/hypertension will receive a bolus of Fentanyl and repeat MMAAS in 30
minutes. The Fentanyl bolus will be equal to one hour total dose of Fentanyl infusion with
considerations for weight. Dosage will be adjusted for weight accordingly: 1mcg/kg for
children less than 50kg and 0.5mcg/kg for children greater than 50kg. If repeat MMAAS score
is again greater than +1 with hypertension/tachycardia the patient will receive another
bolus of Fentanyl (dose as denoted above) and will have increase of Fentanyl infusion by
1mcg/kg/hr. The patient will have repeat MMAAS 30 minutes after change. If repeat MMAAS
score still greater than +1 a physician will be called for assessment and intervention. If
the first repeat MMAAS score is greater than +1 with no hypertension/tachycardia the patient
will receive a bolus of Midazolam. The Midazolam bolus will be either equal to one hour
total dose of Midazolam infusion or 0.1mg/kg with considerations for weight. Dosage will be
adjusted according for weight: 0.1mg/kg for children less than 20kg or 0.05mg/kg for
children greater than 20kg. The patient will have repeat MMAAS in 30 minutes. If second
MMAAS score still greater than +1 a physician will be called for assessment and
intervention. If MMAAS score at any time between +1 and –1 then repeat MMAAS will be
repeated at next scheduled time per protocol (see figure 2).
If patients require an increase of more than 2 mcg/kg/hr within 3 hours, then the patient
will have Midazolam either started or increased. Dosage will be 0.1 mg/kg/hr for children
less than 20kg and 0.05 mg/kg/hr for children over 20kg for starting Midazolam. Dosage for
increase in current infusion will be 0.1mg/kg/hr for children less than 20kg and
0.05mg/kg/hr for children over 20kg.
Patients will be assessed hourly, using the MMAAS, for the first four hours of admission to
the study and then every 2 hours for the subsequent 8 hours. After this initial time period
patients will be assessed every 4 hours until completion of the study. Each assessment will
consist of recording the sedation score, temperature, heart rate, respiratory rate,
ventilator set rate, blood pressure, oxygen saturation, infusion rate of Fentanyl and/or
Midazolam and the need for any intervention and what that intervention included. Patients
with signs of increased pain/discomfort will be assessed using the sedation scale as needed
between scheduled assessments. Interventions will be made per protocol as needed between
scheduled assessments. Once pt MMAAS score between +1 and –1 the patient will resume
scheduled MMAAS evaluations according to protocol.
If the patient has a sedation score of <-1 on MMAAS, among any of the scheduled or
intermittent assessments, the Midazolam infusion will be decreased by 0.05 mg/kg/hr and the
patient will be reassessed in two hours. If there is no Midazolam infusion then, the
Fentanyl infusion will be decreased by 0.5mcg/kg/hr and the patient will be reassessed in
two hours. If the patient continues to have pain score of <-1 on repeat MMAAS then the
Fentanyl or Midazolam continuous infusion will again be decreased as denoted above. The
patient will again be reassessed in two hours. If the patient continues to have MMAAS score
of <-1 a physician will be notified for assessment and intervention. If repeat MMAAS score
>+1 then Fentanyl infusion will be increased and noted above and the patient will be
reassessed in 30 min. If second repeat MMAAS not between +1 and –1 then a physician will be
notified for assessment and intervention. If at any time MMAAS score between +1 and –1 then
MMAAS will be repeated per protocol. If following first decrease in infusion and repeat
MMAAS score >+1 then infusion previous adjusted will be increased to prior dose. The patient
will be reassessed in 30 minutes. If repeat MMAAS score >+1 with hypertension/tachycardia
then Fentanyl infusion will be increased as noted above. If MMAAS score >+1 and not
hypertension/tachycardia then Midazolam infusion will be increases as noted above. After
intervention MMAAS will be repeated in 30 minutes. If repeat MMAAS score remains >+1 then a
physician will be notified for assessment and intervention (see figure 3).
As the patients approach 48-72 hours near the end of the need for continuous infusion or
opioid, per decision by the medical staff, they will be weaned from infusions. The Naloxone
infusion will remain unchanged. The Naloxone infusion or normal saline infusion will be
discontinued when the Fentanyl infusion is discontinued. The Fentanyl infusions will be
decreased by 25% of original dose every 12 hours until off. Once patients start the Fentanyl
wean they will have withdrawal assessed every six hours and as needed using the Modified
Narcotic Withdrawal Scale (MNAS, see appendix 2). Patients receiving two successive scores
of 8 or above will be determined to have withdrawal. These patients will be started on
Methadone as directed by the primary team and Fentanyl infusion will continue to be
decreased by 25% every 12 hours until off. As patients are weaned from continuous infusions
they will continue to have assessments every 6 hours using MNAS until infusions are
discontinued. Once the continuous infusion of Fentanyl is discontinued the patient
information will continue to be monitored using MNAS and vital signs stated earlier for 4
days or until ICU discharge.
Any need for reinstitution of continuous infusion of Fentanyl and the medical reason for
such action will be noted. Increases in oral agents after receiving the first four doses
will be noted. The need for intermittent boluses of IV analgesia or sedation during the
weaning and associated medical reasons will be noted. These things will be monitored for the
duration of the study.
Patients may receive bolus of any medication as ordered by physicians for procedures without
interfering with the study. Notation of such action will be made with next assessment. If at
any time a physician deems it necessary to begin a medication not classified as an opioid or
benzodiazepine the patient will be removed from the study. If at any time a physician begins
a scheduled dose of an additional opioid or benzodiazepine to total more than one of each
class the patient will be removed from the study.
Adverse events (nausea, vomiting, sweating, tachycardia, increased blood pressure,
tremulousness, seizures and cardiac arrest) will be noted in the medical record. If medical
reasons for such events are ruled out then the patient will be unblinded from the study.
Statistical Analysis An SPSS software random number generator was used to create a permuted
block randomization schedule. Patient assignment was unknown to all investigators and
medical team members, with the exception of the PICU pharmacist.
Power analysis was based upon an assumed power of 80%, an effect size of 30% reduction in
maximum cumulative daily dose of fentanyl, and historical data for maximum daily fentanyl
dosing in the PICU at Children’s Medical Center Dallas (Between January and August 2002, the
cumulative maximum daily fentanyl dose of 428 PICU patients was 79 mcg/kg with a standard
deviation of ± 47 mcg/kg). Thus, the sample size was determined to be 62 per group (total
N=124). The alpha criterion for significance was considered 0.05.
All parametric and nonparametric data were analyzed using SPSS for Windows and Microsoft
Excel software packages. Interim monitoring at the midpoint of the study was performed by an
independent Data and Safety Monitoring Board (DSMB), which consisted of both internal and
external reviewers. O’Brien-Fleming stopping boundaries and Lan-DeMets spending functions
were employed in the analysis.
