Ignite Creation Date:
2024-05-05 @ 4:37 PM
Last Modification Date:
2024-10-26 @ 9:22 AM
Study NCT ID:
NCT00286052
Status:
COMPLETED
Last Update Posted:
2006-02-02
First Post:
2006-01-31
Brief Title:
Impact of Low Dose Naloxone on Fentanyl Requirements in Pediatric ICU Patients
Sponsor:
University of Texas Southwestern Medical Center
Organization:
University of Texas Southwestern Medical Center
Study Overview
Official Title:
The Impact of Concomitant Ultra Low Dose Infusion Naloxone and Therapeutic Infusion Opioid on Opioid Requirements in Pediatric ICU Patients
Status:
COMPLETED
Status Verified Date:
2005-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 eg 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 andor 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 andor 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
Detailed 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 Morphines 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 025microgramskilogramhour mcgkghr 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 tachycardiahypertension 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 1mcgkg for children less than 50kg and 05mcgkg for children greater than 50kg If repeat MMAAS score is again greater than 1 with hypertensiontachycardia the patient will receive another bolus of Fentanyl dose as denoted above and will have increase of Fentanyl infusion by 1mcgkghr 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 hypertensiontachycardia the patient will receive a bolus of Midazolam The Midazolam bolus will be either equal to one hour total dose of Midazolam infusion or 01mgkg with considerations for weight Dosage will be adjusted according for weight 01mgkg for children less than 20kg or 005mgkg 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 mcgkghr within 3 hours then the patient will have Midazolam either started or increased Dosage will be 01 mgkghr for children less than 20kg and 005 mgkghr for children over 20kg for starting Midazolam Dosage for increase in current infusion will be 01mgkghr for children less than 20kg and 005mgkghr 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 andor Midazolam and the need for any intervention and what that intervention included Patients with signs of increased paindiscomfort 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 005 mgkghr and the patient will be reassessed in two hours If there is no Midazolam infusion then the Fentanyl infusion will be decreased by 05mcgkghr 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 hypertensiontachycardia then Fentanyl infusion will be increased as noted above If MMAAS score 1 and not hypertensiontachycardia 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 Childrens Medical Center Dallas Between January and August 2002 the cumulative maximum daily fentanyl dose of 428 PICU patients was 79 mcgkg with a standard deviation of 47 mcgkg Thus the sample size was determined to be 62 per group total N124 The alpha criterion for significance was considered 005
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 OBrien-Fleming stopping boundaries and Lan-DeMets spending functions were employed in the analysis
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 Morphines 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 025microgramskilogramhour mcgkghr 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 tachycardiahypertension 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 1mcgkg for children less than 50kg and 05mcgkg for children greater than 50kg If repeat MMAAS score is again greater than 1 with hypertensiontachycardia the patient will receive another bolus of Fentanyl dose as denoted above and will have increase of Fentanyl infusion by 1mcgkghr 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 hypertensiontachycardia the patient will receive a bolus of Midazolam The Midazolam bolus will be either equal to one hour total dose of Midazolam infusion or 01mgkg with considerations for weight Dosage will be adjusted according for weight 01mgkg for children less than 20kg or 005mgkg 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 mcgkghr within 3 hours then the patient will have Midazolam either started or increased Dosage will be 01 mgkghr for children less than 20kg and 005 mgkghr for children over 20kg for starting Midazolam Dosage for increase in current infusion will be 01mgkghr for children less than 20kg and 005mgkghr 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 andor Midazolam and the need for any intervention and what that intervention included Patients with signs of increased paindiscomfort 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 005 mgkghr and the patient will be reassessed in two hours If there is no Midazolam infusion then the Fentanyl infusion will be decreased by 05mcgkghr 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 hypertensiontachycardia then Fentanyl infusion will be increased as noted above If MMAAS score 1 and not hypertensiontachycardia 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 Childrens Medical Center Dallas Between January and August 2002 the cumulative maximum daily fentanyl dose of 428 PICU patients was 79 mcgkg with a standard deviation of 47 mcgkg Thus the sample size was determined to be 62 per group total N124 The alpha criterion for significance was considered 005
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 OBrien-Fleming stopping boundaries and Lan-DeMets spending functions were employed in the analysis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None