Impact of Low Dose Naloxone on Fentanyl Requirements in Pediatric ICU Patients
Impact of Low Dose Naloxone on Fentanyl Requirements in Pediatric ICU Patients
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.
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.
Inclusion Criteria:

 -  Children age one (1) day to eighteen (18) years, requiring admission to the Pediatric
 ICU, requiring continuous infusion of Fentanyl analgesic anticipated to last greater
 than 4 days will be eligible for enrollment. Patients from both genders, all races and
 ethnic backgrounds will be eligible. Patients meeting the above criteria will be
 eligible regardless of nutritional status, performance status or recovery from prior
 medical treatment. They will not be excluded if they require simultaneous infusions of
 sedation with Midazolam. Enrollment will require parental consent.

 Exclusion Criteria:

 -  Patients will not be eligible if they meet any of the following criteria:

 -  Patients who are currently on oral analgesia or sedation

 -  Patients who have a prior history of drug or alcohol dependence/abuse.

 -  History of significant or preexisting cardiovascular disease, they are receiving
 pro-arrhythmia medications, such as class I, II, III or IV antiarrhythmic agents.

 -  Patients who are allergic to opioids or opioid antagonists.

 -  Patients with documented chromosomal abnormality impairing perception of
 pain/discomfort.

 -  Unable to obtain parental or legal guardian's informed consent

 -  Concurrent admission to another study.