- Email: [email protected]
Nalmefene for elective reversal of procedural sedation in children
Brief Reports
Nalmefene for Elective Reversal of Procedural Sedation in Children ATIMA CHUMPA, MD, RON L. KAPLAN, MD, MICHELE M. BURNS, MD, AND MICHAEL W, SHANNON, MD, MPH Nalmefene is a newer, long-acting opioid antagonist. Its use in children for the elective reversal of emergency department procedures has not been investigated. The objective was to evaluate the safety of nalmefene in children. An open-label pediatric clinical trial was performed. The study was conducted at the emergency department of an urban, university-affiliated children's hospital and consisted of children aged 6 months to 12 years who required procedural sedation where an opioid agent was administered. Patients were excluded if there was altered mental status, history of head trauma, history of opioid allergy, or the anticipated need for opioid agents for pain relief after the procedure. At the completion of the procedure, nalmefene was administered in a dose of 0.25 #g/kg increments (max 10 #g) until sedation was resolved, or to a maximum of 1.0 #g/kg (max 40 #g). Serial ECGs, vital signs, and oxygen saturation were recorded. Sedation was assessed using the Clinical Global Impression Scale (CGIS) at baseline, 2, 4, 6, 8, and 10 minutes after the initial nalmefene dose. The observer's assessment of alertness and sedation (OAAJS)was measured at baseline, 10, 30, 60, 90, and 120 minutes after the first dose of nalmefene. Episodes of resedation were recorded. All patients received follow-up by telephone at 4 and 24 hours after the initial dose of nalmefene to identify any potential late adverse effects. Over the study interval 15 patients were enrolled. Mean age was 59.1 _+ 41.5 months. Procedures involved fracture reduction (n=8), laceration repair (n = 4), abscess drainage (n = 2), and arthrocentesis (n = 1). All patients received IV fentanyl and midazolam. The mean dosage of fentanyl and midazolam was 3.21 _+1.03 #g/kg and 0.07 -+ 0.03 mg/kg, respectively. The mean dose of nalmefene at the time of complete response (CGIS = 1 or 2) was 0.55 _+0.29 #g/kg. The median number of nalmefene doses was 2. All but one patient (93%) had a complete response based on CGIS at 10 minutes after the initial dose of nalmefene was given. Nalmefene resulted in a significant improvement in CGIS (1.60 _+0.82 v3.26 +_ 0.88, P = .001) and OAA/S (median score 5 v 4) when compared at baseline with 10 minutes after the initial dose of nalmefene. Nalmefene also resulted in increased diastolic blood pressure (62.6 _+ 10.5 v 55.8 _+ 10.7, P = .04) as well as improved oxygen saturation when compared at 120 minutes to baseline (99.5 -+ 0.74% v 98.5 -+ 0.4%, P = .03). There were no significant changes in pulse, systolic blood pressure, respiratory rate, and ECG. None of the patients From the Division of Emergency Medicine, Children's Hospital, Harvard Medical School, Boston, MA. Presented at Society of Pediatric Research Annual Meeting, San Francisco, May 1999. Manuscript received January 28, 2001, returned February 10, 2001, revision received May 5, 2001, accepted May 5, 2001. Address reprint requests to Atima Chumpa, MD, Division of Emergency Medicine, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected] Key Words: Nalmefene, procedural sedation, opioid antagonist Copyright © 2001 by W.B. Saunders Company 0735-6757/01/1907-0003535.00/0 doi: 10.1053/ajem.2001.27141
became resedated after nalmefene was given. One patient developed nausea and vomiting within the first 2 hours after nalmefene; this resolved without intervention before discharge. No adverse events occurred in any of the patients at 4 and 24 hours postadministration. The results of this study showed that nalmefene is effective and safe for reversal of procedural sedation by opioids in children. (Am J Emerg Med 2001;19:545-548. Copyright © 2001 by W.B. Saunders Company) Opioids are used frequently in pediatric emergency departments (EDs) for procedural sedation and pain control. 1-3 Because opioids can cause respiratory depression and hypotension, availability of an agent that can reverse these effects is necessary. 4-5 In addition, the ability to promptly and safely reverse sedation after a procedure is desirable. Naloxone is the only established conventional reversal agent for opioids. Although naloxone has a long safety record, its duration of action is often shorter than the duration of the opioids administered, 6 which makes renarcotization possible. 7 In 1975, the synthesis of a new derivative of naloxone was reported. 8 This compound, nalmefene hydrochloride, is a pure opioid antagonist structurally similar to naloxone but with a significantly longer half-life. The half-life of nalmefene is 8 to 9 hours 9 compared with 64 minutes of naloxone. 1° Clinical studies have shown that nalmefene has a duration of action significantly longer than naloxoneA 1-14 Furthermore, studies conducted in ED patients have reported the efficacy of nalmefene in reversing both opioidinduced sedation 13 and narcotic overdose. 15,16 However, the drug's use in children has never been investigated. The objectives of this study were to (1) evaluate the efficacy and safety of nalmefene for elective reversal of opioid-induced sedation in children and (2) explore a specific dose range for nalmefene use in children. METHODS
This study was an open-label trial conducted in the ED of an urban, tertiary care, children's hospital between June 1998 and July 1999. Study population included children aged 6 months to 12 years who presented to the ED between 8 a.m. to 6 p.m. Patients who required procedural sedation with an opioid agent and had a home telephone were included in the study. Patients were excluded if there was altered mental status, history of head trauma, or the anticipated need for opioid agents for pain relief after the procedure. Written informed consent was obtained from the parent or guardian before enrollment. The study was approved by the institutional review board. 545
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AMERICAN J O U R N A L OF EMERGENCY MEDICINE • Volume 19, Number 7 • November 2001
TABLE1.
OAA/S
Responsiveness 5 - Responds readily to name spoken in normal tone 4 - Lethargic response to name spoken in normal tone 3 - Responds only after name called loudly and/or repeatedly 2 - Responds only after mild prodding or shaking 1 - Does not respond to mild prodding or shaking
Speech
Facial Expression
Eyes
C o m p o s i t e score
5 - Normal
5 - Normal
5 - Clear, no ptosis
5 - Alert
4 - Mild slowing
4 - Mild relaxation
4
3 - Slurring or prominent slowing 2 - Few recognizable words
3 - Marked relaxation (slack jaw)
4 - Glazed or mild ptosis (less than half the eye) 3 - Glazed and marked ptosis (half the eye or mere)
Patients received procedural sedation according to the sedation protocol used in the ED, 17 with continuous pulse, respiratory, oxygen saturation, and electrocardiogram (ECG) monitoring. Nalmefene in a dosage concentration of 0.1 mg/mL was administered intravenously when the procedure was completed. An initial nalmefene dose of 0.25/xg/kg (maximum 10/xg) was infused over 15 seconds, followed by a 1 minute and 45 second observation period. An additional dose of 0.25/xg/kg (maximum 10/xg) was given if there was no response. Additional doses were administered every 2 minutes until the predetermined response or a maximum dose of 1 /xg/kg (maximum 40 /xg) was reached. Patients with resedation were to receive 1 ~g/kg (maximum 40 /xg) of nalmefene. Patients were observed in the ED for 2 hours after the initial dose of nalmefene for efficacy and safety measures.
3
2 1 - Deep sleep
nalmefene. In addition, each patient was placed on continuous cardiac monitoring during the nalmefene administration. Adverse events were recorded, and their intensity was graded by the investigators as "mild," "moderate," or "severe." The relationship of the adverse events was rated by the investigator as "not related," "remotely related," "possibly related," or "probably related." Patients were discharged 2 hours after the initial nalmefene administration if all postsedation discharge criteria were met. All patients received follow-up by telephone at 4 and 24 hours after the initial dose of nalmefene to identify any potential adverse events. Statistical analyses were performed using Statistical Program for the Social Sciences (SPSS 6.1; SPSS, Chicago, IL). Statistical analyses consisted of student's t-test or one way analysis of variance. Data are expressed as mean + SD unless otherwise indicated. Significance was established at P < .05.
Efficacy Measures Two efficacy measures were used: the clinical global impression scale (CGIS) and the observer's assessment of alertness and sedation (OAA/S). The CGIS is a comparative global scale in which the rater assesses the change in the global condition of the patient relative to baseline (Hoffmann-LaRoche, Inc., Nutley, NJ, data on file). Patients were given a score of 1 to 7, with 1 being very much improved and 7 being very much worse. For this study, those with CGIS of 1 or 2 (very much improved and much improved) were classified as "'complete responders.'" Those with CGIS of 3 (minimally improved) were classified as "partial responders," and those with CGIS of ->4 (no change, minimally worse, much worse and very much worse) were classified as "nonresponders." The CGIS was recorded at baseline, 2, 4, 6, 8, and 10 minutes after the initial dose of nalmefene. The OAA/S is a validated sedation scale (Table 1), 18 which provides a means of assessing resedation in patients who had become alert after nalmefene administration. Unlike the CGIS, the OAA/S is an absolute value rather than a comparison with a baseline. The OAA/S was performed at baseline, 10, 30, 60, 90, and 120 minutes after the initial dose of nalmefene. Resedation was defined as a decrease of 1 point or more in the composite OAA/S score from the highest previous score in a patient who had initially responded to nalmefene. The response to nalmefene in patients who became resedated were determined from comparison of the OAA/S's composite score between immediately preceding nalmefene administration and 10 minutes after the nalmefene administration.
Safety Measures A complete medical history was reviewed and physical examination was performed before enrollment. Respiratory rate, heart rate, oxygen saturation, and blood pressure were recorded at baseline, 10, 30, 60, 90, and 120 minutes after the initial dose of
RESULTS Fifteen patients were enrolled during the study interval. Mean age was 59.1 _+ 41.5 months, with a range of 6.5 months to 123.1 months. Nine (60%) patients were boys. Five patients were taking medication at the time of presentation; these included acetaminophen with codeine, albuterol, cephalexin, guanfacine, nifedipine, dextroamphetamine/amphetamine, and amlodipine. Procedures included fracture reduction (8), laceration repair (4), abscess drainage (2) and arthrocentesis (1). All patients received intravenous fentanyl and midazolam (Table 2). The mean doses of fentanyl and midazolam were 3.21 _+ 1.03 /xg/kg and 0.07 +- 0.03 mg/kg, respectively. Mean duration of the procedure was 29.2 -+ 21 minutes. Five patients developed desaturation during the procedure; all responded immediately to blow by oxygen and head repositioning. One patient had depressed respirations requiring brief bag and mask ventilation. All patients had normal oxygen saturation on room air at the end of procedure. The mean dose of nalmefene given for a complete response (CGIS = 1 or 2) was 0.55 -+ 0.29 /xg/kg. The median number of nalmefene doses was 2. Three patients (20%) received the m a x i m u m dosage (1/xg/kg). All but one patient (93%) had a complete response based on CGIS at 10 minutes after the initial dose of nalmefene was administered. Nalmefene resulted in a significantly improved CGIS when compared at baseline with 10 minutes after the initial dose of nalmefene (l.60 + 0.82 v 3.26 + 0.88, P = .001), as well as an improved OAA/S composite score when compared at baseline with 10 minutes (median score of 5 v 4). Of 6 patients who had baseline OAA/S composite score
CHUMPA ET AL • NALMEFENE FOR PEDIATRIC SEDATION REVERSAL
TABLE 2. Summary of Procedure, Drugs, and Dosages in Each Patient Patient No.
Procedure
Fentanyl (/xg/kg)
Midazolam (mg/kg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Laceration repair Fracture reduction Abscess drainage Fracture reduction Fracture reduction Fracture reduction Fracture reduction Fracture reduction Arthrocentesis Laceration repair Fracture reduction Laceration repair Abscess drainage Fracture reduction Laceration repair
2.00 2.19 2.00 4.11 2.78 4.69 2.38 4.00 3.72 1.88 3.75 3.00 4.00 2.65 5.00
0.05 0.11 0.04 0.04 0.04 0.09 0.10 0.10 0.09 0.08 0.03 0.05 0.10 0.09 0.15
of 3 or less, 5 patients had increased OAA/S composite score to 4 or 5 at 10 minutes. There were no significant changes in respiratory rate, heart rate, systolic blood pressure, or ECG after nalmefene was given compared with baseline. However, there was significant improvement in oxygen saturation when compared at 120 minutes after nalmefene was given to baseline (99.5 - 0.74 v 98.5 --_ 0.4%, P = .03), as well as increased in diastolic blood pressure (62.6 _+ 10.5 v 55.8 + 10.7 mmHg, P = .04). None of the patients experienced resedation. One patient developed nausea and vomiting within the first 2 hours of nalmefene administration; this resolved without intervention before discharge. This adverse event was categorized as possibly related to nalmefene. None of the patients developed any adverse events at 4 and 24 hours after the initial dose of nalmefene. DISCUSSION
Nalmefene is a newer opioid antagonist with a longer duration of action compared with naloxone. Its efficacy has been shown for reversal of opioid-induced sedation and opioid overdose in adults in ED settings, t3.15,16 This study showed the efficacy and safety of nalmefene in children. Nalmefene administered at 0.25 ~g/kg every 2 minutes (up to 4 doses or until the desire effect is produced) resulted in prompt and sustained reversal of opioid-induced sedation without significant adverse effects. The efficacy of nalmefene for reversal of opioid overdose in children is also expected. Nalmefene has potential roles in pediatric patients for reversal of opioid toxicity in unintentional ingestion, iatrogenic overdose, and opioid-induced procedural sedation. Because of its long duration of action, nalmefene use in children may have advantages over naloxone. Naloxone has a shorter half-life than most opioid agents, which makes the return of central nervous system and respiratory depression possible. Subsequently, patients who receive naloxone need close monitoring as these patients may require repeated doses or continuous infusion of naloxone. 19 The use of
547
nalmefene can potentially eliminate these additional interventions. Nalmefene has also been shown to be well tolerated in adult patients. After administration of nalmefene in 1,127 patients in controlled clinical trials for the treatment of opioid overdose or for postoperative opioid reversal, nalmefene was well tolerated and showed no serious toxicity (Ohmeda Pharmaceutical, Liberty Corner, N J, data on file). A dose up to 24 mg approximately 15 times the recommended dose in adults, was given to healthy volunteers in one study with only minor side effects such as light headedness and dizziness. 9 Acute pulmonary edema, a rare adverse reaction, was reported in once case when nalmefene was given postoperatively to an adult patient. 2° Despite the proven efficacy and safety of nalmefene, its use for reversal of opioid toxicity in adult EDs has potential problem. 21 Adult patients who are opioid dependent may have severe and prolonged withdrawal syndrome. Moreover, these patients who are discharged from hospital early while nalmefene is still in effect may use even larger amount of opiates. In contrast, opioid overdose in children is typically a single-dose ingestion; these concerns are, therefore, minimal. Nevertheless, nalmefene should be used with caution in any individual who has a known or suspected tolerance to opiates. In addition, certain opioid synthetics such as methadone have longer half-lives than nalmefene; prolonged observation is therefore still required when toxicity is caused by these agents. 21 Limitations of this study should be noted. First, the number of patients in this study is small, therefore uncommon side effects would not be identified in this cohort. Second, all of the study patients received fentanyl, which is a shortacting opiate. Resedation would not be expected when a short-acting opiate such as fentanyl is used. The efficacy profile of nalmefene after use of a longer action opioid therefore remains unknown. In conclusion, nalmefene appears to be effective and safe for reversal of opioid-induced procedural sedation in children. Its role in the reversal of opioid toxicity in children caused by overdose may be superior to naloxone because of its longer duration of action. REFERENCES 1. Ilkhanipour K, Juels CR, Longdorf MI: Pediatric pain control and conscious sedation: a survey of emergency medicine residency. Acad Emerg Med 1994;1:368-72 2. Billmire DA, Neale HW, Gregory RO: Use of IV fentanyl in outpatient treatment of pediatric facial trauma. J Trauma 1985;25: 1079-80 3. Pohlgeers AP, Friedland LR, Keegan-Jones L: Combination fentanyl and diazepam for pediatric conscious sedation. Acad Emerg Med 1995;2:879-83 4. Chudnofsky CR, Wright SW, Dronen SC, et al: The safety of fentanyl use in the emergency department. Ann Emerg Med 1989; 18:635-39 5. Moore LRC, Bikhazi GB, Tuttle RR, et al: Antagonism of fentanyl-induced respiratory depression with nalmefene. Meth Find Exp Clin Pharmacol 1990;12:29-35 6. Evans JM, Hogg MIJ, Lunn JN, et al: Degree and duration of reversal by naloxone of effects of morphine in conscious subjects. Br Med J 1974;2:589-91 7. Longnecker DE, Grazis PA, Eggers GW: Naloxone for antagonism of morphine-induced respiratory depression. Anesth Analg 1973;52:447-52 8. Hahn EF, Fishman J, Heilman RD: Narcotic antagonists.4.Carbon-6 Derivatives of N-substituted noroxymorphones as narcotic antagonists. J Med Chem 1975;18:259-62
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9. Dixon RD, Howes J, Gentile J, et al: Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986;39:49-53 10. Ngai SH, Berkowitz BA, Yang JC, et al: Pharmacokinetics of naloxone in rats and in man. Anesthesiology 1976;44:398-401 11. Gal TJ, DiFazio CA: Prolonged antagonism of opioid action with intravenous nalmefene in man. Anesthesiology 1986;64:175-80 12. Konieczko KM, Jones JG, Barrowcliffe MP, et al: Antagonist of morphine-induced respiratory depression with nalmefene. Br J Anaesth 1988;61:318-23 13. Barsan WG, Seger D, Danzl DF, et al: Duration of antagonistic effects of nalmefene in opiate-induced sedation for emergency department procedures. Am J Emerg Med 1989;7:155-61 14. Glass PSA, Jhaveri RM, Smith LR: Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg 1994;78:536-41 15. Kaplan JL, Marx JA: Effectiveness and safety of intravenous nalmefene for emergency department patients with suspected narcotic overdose: A pilot study. Ann Emerg Med 1993;22:187-90
16. Kaplan JL, Marx JA, Calabro J J, et al: Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Ann Emerg Med 1999; 34:42-50 17. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110-5 18. Chernik DA, Gillings D, Laine H, et al: Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: Study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244-51 19. Tenenbein M: Continuous naloxone infusion for opiate poisoning in infancy. J Pediatr 1984;105:645-48 20. Henderson CA, Reynolds JE: Acute pulmonary edema in young male after intravenous nalmefene. Anesth Analg 1997;84: 218-9 21. Gaeta TJ, Capodano RJ, Spevack TA: Potential danger of nalmefene use in the emergency department. Ann Emerg Med 1997;29:193-94
Nalmefene for Elective Reversal of Procedural Sedation in Children ATIMA CHUMPA, MD, RON L. KAPLAN, MD, MICHELE M. BURNS, MD, AND MICHAEL W, SHANNON, MD, MPH Nalmefene is a newer, long-acting opioid antagonist. Its use in children for the elective reversal of emergency department procedures has not been investigated. The objective was to evaluate the safety of nalmefene in children. An open-label pediatric clinical trial was performed. The study was conducted at the emergency department of an urban, university-affiliated children's hospital and consisted of children aged 6 months to 12 years who required procedural sedation where an opioid agent was administered. Patients were excluded if there was altered mental status, history of head trauma, history of opioid allergy, or the anticipated need for opioid agents for pain relief after the procedure. At the completion of the procedure, nalmefene was administered in a dose of 0.25 #g/kg increments (max 10 #g) until sedation was resolved, or to a maximum of 1.0 #g/kg (max 40 #g). Serial ECGs, vital signs, and oxygen saturation were recorded. Sedation was assessed using the Clinical Global Impression Scale (CGIS) at baseline, 2, 4, 6, 8, and 10 minutes after the initial nalmefene dose. The observer's assessment of alertness and sedation (OAAJS)was measured at baseline, 10, 30, 60, 90, and 120 minutes after the first dose of nalmefene. Episodes of resedation were recorded. All patients received follow-up by telephone at 4 and 24 hours after the initial dose of nalmefene to identify any potential late adverse effects. Over the study interval 15 patients were enrolled. Mean age was 59.1 _+ 41.5 months. Procedures involved fracture reduction (n=8), laceration repair (n = 4), abscess drainage (n = 2), and arthrocentesis (n = 1). All patients received IV fentanyl and midazolam. The mean dosage of fentanyl and midazolam was 3.21 _+1.03 #g/kg and 0.07 -+ 0.03 mg/kg, respectively. The mean dose of nalmefene at the time of complete response (CGIS = 1 or 2) was 0.55 _+0.29 #g/kg. The median number of nalmefene doses was 2. All but one patient (93%) had a complete response based on CGIS at 10 minutes after the initial dose of nalmefene was given. Nalmefene resulted in a significant improvement in CGIS (1.60 _+0.82 v3.26 +_ 0.88, P = .001) and OAA/S (median score 5 v 4) when compared at baseline with 10 minutes after the initial dose of nalmefene. Nalmefene also resulted in increased diastolic blood pressure (62.6 _+ 10.5 v 55.8 _+ 10.7, P = .04) as well as improved oxygen saturation when compared at 120 minutes to baseline (99.5 -+ 0.74% v 98.5 -+ 0.4%, P = .03). There were no significant changes in pulse, systolic blood pressure, respiratory rate, and ECG. None of the patients From the Division of Emergency Medicine, Children's Hospital, Harvard Medical School, Boston, MA. Presented at Society of Pediatric Research Annual Meeting, San Francisco, May 1999. Manuscript received January 28, 2001, returned February 10, 2001, revision received May 5, 2001, accepted May 5, 2001. Address reprint requests to Atima Chumpa, MD, Division of Emergency Medicine, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected] Key Words: Nalmefene, procedural sedation, opioid antagonist Copyright © 2001 by W.B. Saunders Company 0735-6757/01/1907-0003535.00/0 doi: 10.1053/ajem.2001.27141
became resedated after nalmefene was given. One patient developed nausea and vomiting within the first 2 hours after nalmefene; this resolved without intervention before discharge. No adverse events occurred in any of the patients at 4 and 24 hours postadministration. The results of this study showed that nalmefene is effective and safe for reversal of procedural sedation by opioids in children. (Am J Emerg Med 2001;19:545-548. Copyright © 2001 by W.B. Saunders Company) Opioids are used frequently in pediatric emergency departments (EDs) for procedural sedation and pain control. 1-3 Because opioids can cause respiratory depression and hypotension, availability of an agent that can reverse these effects is necessary. 4-5 In addition, the ability to promptly and safely reverse sedation after a procedure is desirable. Naloxone is the only established conventional reversal agent for opioids. Although naloxone has a long safety record, its duration of action is often shorter than the duration of the opioids administered, 6 which makes renarcotization possible. 7 In 1975, the synthesis of a new derivative of naloxone was reported. 8 This compound, nalmefene hydrochloride, is a pure opioid antagonist structurally similar to naloxone but with a significantly longer half-life. The half-life of nalmefene is 8 to 9 hours 9 compared with 64 minutes of naloxone. 1° Clinical studies have shown that nalmefene has a duration of action significantly longer than naloxoneA 1-14 Furthermore, studies conducted in ED patients have reported the efficacy of nalmefene in reversing both opioidinduced sedation 13 and narcotic overdose. 15,16 However, the drug's use in children has never been investigated. The objectives of this study were to (1) evaluate the efficacy and safety of nalmefene for elective reversal of opioid-induced sedation in children and (2) explore a specific dose range for nalmefene use in children. METHODS
This study was an open-label trial conducted in the ED of an urban, tertiary care, children's hospital between June 1998 and July 1999. Study population included children aged 6 months to 12 years who presented to the ED between 8 a.m. to 6 p.m. Patients who required procedural sedation with an opioid agent and had a home telephone were included in the study. Patients were excluded if there was altered mental status, history of head trauma, or the anticipated need for opioid agents for pain relief after the procedure. Written informed consent was obtained from the parent or guardian before enrollment. The study was approved by the institutional review board. 545
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TABLE1.
OAA/S
Responsiveness 5 - Responds readily to name spoken in normal tone 4 - Lethargic response to name spoken in normal tone 3 - Responds only after name called loudly and/or repeatedly 2 - Responds only after mild prodding or shaking 1 - Does not respond to mild prodding or shaking
Speech
Facial Expression
Eyes
C o m p o s i t e score
5 - Normal
5 - Normal
5 - Clear, no ptosis
5 - Alert
4 - Mild slowing
4 - Mild relaxation
4
3 - Slurring or prominent slowing 2 - Few recognizable words
3 - Marked relaxation (slack jaw)
4 - Glazed or mild ptosis (less than half the eye) 3 - Glazed and marked ptosis (half the eye or mere)
Patients received procedural sedation according to the sedation protocol used in the ED, 17 with continuous pulse, respiratory, oxygen saturation, and electrocardiogram (ECG) monitoring. Nalmefene in a dosage concentration of 0.1 mg/mL was administered intravenously when the procedure was completed. An initial nalmefene dose of 0.25/xg/kg (maximum 10/xg) was infused over 15 seconds, followed by a 1 minute and 45 second observation period. An additional dose of 0.25/xg/kg (maximum 10/xg) was given if there was no response. Additional doses were administered every 2 minutes until the predetermined response or a maximum dose of 1 /xg/kg (maximum 40 /xg) was reached. Patients with resedation were to receive 1 ~g/kg (maximum 40 /xg) of nalmefene. Patients were observed in the ED for 2 hours after the initial dose of nalmefene for efficacy and safety measures.
3
2 1 - Deep sleep
nalmefene. In addition, each patient was placed on continuous cardiac monitoring during the nalmefene administration. Adverse events were recorded, and their intensity was graded by the investigators as "mild," "moderate," or "severe." The relationship of the adverse events was rated by the investigator as "not related," "remotely related," "possibly related," or "probably related." Patients were discharged 2 hours after the initial nalmefene administration if all postsedation discharge criteria were met. All patients received follow-up by telephone at 4 and 24 hours after the initial dose of nalmefene to identify any potential adverse events. Statistical analyses were performed using Statistical Program for the Social Sciences (SPSS 6.1; SPSS, Chicago, IL). Statistical analyses consisted of student's t-test or one way analysis of variance. Data are expressed as mean + SD unless otherwise indicated. Significance was established at P < .05.
Efficacy Measures Two efficacy measures were used: the clinical global impression scale (CGIS) and the observer's assessment of alertness and sedation (OAA/S). The CGIS is a comparative global scale in which the rater assesses the change in the global condition of the patient relative to baseline (Hoffmann-LaRoche, Inc., Nutley, NJ, data on file). Patients were given a score of 1 to 7, with 1 being very much improved and 7 being very much worse. For this study, those with CGIS of 1 or 2 (very much improved and much improved) were classified as "'complete responders.'" Those with CGIS of 3 (minimally improved) were classified as "partial responders," and those with CGIS of ->4 (no change, minimally worse, much worse and very much worse) were classified as "nonresponders." The CGIS was recorded at baseline, 2, 4, 6, 8, and 10 minutes after the initial dose of nalmefene. The OAA/S is a validated sedation scale (Table 1), 18 which provides a means of assessing resedation in patients who had become alert after nalmefene administration. Unlike the CGIS, the OAA/S is an absolute value rather than a comparison with a baseline. The OAA/S was performed at baseline, 10, 30, 60, 90, and 120 minutes after the initial dose of nalmefene. Resedation was defined as a decrease of 1 point or more in the composite OAA/S score from the highest previous score in a patient who had initially responded to nalmefene. The response to nalmefene in patients who became resedated were determined from comparison of the OAA/S's composite score between immediately preceding nalmefene administration and 10 minutes after the nalmefene administration.
Safety Measures A complete medical history was reviewed and physical examination was performed before enrollment. Respiratory rate, heart rate, oxygen saturation, and blood pressure were recorded at baseline, 10, 30, 60, 90, and 120 minutes after the initial dose of
RESULTS Fifteen patients were enrolled during the study interval. Mean age was 59.1 _+ 41.5 months, with a range of 6.5 months to 123.1 months. Nine (60%) patients were boys. Five patients were taking medication at the time of presentation; these included acetaminophen with codeine, albuterol, cephalexin, guanfacine, nifedipine, dextroamphetamine/amphetamine, and amlodipine. Procedures included fracture reduction (8), laceration repair (4), abscess drainage (2) and arthrocentesis (1). All patients received intravenous fentanyl and midazolam (Table 2). The mean doses of fentanyl and midazolam were 3.21 _+ 1.03 /xg/kg and 0.07 +- 0.03 mg/kg, respectively. Mean duration of the procedure was 29.2 -+ 21 minutes. Five patients developed desaturation during the procedure; all responded immediately to blow by oxygen and head repositioning. One patient had depressed respirations requiring brief bag and mask ventilation. All patients had normal oxygen saturation on room air at the end of procedure. The mean dose of nalmefene given for a complete response (CGIS = 1 or 2) was 0.55 -+ 0.29 /xg/kg. The median number of nalmefene doses was 2. Three patients (20%) received the m a x i m u m dosage (1/xg/kg). All but one patient (93%) had a complete response based on CGIS at 10 minutes after the initial dose of nalmefene was administered. Nalmefene resulted in a significantly improved CGIS when compared at baseline with 10 minutes after the initial dose of nalmefene (l.60 + 0.82 v 3.26 + 0.88, P = .001), as well as an improved OAA/S composite score when compared at baseline with 10 minutes (median score of 5 v 4). Of 6 patients who had baseline OAA/S composite score
CHUMPA ET AL • NALMEFENE FOR PEDIATRIC SEDATION REVERSAL
TABLE 2. Summary of Procedure, Drugs, and Dosages in Each Patient Patient No.
Procedure
Fentanyl (/xg/kg)
Midazolam (mg/kg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Laceration repair Fracture reduction Abscess drainage Fracture reduction Fracture reduction Fracture reduction Fracture reduction Fracture reduction Arthrocentesis Laceration repair Fracture reduction Laceration repair Abscess drainage Fracture reduction Laceration repair
2.00 2.19 2.00 4.11 2.78 4.69 2.38 4.00 3.72 1.88 3.75 3.00 4.00 2.65 5.00
0.05 0.11 0.04 0.04 0.04 0.09 0.10 0.10 0.09 0.08 0.03 0.05 0.10 0.09 0.15
of 3 or less, 5 patients had increased OAA/S composite score to 4 or 5 at 10 minutes. There were no significant changes in respiratory rate, heart rate, systolic blood pressure, or ECG after nalmefene was given compared with baseline. However, there was significant improvement in oxygen saturation when compared at 120 minutes after nalmefene was given to baseline (99.5 - 0.74 v 98.5 --_ 0.4%, P = .03), as well as increased in diastolic blood pressure (62.6 _+ 10.5 v 55.8 + 10.7 mmHg, P = .04). None of the patients experienced resedation. One patient developed nausea and vomiting within the first 2 hours of nalmefene administration; this resolved without intervention before discharge. This adverse event was categorized as possibly related to nalmefene. None of the patients developed any adverse events at 4 and 24 hours after the initial dose of nalmefene. DISCUSSION
Nalmefene is a newer opioid antagonist with a longer duration of action compared with naloxone. Its efficacy has been shown for reversal of opioid-induced sedation and opioid overdose in adults in ED settings, t3.15,16 This study showed the efficacy and safety of nalmefene in children. Nalmefene administered at 0.25 ~g/kg every 2 minutes (up to 4 doses or until the desire effect is produced) resulted in prompt and sustained reversal of opioid-induced sedation without significant adverse effects. The efficacy of nalmefene for reversal of opioid overdose in children is also expected. Nalmefene has potential roles in pediatric patients for reversal of opioid toxicity in unintentional ingestion, iatrogenic overdose, and opioid-induced procedural sedation. Because of its long duration of action, nalmefene use in children may have advantages over naloxone. Naloxone has a shorter half-life than most opioid agents, which makes the return of central nervous system and respiratory depression possible. Subsequently, patients who receive naloxone need close monitoring as these patients may require repeated doses or continuous infusion of naloxone. 19 The use of
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nalmefene can potentially eliminate these additional interventions. Nalmefene has also been shown to be well tolerated in adult patients. After administration of nalmefene in 1,127 patients in controlled clinical trials for the treatment of opioid overdose or for postoperative opioid reversal, nalmefene was well tolerated and showed no serious toxicity (Ohmeda Pharmaceutical, Liberty Corner, N J, data on file). A dose up to 24 mg approximately 15 times the recommended dose in adults, was given to healthy volunteers in one study with only minor side effects such as light headedness and dizziness. 9 Acute pulmonary edema, a rare adverse reaction, was reported in once case when nalmefene was given postoperatively to an adult patient. 2° Despite the proven efficacy and safety of nalmefene, its use for reversal of opioid toxicity in adult EDs has potential problem. 21 Adult patients who are opioid dependent may have severe and prolonged withdrawal syndrome. Moreover, these patients who are discharged from hospital early while nalmefene is still in effect may use even larger amount of opiates. In contrast, opioid overdose in children is typically a single-dose ingestion; these concerns are, therefore, minimal. Nevertheless, nalmefene should be used with caution in any individual who has a known or suspected tolerance to opiates. In addition, certain opioid synthetics such as methadone have longer half-lives than nalmefene; prolonged observation is therefore still required when toxicity is caused by these agents. 21 Limitations of this study should be noted. First, the number of patients in this study is small, therefore uncommon side effects would not be identified in this cohort. Second, all of the study patients received fentanyl, which is a shortacting opiate. Resedation would not be expected when a short-acting opiate such as fentanyl is used. The efficacy profile of nalmefene after use of a longer action opioid therefore remains unknown. In conclusion, nalmefene appears to be effective and safe for reversal of opioid-induced procedural sedation in children. Its role in the reversal of opioid toxicity in children caused by overdose may be superior to naloxone because of its longer duration of action. REFERENCES 1. Ilkhanipour K, Juels CR, Longdorf MI: Pediatric pain control and conscious sedation: a survey of emergency medicine residency. Acad Emerg Med 1994;1:368-72 2. Billmire DA, Neale HW, Gregory RO: Use of IV fentanyl in outpatient treatment of pediatric facial trauma. J Trauma 1985;25: 1079-80 3. Pohlgeers AP, Friedland LR, Keegan-Jones L: Combination fentanyl and diazepam for pediatric conscious sedation. Acad Emerg Med 1995;2:879-83 4. Chudnofsky CR, Wright SW, Dronen SC, et al: The safety of fentanyl use in the emergency department. Ann Emerg Med 1989; 18:635-39 5. Moore LRC, Bikhazi GB, Tuttle RR, et al: Antagonism of fentanyl-induced respiratory depression with nalmefene. Meth Find Exp Clin Pharmacol 1990;12:29-35 6. Evans JM, Hogg MIJ, Lunn JN, et al: Degree and duration of reversal by naloxone of effects of morphine in conscious subjects. Br Med J 1974;2:589-91 7. Longnecker DE, Grazis PA, Eggers GW: Naloxone for antagonism of morphine-induced respiratory depression. Anesth Analg 1973;52:447-52 8. Hahn EF, Fishman J, Heilman RD: Narcotic antagonists.4.Carbon-6 Derivatives of N-substituted noroxymorphones as narcotic antagonists. J Med Chem 1975;18:259-62
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9. Dixon RD, Howes J, Gentile J, et al: Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986;39:49-53 10. Ngai SH, Berkowitz BA, Yang JC, et al: Pharmacokinetics of naloxone in rats and in man. Anesthesiology 1976;44:398-401 11. Gal TJ, DiFazio CA: Prolonged antagonism of opioid action with intravenous nalmefene in man. Anesthesiology 1986;64:175-80 12. Konieczko KM, Jones JG, Barrowcliffe MP, et al: Antagonist of morphine-induced respiratory depression with nalmefene. Br J Anaesth 1988;61:318-23 13. Barsan WG, Seger D, Danzl DF, et al: Duration of antagonistic effects of nalmefene in opiate-induced sedation for emergency department procedures. Am J Emerg Med 1989;7:155-61 14. Glass PSA, Jhaveri RM, Smith LR: Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg 1994;78:536-41 15. Kaplan JL, Marx JA: Effectiveness and safety of intravenous nalmefene for emergency department patients with suspected narcotic overdose: A pilot study. Ann Emerg Med 1993;22:187-90
16. Kaplan JL, Marx JA, Calabro J J, et al: Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Ann Emerg Med 1999; 34:42-50 17. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110-5 18. Chernik DA, Gillings D, Laine H, et al: Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: Study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244-51 19. Tenenbein M: Continuous naloxone infusion for opiate poisoning in infancy. J Pediatr 1984;105:645-48 20. Henderson CA, Reynolds JE: Acute pulmonary edema in young male after intravenous nalmefene. Anesth Analg 1997;84: 218-9 21. Gaeta TJ, Capodano RJ, Spevack TA: Potential danger of nalmefene use in the emergency department. Ann Emerg Med 1997;29:193-94