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Groman A, Spyhalsky A, Michienzi K, Breuer R. Impact of Intravenous Methadone Dosing Schedule on Iatrogenic Withdrawal Syndrome in a Pediatric Intensive Care Unit. J Pediatr Pharmacol Ther 2024; 29:266-272. [PMID: 38863852 PMCID: PMC11163900 DOI: 10.5863/1551-6776-29.3.266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 08/14/2023] [Indexed: 06/13/2024]
Abstract
OBJECTIVE To compare median Sophia Observation withdrawal Symptoms scale (SOS) scores between -intravenous methadone dosing scheduled every 6 hours or every 8 hours for iatrogenic withdrawal -syndrome (IWS). METHODS This single-center, retrospective chart review evaluated patients aged 4 weeks through 18 years treated with intravenous methadone for IWS. Children admitted to the pediatric intensive care unit (PICU) of a tertiary care children's hospital between August 2017 and July 2021 and treated for IWS for at least 48 hours were eligible for inclusion. Methadone dosing schedules were compared, with a primary outcome of median Sophia Observation withdrawal Symptoms (SOS) score during the first 24 hours after cessation of continuous fentanyl infusion. Secondary outcomes included PICU and general pediatric unit lengths of stay, extubation failure rates, and mortality. RESULTS Twenty patients met inclusion criteria, with 9 in the 6-hour dosing group. There was no difference in median SOS score, extubation failure, length of stay, or mortality between the 2 groups. CONCLUSIONS During the first 24 hours after cessation of continuous fentanyl, there appears to be no -difference in IWS severity, as determined by bedside nurse scoring, between patients treated with -intravenous methadone every 6 hours compared with every 8 hours.
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Affiliation(s)
- Aleah Groman
- Department of Pharmacy (AG, AS, KM), Kaleida Health John R. Oishei Children’s Hospital, Buffalo, NY
| | - Autumn Spyhalsky
- Department of Pharmacy (AG, AS, KM), Kaleida Health John R. Oishei Children’s Hospital, Buffalo, NY
- PharmD Candidate (AS), State University of New York at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, anticipated graduation 2024
| | - Kelly Michienzi
- Department of Pharmacy (AG, AS, KM), Kaleida Health John R. Oishei Children’s Hospital, Buffalo, NY
| | - Ryan Breuer
- Department of Pediatrics (RB), UBMD Physicians Group, Buffalo, NY
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Methadone: applications in pediatric anesthesiology and critical care medicine. J Anesth 2021; 35:130-141. [PMID: 33432486 DOI: 10.1007/s00540-020-02887-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/12/2020] [Indexed: 10/22/2022]
Abstract
Like morphine, methadone is a pure agonist at the µ opioid receptor. However, in distinction to morphine which has an elimination half-life of 2-3 h, methadone has an elimination half-life of 24-36 h. In addition to its effects at the µ opioid receptor, methadone is an antagonist at the N-methyl-D-aspartate (NMDA) receptor and also inhibits the reuptake of the neurotransmitters, serotonin and norepinephrine, in the central nervous system. Given its long half-life and high oral bioavailability, methadone has had a primary role in the outpatient treatment of patients with a history of opioid abuse or addiction. However, its unique pharmacology and cellular effects make it a valuable agent in the treatment of both acute and chronic pain of various etiologies. The following manuscript reviews the pharmacologic properties of methadone and discusses its clinical applications in the practice of pediatric anesthesiology and pediatric critical care medicine.
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Shortened Taper Duration after Implementation of a Standardized Protocol for Iatrogenic Benzodiazepine and Opioid Withdrawal in Pediatric Patients: Results of a Cohort Study. Pediatr Qual Saf 2018; 3:e079. [PMID: 30229191 PMCID: PMC6132810 DOI: 10.1097/pq9.0000000000000079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 03/30/2018] [Indexed: 01/26/2023] Open
Abstract
Supplemental Digital Content is available in the text. Introduction: Methadone and lorazepam prescribing discrepancies for the use of iatrogenic withdrawal were observed among providers. A standardized pharmacist-managed methadone and lorazepam taper protocol was implemented at a pediatric tertiary care facility with the aim to reduce the length of taper for patients with iatrogenic withdrawal. Methods: A multidisciplinary team of nurses, pharmacists, and physicians reviewed the current literature, then developed and implemented a standardized withdrawal taper protocol. Outcomes were compared with a retrospective control group using past prescribing practices. The primary endpoint was the length of methadone and/or lorazepam taper. Secondary endpoints included evaluation for significant differences between the control and standardized protocol groups regarding additional breakthrough withdrawal medications, pediatric intensive care unit (PICU) and hospital length of stay. We also evaluated provider satisfaction with the protocol. Results: The standardized protocol group included 25 patients who received methadone and/or lorazepam taper. A retrospective control group contained 24 patients. Median methadone taper length before protocol implementation was 9.5 days with an interquartile range (IQR) of 5.5–14.5 days; after protocol implementation, it was 6.0 (IQR, 3.0–9.0) days (P = 0.0145). Median lorazepam taper length before protocol implementation was 13.0 (IQR, 8.0–18.0) days; after protocol implementation, it was 6.0 (4.0–7.0) days (P = 0.0006). A statistical difference between PICU length of stay, hospital length of stay, or the number of additional medications for breakthrough withdrawal was not found. Conclusions: The use of a standardized withdrawal protocol resulted in shorter taper duration for both the methadone and lorazepam groups. There was no difference in PICU or hospital length of stay.
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Fenn NE, Plake KS. Opioid and Benzodiazepine Weaning in Pediatric Patients: Review of Current Literature. Pharmacotherapy 2017; 37:1458-1468. [PMID: 28891099 DOI: 10.1002/phar.2026] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Pediatric opioid and benzodiazepine withdrawal are avoidable complications of pain and sedation management that is well described in the literature. To prevent withdrawal from occurring, practitioners regularly use a steady decrease of pain and sedation medications, also known as a weaning or tapering schedule. The weaning schedule is highly variable based on clinician preference and is usually dependent on the clinician. The purposes of this review are to evaluate the current literature on the process of opioid and benzodiazepine weaning in pediatric patients and to assess the various standardized protocols used to decrease withdrawal occurrences. We conducted a search of the PubMed, MEDLINE, Cochrane Library, Cumulative Index of Nursing and Allied Health (CINAHL), Academic Search Premier, and PsycInfo databases. Studies were included if they described a wean or taper in pediatric patients aged 18 years or younger. Studies describing neonatal abstinence syndrome were excluded from the review. A total of 97 studies published between 2000 and 2014 were retrieved; of those, 15 studies met the inclusion criteria. Studies were evaluated for selection of withdrawal assessment tool, wean protocol summary, preferred weaning agents, benzodiazepine withdrawal, and wean-at-home regimen. The most common opioid-weaning protocol approaches described a 10-20% dose decrease per day. Benzodiazepine weaning was not regularly standardized or described. The use of a standardized opioid-weaning protocol reduced withdrawal rates compared with nonstandardized weaning plans. Benzodiazepine weaning was inconsistently evaluated and may have affected study outcomes. Identified areas of improvement include the use of newer withdrawal assessment tools validated in the older pediatric population and standardized withdrawal assessment and reporting.
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Affiliation(s)
- Norman E Fenn
- Purdue University College of Pharmacy, West Lafayette, Indiana
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Chiu AW, Contreras S, Mehta S, Korman J, Perreault MM, Williamson DR, Burry LD. Iatrogenic Opioid Withdrawal in Critically Ill Patients: A Review of Assessment Tools and Management. Ann Pharmacother 2017; 51:1099-1111. [PMID: 28793780 DOI: 10.1177/1060028017724538] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE To (1) provide an overview of the epidemiology, clinical presentation, and risk factors of iatrogenic opioid withdrawal in critically ill patients and (2) conduct a literature review of assessment and management of iatrogenic opioid withdrawal in critically ill patients. DATA SOURCES We searched MEDLINE (1946-June 2017), EMBASE (1974-June 2017), and CINAHL (1982-June 2017) with the terms opioid withdrawal, opioid, opiate, critical care, critically ill, assessment tool, scale, taper, weaning, and management. Reference list of identified literature was searched for additional references as well as www.clinicaltrials.gov . STUDY SELECTION AND DATA EXTRACTION We restricted articles to those in English and dealing with humans. DATA SYNTHESIS We identified 2 validated pediatric critically ill opioid withdrawal assessment tools: (1) Withdrawal Assessment Tool-Version 1 (WAT-1) and (2) Sophia Observation Withdrawal Symptoms Scale (SOS). Neither tool differentiated between opioid and benzodiazepine withdrawal. WAT-1 was evaluated in critically ill adults but not found to be valid. No other adult tool was identified. For management, we identified 5 randomized controlled trials, 2 prospective studies, and 2 systematic reviews. Most studies were small and only 2 studies utilized a validated assessment tool. Enteral methadone, α-2 agonists, and protocolized weaning were studied. CONCLUSION We identified 2 validated assessment tools for pediatric intensive care unit patients; no valid tool for adults. Management strategies tested in small trials included methadone, α-2 agonists, and protocolized sedation/weaning. We challenge researchers to create validated tools assessing specifically for opioid withdrawal in critically ill children and adults to direct management.
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Affiliation(s)
- Ada W Chiu
- 1 Peace Arch Hospital, Fraser Health Authority, White Rock, British Columbia, Canada
| | - Sofia Contreras
- 2 Hospital Universitari de Bellvitge, L'Hospitalet de Llobretat, Barcelona, Spain
| | - Sangeeta Mehta
- 3 Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
| | - Jennifer Korman
- 3 Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
| | - Marc M Perreault
- 4 The Montreal General Hospital-McGill University Health Center, Montreal, Quebec, Canada
| | - David R Williamson
- 5 Université de Montréal, Montreal, Quebec, Canada.,6 Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada
| | - Lisa D Burry
- 3 Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada.,7 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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Srinivasan V, Pung D, O’Neill SP. Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children. World J Clin Pediatr 2017; 6:110-117. [PMID: 28540195 PMCID: PMC5424279 DOI: 10.5409/wjcp.v6.i2.110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/04/2017] [Accepted: 03/24/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To describe our institutional experience with conversion from intravenous (IV) fentanyl infusion directly to enteral methadone and occurrence of withdrawal in critically ill mechanically ventilated children exposed to prolonged sedation and analgesia.
METHODS With Institutional Review Board approval, we retrospectively studied consecutively admitted invasively mechanically ventilated children (0-18 years) sedated with IV fentanyl infusion > 5 d and subsequently converted directly to enteral methadone. Data were obtained on subject demographics, illness severity, daily IV fentanyl and enteral methadone dosing, time to complete conversion, withdrawal scores (WAT-1), pain scores, and need for rescue opioids. Patients were classified as rapid conversion group (RCG) if completely converted ≤ 48 h and slow conversion group (SCG) if completely converted in > 48 h. Primary outcome was difference in WAT-1 scores at 7 d. Secondary outcomes included differences in overall pain scores, and differences in daily rescue opioids.
RESULTS Compared to SCG (n = 21), RCG (n = 21) had lower median WAT-1 scores at 7 d (2.5 vs 5, P = 0.027). Additionally, RCG had lower overall median pain scores (3 vs 6, P = 0.007), and required less median daily rescue opioids (3 vs 12, P = 0.003) than SCG. The starting daily median methadone dose was 2.3 times the daily median fentanyl dose in the RCG, compared to 1.1 times in the SCG (P = 0.049).
CONCLUSION We observed wide variation in conversion from IV fentanyl infusion directly to enteral methadone and variability in withdrawal in critically ill mechanically ventilated children exposed to prolonged sedation. In those children who converted successfully from IV fentanyl infusion to enteral methadone within a period of 48 h, a methadone:fentanyl dose conversion ratio of approximately 2.5:1 was associated with less withdrawal and reduced need for rescue opioids.
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Dervan LA, Yaghmai B, Watson RS, Wolf FM. The use of methadone to facilitate opioid weaning in pediatric critical care patients: a systematic review of the literature and meta-analysis. Paediatr Anaesth 2017; 27:228-239. [PMID: 28109052 DOI: 10.1111/pan.13056] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/13/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND Continuous opioid infusion therapy is commonly utilized in the pediatric intensive care setting to treat pain and facilitate tolerance of invasive therapies. Transitioning to methadone is one common strategy for weaning from continuous opioid infusions, but in practice this transition can be challenging, and many children still experience iatrogenic withdrawal. AIM We reviewed the literature to evaluate the best available evidence to guide methadone therapy in this setting, and to summarize associated adverse events. METHODS We included all studies of methadone used to facilitate weaning from continuous opioid infusions in pediatric critical care patients, including medical, cardiac, and surgical patients, excluding case reports and studies treating neonatal abstinence syndrome, or acute or chronic pain. Medline, Embase, and CINAHL databases from inception to May 2015 were queried; references of included works and conference proceedings were also reviewed. Two authors independently extracted data from each study. Meta-analysis with fixed- and random-effects models was used to pool results of studies when applicable. RESULTS Twelve studies involving 459 patients met criteria for inclusion. A wide variety of methadone dosing and taper strategies were reported. Mean inpatient methadone taper times varied widely, from 4.3 to 26.2 days. Excessive sedation was the most frequently reported adverse event, occurring in up to 16% of patients. Withdrawal occurred in 27% of patients among studies reporting this outcome. In three of three studies in which a new methadone protocol was introduced, a decreased proportion of patients experienced withdrawal (standardized mean difference, SMD = -0.60, 95% CI = -0.998 to -0.195, P = 0.004). CONCLUSION We did not identify sufficient evidence to recommend any particular methadone weaning strategy, or to recommend methadone over other medications or prescribed infusion weaning, for successful weaning of continuous opioid infusions in the pediatric intensive care setting.
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Affiliation(s)
- Leslie A Dervan
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Beryl Yaghmai
- Department of Pediatrics, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
| | - Robert Scott Watson
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.,Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA, USA
| | - Fredric M Wolf
- Department of Biomedical Informatics and Medical Education, University of Washington School of Medicine, Seattle, WA, USA
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Tobias JD. Pentobarbital for Sedation during Mechanical Ventilation in the Pediatric ICU Patient. J Intensive Care Med 2016. [DOI: 10.1177/088506660001500205] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In most pediatric intensive care units (PICUs), sedation is provided using opioids and benzodiazepines, either alone or in combination. While these agents are effective in most patients, certain situations may arise in which this usual combination is ineffective. There are no large series outlining the use of pentobarbital for sedation in the PICU population. The current report is a retrospective review of the use of pentobarbital for sedation of 50 patients in the PICU and provides information concerning the use of phenobarbital to prevent withdrawal symptoms following the prolonged administration of pentobarbital. The 50 patients ranged in age from 1 month to 14 years and in weight from 3.1 to 56 kg. All required sedation during mechanical ventilation. Prior to changing to pentobarbital, sedation was inadequate despite midazolam doses of ≥0.4 mg/kg/hr, fentanyl doses of ≥10 μg/kg/hr, and morphine doses of ≥100 μg/kg/hr. The duration of pentobarbital infusion ranged from 2 to 37 days (median 4 days) in doses ranging from 1 to 6 mg/kg/hr (median 2 mg/kg/hr). Twelve patients also received an ongoing opioid infusion for more than 48 hours after starting the pentobarbital infusion to control pain related to a surgical procedure or an acute medical illness. There was an increase in pentobarbital infusion requirements over time. In the 14 patients that received pentobarbital for 5 days or more, the requirements increased from 1.2 ± 0.4 mg/kg/hr on day 1 to 3.4 ± 0.7 mg/kg/hr on day 5 ( p < 0.01). Pentobarbital was effective in all 50 patients without significant adverse effects.
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Affiliation(s)
- Joseph D. Tobias
- From the Departments of Child Health and Anesthesiology, Division of Pediatric Critical Care/Pediatric Anesthesiology, University of Missouri, Columbia, MO
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9
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Capino AC, Miller JL, Hughes KM, Miller MJ, Johnson PN. Caregiver Perception, Self-efficacy, and Knowledge of Methadone Tapers for Children With Iatrogenic Opioid Abstinence Syndrome. J Pharm Technol 2016; 32:104-115. [PMID: 34860963 PMCID: PMC5998460 DOI: 10.1177/8755122515622030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2023] Open
Abstract
Background: There are no definitive guidelines regarding the management of iatrogenic opioid abstinence syndrome (IOAS), but methadone tapers are one common approach. Methadone tapers can be complex for caregivers to manage, and there is a paucity of data about caregiver experiences administering medication tapers postdischarge. Objective: The primary objective was to describe caregiver perception, self-efficacy, and knowledge of administering methadone tapers. Secondary objectives included an assessment of the change in self-efficacy and knowledge of methadone and IOAS before and after discharge as well as clinical outcomes occurring postdischarge. Methods: This was an exploratory, descriptive, institutional review board-approved study surveying caregivers of children receiving methadone tapers for IOAS. Caregivers were included if they had a child ≤12 years of age discharged to home on a methadone taper. The study consisted of 2 phases: a questionnaire and observation/counseling session predischarge and a telephone interview after taper completion. Univariate descriptive statistics were utilized for data analysis. Results: Phase 1 of the study was completed by 12 caregivers, and only 5 completed phase 2. The majority of caregivers were completely confident predischarge (83.3%) and postdischarge (80%) in administering methadone as prescribed. However, some caregivers were confused about the purpose of the taper and experienced difficulty in measuring oral solutions. Conclusions: Despite high self-efficacy, caregivers experienced difficulties in understanding taper management and during the observation session. The results of this study suggest presenting information to caregivers utilizing minimal medical jargon, conducting a counseling/observation session predischarge, and utilizing the teach-back method with caregivers to assess for understanding.
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Affiliation(s)
- Amanda C. Capino
- University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA
| | - Jamie L. Miller
- University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA
| | - Kaitlin M. Hughes
- University of Michigan C. S. Mott Children’s Hospital, Ann Arbor, MI, USA
| | | | - Peter N. Johnson
- University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA
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Abdouni R, Reyburn-Orne T, Youssef TH, Haddad IY, Gerkin RD. Impact of a Standardized Treatment Guideline for Pediatric Iatrogenic Opioid Dependence: A Quality Improvement Initiative. J Pediatr Pharmacol Ther 2016; 21:54-65. [PMID: 26997929 DOI: 10.5863/1551-6776-21.1.54] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVES To determine whether utilization of a hospital-based clinical practice guideline for the care of pediatric iatrogenic opioid dependence (IOD) would promote a decrease in opioid exposure and improve management of opioid abstinence syndrome (AS). METHODS This study is a retrospective chart review of critically ill patients from a tertiary care children's hospital. Inclusion criteria included mechanically ventilated patients up to 18 years of age who received continuous opioid infusions for at least 7 days and any length of methadone administration. Data on IOD patients from January 2005 to June 2010 was divided into 3 periods: baseline, phase 1, and phase 2. Primary outcome was decrease in opioid exposure, measured by methadone duration of use and any additional opioid bolus doses used in AS management. Documentation of additional opioid bolus doses was regarded as a surrogate measure of AS. Secondary outcomes included total cumulative fentanyl dose, continuous fentanyl infusion duration of use, and hospital and pediatric intensive care unit length of stay. RESULTS There was a significant decrease in methadone duration of use in IOD patients from 15.3 ± 8.7 days at baseline to 9.5 ± 3.7 days during phase 1 (p = 0.002), to 8.1 ± 3.7 days on phase 2 (reduction not significant, p = 0.106) of this evaluation. Additional opioid bolus doses were significantly lower from baseline to phase 1 (5.5 ± 5.1 vs. 1.8 ± 2.3, p = 0.001) and from phase 1 to phase 2 (1.8 ± 2.3 vs. 0.2 ± 1.5, p = 0.003). For the remaining outcomes, differences were not observed among the evaluation periods, except for the total cumulative fentanyl dose, which was reduced from 2.8 ± 3.7 mg/kg at baseline to 1 ± 1 mg/kg only during phase 1 (p = 0.017). CONCLUSIONS Introduction of a standardized, hospital-based clinical practice guideline for children with IOD reduced the length of exposure to opioids and improved opioid AS management.
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Affiliation(s)
| | | | - Tarek H Youssef
- King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Keogh SJ, Long DA, Horn DV. Practice guidelines for sedation and analgesia management of critically ill children: a pilot study evaluating guideline impact and feasibility in the PICU. BMJ Open 2015; 5:e006428. [PMID: 25823444 PMCID: PMC4386214 DOI: 10.1136/bmjopen-2014-006428] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
AIMS The aim of this study was to develop and implement guidelines for sedation and analgesia management in the paediatric intensive care unit (PICU) and evaluate the impact, feasibility and acceptability of these as part of a programme of research in this area and as a prelude to future trial work. METHOD This pilot study used a pre-post design using a historical control. SETTING Two PICUs at different hospitals in an Australian metropolitan city. PARTICIPANTS Patients admitted to the PICU and ventilated for ≥24 h, aged more than 1 month and not admitted for seizure management or terminal care. INTERVENTION Guidelines for sedation and analgesia management for critically ill children including algorithm and assessment tools. OUTCOME VARIABLES In addition to key outcome variables (ventilation time, medication dose and duration, length of stay), feasibility outcomes data (recruitment, data collection, safety) were evaluated. Guideline adherence was assessed through chart audit and staff were surveyed about merit and the use of guidelines. RESULTS The guidelines were trialled for a total of 12 months on 63 patients and variables compared with the historical control group (n=75). Analysis revealed differences in median Morphine infusion duration between groups (pretest 3.63 days (87 h) vs post-test 2.83 days (68 h), p=0.05) and maximum doses (pretest 120 μg/kg/h vs post-test 97.5 μg/kg/h) with no apparent change to ventilation duration. Chart audit revealed varied use of tools, but staff were positive about the guidelines and their use in practice. CONCLUSIONS The sedation guidelines impacted on the duration and dosage of agents without any apparent impact on ventilation duration or length of stay. Furthermore, the guidelines appeared to be feasible and acceptable in clinical practice. The results of the study have laid the foundation for follow-up studies in withdrawal from sedation, point prevalence and longitudinal studies of sedation practices as well as drug trial work.
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Affiliation(s)
- Samantha J Keogh
- Nursing Research Services, Royal Children's Hospital, Brisbane, Queensland, Australia
- NHMRC Centre of Research Excellence in Nursing (NCREN)—Centre for Health Practice Innovation—Griffith Health Institute, Griffith University, Nathan, Australia
| | - Debbie A Long
- Paediatric Intensive Care Unit, Royal Children's Hospital, Brisbane, Queensland, Australia
- NHMRC Centre of Research Excellence in Nursing (NCREN)—Centre for Health Practice Innovation—Griffith Health Institute, Griffith University, Nathan, Australia
| | - Desley V Horn
- Paediatric Intensive Care Unit, Royal Children's Hospital, Brisbane, Queensland, Australia
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External Validation of the Medication Taper Complexity Score for Methadone Tapers in Children With Opioid Abstinence Syndrome. Ann Pharmacother 2013; 48:187-95. [DOI: 10.1177/1060028013512110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background: Methadone is commonly prescribed for children with opioid abstinence syndrome (OAS) as a taper schedule over several days to weeks. The Medication Taper Complexity Score (MTCS) was developed to evaluate outpatient methadone tapers. Objective: To further validate the MTCS and determine if it is a reliable tool for clinicians to use to assess the complexity of methadone tapers for OAS. Methods: An expert panel of pediatric clinical pharmacists was convened. Panel members were provided 9 methadone tapers (ie, “easy,” “medium,” and “difficult”) to determine construct and face validity of the MTCS. The primary objective was to further establish reliability and construct/face validity of the MTCS. The secondary objective was to assess the reliability of the MTCS within and between tapers. Instrument reliability was assessed using a Pearson correlation coefficient; with 0.8 as the minimum acceptable coefficient. Construct (divergent) validity was assessed via a repeated-measures ANOVA analysis (Bonferroni post hoc analyses) of the mean scores provided by panel members. Results: Six panel members were recruited from various geographical locations. Panel members had 18.3 ± 5.5 years of experience, with practice expertise in general pediatrics, hematology/oncology, and the pediatric and neonatal intensive care unit. The MTCS had a reliability coefficient of .9949. There was vivid discrimination between the easy, medium, and difficult tapers; P = .001. The panel recommended minor modifications to the MTCS. Conclusions: The MTCS was found to be a reliable and valid tool. Overall, the panel felt that the MTCS was easy to use and had potential applications in both practice and research.
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Martin DP, Bhalla T, Beltran R, Veneziano G, Tobias JD. The safety of prescribing opioids in pediatrics. Expert Opin Drug Saf 2013; 13:93-101. [PMID: 24073760 DOI: 10.1517/14740338.2013.834045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Pain management has become a widely discussed topic throughout all medical subspecialties. Although pediatric pain management has evolved significantly in its recent history, there is continued interest in the adequacy of pain treatment, both in the acute inpatient setting as well as the postoperative and chronic pain management setting. Although health care providers are becoming more aggressive concerning prompt and effective treatment of acute and chronic pain, safety data and adverse effects of narcotic analgesics may be overlooked. AREAS COVERED The authors review the current paradigm of acute pain management with an emphasis on oral narcotic medications, and the safety data available concerning prescribing these medications. EXPERT OPINION Further, the authors present their opinions concerning current and future practices regarding the prescribing practice of opiate analgesics, as well as a step-wise approach for acute oral pain management.
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Affiliation(s)
- David P Martin
- Ohio State University, Nationwide Children's Hospital, Department of Anesthesiology and Pain Medicine , 700 Children's Drive, Columbus, OH 43205 , USA +1 614 722 4200 ; +1 614 722 4203 ;
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Gamble C, Wolf A, Sinha I, Spowart C, Williamson P. The role of systematic reviews in pharmacovigilance planning and Clinical Trials Authorisation application: example from the SLEEPS trial. PLoS One 2013; 8:e51787. [PMID: 23554852 PMCID: PMC3598865 DOI: 10.1371/journal.pone.0051787] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 11/07/2012] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Adequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug. METHODOLOGY/PRINCIPAL FINDINGS The Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions. CONCLUSIONS/SIGNIFICANCE No adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions.
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Affiliation(s)
- Carrol Gamble
- Clinical Trials Research Centre, University of Liverpool, Liverpool, Merseyside, United Kingdom.
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Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study. Pediatr Crit Care Med 2013; 14:27-36. [PMID: 23132396 PMCID: PMC3581608 DOI: 10.1097/pcc.0b013e318253c80e] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. DESIGN Prospective, observational study with 100% accrual of eligible patients. SETTING Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network. PATIENTS Four hundred nineteen children treated with morphine or fentanyl infusions. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03). CONCLUSIONS Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.
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Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care 2012; 16:R49. [PMID: 22420584 PMCID: PMC3681375 DOI: 10.1186/cc11250] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 10/29/2011] [Accepted: 03/15/2012] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Patients undergoing mechanical ventilation (MV) are frequently administered prolonged and/or high doses of opioids which when removed can cause a withdrawal syndrome and difficulty in weaning from MV. We tested the hypothesis that the introduction of enteral methadone during weaning from sedation and analgesia in critically ill adult patients on MV would decrease the weaning time from MV. METHODS A double-blind randomized controlled trial was conducted in the adult intensive care units (ICUs) of four general hospitals in Brazil. The 75 patients, who met the criteria for weaning from MV and had been using fentanyl for more than five consecutive days, were randomized to the methadone (MG) or control group (CG). Within the first 24 hours after study enrollment, both groups received 80% of the original dose of fentanyl, the MG received enteral methadone and the CG received an enteral placebo. After the first 24 hours, the MG received an intravenous (IV) saline solution (placebo), while the CG received IV fentanyl. For both groups, the IV solution was reduced by 20% every 24 hours. The groups were compared by evaluating the MV weaning time and the duration of MV, as well as the ICU stay and the hospital stay. RESULTS Of the 75 patients randomized, seven were excluded and 68 were analyzed: 37 from the MG and 31 from the CG. There was a higher probability of early extubation in the MG, but the difference was not significant (hazard ratio: 1.52 (95% confidence interval (CI) 0.87 to 2.64; P = 0.11). The probability of successful weaning by the fifth day was significantly higher in the MG (hazard ratio: 2.64 (95% CI: 1.22 to 5.69; P < 0.02). Among the 54 patients who were successfully weaned (29 from the MG and 25 from the CG), the MV weaning time was significantly lower in the MG (hazard ratio: 2.06; 95% CI 1.17 to 3.63; P < 0.004). CONCLUSIONS The introduction of enteral methadone during weaning from sedation and analgesia in mechanically ventilated patients resulted in a decrease in the weaning time from MV.
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Affiliation(s)
- Raquel Wanzuita
- Adult ICU, Centro Hospitalar Unimed, Rua Orestes Guimarães-905, Joinville, 89204-060, Brazil
- Adult ICU, Hospital Regional Hans Dieter Schmidt, Rua Xavier arp-1, Joinville, 89227-680, Brazil
| | - Luiz F Poli-de-Figueiredo
- LIM-08, Hospital das Clínicas, University of São Paulo, Avenida Doutor Arnaldo-455, São Paulo, 01246-903, Brazil
| | - Felipe Pfuetzenreiter
- Adult ICU, Centro Hospitalar Unimed, Rua Orestes Guimarães-905, Joinville, 89204-060, Brazil
- Adult ICU, Hospital Municipal São José, Avenida Getúlio Vargas-238, Joinville, 89202-000, Brazil
| | | | - Glauco Adrieno Westphal
- Adult ICU, Centro Hospitalar Unimed, Rua Orestes Guimarães-905, Joinville, 89204-060, Brazil
- Adult ICU, Hospital Municipal São José, Avenida Getúlio Vargas-238, Joinville, 89202-000, Brazil
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Johnson PN, Boyles KA, Miller JL. Selection of the initial methadone regimen for the management of iatrogenic opioid abstinence syndrome in critically ill children. Pharmacotherapy 2012; 32:148-57. [PMID: 22392424 DOI: 10.1002/phar.1001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Iatrogenic opioid abstinence syndrome (IOAS) is a common complication in critically ill infants and children receiving prolonged exposure to continuous infusions of opioids. Although no guidelines are available regarding management of IOAS in children, several treatment options are available, including clonidine, morphine, and methadone. Methadone is commonly prescribed due to its long half-life and antagonism of the N-methyl-d-aspartate receptor. Different approaches, such as weight-based and formula-based methods, have been used to determine the initial methadone dosing regimen. Because of the vast differences in the recommended dosing regimen from these sources, we conducted a literature search to identify articles evaluating the initial methadone dosing regimen for prevention and/or treatment of IOAS in children. Specifically, we evaluated the reported frequency of withdrawal and oversedation after initiation of methadone treatment. Our literature search was limited to English-language articles in the MEDLINE (1950-March 2011), EMBASE (1988-March 2011), International Pharmaceutical Abstracts (1970-March 2011), and Cochrane Library (1996-March 2011) databases. Relevant abstracts and reference citations were also reviewed. A total of eight reports representing 183 patients were included in the analysis. There was wide discrepancy in the initial methadone dosing regimen. Approximately one-third of all patients experienced withdrawal after starting methadone, and there did not appear to be a difference between weight-based and formula-based regimens. Seven patients experienced oversedation; however, not all articles reported this complication. It appears that a standard approach to initial methadone dosing does not exist because withdrawal occurred despite the regimen started. Therefore, it seems best to begin with the lowest dose possible and titrate to the child's response to avoid complications such as oversedation. Routine monitoring should be performed in all patients to guide clinicians in the management of IOAS.
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Affiliation(s)
- Peter N Johnson
- Department of Pharmacy, Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, Oklahoma 73117, USA.
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Johnson PN, Harrison DL, Castro CH, Miller JL. A pilot study assessing the frequency and complexity of methadone tapers for opioid abstinence syndrome in children discharged to home. Res Social Adm Pharm 2012; 8:455-63. [PMID: 22222345 DOI: 10.1016/j.sapharm.2011.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 12/07/2011] [Accepted: 12/08/2011] [Indexed: 10/14/2022]
Abstract
BACKGROUND Methadone is often prescribed as a taper schedule to prevent/treat opioid abstinence syndrome (OAS) or neonatal abstinence syndrome (NAS). OBJECTIVE The objective of this study was to determine the percentage of children discharged home on methadone tapers and to develop, assess, and implement an instrument for measuring the complexity of the methadone regimens. METHODS This study used a descriptive retrospective design to examine patients younger than 18 years from January 1, 2008, to December 31, 2008, administered methadone for prevention/treatment of OAS/NAS and discharged home on a methadone taper. Data collection included demographics and characteristics of methadone regimen. The primary objective was to determine the percentage of children discharged on methadone. Secondary objectives included characterization (ie, number of dosage and interval changes), duration, and complexity of the methadone taper. Descriptive statistics were performed using Stata v10 (StataCorp LP, College Station, TX). Complexity was evaluated using the medication taper complexity score (MTCS) between 4 raters. Reliability of the MTCS was established using interrater correlation analyses of the regimen complexity scores. RESULTS Thirty-three patients (41.8%) were discharged on methadone. The median (range) age was 0.42 (0-12) years, with most patients (75.8%) initiated on methadone for prevention of OAS. Thirty-one patients were included for further analysis of medication complexity. The median (range) duration of the home taper was 8 days (2-48), which included a median (range) of 4 (1-11) dose changes and at least 1 (0-2) change in the interval. MTCS ranged from 7 to 42, with the tool demonstrating 95% interrater reliability. CONCLUSIONS More than one-third of patients were discharged home on methadone. The median taper duration was 8 days and included a median of 5 adjustments in either the dose or interval. The MTCS demonstrated very good interrater reliability to measure wide variability in the complexity of individual tapers. Future studies should determine the construct validity of the MTCS and the applicability of this tool for further research and clinical application.
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Affiliation(s)
- Peter N Johnson
- Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK 73117, USA.
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Anghelescu DL, Faughnan LG, Hankins GM, Ward DA, Oakes LL. Methadone use in children and young adults at a cancer center: a retrospective study. J Opioid Manag 2012; 7:353-61. [PMID: 22165034 DOI: 10.5055/jom.2011.0076] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE To augment the literature on methadone applications in pediatric oncology, the authors reviewed the use of methadone at a pediatric cancer center over a 5-year period. DESIGN AND SETTING Forty-one patients received methadone for inpatient or outpatient pain management. The authors retrospectively reviewed their demographic characteristics, diagnoses, type of pain (nociceptive, neuropathic, or mixed) and causes of pain, and the indications, dose regimens, adverse effects, and outcomes of methadone treatment. RESULTS There were four types of clinical uses for methadone in 41 patients (10 patients had two): nociceptive pain unresponsive to other opioids (17 patients, 33.3 percent), neuropathic pain (20 patients, 39.2 percent), facilitation of weaning from opioids (11 patients, 21.6 percent), and end-of-life pain management (3 patients, 5.9 percent). The mean age of the 24 males (58.5 percent) and 17 females (41.5 percent) at the start of treatment was 15.7 years (range, 0.6-23 years). The most common diagnoses were leukemia (n = 10, 24.4 percent), osteosarcoma (n = 7, 17.0 percent), and rhabdomyosarcoma (n = 5, 12.2 percent). The causes of pain were bone marrow transplant (n = 13, 31.7 percent), amputation (n = 6, 14.6 percent), chemotherapy (n = 5, 12.2 percent), tumor (n = 5, 12.2 percent), limb-sparing surgery (n = 4, 9.8 percent), and other (n = 8, 19.5 percent). Efficacy was assessed at the end (or after 6 months) of methadone treatment. For many patients (43.1 percent), methadone showed efficacy in achieving the purpose for which it was prescribed, including reduction of nociceptive or neuropathic pain and prevention of opioid withdrawal. Sedation was the most common side effect (24.4 percent). CONCLUSIONS Methadone was effective for pediatric patients with neuropathic pain or nociceptive pain unresponsive to other opioids, and it effectively prevented opioid withdrawal.
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Affiliation(s)
- Doralina L Anghelescu
- Division of Anesthesia and Pain Management Service, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Jeffries SA, McGloin R, Pitfield AF, Carr RR. Use of methadone for prevention of opioid withdrawal in critically ill children. Can J Hosp Pharm 2012; 65:12-8. [PMID: 22479107 PMCID: PMC3282193 DOI: 10.4212/cjhp.v65i1.1098] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Opioids are commonly administered to critically ill children for analgesia and sedation, but many patients experience opioid withdrawal upon discontinuation. The authors' institution developed a protocol for using methadone to prevent opioid withdrawal in children who have received morphine by continuous IV infusion for 5 days or longer in the pediatric intensive care unit (PICU). OBJECTIVES The primary objectives were to determine if opioids were tapered according to the protocol and to determine the conversion ratio for IV morphine to oral methadone that was used. Secondary objectives were to describe the methadone dosage used and the clinical outcomes, to evaluate adjustments to methadone dosing, and to report the incidence of adverse effects. METHODS A retrospective analysis of charts was conducted for pediatric patients who had received morphine by continuous IV infusion for 5 days or longer followed by methadone in the PICU between May 2008 and August 2009. Validated scoring systems (the Withdrawal Assessment Tool and the State Behavioral Scale) were used to assess symptoms of withdrawal and degree of sedation, respectively. RESULTS Forty-three patients were included in the study, with median age of 8 months (range 0.25-201 months). For 31 patients (72%), the protocol was not used, and there were no patients for whom the protocol was followed to completion. The median duration of weaning was 10 days (range 0-91 days). The conversion ratio for IV morphine to oral methadone was 1:0.78 for anticipated 5-day weaning and 1:0.98 for anticipated 10-day weaning. During the first 10 days of weaning, 18 patients (42%) experienced withdrawal symptoms. The methadone dose was increased for 11 (26%) of the 43 patients. Patients were sedated for a median of 1 day (range 0-9 days), were comfortable for a median of 6.5 days (range 1-64 days), and were agitated for a median of 2.5 days (range 0-23 days). Naloxone was required for 2 patients. CONCLUSIONS The institution's methadone protocol was not followed consistently during the study period, and practices for transitioning from morphine by continuous IV infusion to methadone with tapering were also inconsistent. Further studies are needed to determine the optimal conversion ratio for morphine to methadone and the optimal tapering regimen to minimize withdrawal symptoms and adverse events.
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Affiliation(s)
- Sonia A Jeffries
- , BScPharm, is with the Children's & Women's Health Centre of British Columbia, Vancouver, British Columbia
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A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med 2011; 12:504-11. [PMID: 21076361 DOI: 10.1097/pcc.0b013e3181fe38f5] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES To compare the efficacy of a low-dose methadone tapering schedule to a high-dose methadone tapering schedule in pediatric intensive care unit patients exposed to infusions of fentanyl, with or without infusions of midazolam, for ≥ 5 days. DESIGN Prospective, double-blind, randomized trial. SETTING Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS Seventy-eight patients, 74 of whom had been receiving infusions of both fentanyl and midazolam, were randomized. Forty-one patients were randomized to the low-dose methadone group and 37 were randomized to the high-dose methadone group. Sixty patients successfully completed the trial, 34 were in the low-dose methadone group, and 26 were in the high-dose methadone group. INTERVENTIONS Patients were randomized to receive methadone either at a starting dose of 0.1 mg/kg/dose (low-dose methadone group) or at a starting dose based on both the patient's weight and the most recent fentanyl infusion rate (high-dose methadone group). In each group, methadone was administered every 6 hrs for the first 24 hrs and then every 12 hrs for the second 24 hrs. The methadone was then decreased to once daily and tapered off over the next 10 days. Patients were monitored for withdrawal symptoms using the Modified Narcotic Withdrawal Score. MEASUREMENTS AND MAIN RESULTS The percentage of patients who successfully completed the 10-day methadone taper was the same in the low-dose methadone group as in the high-dose methadone group (56% vs. 62%; p = .79). Patients that failed to complete the assigned methadone taper had a greater total fentanyl dose and longer pediatric intensive care unit length of stay compared to patients who completed the assigned methadone taper. CONCLUSIONS Patients who received infusions of fentanyl for at least 5 days were just as likely to complete a low-dose methadone taper as a high-dose methadone taper. Because of the risks of both withdrawal and oversedation with any fixed methadone schedule, the methadone dose must be adjusted according to each patient's response.
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Anand KJS, Willson DF, Berger J, Harrison R, Meert KL, Zimmerman J, Carcillo J, Newth CJL, Prodhan P, Dean JM, Nicholson C. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010; 125:e1208-25. [PMID: 20403936 PMCID: PMC3275643 DOI: 10.1542/peds.2009-0489] [Citation(s) in RCA: 199] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVE After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis. RESULTS Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.
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Affiliation(s)
- Kanwaljeet J. S. Anand
- Department of Pediatrics, Le Bonheur Children’s Hospital and University of Tennessee Health Science Center, Memphis, Tennessee
| | - Douglas F. Willson
- Department of Pediatrics & Anesthesiology, University of Virginia Children’s Hospital, Charlottesville, Virginia
| | - John Berger
- Department of Pediatrics, Children’s National Medical Center, Washington, DC
| | - Rick Harrison
- Department of Pediatrics, University of California at Los Angeles, Los Angeles, California
| | - Kathleen L. Meert
- Department of Pediatrics, Children’s Hospital of Michigan, Detroit, Michigan
| | - Jerry Zimmerman
- Department of Pediatrics, Children’s Hospital and Medical Center, Seattle, Washington
| | - Joseph Carcillo
- Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Parthak Prodhan
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - J. Michael Dean
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah
| | - Carol Nicholson
- Pediatric Critical Care and Rehabilitation Program, National Center for Medical Rehabilitation Research (NCMRR), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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Fentanyl for Sedation in the Pediatric Intensive Care Unit: Dealing with the Problems. ACTA ACUST UNITED AC 2010. [DOI: 10.1300/j088v04n03_03] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Tobias JD. Dexmedetomidine: Are There Going to be Issues with Prolonged Administration? J Pediatr Pharmacol Ther 2010. [DOI: 10.5863/1551-6776-15.1.4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Joseph D. Tobias
- Departments of Anesthesiology and Pediatrics, University of Missouri, Columbia, Missouri
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Birchley G. Opioid and benzodiazepine withdrawal syndromes in the paediatric intensive care unit: a review of recent literature. Nurs Crit Care 2009; 14:26-37. [PMID: 19154308 DOI: 10.1111/j.1478-5153.2008.00311.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIMS AND OBJECTIVES This paper aims to critically review and analyse available literature to inform and advance patient care. BACKGROUND Withdrawal syndromes related to the routine administration of sedation and analgesia in paediatric intensive care unit (PICU) have been recognized since the 1990 s. Common symptoms include tremors, agitation, inconsolable crying and sleeplessness. SEARCH STRATEGIES A critical review was undertaken to assess developments in this area. Four databases were searched using Ovid Online. These were Ovid Medline, CINAHL, BNI and Embase. Key terms included were 'Paediatric', 'Sedation', 'Withdrawal' and 'Intensive care'. INCLUSION AND EXCLUSION CRITERIA Articles from 1980 onwards were reviewed for their relevance to paediatric iatrogenic withdrawal. Additionally, seminal work from the 1970s was included. Because of the scarcity of literature, relevant editorials and opinion pieces were included. RESULTS A total of 2,232,586 papers resulted from keyword searches. Use of Boolean operators to combine terms reduced the number of results to 62. Exclusion criteria reduced the number of suitable papers to 20. Tracking reference lists yielded a further 18 papers. In total, 38 papers were retrieved examining 1375 patients. Four papers surveyed drug usage on PICU, 14 listed withdrawal symptoms, 4 described the frequency of withdrawal in the PICU population, 9 described risk factors, 4 presented or validated clinical tools and 14 describe treatment strategies. CONCLUSIONS Withdrawal syndromes may affect 20% of exposed children and are related to infusion duration and total dose. Fifty-one symptoms are described in the literature. Future studies need accurate, validated clinical tools to be effective. Risk factors, signs and symptoms have been identified, and validation studies must now take place. RELEVANCE TO CLINICAL PRACTICE Withdrawal syndromes continue to be widespread and difficult to diagnose. Awareness of their causes and treatments should influence clinical decisions at the bedside.
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Affiliation(s)
- Giles Birchley
- Paediatric Intensive Care Unit, Bristol Royal Hospital for Children, Bristol, UK.
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Abstract
BACKGROUND Methadone is frequently used in the treatment of adults with advanced cancer. A criticism of relevant research is the use of single or fixed doses, which does not reflect use in clinical practice. Literature about use of methadone in the treatment of pediatric patients is limited to case reports. The objective of this study is to describe methadone use as primary opioid analgesic for advanced pediatric cancer over a 6.5-year period. PROCEDURE All 17 patients who received methadone as their primary opioid analgesic through the Northern Alberta Children's Cancer Program from January 2000 to June 2007 were included. Children who received combination opioid therapy were excluded. RESULTS Rotation to methadone was usually by a complete switch from primary opioid. Conversion ratios of morphine equivalent daily dose (MEDD)/methadone daily dose (TMDD) ranged widely from 1:2 in one patient with sudden pain crisis just prior to death, to 60:1 in a patient who had been treated with opioids for months. Methadone was used for a total of 925 patient-days. There were no significant adverse events in any patient, and all but one patient remained on methadone until the time of their death. Clinically, the effectiveness of analgesia clearly improved at time of conversion in 16 patients. CONCLUSION With close monitoring, methadone therapy can be done safely in pediatric oncology patient populations in both inpatient and outpatient settings. Our experience suggests improvement in analgesia with the use of methadone, with 16 patients remaining on methadone until they died.
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Affiliation(s)
- Dawn Davies
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
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Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: a first evaluation. Crit Care Med 2008; 36:2427-32. [PMID: 18596622 DOI: 10.1097/ccm.0b013e318181600d] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE To establish frequencies of benzodiazepine and opioid withdrawal symptoms, and correlations with total doses and duration of administration. DESIGN A prospective, repeated-measures design. SETTING Two pediatric intensive care units in a university children's hospital. PATIENTS Seventy-nine children, aged 0 days to 16 yrs, who received intravenous midazolam and/or opioids for >5 days. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Pediatric intensive care unit nurses assessed withdrawal symptoms using the Sophia Benzodiazepine and Opioid Withdrawal Checklist, which includes all withdrawal symptoms (n = 24) described in the pediatric literature. Over 6 months, 2188 observations in 79 children were recorded. Forty-two percent of observations were performed within 24 hrs after tapering off or discontinuation of medication. Symptoms representing overstimulation of the central nervous system, such as anxiety, agitation, grimacing, sleep disturbance, increased muscle tension, and movement disorder, were observed in >10% of observations. Of symptoms reflecting gastrointestinal dysfunction, diarrhea and gastric retention were most frequently observed. Tachypnea, fever, sweating, and hypertension as manifestations of autonomic dysfunction were observed in >13% of observations. The Spearman's rank-correlation coefficient between total doses of midazolam and maximum sum score (of the Sophia Benzodiazepine and Opioid Withdrawal Checklist) was .51 (p < 0.001). The correlation between total doses of opioids and the maximum sum score was .39 (p < 0.01). A significant correlation (.52; p < 0.001) was also found between duration of use and maximum sum score. CONCLUSIONS This is the first study to report frequencies of all 24 withdrawal symptoms observed in children after decrease or discontinuation of benzodiazepines and/or opioids. Agitation, anxiety, muscle tension, sleeping <1 hr, diarrhea, fever, sweating, and tachypnea were observed most frequently. Longer duration of use and high dosing are risk factors for development of withdrawal symptoms in children.
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Abstract
Methadone hydrochloride is an old drug that has been in vogue off and on. It has complex pharmacodynamics and can be potentially fatal in inexperienced settings. Drug switching from an opioid to methadone or vice versa requires knowledge of equianalgesic dosing. It is critical when using the drug to monitor for signs and symptoms of toxicity so that overdosing or toxicity can be identified in a timely manner. This review discusses these important topics so that methadone can be used safely and effectively.
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Affiliation(s)
- Shalini Chhabra
- Department of Medicine, East Tennessee State University, and Home-Based Primary Care, James H. Quillen Veterans Affairs Medical Center at Mountain Home, Johnson City, Tenessse, USA.
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Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: a literature review. "Assessment remains troublesome". Intensive Care Med 2007; 33:1396-406. [PMID: 17541548 DOI: 10.1007/s00134-007-0696-x] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2006] [Accepted: 04/05/2007] [Indexed: 11/28/2022]
Abstract
BACKGROUND Prolonged administration of benzodiazepines and/or opioids to children in a pediatric intensive care unit (PICU) may induce physiological dependence and withdrawal symptoms. OBJECTIVE We reviewed the literature for relevant contributions on the nature of these withdrawal symptoms and on availability of valid scoring systems to assess the extent of symptoms. METHODS The databases PubMed, CINAHL, and Psychinfo (1980-June 2006) were searched using relevant key terms. RESULTS Symptoms of benzodiazepine and opioid withdrawal can be classified in two groups: central nervous system effects and autonomic dysfunction. However, symptoms of the two types show a large overlap for benzodiazepine and opioid withdrawal. Symptoms of gastrointestinal dysfunction in the PICU population have been described for opioid withdrawal only. Six assessment tools for withdrawal symptoms are used in children. Four of these have been validated for neonates only. Two instruments are available to specifically determine withdrawal symptoms in the PICU: the Sedation Withdrawal Score (SWS) and the Opioid Benzodiazepine Withdrawal Scale (OBWS). The OBWS is the only available assessment tool with prospective validation; however, the sensitivity is low. CONCLUSIONS Withdrawal symptoms for benzodiazepines and opioids largely overlap. A sufficiently sensitive instrument for assessing withdrawal symptoms in PICU patients needs to be developed.
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Affiliation(s)
- Erwin Ista
- Department of Pediatrics, Division of Pediatric Intensive Care, Erasmus MC, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.
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Aranda JV, Carlo W, Hummel P, Thomas R, Lehr VT, Anand KJS. Analgesia and sedation during mechanical ventilation in neonates. Clin Ther 2006; 27:877-99. [PMID: 16117990 DOI: 10.1016/j.clinthera.2005.06.019] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2005] [Indexed: 11/20/2022]
Abstract
BACKGROUND Endotracheal intubation and mechanical ventilation are major components of routine intensive care for very low birth weight newborns and sick full-term newborns. These procedures are associated with physiologic, biochemical, and clinical responses indicating pain and stress in the newborn. Most neonates receive some form of analgesia and sedation during mechanical ventilation, although there are marked variations in clinical practice. Clinical guidelines for pharmacologic analgesia and sedation in newborns based on robust scientific data are lacking, as are measures of clinical efficacy. OBJECTIVE This article represents a preliminary attempt to develop a scientific rationale for analgesia sedation in mechanically ventilated newborns based on a systematic analysis of published clinical trials. METHODS The current literature was reviewed with regard to the use of opioids (fentanyl, morphine, diamorphine), sedative-hypnotics (midazolam), nonsteroidal anti-inflammatory drugs (ibuprofen, indomethacin), and acetaminophen in ventilated neonates. Original meta-analyses were conducted that collated the data from randomized clinical comparisons of morphine or fentanyl with placebo, or morphine with fentanyl. RESULTS The results of randomized trials comparing fentanyl, morphine, or midazolam with placebo, and fentanyl with morphine were inconclusive because of small sample sizes. Meta-analyses of the randomized controlled trials indicated that morphine and fentanyl can reduce behavioral and physiologic measures of pain and stress in mechanically ventilated preterm neonates but may prolong the duration of ventilation or produce other adverse effects. Randomized trials of midazolam compared with placebo reported significant adverse effects (P < 0.05) and no apparent clinical benefit; the findings of a meta-analysis suggest that there are insufficient data to justify use of IV midazolam for sedation in ventilated neonates. CONCLUSIONS Despite ongoing research in this area, huge gaps in our knowledge remain. Well-designed and adequately powered clinical trials are needed to establish the safety, efficacy, and short- and long-term outcomes of analgesia and sedation in the mechanically ventilated newborn.
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Affiliation(s)
- J V Aranda
- Pediatric Pharmacology Research Unit Network, Wayne State University and Children's Hospital of Michigan, Detroit, USA.
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Berens RJ, Meyer MT, Mikhailov TA, Colpaert KD, Czarnecki ML, Ghanayem NS, Hoffman GM, Soetenga DJ, Nelson TJ, Weisman SJ. A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg 2006; 102:1045-50. [PMID: 16551896 DOI: 10.1213/01.ane.0000202395.94542.3e] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Critically ill children are treated with opioid medication in an attempt to decrease stress and alleviate pain during prolonged pediatric intensive care. This treatment plan places children at risk for opioid dependency. Once dependent, children need to be weaned or risk development of a withdrawal syndrome on abrupt cessation of medication. We enrolled opioid-dependent children into a prospective, randomized trial of 5- versus 10-day opioid weaning using oral methadone. Children exposed to opioids for an average of 3 wk showed no difference in the number of agitation events requiring opioid rescue (3 consecutive neonatal abstinence scores >8 every 2 h) in either wean group. Most of the events requiring rescue occurred on day 5 and 6 of the wean in both treatment groups. Patients may be able to be weaned successfully in 5 days once converted to oral methadone, with a follow-up period after medication wean to observe for a delayed withdrawal syndrome.
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Affiliation(s)
- Richard J Berens
- Department of Anesthesiology, Medical College of Wisconsin, Children's Hospital of Wisconsin, USA.
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Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs 2005; 20:344-51. [PMID: 15567675 DOI: 10.1016/j.iccn.2004.07.008] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2004] [Indexed: 11/21/2022]
Abstract
The purposes of this prospective repeated measures study were to: (a) describe the occurrence of withdrawal symptoms with the use of a standardised protocol to slowly taper opioids and benzodiazepines; and (b) to test the predictive validity of an opioid and benzodiazepine withdrawal assessment scoring tool in critically ill infants and young children after prolonged opioid and benzodiazepine therapy. Fifteen children (6 weeks-28 months of age) with complex congenital heart disease and/or respiratory failure who received opioids and benzodiazepines for 4 days or greater were evaluated for withdrawal symptoms using a standardized assessment tool. Thirteen children showed moderate to severe withdrawal symptoms a median 3 days after commencement of tapering. Symptom intensity was not related to prior opioid or benzodiazepine exposure, extracorporeal membrane oxygenation (ECMO) therapy or length of tapering. Children who received fentanyl in addition to morphine more often exhibited signs of withdrawal. This study demonstrated that significant withdrawal symptoms occur in critically ill children even with the use of a standardised assessment tool and tapering management protocol. The predictive validity and utility of the Opioid and Benzodiazepine Withdrawal Score (OBWS) was adequate for clinical use, but areas for further improvement of the tool were identified. Problems with the clinical withdrawal prevention and management guidelines were also identified. More research is needed to establish the optimal methods for prevention and management of iatrogenic opioid and benzodiazepine withdrawal in paediatric critical care.
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Affiliation(s)
- Linda S Franck
- Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, Level 7 Old Building, London WC1N 3JH, UK.
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Siddappa R, Fletcher JE, Heard AMB, Kielma D, Cimino M, Heard CMB. Methadone dosage for prevention of opioid withdrawal in children. Paediatr Anaesth 2003; 13:805-10. [PMID: 14617122 DOI: 10.1046/j.1460-9592.2003.01153.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Opioids are frequently used for sedation in the Paediatric Intensive Care Unit (PICU). With time the dosing often increases because of tolerance. On cessation of the sedation there is a risk of the opioid withdrawal syndrome. The aim of our study was to evaluate methadone dosing as a risk factor for opioid withdrawal and to determine optimal dose and efficacy of methadone to prevent withdrawal. METHOD We undertook a clinical, retrospective, chart review study. Data were analysed from the quality improvement initiative database of a tertiary-care 18 bed PICU. RESULTS Data from 30 children who received an opioid infusion for >/=7 days and subsequently received methadone for opioid withdrawal (between January 2000 and July 2001) were analysed. Nurses documented the presence or absence of withdrawal signs daily. Our unit protocol has recommended converting the patient's opioid dose into fentanyl equivalents and a dose of methadone equal to the total daily dose of fentanyl to be given three times a day. Twenty patients had no or minimal withdrawal symptoms and 10 experienced significant withdrawal. Age, weight, PRISM score, lorazepam dose, muscle relaxant use and fentanyl dose were not statistically significantly between these groups. Receiver Operator Characteristics analysis showed that 80% of the suggested methadone dose was effective in minimizing withdrawal symptoms. The odds ratio for withdrawal with <80% of the predicted methadone dose was 21. CONCLUSIONS Inadequate methadone is a risk factor for opioid withdrawal. A daily starting methadone dose equivalent to 2.5 times the daily fentanyl dose is effective in minimizing withdrawal symptoms.
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Affiliation(s)
- Rajashekhar Siddappa
- Division Pediatric Critical Care, Children's Hospital of Buffalo, Buffalo, NY Department of Anesthesiology, UNC, Chapel Hill, NC, USA
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Kost-Byerly S. New concepts in acute and extended postoperative pain management in children. ANESTHESIOLOGY CLINICS OF NORTH AMERICA 2002; 20:115-35. [PMID: 11892501 DOI: 10.1016/s0889-8537(03)00057-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Increased knowledge of the pathophysiology of pain in children and an improved understanding of the pharmacology and pharmacodynamics of multiple agents have provided the clinician with a wide variety of tools to treat postoperative pain in children. The interest in a multimodal approach is kindled by the realization that the combination of a number of therapies can enhance analgesia with fewer untoward side effects. The expertise of other health care professionals should be tapped to open new avenues of treatment. Many therapies still require critical evidence-based evaluations to assess how well they work in larger patient populations. Dedication to research, compassionate patient care, and a willingness to teach the next generation of clinicians will bring us closer to the goal of safe and pain-free surgery.
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Affiliation(s)
- Sabine Kost-Byerly
- Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology, Johns Hopkins University Hospital, Baltimore, Maryland, USA
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Lugo RA, MacLaren R, Cash J, Pribble CG, Vernon DD. Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy 2001; 21:1566-73. [PMID: 11765307 DOI: 10.1592/phco.21.20.1566.34471] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
STUDY OBJECTIVE To determine if enterally administered methadone can facilitate fentanyl discontinuation and prevent withdrawal in children at high risk for opioid abstinence syndrome. DESIGN Retrospective analysis. SETTING Pediatric intensive care unit (PICU) in a tertiary care children's hospital. PATIENTS Twenty-two children (aged 6.1 +/- 5.4 yrs) who received continuous fentanyl infusion for 9 days or longer. INTERVENTION Guidelines for initiating enteral methadone, rapidly tapering and discontinuing fentanyl infusions, and tapering methadone were implemented in the PICU. Development of opioid abstinence syndrome was evaluated during fentanyl and methadone dosage reductions and for 72 hours thereafter. MEASUREMENTS AND MAIN RESULTS Children received fentanyl by continuous infusion for 17.8 +/- 8.4 days. Peak fentanyl infusion rate was 5.9 +/- 3.8 microg/kg/hour, and the median cumulative dose was 1302 microg/kg (range 354-7535 microg/kg). Methadone 0.50 +/- 0.22 mg/kg/day was begun 1.6 +/- 1.9 days before tapering fentanyl. The fentanyl infusion rate on starting the taper was 5.0 +/- 3.6 microg/kg/hour. Fentanyl was tapered and discontinued in a median of 2.6 days (range 0-11.9 days). Twenty-one patients had no opioid abstinence syndrome during or after fentanyl taper. One patient experienced significant opioid withdrawal after fentanyl discontinuation, which resolved after reinstitution of fentanyl and increasing the dosage of methadone to 0.3 mg/kg every 6 hours. Overall, methadone was tapered and discontinued in 18.2 +/- 11.9 days without precipitating opioid abstinence syndrome. CONCLUSION Enteral administration of methadone may expedite fentanyl discontinuation and reduce the risk of withdrawal in critically ill children at high risk for opioid abstinence syndrome.
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Affiliation(s)
- R A Lugo
- Department of Pharmacy Practice, College of Pharmacy, University of Utah, Salt Lake City 84112-5820, USA.
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Affiliation(s)
- S K Chana
- The Royal Free and University College London Medical School, London, UK
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Robertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med 2000; 1:119-23. [PMID: 12813261 DOI: 10.1097/00130478-200010000-00005] [Citation(s) in RCA: 73] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To evaluate the efficacy of a standardized opiate-weaning protocol using methadone compared with methadone weaning before protocol development. DESIGN Time series, prospective study with comparison to historical controls. SETTING Twenty-bed medical-surgical intensive care unit in an academic children's hospital. PATIENTS Ten children, aged 6 months to 18 yrs, who received methadone for weaning from continuous opiate infusions for >or=7 days compared with ten patients undergoing weaning by standardized protocol. INTERVENTIONS Institution of standardized opiate-weaning protocol. MEASUREMENTS AND MAIN RESULTS Patient age, gender, and diagnosis were similar in both nonprotocol (NP) and protocol (P) groups (p = NS). Days of opiate use were also similar between groups. Nine of ten NP and seven of ten P patients were on continuous fentanyl infusions, and the remainder were on continuous morphine infusions. P patients were weaned significantly faster than NP patients (median, 9 days and 20 days, respectively; p <.001). P patients requiring short-term opiate use also weaned significantly faster than short-term NP patients (median, 5 days and 21.5 days, respectively; p <.001). Withdrawal complications were seen in three NP patients with weaning delayed in two. Two P patients had withdrawal complications with no delay in weaning (p = NS). Significant methadone calculation discrepancy occurred in one NP patient but in no P patients. CONCLUSIONS Pediatric intensive care unit patients requiring prolonged opiate use can be weaned by using methadone with minimal signs of withdrawal. Use of a standardized weaning protocol decreased time for weaning without increasing the frequency rate of withdrawal symptoms.
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Affiliation(s)
- R C Robertson
- Critical Care Division, Children's Healthcare of Atlanta at Egleston, GA 30322, USA
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Abstract
Iatrogenic tolerance and physical dependence have been documented in human neonates and infants infused with fentanyl or morphine i.v. to maintain continuous analgesia and sedation during extracorporeal membrane oxygenation (ECMO) and mechanical ventilation for the treatment of life-threatening pulmonary diseases. Using postnatal d 17 infant rats, the hypothesis was tested that sedative tolerance accompanies tolerance to fentanyl analgesia in the tail-flick test. Postnatal d 14 infant rats remained naive or received osmotic minipumps infusing saline (1 microL/h) or fentanyl citrate (60 microg x kg(-1) h(-1)). Seventy-two hours later, fentanyl's antinociceptive potency was reduced 3.1-fold in fentanyl-infused rats. Conscious sedation and deep sedation were examined with the cliff-avoidance and the righting-reflex procedures, respectively. Fentanyl-infused infants were tolerant to both the conscious and deep sedative effects of fentanyl. Another hypothesis tested was that very high receptor intrinsic activity opioids are less likely to produce tolerance, or to be cross-tolerant to other opioids. Dihydroetorphine is 5,000 to 10,000 times more potent than morphine. However, fentanyl-infused infant rats were cross-tolerant to the analgesic and sedative effects of dihydroetorphine. Interestingly, dihydroetorphine's analgesic efficacy was significantly reduced to a maximum analgesic efficacy (Emax) value of 40% maximum possible effect (MPE). Another concern was whether fentanyl tolerance would generalize to another class of sedatives, the benzodiazepines. This was especially relevant considering the widespread use of benzodiazepines like midazolam in ECMO and mechanical ventilation. Midazolam elicited no analgesia in the tail-flick test. Furthermore, fentanyl-tolerant rats were not cross-tolerant to the conscious or deep sedative effects of midazolam.
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Affiliation(s)
- C H Choe
- Pharmacology and Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond 23298-0613, USA
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Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med 2000; 28:2122-32. [PMID: 10890677 DOI: 10.1097/00003246-200006000-00079] [Citation(s) in RCA: 267] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To describe the consequences of the prolonged administration of sedative and analgesic agents to the pediatric intensive care unit (PICU) patient. The problems to be investigated include tolerance, physical dependency, and withdrawal. DATA SOURCES A MEDLINE search was performed of literature published in the English language. Cross-reference searches were performed using the following terms: sedation, analgesia with PICU, children, physical dependency, withdrawal; tolerance with sedative, analgesics, benzodiazepines, opioids, inhalational anesthetic agents, nitrous oxide, ketamine, barbiturates, propofol, pentobarbital, phenobarbital. STUDY SELECTION Studies dealing with the problems of tolerance, physical dependency, and withdrawal in children in the PICU population were selected. DATA EXTRACTION All of the above-mentioned studies were reviewed in the current manuscript. DATA SYNTHESIS A case by case review is presented, outlining the reported problems of tolerance, physical dependency, and withdrawal after the use of sedative/analgesic agents in the PICU population. This is followed up by a review of the literature discussing current treatment options for these problems. CONCLUSIONS Tolerance, physical dependency, and withdrawal can occur after the prolonged administration of any agent used for sedation and analgesia in the PICU population. Important components in the care of such patients include careful observation to identify the occurrence of withdrawal signs and symptoms. Treatment options after prolonged administration of sedative/analgesic agents include slowly tapering the intravenous administration of these agents or, depending on the drug, switching to subcutaneous or oral administration.
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Affiliation(s)
- J D Tobias
- The Department of Child Health, The University of Missouri, Columbia, USA
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Tobias JD. Pentobarbital for Sedation During Mechanical Ventilation in the Pediatric ICU Patient. J Intensive Care Med 2000. [DOI: 10.1046/j.1525-1489.2000.00115.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Tobias JD. Subcutaneous administration of fentanyl and midazolam to prevent withdrawal after prolonged sedation in children. Crit Care Med 1999; 27:2262-5. [PMID: 10548218 DOI: 10.1097/00003246-199910000-00033] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To determine the efficacy of switching to subcutaneous fentanyl with or without midazolam to prevent withdrawal after prolonged sedation in children in the pediatric intensive care unit (PICU). DESIGN Retrospective review of hospital records. SETTING Tertiary care center, PICU. PATIENTS The cohort for the study included patients who had received subcutaneous fentanyl with or without midazolam to prevent withdrawal after prolonged sedation in the PICU. MEASUREMENTS AND MAIN RESULTS Subcutaneous fentanyl with or without midazolam was administered to nine patients ranging in age from 3 to 7 yrs (mean, 4.4 +/- 1.8 yrs) and ranging in weight from 11 to 31 kg (mean, 20.1 +/- 6.8 kg). All patients required prolonged administration of fentanyl with or without midazolam during mechanical ventilation for respiratory failure. The starting infusion rate for subcutaneous fentanyl varied from 5 to 9 microg/kg/hr (mean, 7.1 +/- 1.4 microg/kg/hr). Four patients also received subcutaneous midazolam at a rate of 0.15 to 0.3 mg/kg/hr (mean, 0.24 mg/kg/hr). Subcutaneous access was maintained for 3-7 days (mean, 5.7 +/- 1.4 days) in the nine patients. No problems with the subcutaneous access were noted during treatment. The fentanyl infusion was decreased by 1 microg/kg/hr every 12-24 hrs and the midazolam infusion was decreased by 0.05 mg/kg/hr every 12-24 hrs. No patient demonstrated signs of symptoms of moderate to severe withdrawal. CONCLUSION The subcutaneous route provides an effective alternative to intravenous administration. It allows for gradual weaning from sedative/analgesic agents after prolonged sedation while eliminating the need to maintain intravenous access.
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Affiliation(s)
- J D Tobias
- Department of Child Health, University of Missouri, Columbia 65212, USA.
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Abstract
The indications for sedation in the paediatric intensive care unit (PICU) patient are varied ranging from short term use for various procedures to prolonged administration to provide comfort during mechanical ventilation. When faced with the decision to institute sedation, the healthcare provider must make three decisions: the agent to be used, the route of delivery, and the mode of administration (intermittent versus continuous). There are several agents that have been used to provide sedation in the PICU patient including the inhalational anaesthetic agents, benzodiazepines, opioids, ketamine, propofol, chloral hydrate, phenothiazines, and the barbiturates. This review describes the various agents for sedation and discusses their advantages and disadvantages as they pertain to the PICU. Consequences of and treatment strategies for long term problems with prolonged sedation including tolerance, physical dependency, and withdrawal are reviewed.
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Affiliation(s)
- J D Tobias
- Department of Child Health, University of Missouri, Columbia 65212, USA.
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Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med 1998; 26:947-56. [PMID: 9590327 DOI: 10.1097/00003246-199805000-00034] [Citation(s) in RCA: 152] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To describe the various complications that have been reported with use of midazolam for sedation in the intensive care unit (ICU). DATA SOURCES Publications in scientific literature. DATA EXTRACTION Computer search of the literature. SYNTHESIS Sedation is required in the ICU in order for patients to tolerate noxious stimuli, particularly mechanical ventilation. Under- and oversedation can lead to complications. To sedate patients in the ICU, midazolam is commonly administered via titrated, continuous infusions. Cardiorespiratory effects tend to be minimal; however, hypotension can occur in hypovolemic patients. Prolonged sedation after cessation of the midazolam infusion may be caused by altered kinetics of the drug in critically ill patients or by accumulation of active metabolites. In addition, paradoxical and psychotic reactions have been rarely reported. Tolerance and tachyphylaxis may occur, particularly with longer-term infusions (> or = 3 days). Benzodiazepine withdrawal syndrome has also been associated with high dose/long-term midazolam infusions. Compared with propofol infusions, midazolam infusions have been associated with a decreased occurrence of hypotension but a more variable time course for recovery of function after the cessation of the infusion. Lorazepam is a more cost-effective choice for long-term (> 24 hrs) sedation. CONCLUSION Continuous infusion midazolam provides effective sedation in the ICU with few complications overall, especially when the dose is titrated.
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Affiliation(s)
- A Shafer
- Department of Anesthesia, Stanford University School of Medicine and Veterans Affairs Palo Alto Health Care System, CA, USA
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Abstract
Physical and emotional distress can have important effects on patients in the pediatric intensive care unit (ICU). Intravenous (IV) infusion of benzodiazepines is an important adjunct to assisted ventilation and other potentially distressing ICU procedures. Combined with intermittent or continuous infusion of opioids, the benzodiazepines provide smooth control of anxiety, pain, and agitation. Intravenous midazolam (Versed Roche Laboratories) is distinguished from diazepam (Valium, Roche Products) by its water solubility, short elimination half-life, and generally short duration of action. These pharmacological properties, which are also shared, in part, with the more slowly eliminated drug lorazepam (Ativan, Wyeth-Ayerst), facilitate titration of the rate of infusion against patient response and permit regulation of the depth of sedation. The major adverse effects of long-term benzodiazepine infusion are withdrawal symptoms and, occasionally, delayed awakening. The dosage needed to initiate and maintain sedation must be adjusted to body weight, degree of sedation desired, and concomitant medications, as well as to underlying health and cardiovascular status. Benzodiazepines, such as midazolam and lorazepam, represent important choices among drugs used for sedation in the pediatric ICU.
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Affiliation(s)
- D A Notterman
- Department of Pediatrics, New York Hospital-Cornell Medical Center, New York, USA
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Carnevale FA, Ducharme C. Adverse reactions to the withdrawal of opioids and benzodiazepines in paediatric intensive care. Intensive Crit Care Nurs 1997; 13:181-8. [PMID: 9355422 DOI: 10.1016/s0964-3397(97)80012-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The aim of this study was to examine adverse reactions to the withdrawal of opioids and benzodiazepines among critically ill children. Although withdrawal reactions have been well documented in relation to substance abusers and their newborn infants, there has been little study of this phenomenon as an iatrogenic problem. We developed a graphical case study method for examining patterns over time, and applied this to five cases referred to us by the nursing staff of a 10-bed paediatric intensive care unit. A striking pattern of behavioural distress was clearly associated with the diminution of opioids and benzodiazepines. These adverse reactions were characterized by various combinations of inconsolable crying, tremors, jitteriness, irritability, gagging, vomiting, and feeding problems. These signs appeared as early as 1 h and as late as 24 h following a significant reduction in opioid and benzodiazepine infusion rates, sometimes following very short-term therapy. We elaborate an interpretation of this distress, in light of the multiple disruptions undergone by critically ill children, and conclude by outlining our recommendations for preventing/minimizing these adverse reactions.
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Affiliation(s)
- F A Carnevale
- PICU, Montreal Children's Hospital/McGill University, Quebec, Canada
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Abstract
Following the prolonged administration of opioids for sedation in the PICU, tolerance and physical dependency may occur. In patients who have become tolerant, physical signs of withdrawal may occur when these agents are discontinued. The actual signs and symptoms of withdrawal vary from patient to patient, but the majority of the literature documents problems such as hyperactivity of the sympathetic nervous system included tachycardia, hypertension, diaphoresis, and tremulousness. The author presents two patients who developed symptoms of upper airway obstruction, including stridor, as the major manifestation of opioid withdrawal. Operative inspection of the airway with rigid bronchoscopy and direct laryngoscopy demonstrated no airway abnormalities. Reinstitution of opioid therapy resulted in a prompt resolution of symptoms and a more gradual tapering of the opioid dose prevented recurrence of the problem.
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Affiliation(s)
- Joseph D. Tobias
- Director, Pediatric Anesthesia/Critical Care, Department of Anesthesiology and Pediatrics, The University of Missouri, Columbia, MI
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