Bichaff, Pedro; Setani, Karina T; Motta, Emiliana H. G; Delgado, Artur F; Carvalho, Werther B; Luglio, Michele

doi:10.1590/1806-9282.64.10.909

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Original Article • Rev. Assoc. Med. Bras. 64 (10) • Out 2018 • https://doi.org/10.1590/1806-9282.64.10.909 copiar

Opioid tapering and weaning protocols in pediatric critical care units: a systematic review

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

OBJETIVO:

A síndrome de abstinência de opioides é comum no ambiente de terapia intensiva pediátrica porque a sedação é frequentemente necessária durante o tratamento das crianças. Não existe uma diretriz específica sobre o manejo desse paciente e, ultimamente, a metadona tem sido uma droga importante para a prevenção dos sintomas de abstinência durante o desmame dos opioides. Este estudo reúne as pesquisas disponíveis para estabelecer a dose inicial de metadona, taxa de redução e ferramentas para reconhecer essa síndrome e agir prontamente.

MÉTODOS:

Uma revisão sistemática foi feita a partir de dados de quatro diferentes bases de dados. Quarenta e nove artigos, de estudos observacionais e experimentais, foram selecionados com base nos critérios de inclusão (pacientes críticos pediátricos em uso de opioides agudamente) e critérios de exclusão (uso crônico prévio de opioides, outros medicamentos). Os dados referentes a temas específicos foram separados em seções: dose inicial de metadona, uso de protocolos na prática clínica, escalas de abstinência e drogas adjuvantes.

RESULTADOS:

Os artigos mostraram uma grande heterogeneidade de formas de calcular a dose inicial de metadona. As unidades de terapia intensiva pediátrica do estudo apresentaram diferentes protocolos de desmame, com menor incidência de abstinência quando foi utilizada uma sequência predefinida de redução gradual. A Ferramenta de Avaliação de Retirada – 1 foi a escala mais utilizada durante a redução dos opioides, com boa sensibilidade e especificidade para sinais e sintomas.

CONCLUSÃO:

Ainda há poucas evidências de outros medicamentos que possam ajudar a prevenir a síndrome de abstinência dos opioides. Este estudo tenta promover uma prática melhor durante o desmame dos opioides.

PALAVRAS-CHAVE:
Revisão; Cuidados críticos; Analgésicos opioides; Criança; Síndrome de Abstinência a Substâncias

Author	Study design (evidence)	Population	Initial dose	Withdrawal	Outcomes	Example (weight: 10kg, fentanyl 10mcg/h)
Bowens et al. (⁸8. Bowens CD, Thompson JA, Thompson MT, Breitzka RL, Thompson DG, Sheeran PW. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011;12(5):504-11.)	Prospective Randomized Trial (IB)	n=78, 1-36 mo	“low-dose” (0,1mg/kg/ dose) n=34 vs “high-dose” [0,1mg/kg/dose x recent fentanyl (mcg/ kg/h)] n=26	No difference of incidence between the groups	No significant difference of oversedation incidence. Patients that failed to complete the assigned taper (18/78) had longer PICU length of stay and more days of ventilation	Methadone dose: 1mg
Lugo et al. (⁹9. 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(12):1566-73.)	Retrospective (III)	n=22, 6,1 ± 5,4 yrs	0,5 ± 0,22 mg/kg/dia q6h. Group (1) n=15 no need of dose increase; Group (2) n=7 dose was increased to 0,91 ± 0,37 mg/kg/dia	There was no withdrawal	No significant difference regarding the duration of taper	Methadone dose: 1,25mg
Johnson et al. (¹⁰10. Johnson PN, Miller J, Harrison D. Evaluation of initial methadone dosing for prevention of iatrogenic opioid abstinence syndrome in children. J Pediatr Intensive Care. 2012;1(2):105-13.)	Retrospective (III)	n=55, 0,03-12,2 yrs	initial “low-dose” <0,84mg/kg/dia n=27 vs initial “high-dose” ≥ 0,84mg/kg/dia n=28	No difference of incidence between the groups	No significant difference regarding length of stay in PICU	Methadone dose: 2,1mg
Siddappa et al. (¹¹11. Siddappa R, Fletcher JE, Heard AM, Kielma D, Cimino M, Heard CM, et al. Methadone dosage for prevention of opioid withdrawal in children. Paediatr Anaesth. 2003;13(9):805-10.)	Retrospective (III)	n=30, 0,1 – 16,2 yrs	methadone (mg) = 3 x daily fentanyl dose (mg)	There was a significant difference of withdrawal incidence: 78% (7/9) of those who used ≤ 80% of the initial dose had symptoms in comparison with 14% (3/21) of the patients with the initial dose of >80%		Methadone dose: 0,72mg
Jeffries et al. (¹²12. 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(1):12-8.)	Retrospective (III)	n=43, 0,25-201 mo	methadone (mg) = morphine (mg)	42% had withdrawal symptoms
Meyer et al. (¹³13. Meyer MM, Berens RJ. Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med. 2001;2(4):329-33.)	Prospective (III)	n=29, 1 day – 19,8 yrs	enteral methadone (mg) = morphine IV (mg) x 2 = fentanyl (mcg/h) x 120	14% (4/29) had withdrawal symptoms		Methadone dose: 1,2mg
Robertson et al. (¹⁴14. 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(2):119-23.)	Prospective comparison of protocol vs control groups (III)	n=20, 6 mo – 18 yrs	enteral methadone (mg) = morphine (mg) = daily fentanyl (mcg) x 10	No difference of incidence between the groups (protocol vs control)		Methadone dose: 2,4mg

Author	Study (evidence)	Population	Protocol	Rescue	Abstinence score	Groups	Incidence of abstinence	Secondary outcomes
Berens et al. (¹⁵15. Berens RJ, Meyer MT, Mikhailov TA, Colpaert KD, Czarnecki ML, Ghanayem NS, et al. A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg. 2006;102(4):1045-50.)	Clinical trial (IB)	n=37, ≤ 18 yrs	Switch over fentanyl or morphine to enteral methadone using an initial dosage (“attack dosage ”) and a maintenance daily dosage. Comparison between 5 day weaning protocol reducing 20% of initial dosage + 5 days of placebo vs. 10 days weaning protocol reducing 10% of initial dosage.	Additional dose of methadone equal to the same dose administered the day before or 0,025mg/kg of morphine IV or 0,05mg/kg of methadone incrementally every 30 minutes	Neonatal Abstinence Score - Finnegan (NAS), modified Ramsay.	5 days (n=16) vs. 10 days (n=21)	No difference in incidence of abstinence between groups.	Duration of mechanical ventilation, vasopressor therapy, pediatric intensive care unit (ICU) length of stay and pediatric risk of mortality scores did not differ between the two groups
Steineck et al. (¹⁶16. Steineck KJ, Skoglund AK, Carlson MK, Gupta S. Evaluation of a pharmacist-managed methadone taper. Pediatr Crit Care Med. 2014;15(3):206-10.)	Case - control (III)	n=52, 1m – 16 yrs	Weaning protocol based on the risk of development of abstinence by the duration of opioid and by the accumulate dose of fentanyl. Initial dose ranges from 0,05 to 0,2mg/ kg/dose every 8 or 6 hours with reduction rate of 10% to 33% per day.	Additional dose of 0,05mg/kg of morphine IV every 2 hours if abstinence score between 9-11 or 0,1mg/kg if score ≥ 12	Modified Neonatal Abstinence Score - Finnegan (NAS)	pharmaceutic guided protocol (n=20) vs. regular protocol (n=32)	No difference in incidence of abstinence between groups.	A shorter weaning time of methadone (24,7 days vs. 15 days; p=0,003) and shorter length of hospital stay (38%) in the intervention group
Neunhoeffer et al. (⁴4. Neunhoeffer F, Kumpf M, Renk H, Hanelt M, Berneck N, Bosk A, et al. Nurse-driven pediatric analgesia and sedation protocol reduces withdrawal symptoms in critically ill medical pediatric patients. Pediatric Anesth. 2015;25(8):786-794.)	Clinical trial (IIB)	n=337, 0-18 yrs	Taper based on duration of opioid exposure: < 5 day - decrease of 50% of initial dose every 24hours; > 5 days - decrease of 10 to 20% every 24hours.	Dose of morphine, fentanyl and midazolam is adjusted according to COMFOT-B and NISS scale. The reduction is suspended for 24 hours if SOS ≥ 4	COMFORT-B, Nurse Interpretation Sedation Scale (NISS), Sophia Observation Withdrawal (SOS).	before protocol (n=165) vs. after protocol (n=172)	Lower incidence of abstinence after implementation of protocol (12,8% vs. 23,6%, p=0,005)	No difference in duration of mechanical ventilation, in days in ICU or total dosage of opioid.
Best et al. (¹⁷17. Best KM, Asaro LA, Franck LS, Wypij D, Curley MA; Randomized Evaluation of Sedation Titration for Respiratory Failure Baseline Study Investigators. Patterns of sedation weaning in critically ill children recovering from acute respiratory failure. Pediatr Crit Care Med. 2016;17(1):19-29.)	Prospective cohort (III)	n=145, 2 wks – 17 yrs	Group comparisons were made between patients with an intermittent weaning pattern, defined as a 20% or greater increase in daily opioid dose after the start of weaning, and the remaining patients defined as having a steady weaning pattern.	Not specified in the study	FLACC, Wong-Baker Faces, numerical scales to evaluate analgesia; State Behavior Scale; WAT-1.	intermittent pattern (n=66) vs. steady pattern (n=79)	Lower incidence of abstinence (WAT-1 ≥ 3) in the steady group: 46% vs. 85%, p<0,001. The tapering time of steady group was also shorter.	Comparison between protocol group and non-protocol group: lower length of mechanical ventilation (5,9 vs. 9,1 days, p<0,001), lower length of ICU stay (9,3 days vs. 12,8 days, p<0,001) and lower length of hospital stay (14 days vs. 21,5 days, p<0,001).
Robertson et al. (¹⁴14. 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(2):119-23.)	Clinical trial (III)	n=20, 6 m – 18 yrs	Weaning protocol based on duration of opioid exposure: 7 to 14 days: decrease of 20% every day (taper time of 5 days) > 14 day: decrease of 20% every 2 days (taper time of 10 days)	Not specified in the study	Scale based on signs and symptoms from Neonatal Abstinence Score.	protocol (n=10) vs. non protocol (n=10)	No difference in incidence of abstinence between groups.	Lower weaning time in protocol group (9 days vs. 20 days, p<0,001).

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[1] CORRESPONDING AUTHOR: Pedro Bichaff, Av. Dr Enéas Carvalho de Aguiar, 647 Sao Paulo - São Paulo - Brasil – 05403-000. E-mail: bichaff@gmail.com