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加拿大新生儿重症监护病房早产儿机械通气期间麻醉镇痛药和镇静剂应用趋势的回顾性研究
Jennifer M Toye, Lucia Mirea, Junmin Yang, Koravangattu Sankaran
中国当代儿科杂志 ›› 2018, Vol. 20 ›› Issue (1) : 5-11.
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加拿大新生儿重症监护病房早产儿机械通气期间麻醉镇痛药和镇静剂应用趋势的回顾性研究
Trends in narcotics and sedative use during mechanical ventilation of preterm infants in Canadian neonatal intensive care units
早产儿气管插管有创机械通气可引起患儿不适，但是否导致疼痛仍存有争议。已发表的荟萃分析显示，早产儿机械通气期间应用麻醉镇痛药并未减轻患儿疼痛。因此，不推荐对新生儿重症监护病房（NICU）机械通气早产儿常规应用麻醉镇痛药和镇静剂。假设目前加拿大NICU早产儿机械通气过程中麻醉镇痛药和镇静剂的使用呈下降趋势。该研究回顾性分析了2004~2009年间出生胎龄 < 35周、需要有创机械通气 > 24 h的早产儿接受镇静剂和麻醉镇痛药使用的趋势。入院时处于濒死状态、先天畸形、需要外科手术（除外眼科激光手术）、坏死性小肠结肠炎、胸腔置管引流或孕母有麻醉药品滥用史的早产儿不纳入该研究。根据早产儿是否接受麻醉镇痛药（如吗啡、芬太尼、美沙酮、舒芬太尼、杜冷丁、阿芬太尼和可待因等）或镇静剂（如水合氯醛、咪达唑仑、劳拉西泮、苯巴比妥、戊巴比妥、氯胺酮和丙泊酚）以及早产儿胎龄（胎龄 < 29周和胎龄29~34周）分组，采用Cochrane-Armitage趋势分析方法评估早产儿麻醉镇痛药和镇静剂的应用趋势。5 638名早产儿符合纳入标准，其中2 169名（38.5%）应用了麻醉镇痛药，897名（15.9%）应用了镇静剂，722名（12.8%）同时接受了麻醉镇痛药和镇静剂治疗。最常用的麻醉镇痛药是吗啡（62.2%）和芬太尼（63.8%）；最常用的镇静剂是苯巴比妥（44.9%）和水合氯醛（44.2%）。镇静剂的使用在胎龄 < 29周和胎龄29~34周两组早产儿中均呈明显的下降趋势（P < 0.01）；但胎龄 < 29周组早产儿麻醉镇痛药的使用显著增加（P=0.03），胎龄29~34周组麻醉镇痛药的使用未发现明显的趋势变化。
经历有创机械通气的新生儿有疼痛感受吗?机体会产生应激反应吗?据成人有创通气的研究结果报道，约25%的ICU患者出院后仍记得在ICU住院期间的感受，并承认经历气管插管和有创机械通气的过程是很痛苦的。然而，现实中很难区分患者的疼痛感受是由于ICU住院期间的有创通气引起，抑或是因在ICU住院期间躯体的疾病或其他因素所致。同理，对于住院期间早产儿皮质醇水平的升高，是由于疾病的严重程度或因机械通气引起的疼痛和/或应激所致同样很难鉴别。查阅大量文献发现，有创机械通气期间麻醉镇痛药或镇静剂的使用并没有减轻患者的痛苦，然而药物潜在的不良反应却令人担忧。但目前在NICU住院早产儿有创机械通气过程中，给患儿应用麻醉镇痛药或镇静剂仍然是很普遍的现象。
该研究数据来自于加拿大新生儿协作网，该协作网覆盖了加拿大全国范围内30家三甲医院。样本量大，数据收集方法有效、可靠，这是该研究的主要优势。其主要不足在于机械通气早产儿没有明确的应用镇静或麻醉镇痛药物的指征，一些分析只能是从现有的数据外推。此外，该研究早产儿上机过程中其他非药物镇痛替代措施的应用，也可能会高估或低估麻醉镇痛药/镇静剂的作用。其他的影响因素还包括：缺乏疾病的严重度、上机时间以及麻醉镇痛/镇静药物应用的评估依据，以及研究资料未能收集到上机过程中环境因素或非药物干预措施减轻患儿不适/应激/疼痛的数据，所以不能对机械通气过程中麻醉镇痛/镇静剂使用趋势做出更为深入的解释。目前，令人担忧的是，机械通气过程中接受阿片类药物镇痛的早产儿是受药物不良反应影响的高风险人群，而这些药物在这个群体中的应用又呈现增加趋势；但如果对NICU住院早产儿经历的疼痛和应激不予管理，也会对其神经系统发育产生近期和远期的不良影响。因此，在临床实践中，必须对早产儿的疼痛采用量表进行评估，根据循证医学指南指导麻醉镇痛药和镇静剂的应用，从患儿舒适的角度制定治疗和护理方案。
尽管麻醉镇痛药和镇静剂可能的潜在不良反应的否定证据也逐渐增加，但加拿大新生儿医师仍然担忧机械通气早产儿连续应用麻醉镇痛药和镇静剂以及肌松剂的不良反应。用非药物的措施减轻机械通气患儿的不适/应激/疼痛的研究日益增多并受到广泛的关注，且有巨大的应用前景。一些在研的、旨在减轻早产儿上机过程中经历的中等程度的疼痛/应激、同时又尽可能限制药物不良反应并考虑到对患儿远期神经发育影响药物的研究已经得到批准。另外，住院新生儿经历的慢性疼痛也引起了许多学者的重视，且也成为一个新兴的研究热点，需要学者们开展更深入的研究。
小结：加拿大NICU胎龄 < 35周的机械通气早产儿镇静剂的使用呈下降趋势，临床应用遵循了循证医学的证据，但麻醉镇痛药的使用在胎龄29~34周早产儿组并没有变化，且超低胎龄早产儿组（胎龄 < 29周）麻醉镇痛药的使用呈增加趋势。加拿大的新生儿医师在决定是否给有创机械通气的早产儿使用麻醉镇痛/镇静剂时是慎重的，但该研究结果显示加拿大NICU早产儿机械通气期间麻醉镇痛药的使用并没有呈下降趋势，其原因尚需进一步深入研究。
Objective Mechanical ventilation (MV) in preterm infants (PTI) causes discomfort. Whether it causes pain is controversial. Meta analysis reviews of published work on PTI during MV have shown no clinically significant impact of opioids on pain scales, and hence not recommended for routine use in neonatal intensive care units (NICUs). Similarly regular use of sedative midazolam is also not recommended. Therefore we hypothesized a downward trend in narcotics and sedatives used in MV of PTI in NICUs. This study aimed to assess trends of sedatives and narcotics use during MV of PTI in Canadian NICUs during 2004-2009.Methods PTI born at gestational age (GA) of < 35 weeks requiring invasive MV for > 24 hours were identified retrospectively from the Canadian Neonatal Network database for 2004-2009. PTI were excluded if moribund on admission, had major congenital anomalies, surgery (except laser eye surgery), necrotizing enterocolitis, chest tube or history of maternal narcotic abuse. PTI were classified according to whether they received any narcotics (morphine, fentanyl, methadone, sufentanyl, meperidine, alfentynl and codiene) or sedatives (chloral hydrate, midazolam, lorazepam, phenobarbital, pentobarbital, ketamine and propofol) for > 24 consecutive hours during MV. Trends of narcotics and sedatives were assessed using the Cochrane-Armitage Trend test separately for PTI born at < 29 and 29-34 weeks of GA.Results Among 5 638 study subjects, 2 169 (38.5%) received narcotics and 897 (15.9%) received sedatives. The most common narcotics were morphine (62.2%) and fentanyl (63.8%) and sedatives were phenobarbital (44.9%) and chloral hydrate (44.2%). A significant decreasing trend (P<0.01) in the use of any sedatives during MV was observed in PTI < 29 and 29-34 weeks of GA. However, the use of any narcotics during MV increased significantly (P=0.03) among PTI < 29 weeks of GA, and no change in trend was detected for PTI born at 29-34 weeks of GA.Conclusions The use of sedatives during MV in PTI born at < 35 weeks of GA was positively affected, however the narcotics use during MV remained constant for PTI born at 29-34 weeks, and increased in extremely low GA group (less than 29 weeks) suggesting evidence based practice change was not observed during the study period.
Narcotic / Sedative / Mechanical ventilation / Trend / Preterm infant
[1] Anand KJ. Neonatal stress response to anesthesia and surgery[J]. Clin Perinatol, 1990, 17(1):207-214.
[2] American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pediatrics Section on Surgery; Canadian Paediatric Society Fetus and Newborn Committee, et al. Prevention and management of pain in the neonate:an update[J]. Pediatrics, 2006, 118(5):2231-2241.
[3] Bellù R, de Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation[J]. Cochrane Database Syst Rev, 2008, (1):CD004212.
[4] Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit[J]. Cochrane Database Syst Rev, 2012, (6):CD002052.
[5] Bellù R, de Waal K, Zanini R. Opioids for neonates receiving mechanical ventilation:a systematic review and meta-analysis[J]. Arch Dis Child Fetal Neonatal Ed, 2010, 95(4):F241-F251.
[6] Anand KJ, Barton BA, McIntosh N, et al. Analgesia and sedation in preterm neonates who require ventilatory support:results from the NOPAIN trial. Neonatal outcome and prolonged analgesia in neonates[J]. Arch Pediatr Adolesc Med, 1999, 153(4):331-338.
[7] Harte GJ, Gray PH, Lee TC, et al. Haemodynamic responses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates[J]. J Paediatr Child Health, 1997, 33(4):335-338.
[8] van Straaten HL, Rademaker CM, de Vries LS. Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn[J]. Dev Pharmacol Ther, 1992, 19(4):191-195.
[9] Lee SK, McMillan DD, Oholsson A, et al. Variations in practice and outcomes in the Canadian NICU network:1996-1997[J]. Pediatrics, 2000, 106(5):1070-1079.
[10] Canadian Neonatal Network (CNN). Abstractor's Manual[S/OL].[May 20, 2017]. http://www.canadianneonatalnetwork.org/portal/. 2011.
[11] Granja C, Lopes A, Moreira S, et al. Patients' recollections of experiences in the intensive care unit may affect their quality of life[J]. Crit Care, 2005, 9(2):R96-R109.
[12] Hughes D, Murphy JF, Dyas J, et al. Blood spot glucocorticoid concentrations in ill preterm infants[J]. Arch Dis Child, 1987, 62(10):1014-1018.
[13] Anand KJ, Hall RW. Pharmacological therapy for analgesia and sedation in the newborn[J]. Arch Dis Child Fetal Neonatal Ed, 2006, 91(6):F448-F453.
[14] Knight M. Adverse drug reactions in neonates[J]. J Clin Pharmacol, 1994, 34(2):128-135.
[15] Mayers DJ, Hindmarsh KW, Gorecki DK, et al. Sedative/hypnotic effects of chloral hydrate in the neonate:trichloroethanol or parent drug?[J]. Dev Pharmacol Ther, 1992, 19(2-3):141-146.
[16] Laptook AR, Rosenfeld CR. Chloral hydrate toxicity in a preterm infant[J]. Pediatr Pharmacol (New York), 1984, 4(3):161-165.
[17] Hall RW, Anand KJ. Pain management in newborns[J]. Clin Perinatol, 2014, 41(4):895-924.
[18] Shankaran S, Cepeda EE, Ilagan N, et al. Antenatal phenobarbital for the prevention of neonatal intracerebral hemorrhange[J]. Am J Obstet Gynecol, 1986, 154(1):53-57.
[19] Smit E, Odd D, Whitelaw A. Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants[J]. Cochrane Database Syst Rev, 2013, (8):CD001691.
[20] Loepke AW. Developmental neurotoxicity of sedatives and anesthetics:a concern for neonatal and pediatric critical care medicine?[J]. Pediatr Crit Care Med, 2010, 11(2):217-226.
[21] Kaija M, Metsarnta M, Vanhatalo S. Drug effects on endogenous brain activity in preterm babies[J]. Brain Dev, 2014, 36(2):116-123.
[22] Benders MJ, Palmu K, Menache C, et al. Early brain activity relates to subsequent brain growth in premature infants[J]. Cereb Cortex, 2015, 25(9):3014-3024.
[23] Shah PS, Dunn M, Lee SK, et al. Early opioid infusion and neonatal outcomes in preterm neonates ≤ 28 weeks' gestation[J]. Am J Perinatol, 2011, 28(5):361-366.
[24] Hall RW, Kronsberg SS, Barton BA, et al. Morphine, hypotension, and adverse outcomes among preterm neonates:who's to blame? Secondary results from the NEOPAIN trial[J]. Pediatrics, 2005, 115(5):1351-1359.
[25] Ferguson SA, Ward WL, Paule MG, et al. A pilot study of preemptive morphine analgesia in preterm neonates:effects on head circumference, social behavior, and response latencies in early childhood[J]. Neurotoxicol Teratol, 2012, 34(1):47-55.
[26] MacGregor R, Evans D, Sugden D, et al. Outcome at 5-6 years of prematurely born children who received morphine as neonates[J]. Arch Dis Child Fetal Neonatal Ed, 1998, 79(1):F40-F43.
[27] Zwicker JG, Miller SP, Grunau RE, et al. Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine[J]. J Pediatr, 2016, 172:81-87.
[28] Steinhorn R, McPherson C, Anderson PJ, et al. Neonatal morphine exposure in very preterm infants-cerebral development and outcomes[J]. J Pediatr, 2015, 166(5):1200-1207.e4.
[29] Barrington K. Premedication for endotracheal intubation in the newborn infant[J]. Paediatr Child Health, 2011, 16(3):159-171.
[30] Fleishman R, Zhou C, Gleason C, et al. Standardizing morphine use for ventilated preterm neonates with a nursing-driven comfort protocol[J]. J Perinatol, 2015, 35(1):46-51.
[31] Zimmerman KO, Smith PB, Benjamin DK, et al. Sedation, analgesia, and paralytics during mechanical ventilation of premature infants[J]. J Pediatr, 2017, 180:99-104.
[32] McPherson C. Sedation and analgesia in mechanically ventilated preterm neonates:continue standard of care or experiment?[J]. J Pediatr Pharmacol Ther, 2012, 17(4):351-364.
