背景:呼吸暂停和间歇性低氧血症(IH)是妊娠37周前出生的婴儿常见的发育障碍。咖啡因给药已被证明可以降低这些疾病在早产儿中的发病率。停止咖啡因治疗是基于不同的月经后年龄(PMA)和症状的解决。关于咖啡因停药的最佳时机存在不确定性。
目的:评估早产儿早期和晚期停止咖啡因给药的效果。
方法:我们搜索了CENTRAL,PubMed,Embase,和2023年8月的三个试验登记处;我们没有应用日期限制。我们检查了纳入研究的参考文献和相关的系统综述。
方法:我们纳入了妊娠37周前出生的早产儿的随机对照试验(RCT),长达44周0天的PMA,接受咖啡因治疗至少七天。我们比较了三种不同的咖啡因停止策略:1.在不同的PMA中,2.在没有症状的五天之前或之后,and3.在预定的PMA与症状消退时。
方法:我们使用标准Cochrane方法。主要结果是:重新启动咖啡因治疗,停止治疗后一周内插管,以及在治疗停止后一周内需要无创呼吸支持。次要结果是:治疗停止后7天的呼吸暂停发作次数,在治疗停止后七天内至少有一次呼吸暂停发作的婴儿数量,治疗停止后7天内间歇性低氧血症(IH)的发作次数,在治疗停止后七天内至少有一次IH发作的婴儿人数,出院前的全因死亡率,严重的神经发育障碍,治疗停止后呼吸支持的天数,住院时间,和新生儿护理的费用。我们使用等级来评估每个结果的证据的确定性。
结果:我们纳入了3项随机对照试验(392名早产儿)。在PMA小于35周的妊娠与PMA等于或长于35周的妊娠停止咖啡因。该比较包括一个单一的完成RCT,其中98名早产儿出生时的胎龄在250和320周之间。所有婴儿在随机分组时停止咖啡因治疗五天。婴儿随机接受口服负荷剂量的咖啡因柠檬酸盐(20mg/kg),然后口服维持剂量(6mg/kg/天),直到40周PMA,或常规护理(控制),在PMA前37周停止咖啡因。PMA小于35周的早产儿早期停止咖啡因给药可能导致IH发作次数在停药后7天内增加。与超过35周的长期咖啡因治疗相比(平均差[MD]4.80,95%置信区间[CI]2.21至7.39;1RCT,98名婴儿;低确定性证据)。与35周PMA后的晚期停药相比,早期停药可能导致出院前的全因死亡率几乎没有差异(风险比[RR]不可估计;98名婴儿;低确定性证据)。没有以下结果的数据:重新启动咖啡因治疗,停止治疗后一周内插管,在治疗停止后一周内需要无创呼吸支持,呼吸暂停的发作次数,在停止治疗后7天内至少有一次呼吸暂停发作的婴儿数量,或在停止治疗后7天内出现至少一次IH发作的婴儿人数。基于PMA的停药与症状的消退该比较包括两个RCTs,总共294名早产儿。与在预定的PMA下停止治疗相比,在症状缓解时停止咖啡因可能会导致出院前的全因死亡率几乎没有差异(RR1.00,95%CI0.14至7.03;2项研究,294名参与者;低确定性证据),或在停止治疗后7天内出现至少一次呼吸暂停发作的婴儿数量(RR0.60,95%CI0.31~1.18;2项研究;294名婴儿;低确定性证据).根据症状的缓解停止咖啡因可能会导致在停止治疗后7天内更多的IH婴儿(RR0.38,95%CI0.20至0.75;1项研究;174名参与者;中度确定性证据)。没有以下结果的数据:重新启动咖啡因治疗,停止治疗后一周内插管,在治疗停止后一周内需要无创呼吸支持,或停药后7天内IH的发作次数。Rhein2014研究中的不良反应,根据临床团队的判断,随机接受咖啡因治疗的婴儿中有五名停止了咖啡因治疗,因为心动过速.Pradhap2023研究报告了不良事件,包括早产儿呼吸暂停的复发(短期为15%,常规咖啡因治疗组为13%),不同程度的支气管肺发育不良,高血糖症,宫外生长受限,需要激光治疗的早产儿视网膜病变,喂养不耐受,骨质减少,和心动过速,组间无显著差异。Prakash2021研究报告说,咖啡因治疗早产儿呼吸暂停的不良反应包括心动过速,喂养不耐受,和潜在的神经发育影响,虽然大多数是温和和短暂的。我们确定了三项正在进行的研究。
结论:在被随机分配到以后停止咖啡因治疗的婴儿中,全因死亡率和呼吸暂停的发生率可能几乎没有差异。然而,至少有一次IH发作的婴儿数量可能随着戒烟时间的延长而减少.没有数据可以评估以后停用咖啡因的益处和危害:重新启动咖啡因治疗,停止治疗后一周内插管,或在治疗停止后一周内需要无创呼吸支持。需要进一步的研究来评估不同的咖啡因戒烟策略对早产儿的短期和长期影响。
BACKGROUND: Apnea and intermittent hypoxemia (IH) are common developmental disorders in infants born earlier than 37 weeks\' gestation. Caffeine administration has been shown to lower the incidence of these disorders in preterm infants. Cessation of caffeine treatment is based on different post-menstrual ages (PMA) and resolution of symptoms. There is uncertainty about the best timing for caffeine discontinuation.
OBJECTIVE: To evaluate the effects of early versus late discontinuation of caffeine administration in preterm infants.
METHODS: We searched CENTRAL, PubMed, Embase, and three trial registries in August 2023; we applied no date limits. We checked the references of included studies and related systematic reviews.
METHODS: We included randomized controlled trials (RCTs) in preterm infants born earlier than 37 weeks\' gestation, up to a PMA of 44 weeks and 0 days, who received caffeine for any indication for at least seven days. We compared three different strategies for caffeine cessation: 1. at different PMAs, 2. before or after five days without symptoms, and 3. at a predetermined PMA versus at the resolution of symptoms.
METHODS: We used standard Cochrane methods. Primary outcomes were: restarting caffeine therapy, intubation within one week of treatment discontinuation, and the need for non-invasive respiratory support within one week of treatment discontinuation. Secondary outcomes were: number of episodes of
apnea in the seven days after treatment discontinuation, number of infants with at least one episode of
apnea in the seven days after treatment discontinuation, number of episodes of intermittent hypoxemia (IH) within seven days of treatment discontinuation, number of infants with at least one episode of IH in the seven days after of treatment discontinuation, all-cause mortality prior to hospital discharge, major neurodevelopmental disability, number of days of respiratory support after treatment discontinuation, duration of hospital stay, and cost of neonatal care. We used GRADE to assess the certainty of evidence for each outcome.
RESULTS: We included three RCTs (392 preterm infants). Discontinuation of caffeine at PMA less than 35 weeks\' gestation versus PMA equal to or longer than 35 weeks\' gestation This comparison included one single completed RCT with 98 premature infants with a gestational age between 25 + 0 and 32 + 0 weeks at birth. All infants had discontinued caffeine treatment for five days at randomization. The infants received either an oral loading dose of caffeine citrate (20 mg/kg) at randomization followed by oral maintenance dosage (6 mg/kg/day) until 40 weeks PMA, or usual care (controls), during which caffeine was stopped before 37 weeks PMA. Early cessation of caffeine administration in preterm infants at PMA less than 35 weeks\' gestation may result in an increase in the number of IH episodes in the seven days after discontinuation of treatment, compared to prolonged caffeine treatment beyond 35 weeks\' gestation (mean difference [MD] 4.80, 95% confidence interval [CI] 2.21 to 7.39; 1 RCT, 98 infants; low-certainty evidence). Early cessation may result in little to no difference in all-cause mortality prior to hospital discharge compared to late discontinuation after 35 weeks PMA (risk ratio [RR] not estimable; 98 infants; low-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, number of episodes of apnea, number of infants with at least one episode of apnea in the seven days after discontinuation of treatment, or number of infants with at least one episode of IH in the seven days after discontinuation of treatment. Discontinuation based on PMA versus resolution of symptoms This comparison included two RCTs with a total of 294 preterm infants. Discontinuing caffeine at the resolution of symptoms compared to discontinuing treatment at a predetermined PMA may result in little to no difference in all-cause mortality prior to hospital discharge (RR 1.00, 95% CI 0.14 to 7.03; 2 studies, 294 participants; low-certainty evidence), or in the number of infants with at least one episode of
apnea within the seven days after discontinuing treatment (RR 0.60, 95% CI 0.31 to 1.18; 2 studies; 294 infants; low-certainty evidence). Discontinuing caffeine based on the resolution of symptoms probably results in more infants with IH in the seven days after discontinuation of treatment (RR 0.38, 95% CI 0.20 to 0.75; 1 study; 174 participants; moderate-certainty evidence). No data were available for the following outcomes: restarting caffeine therapy, intubation within one week of treatment discontinuation, need for non-invasive respiratory support within one week of treatment discontinuation, or number of episodes of IH in the seven days after treatment discontinuation. Adverse effects In the Rhein 2014 study, five of the infants randomized to caffeine had the caffeine treatment discontinued at the discretion of the clinical team, because of tachycardia. The Pradhap 2023 study reported adverse events, including recurrence of
apnea of prematurity (15% in the short and 13% in the regular course caffeine therapy group), varying severities of bronchopulmonary dysplasia, hyperglycemia, extrauterine growth restriction, retinopathy of prematurity requiring laser treatment, feeding intolerance, osteopenia, and tachycardia, with no significant differences between the groups. The Prakash 2021 study reported that adverse effects of caffeine therapy for apnea of prematurity included tachycardia, feeding intolerance, and potential neurodevelopmental impacts, though most were mild and transient. We identified three ongoing studies.
CONCLUSIONS: There may be little or no difference in the incidence of all-cause mortality and apnea in infants who were randomized to later discontinuation of caffeine treatment. However, the number of infants with at least one episode of IH was probably reduced with later cessation. No data were found to evaluate the benefits and harms of later caffeine discontinuation for: restarting caffeine therapy, intubation within one week of treatment discontinuation, or need for non-invasive respiratory support within one week of treatment discontinuation. Further studies are needed to evaluate the short-term and long-term effects of different caffeine cessation strategies in premature infants.