In contrast to older children and adults, premature neonates have decreased sensitivity to carbon dioxide and often experience hypoxic ventilatory depression. This can result in deleterious and prolonged periods of hypoventilation and apnea in response to hypoxemia. Caffeine is a trimethylxanthine which stimulates the respiratory control centers in the medulla through competitive inhibition of adenosine. This increases the ventilatory responsiveness to carbon dioxide and attenuates central hypoxic ventilatory depression. For this reason, caffeine is a commonly prescribed medication administered to many premature neonates in the neonatal intensive care unit (NICU).¹ Other pharmacological effects of caffeine include enhanced diaphragmatic contractility, mild diuresis, and increased minute ventilation. Through these physiologic effects and others, caffeine has substantially reduced common morbidities among premature neonates including apnea of prematurity, bronchopulmonary dysplasia (BPD), and patent ductus arteriosus (PDA).² Most importantly, neonates who receive caffeine have better neurodevelopmental outcomes (e.g., less cerebral palsy and cognitive delays) and a decreased incidence of severe retinopathy of prematurity (ROP).^2,3 When considering all the medications administered in the NICU, caffeine has played a very prominent role in improving important neonatal outcomes.

Caffeine has a wider therapeutic index and fewer side effects compared to other methylxanthines such as theophylline and aminophylline.^4,5 Despite the profound impact that caffeine has had on the care of premature neonates, the dosing and timing of caffeine administration has changed little since the initial trials of this groundbreaking medication several decades ago.⁶ In addition, despite the widespread use of caffeine, BPD, neurodevelopmental impairment, ROP, and other morbidities continue to occur frequently in premature neonates.⁷ Although the efficacy, effectiveness, and safety of caffeine are well established, questions remain about of how clinicians can devise strategies to maximize the benefits. A post hoc analyses of the Caffeine of Prematurity (CAP) Trial in 2010 demonstrated that the duration of positive pressure ventilation was significantly less with earlier treatment (started at <3 postnatal days) compared to later treatment starting at >3 days, suggesting that earlier initiation of caffeine therapy may further improve neonatal outcomes.⁸ Subsequent large cohort studies, small randomized controlled trials, and metanalyses have favored earlier caffeine administration. However, how early is too early?

与年龄较大的儿童和成人相比，早产儿对二氧化碳的敏感性降低，经常出现缺氧通气抑制。这可能导致因低氧血症而导致有害且长时间的通气不足和呼吸暂停。咖啡因是一种三甲基黄嘌呤，通过竞争性抑制腺苷来刺激髓质的呼吸控制中心。这增加了对二氧化碳的通气反应性并减弱了中枢性缺氧通气抑制。因此，咖啡因是新生儿重症监护病房 (NICU) 中许多早产儿常用的处方药物。¹咖啡因的其他药理作用包括增强膈肌收缩力、轻度利尿和增加每分钟通气量。通过这些生理作用和其他作用，咖啡因大大减少了早产儿的常见发病率，包括早产儿呼吸暂停、支气管肺发育不良 (BPD) 和动脉导管未闭 (PDA)。²最重要的是，摄入咖啡因的新生儿具有更好的神经发育结果（例如，脑瘫和认知迟缓较少），并且严重早产儿视网膜病变 (ROP) 的发生率降低。^2,3考虑到新生儿重症监护室使用的所有药物，咖啡因在改善重要的新生儿结局方面发挥了非常突出的作用。

与茶碱和氨茶碱等其他甲基黄嘌呤类药物相比，咖啡因具有更广泛的治疗指数和更少的副作用。^4,5尽管咖啡因对早产儿的护理产生了深远的影响，但自几十年前这种突破性药物的初步试验以来，咖啡因的给药剂量和时间几乎没有变化。⁶此外，尽管咖啡因的广泛使用，BPD、神经发育障碍、ROP 和其他疾病在早产儿中仍然频繁发生。⁷尽管咖啡因的功效、有效性和安全性已得到充分证实，但临床医生如何制定策略以最大限度地提高其益处仍然存在疑问。 2010 年咖啡因早产 (CAP) 试验的事后分析表明，与 >3 天开始的较晚治疗相比，早期治疗（产后 <3 天开始）的正压通气持续时间显着缩短，这表明早期治疗的正压通气持续时间明显较短。开始咖啡因治疗可能会进一步改善新生儿结局。⁸随后的大型队列研究、小型随机对照试验和荟萃分析都支持早期服用咖啡因。然而，多早才算太早呢？