Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
(Formerly) Division of Neonatology, Department of Child Health, Queen Mary's Hospital for Children, Wrythe Lane, Carshalton, UK.
Cochrane Database Syst Rev. 2023 Jun 20;6(6):CD004205. doi: 10.1002/14651858.CD004205.pub4.
Mortality and morbidity due to neonatal sepsis and necrotising enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline (PTX), a phosphodiesterase inhibitor, is one such agent. This is an update of a review first published in 2003 and updated in 2011 and 2015.
To assess the effectiveness and safety of intravenous PTX as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis and neonates with NEC.
We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registries in July 2022. We also searched the reference lists of identified clinical trials and handsearched conference abstracts. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs assessing the efficacy of PTX with antibiotics (any dose or duration) for treatment of suspected or confirmed sepsis or NEC in neonates. We included three comparisons: (1) PTX with antibiotics compared to placebo or no intervention with antibiotics; (2) PTX with antibiotics compared to PTX with antibiotics and adjunct treatments such as immunoglobulin M-enriched intravenous immunoglobulin (IgM-enriched IVIG); (3) PTX with antibiotics compared to adjunct treatments such as IgM-enriched IVIG with antibiotics.
We reported typical risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes derived from a fixed-effect model of meta-analysis. We calculated the number needed to treat for an additional beneficial outcome (NNTB) if there was a statistically significant reduction in RD.
We identified no new studies for this update. We included six RCTs (416 neonates). All of the included studies examined neonates with sepsis; we identified no studies on neonates with NEC. Four of the six trials had high risk of bias for at least one risk of bias domain. Comparison 1: PTX with antibiotics compared to placebo with antibiotics, or antibiotics alone, in neonates with sepsis may reduce all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-certainty evidence) and may decrease length of hospital stay (LOS) (MD -7.74, 95% CI -11.72 to -3.76; 2 studies, 157 participants, low-certainty evidence). The evidence is very uncertain that PTX with antibiotics compared to placebo or no intervention results in any change in chronic lung disease (CLD) (RR 1.50, 95% CI 0.45 to 5.05; 1 study, 120 participants, very low-certainty evidence), severe intraventricular haemorrhage (sIVH) (RR 0.75, 95% CI 0.28 to 2.03; 1 study, 120 participants, very low-certainty evidence), periventricular leukomalacia (PVL) (RR 0.50, 95% CI 0.10 to 2.63; 1 study, 120 participants, very low-certainty evidence), NEC (RR 0.56, 95% CI 0.29 to 1.06; 6 studies, 405 participants, very low-certainty evidence), or retinopathy of prematurity (ROP) (RR 0.40, 95% CI 0.08 to 1.98; 1 study, 120 participants, very low-certainty evidence) in neonates with sepsis. Comparison 2: the evidence is very uncertain that PTX with antibiotics compared to PTX with antibiotics and IgM-enriched IVIG has any effect on mortality (RR 0.71, 95% CI 0.24 to 2.10; 102 participants, 1 study, very low-certainty evidence) or development of NEC in neonates with sepsis (RR 1.33, 95% CI 0.31 to 5.66; 1 study, 102 participants, very low-certainty evidence). The outcomes of CLD, sIVH, PVL, LOS, and ROP were not reported. Comparison 3: the evidence is very uncertain that PTX with antibiotics compared to IgM-enriched IVIG with antibiotics has any effect on mortality (RR 1.25, 95% CI 0.36 to 4.39; 102 participants, 1 study, very low-certainty evidence) or development of NEC (RR 1.33, 95% CI 0.31 to 5.66; 102 participants, 1 study, very low-certainty evidence) in neonates with sepsis. The outcomes of CLD, sIVH, PVL, LOS, and ROP were not reported. All of the included studies evaluated adverse effects due to PTX, but none were reported in the intervention group in any of the comparisons.
AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that adjunct PTX therapy in neonatal sepsis may decrease mortality and length of hospital stay without any adverse effects. The evidence is very uncertain if PTX with antibiotics compared to PTX with antibiotics and IgM-enriched IVIG, or PTX with antibiotics compared to IgM-enriched IVIG with antibiotics, has any effect on mortality or development of NEC. We encourage researchers to undertake well-designed multicentre trials to confirm or refute the effectiveness and safety of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.
尽管使用了强效的抗菌药物，新生儿败血症和坏死性小肠结肠炎（NEC）的死亡率和发病率仍然很高。能够调节炎症的药物可能会改善结局。己酮可可碱（PTX）是一种磷酸二酯酶抑制剂，就是这样一种药物。这是一篇 2003 年首次发表并于 2011 年和 2015 年更新的综述的更新。
评估静脉注射 PTX 作为辅助抗生素治疗疑似或确诊败血症和 NEC 的新生儿的死亡率和发病率的有效性和安全性。
我们于 2022 年 7 月检索了 CENTRAL、MEDLINE、Embase、CINAHL 和试验注册库。我们还检索了已确定的临床试验的参考文献列表，并查阅了会议摘要。
我们纳入了评估 PTX 与抗生素（任何剂量或持续时间）联合治疗疑似或确诊败血症或 NEC 的新生儿的疗效的随机对照试验（RCT）或准 RCT。我们纳入了三个比较：（1）PTX 与抗生素相比安慰剂或无抗生素的干预；（2）PTX 与抗生素相比 PTX 与免疫球蛋白 M 浓缩静脉免疫球蛋白（IgM-enriched IVIG）等辅助治疗；（3）PTX 与抗生素相比 IgM-enriched IVIG 与抗生素等辅助治疗。
我们报告了典型的风险比（RR）和风险差异（RD），以及来自荟萃分析固定效应模型的连续结局的均数差（MD）。如果 RD 有统计学显著减少，我们计算了额外有益结果的需要治疗人数（NNTB）。
我们没有为本次更新发现新的研究。我们纳入了 6 项 RCT（416 名新生儿）。所有纳入的研究都评估了患有败血症的新生儿；我们没有发现研究患有 NEC 的新生儿。这 6 项试验中有 4 项至少在一个偏倚风险领域存在高偏倚风险。比较 1：PTX 与抗生素相比安慰剂加抗生素或单独使用抗生素，可能降低败血症患儿住院期间的全因死亡率（典型 RR 0.57，95% CI 0.35 至 0.93；典型 RD -0.08，95% CI -0.14 至 -0.01；NNTB 13，95% CI 7 至 100；6 项研究，416 名参与者，低质量证据），并可能缩短住院时间（MD -7.74，95% CI -11.72 至 -3.76；2 项研究，157 名参与者，低质量证据）。PTX 与抗生素相比安慰剂或无干预对慢性肺病（CLD）（RR 1.50，95% CI 0.45 至 5.05；1 项研究，120 名参与者，极低质量证据）、严重脑室内出血（sIVH）（RR 0.75，95% CI 0.28 至 2.03；1 项研究，120 名参与者，极低质量证据）、脑室周围白质软化（PVL）（RR 0.50，95% CI 0.10 至 2.63；1 项研究，120 名参与者，极低质量证据）、NEC（RR 0.56，95% CI 0.29 至 1.06；6 项研究，405 名参与者，极低质量证据）或早产儿视网膜病变（ROP）（RR 0.40，95% CI 0.08 至 1.98；1 项研究，120 名参与者，极低质量证据）无影响的证据非常不确定。比较 2：PTX 与抗生素相比 PTX 与免疫球蛋白 M 浓缩静脉免疫球蛋白（IgM-enriched IVIG）的联合治疗对死亡率（RR 0.71，95% CI 0.24 至 2.10；102 名参与者，1 项研究，极低质量证据）或败血症患儿 NEC 的发展（RR 1.33，95% CI 0.31 至 5.66；1 项研究，102 名参与者，极低质量证据）无影响的证据非常不确定。CLD、sIVH、PVL、住院时间和 ROP 的结局未报告。比较 3：PTX 与抗生素相比 IgM-enriched IVIG 与抗生素的联合治疗对死亡率（RR 1.25，95% CI 0.36 至 4.39；102 名参与者，1 项研究，极低质量证据）或 NEC 的发展（RR 1.33，95% CI 0.31 至 5.66；102 名参与者，1 项研究，极低质量证据）无影响的证据非常不确定。CLD、sIVH、PVL、住院时间和 ROP 的结局未报告。所有纳入的研究都评估了 PTX 的不良反应，但在任何比较中，干预组都没有报告。
低质量证据表明，新生儿败血症辅助 PTX 治疗可能降低死亡率和住院时间，且无不良反应。PTX 与抗生素相比 PTX 与免疫球蛋白 M 浓缩静脉免疫球蛋白（IgM-enriched IVIG），或 PTX 与抗生素相比 IgM-enriched IVIG 与抗生素，对死亡率或 NEC 的发展是否有影响，证据非常不确定。我们鼓励研究人员进行精心设计的多中心试验，以证实或反驳己酮可可碱降低败血症或 NEC 新生儿死亡率和发病率的有效性和安全性。
