Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial.

BACKGROUND: Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits. OBJECTIVE: We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks' gestation. STUDY DESIGN: This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks' gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept. RESULTS: Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41-1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33-0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24-0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62-1.06), or a serious adverse event composite of death before discharge. CONCLUSION: Among nonvigorous infants born at 35 to 42 weeks' gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.

The protective role of MnTBAP in oxidant-mediated injury and inflammation in a rat model of lung contusion.

BACKGROUND: Lung contusion (LC) is a unique direct and focal insult that is considered a major risk factor for the initiation of acute lung injury and acute respiratory distress syndrome. We have shown recently that consumption of nitric oxide (due to excess superoxide) resulting in peroxynitrite formation leads to decreased vascular reactivity after LC. In this study, we set out to determine whether the superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) plays a protective role in alleviating acute inflammatory response and injury in LC. METHODS: Nonlethal, closed-chest, bilateral LC was induced in a rodent model. Administration of the superoxide dismutase mimetic MnTBAP concurrently in LC in rats was performed, and bronchoalveolar lavage (BAL) and lung samples were analyzed for degree of injury and inflammation at 5 and 24 h after the insult. The extent of injury was assessed by the measurement of cells and albumin with cytokine levels in the BAL and lungs. Lung samples were subjected to H&E and superoxide staining with dihydro-ethidium. Protein-bound dityrosine and nitrotyrosine levels were quantified in lung tissue by tandem mass spectrometry. RESULTS: The degrees of lung injury after LC as determined by BAL albumin levels were significantly decreased in the MnTBAP-administered rats at all the time points when compared to the corresponding controls. The release of proinflammatory cytokines and BAL neutrophils was significantly less in the rats administered MnTBAP after LC. Administration of MnTBAP decreased tissue damage and decreased necrosis and neutrophil-rich exudate at the 24-h time point. Staining for superoxide anions showed significantly greater intensity in the lung samples from the LC group compared to the LC+ MnTBAP group. High-performance liquid chromatography/tandem mass spectrometry revealed that MnTBAP treatment significantly attenuated dityrosine and nitrotyrosine levels, consistent with decreased oxidant injury. CONCLUSION: Superoxide dismutase mimetic-MnTBAP reduced permeability and oxidative injury in LC and may have a therapeutic role in diminishing inflammation in LC.

Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn.

In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O(2) for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg(-1)·dose(-1) times two doses (PPHN-loHC), and six lambs were ventilated with O(2) alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O(2) ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O(2.) We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress.

Exposure to supplemental oxygen downregulates antioxidant enzymes and increases pulmonary arterial contractility in premature lambs.

BACKGROUND: The optimal oxygen concentration for the resuscitation of premature infants remains controversial. OBJECTIVES: We studied the effects of 21 versus 100% oxygen at initial resuscitation and also the effects of 24-hour exposure to 100% oxygen on arterial blood gases, oxidant lung injury, activities of lung antioxidant enzymes (AOEs) and isolated pulmonary artery (PA) contractility in preterm newborn lambs. METHODS: Preterm lambs at 128 days' gestation (term = 145 days) were delivered and ventilated with 21 (RAR; n = 5) or 100% oxygen (OXR; n = 5) for the first 30 min of life. Subsequently, FiO2 was adjusted to maintain an arterial PO2 (PaO2) between 45 and 70 mm Hg for 24 h. A third group of lambs was mechanically ventilated with 100% oxygen for 24 h (OX24; n = 5). RESULTS: Oxidized glutathione levels in whole blood correlated highly with PaO2. Reduced to oxidized glutathione ratio was significantly different between the groups, the ratio increasing with decreasing oxygen exposure. The OX24 group had significantly higher activities of lipid hydroperoxide and myeloperoxidase and significantly lower activities of superoxide dismutase, catalase and glutathione peroxidase in the lung at 24 h. Activities of AOEs correlated inversely with alveolar PO2. PA contractility to norepinephrine and KCl was greater with increasing oxygen exposure. Pretreatment with superoxide dismutase and catalase significantly reduced PA contractility in the OXR and OX24 groups, but not in the RAR group. CONCLUSIONS: We conclude that ventilated premature lambs are unable to appropriately increase AOE activity in response to hyperoxia and that increasing exposure to oxygen aggravates systemic oxidant stress, oxidant lung injury and pulmonary arterial contractility in these lambs.