Perioperative hypothermia in NICU infants: its occurrence and impact on infant outcomes.

Infants admitted to the neonatal intensive care unit (NICU) often require surgical intervention and maintaining normothermia perioperatively is a major concern. In our preliminary study of 31 normothermic infants undergoing operative procedures in the operating room (OR), 58% (N = 18) returned hypothermic while all 5 undergoing procedures in the NICU remained normothermic (P = .001). To describe perioperative thermal instability (temperatures lower than 36.0°C) and frequency of associated adverse events, support interventions, and diagnostic tests in infants undergoing operative procedures in the OR and the NICU. This prospective, case-control study included 108 infants admitted to the NICU who were sequentially scheduled for an operative procedure in the OR (50.93%; N = 55) or the NICU (49.07%; N = 53). Existing data from the medical record were collected about temperatures and frequency of adverse cardiovascular, respiratory, and metabolic events, associated support interventions, and diagnostic tests during the perioperative period. Analyses examined the relative risks and proportional differences in rates of hypothermia between the OR group and the NICU group and associated adverse events, support interventions, and diagnostic tests between hypothermic and normothermic infants. Hypothermia developed in 40% (N = 43) of infants during the perioperative period. The OR group had a higher rate of perioperative hypothermia (65.45%, N = 36; P < .001) and were 7 times more likely to develop perioperative hypothermia (P = .008) than the NICU group (13.21%, N = 7). Likewise, infants in the OR group were 10 times more likely to develop hypothermia during the intra- and postoperative periods than those in the NICU group (P = .001). The hypothermic group had significantly more respiratory adverse events (P = .025), were 6 times more likely to require thermoregulatory interventions (P < .001), 5 times more likely to require cardiac support interventions (P < .006), and 3 times more likely to require respiratory interventions (P = .02) than normothermic infants. Although infants undergoing operative procedures in the OR experienced significantly higher rates of hypothermia than those undergoing procedures in the NICU, both groups experienced unacceptable rates of clinical hypothermia. Hypothermic infants experienced more adverse events and required more support interventions during the intra- and postoperative periods than normothermic infants, thereby demonstrating the negative sequelae associated with thermal instability. As a result, a translational team of key stakeholders has been created to explore multifaceted strategies based on translation science to implement, embed, and sustain perioperative thermoregulation best practices for the infant, regardless of the operative setting.

Therapeutic hypothermia for neonatal encephalopathy and extracorporeal membrane oxygenation.

This case series describes the clinical management of 5 infants who underwent whole-body cooling during extracorporeal membrane oxygenation (ECMO). In all 5 infants, systemic hypothermia was maintained during ECMO with acceptable clinical outcomes.

A tale of two bridges: effect of the bloodless bridge on renal function and blood pressure in neonates managed with venoarterial extracorporeal membrane oxygenation.

OBJECTIVE: To investigate if a change in bridge design of the extracorporeal membrane oxygenation (ECMO) circuit had an impact on renal function and blood pressure in neonates requiring venoarterial ECMO support. DESIGN: : Retrospective chart review. SETTING: A tertiary care neonatal intensive care unit and ECMO center. PATIENTS: The medical records of neonates admitted to the neonatal intensive care unit and treated with venoarterial ECMO were reviewed. Data were collected on 50 consecutive neonates treated previous to (prebridge group) and following (postbridge group) transition to a new bridge design on the ECMO circuit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Gestational age, gender, racial distribution, and use of hypertensive therapy were similar between the two groups. Daily blood urea nitrogen, serum creatinine, urine output, fluid balance, and average and maximum systolic and mean arterial blood pressures were recorded for the first 3 days on bypass. The postbridge group had lower maximum mean arterial blood pressure and systolic blood pressure on day 2 of ECMO and lower average mean arterial blood pressure and systolic blood pressure on days 2 and 3 of ECMO. These differences remained significant after controlling for covariates in a multiple regression model. A higher percentage of patients were hypertensive (mean arterial blood pressure >60) in the prebridge group compared with the postbridge group. There were no differences in blood urea nitrogen, serum creatinine, fluid balance, and urine output between the two groups. CONCLUSIONS: Patients managed on venoarterial ECMO after the transition to the "bloodless" bridge had less hypertension compared with those managed before the bridge change. This may reflect improved maintenance of renal perfusion associated with transition to an ECMO bridge design that does not require intermittent circulation with associated arterial-venous shunting.

Impact of decolonization on methicillin-resistant Staphylococcus aureus transmission and infection in a neonatal intensive care unit.

BACKGROUND: The value of decolonization as a strategy for preventing methicillin-resistantStaphylococcus aureus (MRSA) in the neonatal intensive care unit (NICU) remains to be determined. OBJECTIVE: After adding decolonization to further reduce MRSA transmission in our NICU, we conducted this retrospective review to evaluate its effectiveness. METHOD: The review included patients who were admitted to our NICU between April 2015 and June 2018 and were eligible for decolonization including twice daily intranasal mupirocin and daily chlorhexidine gluconate bathing over 5 consecutive days. Patients were considered successfully decolonized if 3 subsequent MRSA screenings conducted at 1-week intervals were negative. The MRSA acquisition rate (AR) was calculated as hospital-acquired (HA) MRSA per 1,000 patient days (PD) and was used to measure the effectiveness of the decolonization. RESULTS: Of the 151 MRSA patients being reviewed, 78 (51.6%) were HA-MRSA, resulting in an overall AR of 1.27 per 1,000 PD. Between April 2015 and February 2016, when only the decolonization was added, the AR was 2.38 per 1,000 PD. Between March 2016 and June 2018 after unit added a technician dedicated to the cleaning of reusable equipment, the AR decreased significantly to 0.92 per 1,000 PD (P < .05). Of the 78 patients who were started on the decolonization, 49 (62.8%) completed the protocol, 11 (14.1%) remained colonized, and 13 (16.7%) were recolonized prior to NICU discharge. CONCLUSION: In a NICU with comprehensive MRSA prevention measures in place, enhancing the cleaning of reusable equipment, not decolonization, led to significant reduction of MRSA transmission.

NF-kappaB activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/reoxygenation.

BACKGROUND AND PURPOSE: Cerebral vascular injury occurs in response to hypoxia/reoxygenation (H/R). However, the cellular signaling pathways that regulate this event remain unclear. The present study was designed to determine whether reactive oxygen species (ROS) mediate endothelial dysfunction after H/R in cerebral resistance arteries and, if so, the relative contribution of ROS, NADPH oxidase, and a nuclear factor-kappaB (NF-kappaB) pathway. METHODS: Arterial diameter and intraluminal pressure were simultaneously measured on rat posterior cerebral arteries (PCA). Superoxide was measured by 5-micromol/L lucigenin-enhanced chemiluminescence. RESULTS: Hypoxia/reoxygenation selectively inhibited cerebral vasodilation to the endothelium-dependent agonist acetylcholine (Ach) (0.01 to 10 micromol/L) by approximately 50%. Impaired vasodilation after H/R was reversed by 2,2,6,6-tetramethylpiperidine-N-oxyl (Tempo) (100 micromol/L), a cell-permeable superoxide dismutase mimetic, and partially by ebselen (10 micromol/L), a peroxynitrite scavenger. H/R-impaired vasodilation to Ach was also preserved by apocynin (1 mmol/L), a specific inhibitor for NADPH oxidase. Correspondingly, H/R significantly increased lucigenin-detectable superoxide, which was reduced by either Tempo or apocynin, but not by allopurinol (10 micromol/L), an inhibitor of xanthine oxidase. Finally, the NF-kappaB inhibitors helenalin (10 micromol/L) and MG-132 (1 micromol/L) independently antagonized H/R-impaired Ach-induced vasodilation without affecting dilator response to sodium nitroprusside, an endothelium-independent vasodilator. CONCLUSIONS: These results indicate that superoxide mediates cerebral endothelial dysfunction after hypoxia/reoxygenation largely via activation of NADPH oxidase and possibly activation of NF-kappaB pathway.

The effect of extracorporeal life support on the brain: a focus on ECMO.

Extracorporeal membrane oxygenation (ECMO) therapy has significantly improved outcome in the newborn, pediatric, and adult patient in respiratory and cardiac failure. Despite this therapy providing a life-saving technology, the morbidity in patients treated with ECMO therapy is primarily related to neurologic alterations and not pulmonary findings. For ECMO, this is not unexpected since most patients are being placed on ECMO support because of severe hypoxemia, with ECMO being considered a rescue therapy for respiratory failure in most instances. As use of ECMO becomes common place for infants and children in respiratory failure, our investigations into the outcome of these children must focus not only on survival versus nonsurvival, but on the causes of morbidity in this population. A further understanding of factors associated with morbidity may allow us to alter techniques used in extracorporeal life support (ECLS), hopefully to improve our long-term outcome in this population, while allowing us to expand use of these technologies to other populations such as the premature infant. This article will focus on the effect of ECMO on the brain, with the following chapter by Dr. Richard Jonas outlining the effect of cardiopulmonary bypass on the brain.

The association of type of surgical closure on length of stay among infants with gastroschisis born≥34 weeks' gestation.

BACKGROUND/PURPOSE: The optimal surgical approach in infants with gastroschisis (GS) is unknown. The purpose of this study was to estimate the association between staged closure and length of stay (LOS) in infants with GS. DESIGN/METHODS: We used the Children's Hospital Neonatal Database to identify surviving infants with GS born ≥34 weeks' gestation referred to participating NICUs. Infants with complex GS, bowel atresia, or referred after 2 days of age were excluded. The primary outcome was LOS; multivariable linear regression was used to quantify the relationship between staged closure and LOS. RESULTS: Among 442 eligible infants, staged closure occurred in 68.1% and was associated with an increased median LOS relative to odds ration (OR):primary closure (37 vs. 28 days, p<0.001). This association persisted in the multivariable equation (ß=1.35, 95% CI: 1.21, 1.52, p<0.001) after adjusting for the presence of necrotizing enterocolitis, short bowel syndrome, and central-line associated bloodstream infections. CONCLUSIONS: In this large, multicenter cohort of infants with GS, staged closure was independently associated with increased LOS. These data can be used to enhance antenatal and pre-operative counseling and also suggest that some infants who receive staged closure may benefit from primary repair.

Heparin inhibits angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways.

Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistance arteries through modulating the Rho-A/Rho kinase pathway. Vascular contractility was studied by using pressurized, resistance-sized mesenteric arteries from mice. Rho-A activation was measured by pull-down assay, and myosin light chain or PKA phosphorylation by immunoblotting. We found that heparin significantly attenuated vasoconstriction induced by Ang II but not that by KCl. The combined effect of Ang II with heparin was almost abolished by a specific Rho kinase inhibitor Y27632. Ang II stimulated Rho-A activation and myosin light chain phosphorylation, both responses were antagonized by heparin. Moreover, the inhibitory effect of heparin on Ang II-induced vasoconstriction was reversed by Rp-cAMPS (cAMP-dependent PKA inhibitor), blunted by ODQ (soluble guanylate cyclase inhibitor), and mimicked by a cell-permeable cGMP analogue, 8-Br-cGMP, but not by a cAMP analogue. PKC and Src kinase were not involved. We conclude that heparin inhibits Ang II-induced vasoconstriction through Rho-A/Rho kinase- and cGMP/PKA-dependent pathways.

Survival in congenital diaphragmatic hernia: use of predictive equations in the ECMO population.

BACKGROUND: Equations have been proposed by the Wilford Hall/Santa Rosa (WHSR) and Congenital Diaphragmatic Hernia Study Group (CDHSG) for predicting survival in patients with CDH. The CDHSG stratifies risk based on a logistic regression equation incorporating birth weight and 5-min Apgar score, while the WHSR group uses the difference between maximum pO(2) and maximum pCO(2) as an index of risk. These models have not been applied specifically to the CDH ECMO (extracorporeal membrane oxygenation) population, a group at highest mortality risk. OBJECTIVES: To evaluate the WHSR and CDHSG predictive equations when applied to a population of patients with CDH requiring ECMO life support. METHODS: A single-center retrospective review was conducted on infants with CDH treated with ECMO between 1993 and 2007. Predicted and actual outcomes were compared using receiver operating curve (ROC) analyses in which an area under the curve (AUC) of 1 denotes 100% agreement between predicted and actual outcomes. Kaplan-Meier analyses were also used to compare survival of patients who were risk-categorized according to each prediction model. Minimum pre-ECMO pCO(2) was likewise evaluated as a predictor of survival. RESULTS: Overall survival was 50% in 62 CDH patients treated with ECMO during the study period. The CDHSG equation did not discriminate between survivors and nonsurvivors (AUC 0.55, p = 0.499). The modified WHSR formula showed better discrimination of survival (AUC 0.71, p = 0.004). Lowest achievable pre-ECMO pCO(2) had the highest AUC (0.723, p = 0.003). Patients with minimum pre-ECMO pCO(2) <50 mm Hg had 56% survival, while those with >70 mm Hg had 0% survival. CONCLUSIONS: Equations proposed to predict survival in CDH patients may not discriminate survivors from nonsurvivors in the ECMO population. In this highest risk group, factors such as birth weight and Apgar score are less critical in estimating mortality risk than indicators of ventilation and oxygenation that reflect the degree of pulmonary hypoplasia.

Role of sensory C fibers in hypoxia/reoxygenation-impaired myogenic constriction of cerebral arteries.

OBJECTIVE: Hypoxia/reoxygenation (H/R) associated with extracorporeal membrane oxygenation disrupts cerebral autoregulation. However, the underlying mechanisms remain poorly understood. The present study was designed to investigate the role of sensory C-fibers in myogenic responsiveness of cerebral arteries. METHODS: Arterial diameter and intraluminal pressure were simultaneously measured in vitro on rat posterior cerebral arteries. RESULTS: Cerebral arteries constricted in response to graded increase in intraluminal pressure (20-100 mmHg, in 20 mmHg increments). In vitro C-fiber desensitization with capsaicin (1 micromol/l, 20 minutes) significantly suppressed myogenic constriction by over 50%, but did not affect 5-hydroxytryptamine (0.01-10 micromol/l) and KCl (120 mmol/l)-induced constriction. Capsazepine (5 micromol/l, 30 minutes), a selective blocker of neuronal vanilloid receptor TRPV1, had similar inhibitory effect on cerebral myogenic constriction to elevated pressure. Cerebral myogenic constriction was significantly attenuated by H/R; the impairment by H/R was further enhanced after C-fiber desensitization (except at a pressure level of 100 mmHg). DISCUSSION: These findings indicate that C-fiber activity contributes to myogenic constriction of cerebral arteries under normal and H/R conditions. H/R-impaired myogenic responsiveness is exaggerated by C-fiber dysfunction. These results raise the possibility that therapeutic strategies directed toward preserving C-fiber nerve endings or supplying its constituent neuropeptides could be developed.

Rho-kinase contributes to hypoxia/reoxygenation-induced cerebral endothelial dysfunction.

Hypoxia/reoxygenation (H/R) in vitro induced cerebral endothelial dysfunction is mediated by superoxide production. However, the intracellular pathways involved remain unclear. The present study was designed to investigate the involvement of Rho-kinase and its interaction with nitric oxide (NO) in cerebral endothelial dysfunction after H/R. Arterial diameter and intraluminal pressure were simultaneously measured in vitro on rat posterior cerebral arteries. Vascular NO production was determined by measuring stable NO metabolites nitrate/nitrite. H/R selectively inhibited cerebral vasodilation to the endothelium-dependent agonist acetylcholine (ACh, 0.01 to 10 micromol/L) and caused NO deficiency. H/R-impaired vasodilation to ACh was reversed by Y27632 (1 micromol/L), a specific inhibitor of Rho-kinase, but not by chelerythrine (1 micromol/L), a selective inhibitor of protein kinase C. Y27632 had no protective effect in the presence of N-nitro-L-arginine methyl ester (L-NAME; 100 micromol/L), a specific endothelial NO synthase inhibitor. L-NAME (100 micromol/L) alone failed to modulate H/R-impaired vasodilation, so did L-arginine (3 mmol/L), a substrate for NO synthase. However, a stable NO donor diethylenetetra amine-NONOate (5 micromol/L) normalized H/R-impaired dilation to ACh. In conclusion, H/R-induced endothelial dysfunction is associated with activation of Rho-kinase-dependent pathway and NO deficiency. Pretreatment with either Y27632 or the stable NO donor profoundly prevented H/R-mediated cerebral endothelial dysfunction.

Summary proceedings from the cardiology group on cardiovascular instability in preterm infants.

The appropriate determination of adequate tissue perfusion and the best approach to treatment of perceived abnormalities in blood pressure in the neonate remain controversial. There is no consensus regarding the actual definition of hypotension in the neonate or how best to raise perceived low blood pressure. In addition, there is no direct and prospectively collected information available on the result of treatment of a "low" blood pressure on neonatal morbidity and mortality. It also has not been clearly demonstrated that bringing systemic blood pressure to a "normal" range improve outcomes. However, it is widely accepted by clinicians that early and aggressive treatment of hypotension leads to improved neurologic outcome and survival in the neonate. Commonly used therapeutic maneuvers to correct systemic hypotension in the neonate include volume expansion, inotropic agents, and corticosteroids. Although there is a paucity of research on the cardiovascular response to these commonly used agents in neonates, among the commonly used inotropic drugs dopamine has been shown to be more effective than dobutamine in raising blood pressure in the neonate. The cardiology group focused on the use of inotropes, particularly dopamine and dobutamine, to treat very low birth weight infants with cardiac instability and neonatal postoperative cardiac patients. The cardiology group identified key issues that must be considered when designing studies of inotropic agents in preterm infants and proposed 2 clinical-trial designs: (1) a placebo-controlled trial with rescue for symptomatic infants; and (2) a targeted-blood pressure study. The first trial design would answer questions concerning efficacy of treatment with inotropic agents in this population. The second trial design would address concerns related to the lack of knowledge on normal blood pressure ranges in this population. The group identified specific design elements that would need to be addressed for the complicated trial design to study inotropic agents in neonates.