Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations. Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants. Design, Setting, and Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes. Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211). Main Outcome and Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours. Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups. Conclusions and Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions. Trial Registration: clinicaltrials.gov Identifier: NCT02139800.

Ethical and Legal Perspectives on the Treatment of Hypoxic Ischemic Encephalopathy in the Newborn.

Hypoxic ischemic encephalopathy (HIE) in neonates can cause severe, life-long functional impairments or death. Treatment of these neonates can involve ethically challenging questions about if, when, and how it may be appropriate to limit life-sustaining medical therapy. Further, parents whose infants suffer severe neurologic damage may seek recourse in the form of a medical malpractice lawsuit. This study uses several hypothetical cases to highlight important ethical and legal considerations in the care of infants with HIE.

Esophageal and rectal temperatures as estimates of core temperature during therapeutic whole-body hypothermia.

We monitored whole-body cooling concurrently by both esophageal and rectal probes. Esophageal temperature was significantly higher compared with simultaneous rectal temperature during cooling, with a temperature gradient ranging from 0.46 to 1.03°C (median, 0.8°C; IQR, 0.6-0.8°C). During rewarming, this temperature difference disappeared.

When bad things happen: adverse event reporting and disclosure as patient safety and risk management tools in the neonatal intensive care unit.

The Institute of Medicine has recommended a change in culture from "name and blame" to patient safety. This will require system redesign to identify and address errors, establish performance standards, and set safety expectations. This approach, however, is at odds with the present medical malpractice (tort) system. The current system is outcomes-based, meaning that health care providers and institutions are often sued despite providing appropriate care. Nevertheless, the focus should remain to provide the safest patient care. Effective peer review may be hindered by the present tort system. Reporting of medical errors is a key piece of peer review and education, and both anonymous reporting and confidential reporting of errors have potential disadvantages. Diagnostic and treatment errors continue to be the leading sources of allegations of malpractice in pediatrics, and the neonatal intensive care unit is uniquely vulnerable. Most errors result from systems failures rather than human error. Risk management can be an effective process to identify, evaluate, and address problems that may injure patients, lead to malpractice claims, and result in financial losses. Risk management identifies risk or potential risk, calculates the probability of an adverse event arising from a risk, estimates the impact of the adverse event, and attempts to control the risk. Implementation of a successful risk management program requires a positive attitude, sufficient knowledge base, and a commitment to improvement. Transparency in the disclosure of medical errors and a strategy of prospective risk management in dealing with medical errors may result in a substantial reduction in medical malpractice lawsuits, lower litigation costs, and a more safety-conscious environment.

Persistent pulmonary hypertension of the newborn: Historical perspectives.

For many decades, persistent pulmonary hypertension of the newborn (PPHN) remained a baffling disorder, often confused with cyanotic congenital heart disease, with a very high mortality. Originally described as a condition characterized by clear lung fields and profound hypoxemia, modern diagnostic techniques and novel therapeutics have improved the outcomes of affected newborns. This paper will review the historical aspects of PPHN and enable the reader to see how far we have come but also how far we have to go in conquering this unique disorder.

Hemodynamic management of the micropreemie: When inotropes are not enough.

Managing perfusion in the micropreemie is challenging and should be guided by the patho-physiology, gestational and postnatal age of the baby, perinatal history, and the persistence of fetal shunts. The assessment should incorporate bedside tools such as blood pressure, clinical perfusion markers, and functional echocardiography. The multimodal approach to diagnose and identify the cause of hemodynamic compromise paves the way to a targeted approach to treatment. Characterizing the predominant pathophysiologic cause of low cardiac output and impaired cellular metabolism enables a more accurate use of inotropes, vasopressors, and volume support to suit a particular pathophysiologic situation.

The relationship between clinically identifiable intrapartum sentinel events and short-term outcome after therapeutic hypothermia.

OBJECTIVE: To determine the impact of intrapartum sentinel events on short-term outcome post-hypothermia. STUDY DESIGN: Records of 77 infants of 36 weeks' gestation or more, who received therapeutic hypothermia, were reviewed. Some were delivered after a clinically identifiable intrapartum sentinel event (IISE). All survivors had brain magnetic resonance imaging (MRI) at 7 to 10 days of life. The primary outcome of neonatal death related to hypoxic-ischemic encephalopathy was compared in infants born with (n = 39) or without an IISE (n = 38). MRI abnormalities were also compared. Logistic regression analysis was used to determine the variables predicting the primary outcome. RESULTS: The two groups had similar Apgar scores, initial blood pHs, and early neurologic examinations. Base deficit was more severe in the IISE group. Neonatal death and hypoxic-ischemic injury was shown on brain MRI with basal nuclei, cortical, and subcortical white matter lesions extending beyond the watershed areas in infants surviving beyond the neonatal period were more common in the IISE group (P = .014; OR 11.1; 95% CI 1.3-92.6; and P = .034; OR 4.1; 95% CI 1.1-14.9, respectively). Multivariate analysis identified IISE (P = .023; OR 12.2; 95% CI 1.4-105.8) to be independently associated with neonatal death. CONCLUSIONS: IISEs are associated with neonatal death and severe injury as shown in brain MRI, even after hypothermia.

Clinical course of symptomatic spontaneous pneumothorax in term and late preterm newborns: report from a large cohort.

The purpose of this observational study was to characterize the clinical course of newborn infants with spontaneous pneumothorax and to identify those infants who eventually required further interventions. We performed a retrospective review of newborns with symptomatic spontaneous pneumothorax, born between January 2002 and December 2007. Seventy-six infants ≥36 weeks' gestation were identified with symptomatic spontaneous pneumothorax. Twenty-two (29%) of the 76 infants with spontaneous pneumothorax required either thoracentesis or/and thoracostomy drainage, and 54 (71%) were managed without such intervention. In all, 18 (24%) infants received mechanical ventilation and 12 (16%) infants developed persistent pulmonary hypertension (PPHN) during the course of illness. Ten of the 22 infants requiring thoracentesis and/or thoracostomy for progressively worsening respiratory distress developed PPHN. Seven of these 10 infants with PPHN received inhaled nitric oxide, and four infants subsequently required extracorporeal membrane oxygenation. In contrast, the majority of the infants (50 of 54, 93%) not requiring thoracentesis or/and thoracostomy could be managed simply with supplemental oxygen or close observation. Progressively worsening respiratory distress prompting intervention in infants with spontaneous pneumothorax may indicate presence of PPHN that needs prompt recognition and referral to tertiary-level neonatal units for escalating respiratory support.

New Pharmacologic Approaches to Bronchopulmonary Dysplasia.

Bronchopulmonary Dysplasia is the most common long-term respiratory morbidity of preterm infants, with the risk of development proportional to the degree of prematurity. While its pathophysiologic and histologic features have changed over time as neonatal demographics and respiratory therapies have evolved, it is now thought to be characterized by impaired distal lung growth and abnormal pulmonary microvascular development. Though the exact sequence of events leading to the development of BPD has not been fully elucidated and likely varies among patients, it is thought to result from inflammatory and mechanical/oxidative injury from chronic ventilatory support in fragile, premature lungs susceptible to injury from surfactant deficiency, structural abnormalities, inadequate antioxidant defenses, and a chest wall that is more compliant than the lung. In addition, non-pulmonary issues may adversely affect lung development, including systemic infections and insufficient nutrition. Once BPD has developed, its management focuses on providing adequate gas exchange while promoting optimal lung growth. Pharmacologic strategies to ameliorate or prevent BPD continue to be investigated. A variety of agents, to be reviewed henceforth, have been developed or re-purposed to target different points in the pathways that lead to BPD, including anti-inflammatories, diuretics, steroids, pulmonary vasodilators, antioxidants, and a number of molecules involved in the cell signaling cascade thought to be involved in the pathogenesis of BPD.

Medico-legal considerations in the context of neonatal encephalopathy and therapeutic hypothermia.

Neonatal encephalopathy (NE) is a significant complication of the peripartum period. It can lead to lifelong neurologic disabilities, including cerebral palsy, cognitive impairments, developmental delays, and epilepsy. Induced hypothermia is the first therapy, which has shown promise in improving the outcomes for neonates with moderate to severe NE following a presumed intrapartum insult. NE is also a frequent source of medical malpractice litigation. In this paper, we will review salient features of the American Tort System as it pertains to medical malpractice. We will discuss the obstetric medico-legal implications of therapeutic hypothermia and suggest a five-step approach to analyzing neonatal cases for causation, etiology, timing of occurrence, responsibility, and liability. We will close with three illustrative clinical cases.

Assessment of neonatal perfusion.

Disorders of perfusion in newborn infants are frequently observed in neonatal intensive care units. The current assessment practices are primarily based on clinical signs. Significant technologic advances have opened new avenues for continuous assessment at the bedside. Combining these devices with functional echocardiography provides an in-depth understanding of perfusion and allows targeting therapy to the pathophysiology rather than monitoring and targeting blood pressure. This change in approach is guided by the fact that perfusion disorders can result from a number of causes and a single management approach might do more harm than good. This approach has the potential to improve long term outcomes but needs to be tested in well-designed trials.

Medico-legal implications of the fetal inflammatory response syndrome.

Babies who sustain long term neurologic injury and disability are frequent subjects in medical malpractice litigation. In the United States, the tort system enables adjudication of claims through a proscribed system. This paper will review salient elements of the tort system-duty, breach, causation, and damages- and how they apply to encephalopathic infants whose injuries are believed to be the result of fetal inflammatory response syndrome (FIRS) and/or hypoxic-ischemic damage. FIRS may confound the diagnosis of neonatal encephalopathy but may be a credible explanation for it as well. The ways in which FIRS may impact malpractice lawsuits are presented.

Systematic Reviews in Neonatal Respiratory Care: Are Some Conclusions Misleading?

An increasing amount of information is currently available in neonatal respiratory care. Systematic reviews are an important tool for clinical decision-making. The challenge is to combine studies that address a specific clinical question and have similar characteristics in terms of populations, interventions, comparators, and outcomes, so that their combined results provide a more precise estimate of the effect that can be validly extrapolated into clinical practice. The concept of heterogeneity is reviewed, emphasizing that it should be considered in a wider perspective and not just as a mere statistical test. A case is made of how well-designed studies of the neonatal respiratory literature, when equivocally combined, can provide very precise but potentially biased results. Systematic reviews in this field and others should be rigorously peer-reviewed before publication to avoid misleading readers to potentially biased conclusions.

Persistent Respiratory Distress in the Term Neonate: Genetic Surfactant Deficiency Diseases.

Respiratory distress is one of the most common clinical presentations in newborns requiring admission to a Neonatal Intensive Care Unit (NICU). Many of these infants develop respiratory distress secondary to surfactant deficiency, which causes an interstitial lung disease that can occur in both preterm and term infants. Pulmonary surfactant is a protein and lipid mixture made by type II alveolar cells, which reduces alveolar surface tension and prevents atelectasis. The etiology of surfactant deficiency in preterm infants is pulmonary immaturity and inadequate production. Term infants may develop respiratory insufficiency secondary to inadequate surfactant, either from exposure to factors that delay surfactant synthesis (such as maternal diabetes) or from dysfunctional surfactant arising from a genetic mutation. The genetics of surfactant deficiencies are very complex. Some mutations are lethal in the neonatal period, while others cause a wide range of illness severity from infancy to adulthood. Genes that have been implicated in surfactant deficiency include SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD (which encode for surfactant proteins A, B, C, and D, respectively); ABCA3 (crucial for surfactant packaging and secretion); and NKX2 (a transcription factor that regulates the expression of the surfactant proteins in lung tissue). This article discusses the interplay between the genotypes and phenotypes of newborns with surfactant deficiency to assist clinicians in determining which patients warrant a genetic evaluation.

A randomized controlled trial of post-extubation bubble continuous positive airway pressure versus Infant Flow Driver continuous positive airway pressure in preterm infants with respiratory distress syndrome.

OBJECTIVE: To compare the efficacy and safety of bubble continuous positive airway pressure (CPAP) and Infant Flow Driver (IFD) CPAP for the post-extubation management of preterm infants with respiratory distress syndrome (RDS). STUDY DESIGN: A total of 140 preterm infants at 24 to 29 weeks' gestation or with a birth weight of 600 to 1500 g who were ventilated at birth for RDS were randomized to receive either IFD CPAP (a variable-flow device) or bubble CPAP (a continuous-flow device). A standardized protocol was used for extubation and CPAP. No crossover was allowed. The primary outcome was successful extubation maintained for at least 72 hours. Secondary outcomes included successful extubation maintained for 7 days, total duration of CPAP support, chronic lung disease, and complications of prematurity. RESULTS: Seventy-one infants were randomized to bubble CPAP, and 69 were randomized to IFD CPAP. Mean gestational age and birth weight were similar in the 2 groups, as were the proportions of infants who achieved successful extubation for 72 hours and for 7 days. However, the median duration of CPAP support was 50% shorter in the infants on bubble CPAP. Moreover, in the subset of infants who were ventilated for less than 14 days, the infants on bubble CPAP had a significantly lower extubation failure rate. There was no difference in the incidence of chronic lung disease or other complications between the 2 study groups. CONCLUSIONS: Bubble CPAP is as effective as IFD CPAP in the post-extubation management of infants with RDS; however, in infants ventilated for < or = 14 days, bubble CPAP is associated with a significantly higher rate of successful extubation. Bubble CPAP also is associated with a significantly reduced duration of CPAP support.

Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates.

OBJECTIVE: To document neonatal exposures to the potentially harmful pharmaceutical excipients benzyl alcohol (BA) and propylene glycol (PG) present in parenteral medications routinely administered in the intensive care unit. DESIGN: Retrospective, observational study. SETTING: Neonatal and pediatric intensive care units of a tertiary care, university hospital. PATIENTS: Randomly selected sample of 170 episodes of exposure to parenteral medications containing BA (n = 88) or PG (n = 82). MEASUREMENTS: We identified all medication sources of BA or PG administered to study neonates during hospitalization, and calculated cumulative doses (mg/kg/day and mg/day) of BA or PG received as a result of exposure to those medications. MAIN RESULTS: We observed a wide range in the cumulative excipient dose received by neonates. Median (range) cumulative dose was 4.5 mg/kg/day (0.6-319.5 mg/kg/day) for BA, and 204.9 mg/kg/day (17.3-9472.7 mg/kg/day) for PG. Patients who received medications via continuous infusion received significantly higher excipient doses than patients who received medications intermittently (p < 0.0001). In this subset of patients, median cumulative excipient doses (BA, 106.3 mg/kg/day and PG, 4554.5 mg/kg/day) were approximately 21 and 180 times the acceptable daily intakes of BA and PG (5 and 25 mg/kg/day), respectively, and exceeded the doses above which toxicity has been reported in infants. No significant correlation between duration of medication administration and cumulative excipient exposure was identified for BA or PG. Midazolam and lorazepam were involved in over two-thirds of BA and PG exposures, respectively. CONCLUSIONS: Critically ill neonates, especially those receiving medications by continuous infusion, are at risk of being exposed to BA and PG at potentially toxic doses during routine medication administration. Given the serious adverse reactions known to be associated with BA and PG, future studies are warranted to determine the clinical consequences associated with this degree of excipient exposure.

Surfactant replacement therapy in the neonate: beyond respiratory distress syndrome.

Surfactant-replacement therapy is a life-saving treatment for preterm infants with respiratory distress syndrome, a disorder characterized by surfactant deficiency. Repletion with exogenous surfactant decreases mortality and thoracic air leaks and is a standard practice in the developed world. In addition to respiratory distress syndrome, other neonatal respiratory disorders are characterized by surfactant deficiency, which may result from decreased synthesis or inactivation. Two of these disorders, meconium aspiration syndrome and bronchopulmonary dysplasia, might also be amenable to surfactant-replacement therapy. This paper discusses the use of surfactant-replacement therapy beyond respiratory distress syndrome and examines the evidence to date.

Mechanical ventilation of the neonate: should we target volume or pressure?

For more than 40 years conventional mechanical ventilation has been used for the treatment of neonatal respiratory failure. Until relatively recently, this was accomplished with time-cycled pressure-limited ventilation, using intermittent mandatory ventilation. Earlier attempts at volume-targeted ventilation were largely ineffective because of technological limitations. The advent of microprocessor-based devices gives the clinician an option to choose either target variable to treat neonatal patients. This paper reviews the principles of each and the accumulated evidence.

Severe intraventricular hemorrhage in preterm infants: comparison of risk factors and short-term neonatal morbidities between grade 3 and grade 4 intraventricular hemorrhage.

Grade 3 intraventricular hemorrhage (IVH) (without parenchymal involvement) and grade 4 IVH (with parenchymal involvement) are often combined into description of a single entity, usually "severe" IVH, despite different long-term neurodevelopmental outcome. Although risk factors for severe IVH have already been well described, it is not known if these risk factors and associated short-term neonatal morbidities are different for grade 3 and grade 4 IVH, and indeed, this clustering of grade 3 and grade 4 IVH into severe IVH precludes further delineation of the potential risk and protective factors that can be altered to reduce the incidence of grade 4 IVH, which is presumably associated with worse outcome compared with grade 3 IVH. We sought to characterize and compare commonly cited risk factors and associated short-term neonatal morbidities between grade 3 and grade 4 IVH in very low-birth-weight (VLBW) infants. We performed a retrospective review of VLBW (birth weight < 1500 g) infants with severe IVH born between January 2001 and March 2007. Fifty-nine (10.5%) of 562 infants surviving beyond 3 days of age had severe IVH as recorded on routine cranial sonography during the first 7 to 10 days of life, 28 had grade 3, and 31 had grade 4 IVH. Infants with grade 4 IVH were younger [gestational age (weeks), grade 4 IVH versus grade 3 IVH: 25.5 +/- 1.7 versus 26.7 +/- 1.7, p = 0.02) and weighed less at birth [birth weight (g), grade 4 IVH versus grade 3 IVH: 860 +/- 214 versus 1007 +/- 253, p = 0.03) compared with infants with grade 3 IVH. Other commonly cited clinical factors that alter the risk for severe IVH, including mode of delivery, pregnancy-induced hypertension, premature and/or prolonged rupture of membranes, maternal fever, maternal bleeding, prenatal steroid administration, maternal magnesium sulfate therapy, 1-minute and 5-minute Apgar scores, need for delivery room resuscitation (epinephrine and chest compressions), surfactant therapy, presence of refractory hypotension, evidence of early onset culture-proven sepsis, use of high-frequency ventilation, presence of pneumothorax, and hemodynamically significant patent ductus arteriosus, were similar between infants with grade 3 and grade 4 IVH. Carbon dioxide tensions (minimum PaC (2), maximum PaCO(2), mean PaCO(2), standard deviation of PaCO(2), and coefficient of variation of PaCO (2)) in infants receiving mechanical ventilation during first 3 postnatal days were also not statistically dissimilar. To determine the variables differentiating grade 3 from grade 4 IVH in the study population, logistic regression analysis confirmed only the independent association of gestational age (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.5 to 0.9, P = 0.012) and maternal magnesium sulfate therapy (OR 0.3, 95% CI 0.07 to 0.9, P = 0.04) with the development of grade 4 IVH. Short-term neonatal morbidities were also similar between infants with grade 3 and grade 4 IVH. Among VLBW infants, the risk of a grade 4 versus grade 3 IVH increases with declining gestational age, but does not appear to be related to other commonly cited clinical factors. This information may be useful for prognostication and may improve the quality of parental counseling.

Pulmonary dysfunction and therapeutic hypothermia in asphyxiated newborns: whole body versus selective head cooling.

Compared with whole body cooling (WBC), selective head cooling (SHC) of asphyxiated newborns presumably allows effective brain cooling with less systemic hypothermia and potentially fewer systemic adverse effects. It is not known if pulmonary dysfunction, one of the potential adverse systemic effects of therapeutic hypothermic neuroprotection, differs with the method of cooling. We sought to investigate if pulmonary mechanics and gas exchange during therapeutic hypothermia differ between WBC and SHC. The severity of pulmonary dysfunction was determined in 59 asphyxiated newborns receiving therapeutic hypothermic neuroprotection by either SHC ( N = 31) or WBC ( N = 28). Ventilatory parameters and simultaneous alveolar-arterial oxygen gradient (A-a DO (2)) and partial pressure of carbon dioxide, arterial (PaCO (2)) were measured before the start of cooling (baseline), and at 4, 8, 12, 24, 48, and 72 hours of cooling. The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was established by echocardiography. Clinical monitoring and treatment during cooling, whether SHC or WBC, were similar. All (96%) but two infants (from the SHC group) required mechanical ventilation of varying duration during cooling, and nine infants (15%) developed PPHN. The baseline ventilator pressures requirement, and A-a DO (2) were similar among the 48 ventilated infants without PPHN (WBC 23, SHC 25) at the start of cooling. Ventilatory requirements remained modest and did not differ with the method of cooling. Similar numbers of infants without PPHN were able to be extubated after improvement in respiratory status while being cooled (WBC 42.8% versus SHC 37.9%, P = 0.79, odds ratio [OR] 1.2, 95% confidence interval [CI] 0.4 to 3.5). Nine infants (WBC 5, SHC 4) developed PPHN. Six of the nine (WBC 4, SHC 2) required inhaled nitric oxide therapy, and one infant from the WBC group subsequently required extracorporeal membrane oxygenation. The incidence of PPHN was similar in both the WBC and SHC groups (17.8% versus 12.9%, P = 0.72, OR 1.5, 95% CI 0.3 to 6.1). Pulmonary dysfunction is common but not severe in asphyxiated infants during therapeutic hypothermia. Pulmonary mechanics and gas exchange do not differ with the method of achieving hypothermia.