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.

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 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.

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.

Bronchopulmonary dysplasia: Myths of pharmacologic management.

Bronchopulmonary dysplasia (BPD) is the leading cause of long-term respiratory morbidity in newborns who require respiratory support at birth. BPD is a multifactorial disorder, and infants are frequently subjected to treatment with multiple pharmacologic agents of dubious efficacy and questionable safety, including diuretics, bronchodilators, corticosteroids, anti-reflux medications, and pulmonary vasodilators. These agents, with narrow therapeutic indices, are widely used despite the lack of an evidence base, and some may do more harm than good. It is incumbent on the clinician to establish a risk:benefit ratio and to avoid drugs that have little efficacy and a high rate of toxicity.

Pulmonary diagnostics.

Term infants with respiratory distress may have extremely varied etiologies of their illnesses. These range from anatomical malformations to infectious or inflammatory conditions to genetic, metabolic, or neurological abnormalities. This article reviews the present array of diagnostic studies available to the clinician, including the physical examination, imaging (radiography, computed tomography, magnetic resonance imaging, ultrasound, and nuclear scanning techniques), lung mechanics and function testing, evaluation of gas exchange (blood gases, pulse oximetry, transcutaneous monitoring, and end-tidal carbon monoxide measurements), and anatomical studies (bronchoscopy and lung biopsy). These tests and procedures are reviewed and a stepwise approach recommended.

Congenital chylothorax.

Congenital chylothorax (CC) results from multiple lymphatic vessel anomalies or thoracic cavity defects and may accompany other congenital anomalies. Fetal chylothorax may increase the risk of death and complications from pleural space lymphatic fluid accumulation, which compromises lung development, pulmonary, and cardiovascular function and from complications arising from the loss of drained lymphatic contents. Prenatal interventions might improve survival in severe cases of fetal chylothorax. The neonatal treatment strategy is generally supportive with interventions that include thoracostomy drainage and attempts to decrease chyle flow using a stepwise approach that begins with the least invasive means. Evidence-based treatment choices are lacking and are much needed. Most cases of CC resolve with time even without specific lymphatic system studies to identify the exact pathology. Expertise in performing lymphatic studies is not universally available. Data on both efficacy and safety of the various therapeutic options are needed to determine the best approach to the treatment of CC.

Surfactant-associated proteins: structure, function and clinical implications.

Surfactant replacement therapy is now the standard of care for infants with respiratory distress syndrome. As the understanding of surfactant structure and function has evolved, surfactant-associated proteins are now understood to be essential components of pulmonary surfactant. Their structural and functional diversity detail the complexity of their contributions to normal pulmonary physiology, and deficiency states result in significant pathology. Engineering synthetic surfactant protein constructs has been a major research focus for replacement therapies. This review highlights what is known about surfactant proteins and how this knowledge is pivotal for future advancements in treating respiratory distress syndrome as well as other pulmonary diseases characterized by surfactant deficiency or inactivation.

Sildenafil for pulmonary hypertension complicating bronchopulmonary dysplasia.

Sildenafil, a phospohodiesterase-5 inhibitor, is widely used to treat pulmonary hypertension in infants with bronchopulmonary dysplasia despite a lack of evidence to support either safety or efficacy and US FDA advice against its use.

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.

Ventilatory management and bronchopulmonary dysplasia in preterm infants.

Improvements in antenatal and neonatal care have resulted in increased survival of very preterm infants. However, the incidence of bronchopulmonary dysplasia (BPD) has not changed, probably as a consequence of a demographic shift. The underlying pathophysiology of BPD appears to differ for the current population of preterm infants compared to that described by Northway et al., and management strategies should be targeted to limit ventilator-induced lung injury. Non-invasive respiratory support techniques are currently under evaluation, but results of the trials have thus far failed to show a reduction in BPD. This review will focus upon various ventilation modalities for preventing and managing bronchopulmonary dysplasia.

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.

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.

Newer forms of conventional ventilation for preterm newborns.

Although life saving, mechanical ventilation can cause complications such as ventilator-induced lung injury and bronchopulmonary dysplasia in very preterm babies. The ventilator-induced lung injury is multi-factorial. There has been an introduction of a number of newer forms of mechanical ventilation, which are aimed to reduce such complications. These are based on sound physiologic principles and clinicians should familiarize themselves with these advances.

Matching ventilatory support strategies to respiratory pathophysiology.

Neonates can suffer from various diseases that impact differently on lung function according to the specific pulmonary pathophysiology. As a consequence, the optimal respiratory support will vary according to disorder. Most randomized trials have only included prematurely born infants who have respiratory distress syndrome (RDS) or infants who have severe respiratory failure. Meta-analysis of the results has demonstrated that for the prematurely born infant who has RDS, prophylactic high-frequency oscillatory ventilation only results in a modest reduction in bronchopulmonary dysplasia, and patient-triggered ventilation (assist/control or synchronized intermittent mandatory ventilation) reduces the duration of ventilation if started in the recovery phase. Whether the newer triggered modes are more efficacious remains to be appropriately tested. In term infants who have severe respiratory failure, extracorporeal membrane oxygenation increases survival, but inhaled nitric oxide only reduces the need for extracorporeal membrane oxygenation. Research is required to identify the optimum respiratory strategy for infants who have other respiratory disorders, particularly bronchopulmonary dysplasia.

Lucinactant: a novel synthetic surfactant for the treatment of respiratory distress syndrome.

Lucinactant (Surfaxin, Discovery Laboratories) is a synthetic surfactant, which contains the novel peptide, sinapultide, a surfactant-associated protein B mimic. Randomised clinical trials suggest that this compound is a safe and effective treatment for respiratory distress syndrome in preterm infants. It is also being actively investigated for other indications, including meconium aspiration syndrome, treatment of bronchopulmonary dysplasia in neonates, acute respiratory distress syndrome and asthma. A novel aerosol formulation administered with nasal continuous positive airway pressure is also under development for treatment of respiratory insufficiency in neonates. Its non-animal origin may make it an attractive alternative to present animal-derived surfactants by eliminating the risks of infection and immunogenicity related to the latter.

Severe neutrophilia in an infant with persistent pulmonary hypertension of the newborn.

We report the case of a term male infant with severe persistent pulmonary hypertension of the newborn, who developed massive neutrophilia of unknown etiology. An extensive evaluation failed to disclose an obvious cause for his neutrophilia. A bone marrow aspirate was performed and was consistent with a leukemoid reaction. This paper reviews the neonatal leukemoid reaction and its significance.

Can mechanical ventilation strategies reduce chronic lung disease?

Chronic lung disease (CLD) continues to be a significant complication in newborn infants undergoing mechanical ventilation for respiratory failure. Although the aetiology of CLD is multifactorial, specific factors related to mechanical ventilation, including barotrauma, volutrauma and atelectrauma, have been implicated as important aetiologic mechanisms. This article discusses the ways in which these factors might be manipulated by various mechanical ventilatory strategies to reduce ventilator-induced lung injury. These include continuous positive airway pressure, permissive hypercapnia, patient-triggered ventilation, volume-targeted ventilation, proportional assist ventilation, high-frequency ventilation and real-time monitoring.

Mechanisms of ventilator-induced lung injury in premature infants.

Mechanical ventilation in premature infants may injure the lungs or exacerbate the pre-existing condition that led to the need for mechanical ventilation. Ventilator-induced lung injury (VILI) may be associated with alveolar structural damage, pulmonary oedema, inflammation, and fibrosis. This injury is not uniform and is associated with surfactant dysfunction. Recovery from VILI includes clearance of pulmonary oedema and alveolar structural repair. Mechanisms of VILI include high airway pressure (barotrauma), large gas volumes (volutrauma), alveolar collapse and re-expansion (atelectotrauma), and increased inflammation (biotrauma). Injury to the lung may lead to other organ dysfunction. The premature lung is more susceptible to VILI, and lung injury may exacerbate the disturbance of lung development that occurs after birth. Therapies targeting specific processes in lung injury, and which complement the protective ventilator management strategies to avoid atelectotrauma and lung overdistension are an area of active research.