急性呼吸窘迫综合征机械通气策略的新进展

急性呼吸窘迫综合征（ARDS）机械通气的目标是保证足够的氧合和最小的呼吸机相关肺损伤。无创机械通气应慎用于ARDS。小潮气量通气的肺保护性通气策略能降低ARDS死亡率,以驱动压为导向设置潮气量更合理。建议根据静态压力-容积曲线采用低位转折点法来确定理想的呼气末正压（PEEP）,不支持常规使用高水平PEEP。俯卧位通气、高频振荡通气和体外膜氧合技术可用于拯救重症ARDS。机械通气中保持ARDS患者自主呼吸很重要,可采用双相气道正压通气、压力支持通气和神经电活动辅助通气等辅助通气模式。不推荐补充外源性肺泡表面活性物质、吸入一氧化氮或支气管扩张剂、气道压力释放通气和部分液体通气。     

Ventilation in special situations. Mechanical ventilation in acute respiratory distress syndrome/acute pulmonary lesion

Acute respiratory distress syndrome (ARDS), which was first described by Ashbaugh in 1967, consists of acute hypoxemic respiratory failure (PaO2/FiO2< or =200) associated with bilateral infiltrates on the chest radiograph caused by noncardiac diffuse pulmonary edema. Although ARDS is of multiple etiology, pulmonary or extrapulmonary injury can produce systemic inflammatory response that perpetuates lung disturbances once the initial cause has been eliminated. Most patients with ARDS require mechanical ventilation. Currently, the old standard is conventional ventilation optimized to protect against ventilator-associated lung injury. Other mechanical ventilation strategies such as high-frequency oscillatory ventilation, which is also based on alveolar recruitment and adequate lung volume, can be useful alternatives. In this review, the level of evidence for other therapies, such as prone positioning, nitric oxide and prostacyclin inhalation, exogenous surfactant, and extracorporeal vital support techniques are also analyzed.     

Approaches in the management of acute respiratory failure in children

PURPOSE OF REVIEW: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are conditions that are associated with significant morbidity and mortality in children. There have been no advances in preventing ARDS, but this review highlights strategies directed at minimizing ventilator-induced lung injury and other new adjunctive therapies in the care of these patients. RECENT FINDINGS: High-frequency oscillatory ventilation, airway pressure release ventilation, and partial liquid ventilation are potential protective ventilatory modes for children with ALI or ARDS. Recruitment maneuvers, prone positioning, and kinetic therapy are all reported to improve oxygenation by opening the lung while positive end-expiratory pressure maintains functional residual capacity. Inhaled nitric oxide and surfactant are used to reduce inspired oxygen concentration and facilitate gas exchange, but their efficacy in ARDS continues to be investigated. Also, early investigations suggest that a specialized enteral formula can be a useful adjunctive therapy by reducing lung inflammation and improving oxygenation. When mechanical ventilation and adjunctive therapies fail, extracorporeal life support continues to be used as a rescue therapy. SUMMARY: It is likely that a combination of these therapies will maximize treatment and clinical outcomes in the future, but the only way that will be proven is through large controlled clinical trials in pediatric patients.     

Acute lung injury: pathophysiology, assessment and current therapy

Acute respiratory distress syndrome (ARDS) is a clinically defined entity describing the severity of diffuse alveolar injury caused by direct or indirect injury to the lung. Pathophysiology, clinical course and outcome of ARDS depend on the underlying cause, the severity of the disease and co-morbidities. Pulmonary function tests show restrictive lung disease, which is characterised by a reduction in lung compliance and functional residual capacity, resulting in marked ventilation-perfusion inequality. Current ventilator strategies aim to minimise ventilator-induced lung injury by targeting mechanical ventilation between the lower and upper inflection point of the pressure volume curve. This includes recruitment manoeuvres and the use of high PEEP to open the atelectatic lung and the use of permissive hypercapnia and the limitation of peak inspiratory pressure below 35 cm H2O to avoid overinflation. The clinical benefit of newer modes of ventilatory support such as inverse ratio ventilation, high frequency oscillatory ventilation, surfactant replacement, prone positioning and inhaled nitric oxide has yet to be determined in children.     

Recent developments in inhaled nitric oxide therapy of the newborn

Inhaled nitric oxide therapy improves oxygenation and reduces the need for extracorporeal life support in near-term and term newborns with hypoxemic respiratory failure and persistent pulmonary hypertension of the newborn. Previous studies demonstrated that the efficacy of inhaled nitric oxide therapy is related to the underlying disease associated with persistent pulmonary hypertension and that lung recruitment strategies augment the response to this inhalational vasodilator. This review of recent studies evaluates new insight into important questions regarding the optimal dose of inhaled nitric oxide, potential adverse effects associated with inhaled nitric oxide therapy, and the potential role of inhaled nitric oxide in the premature newborn with hypoxemic respiratory failure.     

Adjunct pharmacotherapy in acute lung disease in children

Mechanical ventilation, while accepted as standard therapy for critically ill infants and children with respiratory failure, has significant morbidity and mortality. While recent emphasis on low tidal volume ventilation and low airway pressures may result in decreased lung stretch and limit lung disease, adjunctive therapies have been tried to reduce the stressors of mechanical ventilation. Therapies included inhaled nitric oxide, heliox and surfactant. There are compelling physiological reasons why these drugs may be of benefit in these patients. However, our understanding of their role is hindered by studies with small numbers of patients and its use in diseases with varied pulmonary pathology. Studies have shown potential for benefit of inhaled nitric oxide in newborns with hypoxemic respiratory failure and pulmonary hypertension, surfactant in respiratory distress syndrome in preterm neonates and heliox in severe upper airway obstruction. However, the use in other respiratory conditions has led to mixed results and hence paucity of firm recommendations.     

Inhaled nitric oxide therapy for acute respiratory distress syndrome in children

The aim of this study was to evaluate the effects of inhaled nitric oxide (iNO) therapy on oxygenation and mortality in children with acute respiratory distress syndrome (ARDS). Thirty-three children with ARDS and an arterial SatO2 <88% despite mechanical ventilation were analyzed. Patients in the iNO group were prospectively enrolled and treated with conventional therapy plus iNO. The control group consisted of retrospectively analyzed patients treated only with conventional therapy. A significant increase in PaO2/FiO2 ratio (25.6%) and decrease in oxygenation index (19.5%) was observed after 4 h of iNO treatment, when compared to baseline values. A positive response to iNO was detected in 69% of patients, and there was no difference between pulmonary and extrapulmonary ARDS. There was no difference in mortality and duration of mechanical ventilation between iNO and control group.     

Current concepts in adult respiratory distress syndrome in children

Acute respiratory distress syndrome (ARDS) is an acute form of severe alveolar-capillary injury that evolves after a direct or indirect lung insult. It begins as noncardiogenic pulmonary edema and develops into a neutrophilic alveolitis, and, later, pulmonary fibrosis. Mortality remains high among children with ARDS, particularly when serious underlying conditions co-exist, sepsis occurs, and when there is multi-organ failure. Lung function improves with time among survivors, but pulmonary fibrosis may persist. Advances in the care of children with ARDS include the use of lung-protective ventilator strategies, permissive hypercapnia, inhaled nitric oxide, high-frequency ventilation, and extra-corporeal life support. These approaches reduce ventilator-associated lung injury and may improve survival when used in combination with one another. Interventions that reduce alveolar inflammation, enhance alveolar fluid removal, and reduce pulmonary fibrosis will further improve survival and recovery from ARDS in the future.     

Life-threatening effects of discontinuing inhaled nitric oxide in children

We treated 40 children, aged between 15 d and 17 y, diagnosed with acute respiratory distress syndrome and/ or pulmonary hypertension, with inhaled nitric oxide. The most frequent underlying diagnosis associated with ARDS were bronchopneumonia (eight), cardiac surgery (five), and sepsis (three). Pulmonary hypertension was secondary to cardiomyopathy in 2 patients and occurred in the postoperative period of cardiac surgery in 17 patients–the most frequent were ventricular septal defect (5), transposition of great arteries (4), and atrioventricular septal defect (3). In 11 patients, sudden discontinuation of nitric oxide induced a decrease in oxygenation associated in some of the patients with an increase in pulmonary artery pressure. In two patients discontinuation of nitric oxide induced severe pulmonary hypertension, extreme bradycardia and hypoxaemia, which required cardiopulmonary resuscitation. When exogenous nitric oxide is abruptly interrupted, hypoxaemia and pulmonary hypertension are found in some patients, due to a decrease in the nitric oxide concentration in the pulmonary circulation. This may be caused by the exogenous nitric oxide administration that may have inhibited endogenous production. We recommend making a progressive withdrawal of inhaled nitric oxide to avoid the side effects observed in the sudden discontinuation.     

儿童急性呼吸窘迫综合征的治疗进展

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that lacks definitive treatment. The cornerstone of management is sound intensive care treatment and early anticipatory ventilation support. A mechanical ventilation strategy aiming at optimal alveolar recruitment, judicious use of positive end-respiratory pressure (PEEP) and low tidal volumes (VT) remains the mainstay for managing this lung disease. Several treatments have been proposed in rescue settings, but confirmation is needed from large controlled clinical trials before they be recommended for routine care. Non-invasive ventilation (NIV) is suggested with a cautious approach and a strict selection of candidates for treatment. Mild and moderate cases can be efficiently treated by NIV, but this is contra-indicated with severe ARDS. The extra-corporeal carbon dioxide removal (ECCO₂R), used as an integrated tool with conventional ventilation, is playing a new role in adjusting respiratory acidosis and CO₂. The proposed benefits of ECCO₂R over extra-corporeal membrane oxygenation (ECMO) consist in a reduction of artificial surface contact, avoidance of pump-related side effects and technical complications, as well as lower costs. The advantages and disadvantages of inhaled nitric oxide (iNO) are better recognized today and iNO is not recommended for ARDS and acute lung injury (ALI) in children and adults because iNO results in a transient improvement in oxygenation but does not reduce mortality, and may be harmful. Several trials have found no clinical benefit from various surfactant supplementation methods in adult patients with ARDS. However, studies which are still controversial have shown that surfactant supplementation can improve oxygenation and decrease mortality in pediatric and adolescent patients in specific conditions and, when applied in different modes and doses, also in neonatal respiratory distress syndrome (RDS) of preemies. Management of ARDS remains supportive, aimed at improving gas exchange and preventing complications. Progress in the treatment of ARDS must be addressed toward the new paradigm of the disease pathobiology to be applied to the disease definition and to predict the treatment outcome, also with the perspective to develop predictive and personalized medicine that highlights new and challenging opportunities in terms of benefit for patient''s safety and doctor''s responsibility, with further medico-legal implication.     

Uncertainties about the use of inhaled nitric oxide in preterm infants

Respiratory failure in the premature neonate is frequently complicated by pulmonary hypertension. When conventional therapies including administration of exogenous surfactant, conventional mechanical ventilation or high-frequency oscillatory ventilation using an appropriate high-volume strategy have failed, one should assess the pulmonary circulation status with colour-coded Doppler echocardiography. There is now considerable evidence that the regulation of foetal and postnatal pulmonary circulation occurs via nitric oxide (NO), and that persistent pulmonary hypertension of the neonate may be related to a relative deficiency in NO release. Low-dose (10–20 ppm), short-duration (1–2 d) inhaled NO has generally been shown to improve the oxygenation and relieve pulmonary hypertension in premature neonates with severely hypoxaemic respiratory failure. Whether this therapy (eventually prolonged >1-3 wk?) would improve survival and lessen morbidity (e.g. intracranial haemorrhage and chronic lung disease) remains to be proven by appropriately designed controlled trials. Until these issues can be clarified, NO therapy for premature neonates should be still considered as an experimental drug, and its use restricted to clinical studies.     

Uncertainties about the use of inhaled nitric oxide in preterm infants

Respiratory failure in the premature neonate is frequently complicated by pulmonary hypertension. When conventional therapies including administration of exogenous surfactant, conventional mechanical ventilation or high-frequency oscillatory ventilation using an appropriate high-volume strategy have failed, one should assess the pulmonary circulation status with colour-coded Doppler echocardiography. There is now considerable evidence that the regulation of foetal and postnatal pulmonary circulation occurs via nitric oxide (NO), and that persistent pulmonary hypertension of the neonate may be related to a relative deficiency in NO release. Low-dose (10-20 ppm), short-duration (1-2 d) inhaled NO has generally been shown to improve the oxygenation and relieve pulmonary hypertension in premature neonates with severely hypoxaemic respiratory failure. Whether this therapy (eventually prolonged >1-3 wk?) would improve survival and lessen morbidity (e.g. intracranial haemorrhage and chronic lung disease) remains to be proven by appropriately designed controlled trials. Until these issues can be clarified, NO therapy for premature neonates should be still considered as an experimental drug, and its use restricted to clinical studies.     

Respiratory failure: current status of experimental therapies.

A number of advances in the treatment of infants and children with respiratory failure have been investigated in the laboratory with translation to clinical practice. Investigators have recognized that application of high ventilating pressures and failure to apply adequate levels of positive end-expiratory pressure (PEEP) can inflict injury to the already failing lung. Other interventions such as prone positioning and application of new ventilating strategies such as proportional assist ventilation (PAV), inverse ratio ventilation (IRV), high frequency ventilation, liquid ventilation, and intratracheal pulmonary ventilation (ITPV), continue to be developed and explored. Administration of inhaled nitric oxide (iNO) may improve pulmonary physiology and gas exchange in patients with respiratory insufficiency. Finally, the technique of extracorporeal life support (ECLS) is being simplified and refined. This report summarizes the status of these advances and describes the basic science and clinical research that brought them to clinical application.     

Neonatal acute respiratory failure

Acute respiratory failure is the most common problem seen in the preterm and term infants admitted to neonatal intensive care units. In preterm infants, the most common cause of acute respiratory failure is respiratory distress syndrome caused by surfactant deficiency. Acute respiratory failure in term and near term infants is usually a result of meconium aspiration syndrome, sepsis, pulmonary hypoplasia, and primary pulmonary hypertension of the newborn. The response to various methods of treatment may vary, depending on the severity of respiratory failure and the cause of the acute respiratory failure. We reviewed the evidence for efficacy and current utilization of newer treatment modalities, including exogenous surfactant administration, high frequency ventilation, inhaled nitric oxide therapy, antenatal steroids for the prevention of respiratory distress syndrome, and use of postnatal steroids for the prevention of chronic lung disease.     

新生儿急性呼吸窘迫综合征研究进展

新生儿急性呼吸窘迫综合征（ARDS）是新生儿常见的临床危重症,是新生儿致死、致残的主要原因之一。新生儿ARDS病因及发病机制复杂,与各种病理因素导致的继发性肺表面活性物质（PS）缺乏有关,具有炎症性特点。新生儿ARDS作为一种临床综合征,与其他疾病难以鉴别。该病的治疗目前缺乏特效手段,仍是以呼吸支持、PS替代、体外膜肺氧合治疗、营养支持及液体管理等对症及综合治疗为主。该文就新生儿ARDS的病因分类、临床特点、诊断治疗策略等方面的研究进展做一综述。     

Neonatal ECMO: Current controversies and trends

Extracorporeal membrane oxygenation (ECMO), a technique for providing life support to patients with cardiac and/or respiratory dysfunction, allows the heart and lungs to "rest." The neonatal respiratory population has been a major benefactor of ECMO since 1982. Its use for neonatal respiratory disease increased dramatically until the past few years, when the number of neonatal respiratory ECMO cases began a downward trend. Fewer patients with persistent pulmonary hypertension of the newborn (PPHN), meconium aspiration syndrome, respiratory distress syndrome, or sepsis are requiring ECMO support as frequently as in the past. Many attribute this decline to the newer respiratory therapies-mainly, surfactant, high-frequency oscillatory ventilation, and inhaled nitric oxide. Neonates who continue to require ECMO today are sicker than the historic norm and have more complicated and lengthy ECMO runs. Patients with congenital diaphragmatic hernia, PPHN, and sepsis remain the most consistent in their representation among ECMO recipients within this author's institution, suggesting that the newer respiratory therapies have not had the same impact on these patients' needs for ECMO support. Better guidelines for determining which patients would benefit from earlier inititation of ECMO are needed.     

Treatment of persistent pulmonary hypertension of the newborn

OBJECTIVE: To review the medical literature, emphasizing the new scientific advances in the treatment of persistent pulmonary hypertension of the newborn. SOURCES: Literature review using Medline and Cochrane library. SUMMARY OF THE FINDINGS: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by an increase in pulmonary vascular resistance associated with right to left shunt through the foramen ovale or ductus arteriosus, leading to marked hypoxemia and respiratory failure. The balance between the vasoconstrictor (endothelin) and vasodilator (nitric oxide and prostaglandin I2) mediators plays an important role in the regulation of the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance. In addition to general management, cardiovascular support, the treatment of the cause of the PPHN, and the use of selective pulmonary vasodilator such as inhaled nitric oxide (iNO) are indicated. Furthermore, the combined therapy with iNO and high-frequency oscillatory ventilation significantly improved the oxygenation of patients who were refractory to iNO therapy and conventional ventilation. The practice of hyperventilation and the administration of nonspecific pulmonary vasodilators (tolazoline) should be avoided. On the other hand, the administration of surfactant to patients with PPHN due to meconium aspiration should be considered. However, if all these therapies fail, extracorporeal membrane oxygenation (ECMO) should be considered as rescue therapy. CONCLUSIONS: The mortality due to PPHN has significantly decreased with the use of new therapies, and the major concern today is the quality of life of these patients, especially in terms of neuropsychomotor development.     

Nitric oxide treatment and acute pulmonary inflammatory response in very premature infants with intractable respiratory failure shortly after birth

Aim: Premature infants with respiratory failure and early-onset pneumonia have low inducible nitric oxide synthase (NOS2) and no evidence of nitric oxide (NO) toxicity. However, inhalation of NO may not be indicated in sepsis because excessive NO generation has been reported. This prospective study was designed to test the hypothesis that inhaled NO is effective in a select group of small premature infants and that the responsiveness to NO is associated with low NOS2 enzyme. Methods: 246 very low birthweight infants (birthweight 31500 g, VLBW) were screened for severe, intractable respiratory failure (oxygenation index 340, arterial-alveolar ratio for oxygen tension 30.10) that does not respond to two doses of surfactant within 5 h from birth. Infants with severe cardiac failure or a bleeding disorder were excluded. Five of the nine eligible cases received inhaled NO. They all had prolonged rupture of foetal membranes, early-onset pneumonia and persistent pulmonary hypertension. Results: All five responded strikingly, survived and appeared normal in follow-up. Airway specimens during the first day of life revealed very low NOS2, interleukin-13 and surfactant protein A, compared with VLBW infants who had no acute infection despite histological chorioamnionitis. In early-onset pneumonia, NOS2 and other inflammatory mediators increased first during the recovery 1-2 d after birth. Conclusion: VLBW infants with progressive respiratory failure and infection at birth have deficient pulmonary NOS2 and cytokine response. After surfactant therapy, these infants responded strikingly to inhaled NO. An acute pulmonary inflammatory response may contribute to respiratory adaptation in early-onset pneumonia.     

肺泡表面活性物质对新生儿急性肺损伤氧合功能的影响

目的 研究肺泡表面活性物质（pulmonary surfactant,PS）对新生儿急性肺损伤、急性呼吸窘迫综合征氧合功能的影响.方法 纳入符合急性肺损伤、急性呼吸窘迫综合征诊断标准的新生儿98例,分为PS治疗组30例及常规治疗组68例,PS治疗组经气管插管注入PS 70 ～ 100 mg/kg,其余治疗同常规治疗组.结果 两组新生儿的性别、胎龄、出生体重、肺损伤程度差异无统计学意义;PS治疗组在急性肺损伤、急性呼吸窘迫综合征治疗后6h、12h、24 h、48 h的PaO3/FiO2、呼吸机有效指数均高于常规治疗组,而氧合指数、呼吸指数均低于常规治疗组,差异有统计学意义（P＜0.05）;PS治疗组在急性肺损伤、急性呼吸窘迫综合征治疗后机械通气时间[（66±13）h、（82 ±26）h]和用氧时间[（86±13）h、（103±25）h）]均较常规治疗组[（80 ±18）h、（101 ±36）h和（104±16）h、（125 ±29） h]缩短,差异有统计学意义（P＜0.05）.结论 应用PS治疗新生儿急性肺损伤、急性呼吸窘迫综合征可改善肺顺应性及氧合功能,缩短机械通气及氧疗时间,有利于改善预后.