Genetic basis of apnoea of prematurity and caffeine treatment response: role of adenosine receptor polymorphisms: genetic basis of apnoea of prematurity

Aim: Caffeine treatment reduces the frequency of apnoea of prematurity (AOP) and eliminates the need for mechanical ventilation by acting as a nonspecific inhibitor of adenosine A1 and adenosine 2A receptors. Patients with AOP have demonstrated variant responses to caffeine therapy. We proposed to investigate the role of A1 and 2A polymorphisms in the development of AOP and individual differences in caffeine response. Secondly, we aimed to determine whether these polymorphisms have any effect on bronchopulmonary dysplasia (BPD) development. Methods: Cord blood samples were collected from infants born with gestational ages between 24 and 34 weeks. Two groups were defined: patients without apnoea (n = 60) and patients with apnoea (n = 55). Patients with apnoea were divided into two subgroups: a caffeine‐responsive group (n = 30) and an unresponsive group (n = 25). Six single‐nucleotide polymorphisms were chosen for genotyping. Results: Patients with apnoea over 28 weeks of gestational age who responded to the caffeine treatment were found to carry the rs16851030 C/C genotype rather than the C/T or T/T genotype. Logistic regression analysis showed a significant correlation between rs35320474‐C/T and T/T genotypes and apnoea and BPD development. Conclusion: Our results indicate a role for adenosine receptor gene polymorphisms in susceptibility to AOP and BPD and in interindividual variability to caffeine response.     

早产儿呼吸暂停诊治进展

新生儿原发性呼吸暂停最主要的原因是早产,即早产儿呼吸暂停(AOP),也是目前新生儿重症监护中面临的主要临床问题之一。AOP的发病机制仍不清楚,目前多倾向于与早产儿呼吸中枢发育尚不完善有关,对低氧、高碳酸血症的呼吸反应不成熟,肺牵张反射过度抑制以及中枢神经介质在AOP的发生发展中起重要作用。而某些中枢神经系统和感染性疾病及早产儿行为状态可能诱发或加重呼吸暂停的发生。俯卧位、甲基黄嘌呤类药物和持续气道正压通气(CPAP)是治疗AOP的主要方法。其他治疗方法包括CO2吸入、输血以及触觉刺激等的临床应用仍需进一步研究。文章就新生儿呼吸暂停的发病机制以及治疗策略的最新研究进展进行综述。     

Apnea of prematurity: from cause to treatment

Apnea of prematurity (AOP) is a common problem affecting premature infants, likely secondary to a “physiologic” immaturity of respiratory control that may be exacerbated by neonatal disease. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of AOP includes prone positioning and continuous positive or nasal intermittent positive pressure ventilation to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO₂ inhalation, require further study. The physiology and pathophysiology behind AOP are discussed, including the laryngeal chemoreflex and sensitivity to inhibitory neurotransmitters, as are the mechanisms by which different therapies may work and the potential long-term neurodevelopmental consequences of AOP and its treatment.     

A randomised controlled trial of two methods of delivering nasal continuous positive airway pressure after extubation to infants weighing less than 1000 g: binasal (Hudson) versus single nasal prongs

OBJECTIVES: Primary: to determine whether nasal continuous positive airway pressure (CPAP) delivered through binasal prongs results in a greater proportion of extremely low birthweight infants being successfully extubated, after a period of intermittent positive pressure ventilation, than nasal CPAP delivered by a single nasal prong. Secondary: to evaluate the effect of mode of delivery of nasal CPAP after extubation on the need for endotracheal reintubation, weight gain, rates of feeding intolerance, sepsis, suspected sepsis, cranial ultrasound abnormalities, retinopathy of prematurity, chronic lung disease, and the duration of assisted ventilation and care in the tertiary neonatal unit. DESIGN AND SETTING: Randomised, controlled, clinical trial conducted at the neonatal intensive care unit of the Royal Women's Hospital, Melbourne, Australia. PATIENTS: Infants of birth weight less than 1000 g, ventilated, requiring < 50% oxygen and ventilator rate less than or equal to 20/minute, and considered by the clinical management team to be ready for extubation. INTERVENTION: Infants were randomly allocated to receive nasal CPAP delivered through binasal (Hudson) prongs or a single nasal prong. PRIMARY OUTCOME MEASURE: Failure of extubation as defined by the following criteria: (a) apnoea (more than one episode/hour over a six hour period or one episode requiring bag and mask ventilation); (b) absolute increase in oxygen requirement greater than 15% above that required before extubation; (c) respiratory acidosis (pH < 7.25 with PCO(2) > 6.67 kPa). RESULTS: Ten of the 41 (24%) infants randomised to binasal prongs reached predetermined failure criteria compared with 26 of the 46 (57%) infants randomised to a single nasal prong (p = 0.005). Four of 17 (24%) infants of birth weight less than 800 g extubated to binasal prongs reached failure criteria compared with 14 of 16 (88%) extubated to a single nasal prong (p < 0.001). There were no significant differences in any of the secondary outcomes. CONCLUSIONS: For extremely low birthweight infants ventilated using an endotracheal tube, nasal CPAP delivered through binasal (Hudson) prongs is more effective in preventing failure of extubation than that delivered through a single nasal prong.     

Current options in the management of apnea of prematurity

Apnea of prematurity (AOP) is a common problem that affects premature infants and, to a lesser degree, term infants. Apnea of prematurity appears to be due to immaturity of the infant's neurologic and respiratory systems. Apnea of prematurity is a diagnosis of exclusion that can be made only when other possible infectious, cardiologic, physiologic, and metabolic causes of apnea have been ruled out. The fundamental principles for managing apnea of prematurity include monitoring the infant closely while instituting supportive care measures such as tactile stimulation, continuous positive airway pressure, or mechanical ventilation. When necessary, pharmacologic therapy may be used to stimulate breathing. The first-line agents of choice for the management of AOP are the methylxanthines. And, for second-line therapy, a switch to a different class of agent, such as the respiratory stimulant doxapram, is an option. Of the methylxanthines, theophylline is the most extensively used. However, a review of the literature suggests that caffeine citrate may be the agent of choice for AOP. Comparative clinical studies have demonstrated that caffeine is at least as effective as theophylline, has a longer half-life, is associated with fewer adverse events, and, in addition, has a greater ease of administration. Caffeine stimulates the respiratory and central nervous systems more effectively and penetrates into the cerebrospinal fluid more readily than theophylline. In addition, because of stable plasma levels, caffeine has a wide therapeutic margin and few side effects. In contrast, theophylline plasma levels may fluctuate widely, which necessitates frequent monitoring and has a higher incidence of adverse events than caffeine. Before the FDA approval of caffeine citrate (Cafcit) for administration either intravenously and/or orally, caffeine preparations were "homemade." A few studies suggest that use of pharmacotherapy to treat AOP is not generally associated with long-term sequelae, although more data are needed before this can be definitively concluded.     

Management of apnoea and bradycardia in the newborn

Apnoea and associated bradycardia are common in preterm newborn infants. Apnoea of prematurity is a developmental disorder, which requires careful evaluation to exclude other pathological causes contributing to the apnoeas. The long-term effects of apnoea and bradycardia are unclear, but may be associated with long-term neurodevelopmental problems. Severe apnoeas may need resuscitation, mechanical ventilation or CPAP. Caffeine is currently the drug of choice for treatment of apnoea of prematurity. The effects of may other interventions, including stimulation, Kangaroo care, RBC transfusion, etc need further evaluation. Further research into the pathophysiological mechanisms underlying apnoeas, neurodevelopmental effects and long-term follow up of affected infants will help in optimizing management strategies for apnoea of prematurity.     

Effects of nasal continuous positive airway pressure on apnoea index and sleep in infants

Objectives: We examined the effectiveness of nasal continuous positive airway pressure (CPAP) for treatment of sleep apnoea in infants.
Methodology: We studied five infants who all had significant central and mixed apnoea and severe sleep fragmentation. Polysomnographic recordings were performed on 2 consecutive nights in these infants. One night was used as a control study and during the second night nasal CPAP was applied throughout the night
Results: Nasal CPAP significantly reduced apnoea in each infant, with the apnoea index (apnoeas/h) decreasing from 65.6± 14.6 during the control study to 10.5± 14.6 during CPAP in non-rapid eye movement (non-REM) sleep, and from 106± 13.9 during the control study to 26.6± 13.9 during CPAP in REM sleep. Nasal CPAP also improved the sleep fragmentation markedly; REM sleep increased from 14.2± 1.2% of sleep during the control study to 27.1 ± 1.2% of sleep during CPAP.
Conclusions: We conclude that nasal CPAP is an effective treatment for infantile apnoea. Sleep apnoea in these infants is associated with profound sleep fragmentation, which is reversed by nasal CPAP.     

早产儿呼吸暂停与间歇性缺氧

早产儿呼吸暂停（apnea of prematurity,AOP）定义一直是缺少充分的临床证据的,以呼吸停止时间≥20S,或〈20S伴有心动过缓、发绀为通常临床定义。目前还没有统一的AOP管理规范,但是反复发作的AOP,导致反复的间隙性缺氧（intermittent hypoxic episodes,IHE）是血氧波动的主要原因,同时,使早产儿发生严重早产儿视网膜病变和神经精神发育障碍的风险增加。当然,IHE的原因不仅局限于AOP,呼吸支持规程中,无论是持续气道正压通气,还是有创通气过程中都有发生IHE的可能。降低IHE是早产儿呼吸管理的核心内容之一,合理目标氧饱和度应是动态变化的,90％～95％的目标有助于减轻IHE和降低病死率,但有可能使早产儿视网膜病变增加。咖啡因是治疗AOP的首选药物,但是对混合型AOP廊注意呼吸支持。减少肺容积和气道阻力。     

Nasal continuous positive airway pressure versus nasal intermittent positive pressure ventilation for preterm neonates: a systematic review and meta-analysis

Aim: To determine whether nasal intermittent positive pressure ventilation (NIPPV) is more effective in preterm infants than nasal continuous positive airway pressure (NCPAP) in reducing the rate of extubation failure following mechanical ventilation, and reducing the frequency of apnoea of prematurity and subsequent need for endotracheal intubation. Methods: Randomized trials of NIPPV versus NCPAP were sought and their data extracted and analysed independently by the authors using the methodology of the Cochrane Collaboration. The analysis used relative risk (RR), risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals. Results: The three studies identified, comparing NIPPV with NCPAP in the postextubation period, all used synchronized NIPPV (SNIPPV), which was more effective than NCPAP in preventing failure of extubation [RR 0.21 (0.10, 0.45), RD 30.32 (30.45, 30.20), NNT 3 (2, 5)]. Two studies compared NIPPV versus NCPAP for the treatment of apnoea of prematurity. Although meta-analysis was not possible one trial showed a reduction in apnoea frequency with NIPPV and the other a trend favouring NIPPV. Conclusion: SNIPPV is an effective method of augmenting the beneficial effects of NCPAP in preterm infants in the postextubation period. Further research is required to delineate the role of NIPPV in the management of apnoea of prematurity.     

Newer experience with CPAP

Progress in neonatal intensive care is closely linked to improvements in the management of respiratory failure in small infants. Current modalities of ventilatory assistance range from more benign continuous positive airway pressure (CPAP) to various modes of mechanical ventilation (including high frequency ventilation). The advent of less invasive methods of delivering CPAP has permitted earlier treatment of infants with respiratory distress syndrome and avoided the need for mechanical ventilation. Children's Hospital of New York (Columbia University) places all spontaneously breathing infants on nasal prong CPAP as the first mode of respiratory support. The early initiation of nasal prong CPAP in combination with a tolerance to elevated PCO₂ levels has reduced the incidence of chronic lung disease to <5% in infants weighing less than 1500 g. This report will present an historical review and summarize the experience with CPAP at Columbia and other centres. In addition, it reviews the clinical applications and physiological effects of CPAP in preterm infants with respiratory distress syndrome.     

Effects of continuous positive airway pressure after oleic acid-induced lung injury in dogs.

The physiologic effects of continuous positive airway pressure (CPAP) of 5,10,15, and 20 cm H2O during spontaneous ventilation were studied in six anesthetized dogs with simulated respiratory distress syndrome (RDS) induced by iv infusion of oleic acid and in three normal controls. After oleic acid, mean PaO2 dropped to 63.6 +/- 3.1 mm Hg while breathing 100% oxygen and mean shunt fraction was 48.3 +/- 3.0%. PaO2 and shunt fraction improved significantly at the two highest levels of CPAP (e.g.,PaO2 271.3 +/- 41.3 mm Hg and shunt fraction 17.8 +/-2.2% at 20 cm H2O CPAP). Mean mixed venous PO2 rose from 37.4 +/- 1.5 mm Hg with no CPAP TO 60.8 +/- 3.1 mm Hg at 20 cm H2O CPAP. Tissue oxygenation appeared to improve during CPAP, since cardiac output, oxygen delivery, and serum lactate were not significantly affected and mixed venous PO2 rose significantly. However, significant hypoventilation occurred at all but the lowest level of CPAP, mean PaCO2 rising from 44.1 +/- 1.8 mm Hg with no CPAP to 77.6 +/-6.8 mm Hg at 20 cm H2O CPAP. The hypoventilation during CPAP is consistent with increased work of breathing due to a combination of decreased lung compliance and increased dead space ventilation due to rapid, shallow breathing.     

Variables associated with the early failure of nasal CPAP in very low birth weight infants

OBJECTIVE: To identify risk factors and neonatal outcomes associated with the early failure of "bubble" nasal continuous positive airway pressure (CPAP) in very low birth weight (VLBW) infants with respiratory distress syndrome (RDS). STUDY DESIGN: Following resuscitation and stabilization at delivery, a cohort of 261 consecutively inborn infants (birth weight < or = 1250 g) was divided into three groups based on the initial respiratory support modality and outcome at 72 hours of age: "ventilator-started" group, "CPAP-failure" group, and "CPAP-success" group. RESULTS: CPAP was successful in 76% of infants < or = 1250 g birth weight and 50% of infants < or = 750 g birth weight. In analyses adjusted for postmenstrual age (PMA) and small for gestational age (SGA), CPAP failure was associated with need for positive pressure ventilation (PPV) at delivery, alveolar-arterial oxygen tension gradient (A-a DO2) >180 mmHg on the first arterial blood gas (ABG), and severe RDS on the initial chest x-ray (adjusted odds ratio [95% CI] = 2.37 [1.02, 5.52], 2.91 [1.30, 6.55] and 6.42 [2.75, 15.0], respectively). The positive predictive value of these variables ranged from 43% to 55%. In analyses adjusted for PMA and severe RDS, rates of mortality and common premature morbidities were higher in the CPAP-failure group than in the CPAP-success group. CONCLUSION: Although several variables available near birth were strongly associated with early CPAP failure, they proved weak predictors of failure. A prospective controlled trial is needed to determine if extremely premature spontaneously breathing infants are better served by initial management with CPAP or mechanical ventilation.     

Predicting successful extubation of very low birthweight infants

OBJECTIVE: To determine the accuracy of three tests used to predict successful extubation of preterm infants. STUDY DESIGN: Mechanically ventilated infants with birth weight <1250 g and considered ready for extubation were changed to endotracheal continuous positive airway pressure (ET CPAP) for three minutes. Tidal volumes, minute ventilation (V e), heart rate, and oxygen saturation were recorded before and during ET CPAP. Three tests of extubation success were evaluated: (a) expired V e during ET CPAP; (b) ratio of V e during ET CPAP to V e during mechanical ventilation (V e ratio); (c) the spontaneous breathing test (SBT)-the infant passed this test if there was no hypoxia or bradycardia during ET CPAP. The clinical team were blinded to the results, and all infants were extubated. Extubation failure was defined as reintubation within 72 hours of extubation. RESULTS: Fifty infants were studied and extubated. Eleven (22%) were reintubated. The SBT was the most accurate of the three tests, with a sensitivity of 97% and specificity of 73% and a positive and negative predictive value for extubation success of 93% and 89% respectively. CONCLUSION: The SBT used just before extubation of infants <1250 g may reduce the number of extubation failures. Further studies are required to establish whether the SBT can be used as the primary determinant of an infant's readiness for extubation.     

Nasal high-frequency ventilation for premature infants

Aim: To assess the use of nasal high‐frequency ventilation (HFV) to provide noninvasive ventilatory support for very low birthweight (VLBW) infants. Study Design: VLBW infants, >7 days of age on nasal continuous positive airway pressure (CPAP), were placed on nasal HFV for 2 h using the Infant Star high‐frequency ventilator (Mallinckrodt, Inc., St. Louis, MO, USA). Mean airway pressure was set to equal the previous level of CPAP, and amplitude was adjusted to obtain chest wall vibration. Capillary blood was sampled before starting HFV and after 2 h to determine change in pH and partial pressure of carbon dioxide (pCO₂). Results: Fourteen subjects were studied, 10 males and 4 females. Gestational age was 26–30 weeks (median 27). Age at study was 18–147 days (median 30). Median birth weight was 955 g; median weight at study was 1605 g. Nasal CPAP pressure was 4–7 cm H₂O (mean 5). Amplitude was 30–60 (median 50). After 2 h, PCO₂ (mean 45 torr) was significantly lower than initial PCO₂ (mean 50 torr) (p = 0.01), and pH had increased significantly (7.40 vs. 7.37, p = 0.04). Conclusions: Nasal HFV is effective in decreasing pCO₂ in stable premature infants requiring nasal CPAP support. Long‐term use of nasal HFV requires further study.     

Effect of positioning on the breathing pattern of preterm infants.

Respiration, as judged by gas exchange and pulmonary function, is improved in preterm infants kept in the prone rather than the supine position. The influence of position on the breathing pattern as documented by the pneumogram was studied in 14 stable preterm infants with recent clinical apnoea. Ten of the infants had oximetry and nasal flow studies simultaneously with the impedance pneumogram. Each infant had consecutive nocturnal pneumograms, one in the prone, one in the supine position. The infants were kept for more than six hours in the assigned position. A significant increase in apnoea density and in periodic breathing was found in the supine v the prone position (mean (SE) 4.5 (0.7)% v 2.5 (0.5)%, and 13.6 (3.2)% v 7.7 (2.2)%, respectively). There was no positional difference in the incidence of bradycardia and prolonged apnoea. The examination of obstructive apnoea, mixed apnoea, and cyanotic spells did not reveal a consistent disparity between the two positions. These findings indicate an increase in central apnoea in preterm infants kept predominantly in the supine position. Possible relations of positional changes to lung mechanics are discussed. When evaluating pneumograms, attention must be given to the position in which they were performed.     

Impact of introducing binasal continuous positive airway pressure for acute respiratory distress in newborns during retrieval: Experience from Western Australia

Aim: We aimed to review the impact of introducing binasal continuous positive airway pressure (CPAP) for acute respiratory distress in newborns ≥32 weeks gestation during retrieval in Western Australia. Methods: Retrospective review of newborns ≥32 weeks gestation with acute respiratory distress, transported by the Western Australian Neonatal Transport Service between February 2002 and December 2004. Results: Respiratory management of 369 newborns was examined. CPAP use increased significantly during the study period from 33% in 2002 to 59% in 2004. Overall, endotracheal tube (ETT) ventilation was required in 108 (29%), nasal CPAP in 166 (45%) and cot oxygen in 95 (26%) patients. Twenty‐two (13%) newborns in the CPAP group subsequently required ETT ventilation within 24 h: these babies had higher initial oxygen requirements than those successfully transported on CPAP alone. There was no significant morbidity or mortality in patients retrieved on CPAP. Conclusion: CPAP was increasingly utilised as an alternative to ETT ventilation for the management of most cases of less severe acute respiratory distress in near‐term neonates on retrieval. This review demonstrated that newborns requiring more than 45–50% oxygen at the time of retrieval were more likely to require intubation at a later time, and hence may benefit from intubation at the time of retrieval. A prospective randomised trial would assist in ascertaining the true benefit of CPAP during retrieval in the newborn period.     

Clinical experience with the use of continuous positive airway pressure delivered by the nasal route (N-CPAP) (author's transl)]

The nasal CPAP modification of spontaneous positive pressure breathing is technically simple, non-invasive for the patient, and does not interfere with routine infant care, yet provides most of the advantages of other CPAP modifications. Endotracheal intubation is eliminated since airway pressure is delivered by two short canules attached by means of adhesive tape to the patient's nose. The CPAP system was used in the care of 35 newborns and premature infants admitted to the University Children's Clinic Graz, with the diagnosis of respiratory distress (31 cases) or apnea-syndrome (4 cases) between Sept. 1973 and July 1975. The indications for the use of this system was based on the arterial oxygen tension values while breathing 100% O2 for 15 min. 22 of the 28 patients surviving were treated with N-CPAP alone, whereas 13 patients were CPAP-failures and required further ventilation (IPPV,PEEP). In the latter group apnea and 2 cases of pneumothorax necessitated intubation and ventilation, rather than the respiratory distress for which they had been initially treated. All 7 patients who died during this study were from this group of N-CPAP-failures (20% of the total, 54% of all N-CPAP-failures). Keeping ambient oxygen concentrations constant, an increase in arterial oxygen tension was measured in almost all patients surviving on N-CPAP and was initially even seen in those who later died, so that the ambient oxygen concentration could eventually be decreased.     

咖啡因治疗早产儿呼吸暂停相关基因多态性的研究进展北大核心CSCD

早产儿呼吸暂停(apnea of prematurity,AOP)是早产儿的常见疾病之一,发病原因主要是呼吸控制中枢发育的不成熟。AOP如果得不到及时有效的处理会引发呼吸衰竭,引起脑缺氧损伤,严重者会导致死亡。咖啡因是治疗早产儿AOP的首选药物,但在早产儿中的治疗效果存在差异。随着对AOP研究的深入,越来越多的遗传学因素已被证实在AOP的发病和治疗中起重要作用,尤其是基因单核苷酸多态性对咖啡因疗效的影响已成为近年来研究的热点。该文就影响咖啡因疗效的相关基因多态性进行综述,以期为咖啡因的个体化治疗提供参考。     

早产儿支气管肺发育不良防治环节中早期呼吸支持的策略

虽然呼吸窘迫综合征( RDS)仍然是导致极早和超早早产儿呼吸衰竭最常见疾病,但由于NICU呼吸技术的进步,其已经不再是死亡的主要病因。伴随着 RDS的发生,支气管肺发育不良( BPD)这一成熟依赖性肺疾病的发生和发展成为现代NICU防治的核心疾病之一。在早期呼吸支持策略环节中有以下共识与建议：(1)最大可能的使具有高风险RDS或RDS的极早和超早早产儿期避免气管插管,接受无创通气(nCPAP);(2)早期选择合适的方式接受肺表面活性物质(PS)治疗;(3)个体化的制定nCPAP或其他无创通气失败的标准,尽早接受PS救治和适宜的有创通气模式;(4)缩短通气时间,应用无创通气方式辅以咖啡因治疗降低拔管失败率。这些临床研究成果仍需要不断在实践中改进与完善,BPD的发生是多因素作用的结果,需要多维度的管理的进步才能真正实现有效的防治。     

Predictors of chronic lung disease in the 'CPAP era'

OBJECTIVE: To assess predictors of chronic lung disease (CLD), in infants requiring nasal continuous positive airway pressure (CPAP) support in the first 4 weeks of life. METHODS: A retrospective case note audit of infants of birthweight 1250 g or less was undertaken. RESULTS: Of 290 infants identified, 50% were initially treated with ventilation, 41% with CPAP, 4% required no support, and 5% had care withdrawn. Of infants initially treated with CPAP, 23% subsequently required ventilation. Overall mortality was 19%, with a further 21% of infants developing CLD. For infants requiring CPAP support, requirement for supplementary oxygen at between 10 and 21 days predicted increased risk of CLD, and receiver operating characteristic curves suggest requirement for supplementary oxygen at 14 days to be the most reliable cut-off (area under curve = 0.72). Positive predictive values for future CLD or death for FiO2 .25, .30 and .40 while on CPAP at 14 days were 0.56, 0.61 and 0.76, respectively. CONCLUSIONS: CLD remains prevalent in very low birthweight infants in the CPAP era. Oxygen requirement at 14 days is the strongest predictor of CLD. Infants requiring 30% oxygen or more while on CPAP at 14 days have a 60% risk of subsequent CLD or death.