Experiences with high-frequency oscillatory ventilation in premature infants with respiratory distress syndrome

BACKGROUND: High-frequency oscillatory ventilation (HFOV) has been used in treating premature infants with respiratory distress syndrome who have a low incidence of ventilation-associated lung injury. Herein, we report our initial clinical experience in using HFOV to treat such infants. METHODS: From October 1996 to February 1997, 10 premature infants with severe respiratory distress syndrome treated with HFOV were retrospectively evaluated. Clinical course and laboratory data collected during treatment were analyzed. Parameters evaluated included patient survival rate, incidence of chronic lung disease and morbidity associated with HFOV usage. RESULTS: The mean gestational age was 29 +/- 2 weeks; mean birth weight, 1,182 +/- 342 g; and mean period of HFOV treatment, 3.4 +/- 1.9 days. One patient died of sepsis due to infective pancarditis. Two patients developed moderate chronic lung disease at 30 days post delivery and in one of these patients, the disease persisted at 36 weeks' of age. The overall survival rate was 90%. No patient developed air-leak syndrome during the course of treatment. CONCLUSIONS: Our initial experience demonstrated that using HFOV in treating premature infants with severe respiratory distress syndrome was safe and effective. The incidence of moderate to severe chronic lung disease or air-leak syndrome following HFOV was low.     

The association between idiopathic spontaneous preterm delivery, an infected intra-uterine environment and hyaline membrane disease

A total of 110 preterm infants delivered as a result of the spontaneous onset of labour in the absence of obvious maternal and/or neonatal lesions and without premature rupture of the membranes was examined prospectively. Thirty per cent had more than 5 pus cells per high-power field in the gastric aspirate at birth. This finding correlated significantly with a lower incidence of hyaline membrane disease (HMD). All infants who developed HMD had negative or intermediate foam test results. There was no consistent relationship between either the pus cell count or the foam test result and the development of the wet lung syndrome. Data from our community suggest that many spontaneous deliveries occur in association with an infected itra-uterine environment.     

Surfactant treatment may accelerate epithelial cell regeneration in hyaline membrane disease of the newborn

Previous studies of histologic changes in the lungs of infants with hyaline membrane (HMD) disease of the newborn treated with surfactant have focused on the occurrence of hemorrhage and bronchopulmonary dysplasia (BPD). Observations in autopsied infants with HMD suggested a possible acceleration of epithelial cell regeneration in those receiving surfactant. We studied lungs of the 11 autopsied infants with HMD treated with surfactant, who survived less than 1 week, and compared them to 22 infants with HMD not given surfactant. Epithelial cell regeneration, BPD, and airway and interstitial hemorrhage were graded on a 0-to-3 scale. Treated infants showed significantly more epithelial cell regeneration (p<0.05) and airway hemorrhage (p<0.05). Also, treated infants showed recognizable epithelial regeneration 1 day earlier than the nontreated group. The study supports the observation that regeneration of the necrotic respiratory epithelium of HMD is accelerated in infants treated with surfactant.     

Epidemiology of hyaline membrane disease in the United States: analysis of national mortality statistics

National mortality statistics for hyaline membrane disease (HMD) and respiratory distress syndrome (RDS) were examined in this study for the years 1968 to 1973. Detailed data were obtained by computer analysis of magnetic tapes from the National Center for Health Statistics. During the six-year interval, HMD/RDS was determined to be the underlying cause of death in 54,064 infants or 9,010 +/- 560 (mean +/- SD) infants per year. Analysis of individual death certificates for 1968 revealed the disease to a major contributing factor in another 24%. Thus, it may be estimated that HMD was involved in the demise of nearly 12,000 neonates per year over this period. This amounts to approximately 20% of all neonatal deaths. On the basis of mortality rates, a trend toward an increased incidence of fatal HMD/RDS was established from 1968 to 1973. Deaths tend to cluster in the summer months and January-February represent the lowest months of recorded fatalities. Analysis of the age at death, reflecting time course of the disease, revealed idential patterns for 1968 to 1970. The number of deaths was found to decline exponentially between the first and fourth 24-hour periods so that 92% of all deaths occurred by 4 days of age. Boys contributed more prominently to the death totals than girls with ratios from 1.62 to 1.76. Examination of mortality rates by race suggested that black permatures have a lower incidence of fatal HMD/RDS. In addition to nationwide figures, those of individual states were compared for three years. Generally, HMD/RDS mortality rates correlated with overall neonatal mortality statistics. Exceptions were observed, however, such as Illinois where low rates for the former coexist with relatively high neonatal death rates. These data respresent the first national mortality statistics for HMD and may prove useful in planning and providing intensive neonatal care.     

Antenatal ambroxol treatment does not prevent the respiratory distress syndrome in premature infants

The effectiveness of ambroxol in the prevention of neonatal respiratory distress syndrome and in reducing the need for intermittent mandatory ventilation and oxygen therapy was studied in 88 mothers whose infants was born between 24 and 34 weeks of gestation and who were randomized either for treatment with ambroxol (group A = 42) or served as control (group B = 46). There were no significant differences in the mean gestational age, birth weight or Apgar score between the two groups. We found no significant differences in occurrence of respiratory distress syndrome (55% vs 45%), in support by intermittent mandatory ventilation (71% vs 72%) or oxygen therapy (74% vs 75%) at 12 h of age between groups A and B. CONCLUSION: This study does not suggest the efficacy of antenatal ambroxol treatment both for the prevention of neonatal respiratory distress syndrome and for the reduction of its severity.     

Decreased sodium ion absorption across nasal epithelium of very premature infants with respiratory distress syndrome

OBJECTIVE AND STUDY DESIGN: Successful adaptation to air breathing at birth depends on rapid absorption of fetal lung liquid that is mediated by activation of amiloride-sensitive sodium ion channels. To test the relationship between respiratory epithelial Na+ transport and development of respiratory distress syndrome (RDS), we measured nasal transepithelial potential difference (PD) in 31 very premature (< or = 30 weeks of gestation) newborn infants. Infants were retrospectively assigned to RDS (22 infants) and non-RDS (9 infants) groups on the basis of clinical and chest x-ray criteria. RESULTS: Maximal nasal epithelial PD increased with birth weight (-1.2 mV/100 gm) and was lower in infants with RDS (-16.5 +/- 0.6 mV) than in those without RDS (-22.0 +/- 1.3 mV). Infants without RDS had PD values similar to normal fullterm infants. Amiloride inhibition of PD, an index of Na+ absorption, was significantly lower, within the first 24 hours of life, in infants in whom RDS developed (3.8 +/- 0.2 mV; 29.5% +/- 0.8% inhibition) than in those without RDS (6.1 +/- 0.6 mV; 38.6% +/- 0.5% inhibition). Maximal and amiloride-sensitive PD returned to normal during the recovery phase of RDS. CONCLUSIONS: We conclude that Na+ absorption across nasal epithelium increases with increasing birth weight and that impairment of Na+ absorption across the respiratory epithelia of very premature infants may contribute to the pathogenesis of RDS.     

Intracerebral haemorrhages in surfactant treated neonates with severe respiratory distress syndrome: age at diagnosis, severity and risk factors

Within a randomized European multicentre trial the time of onset, severity and progression of intracerebral haemorrhages (ICH) were investigated prospectively by serial cranial ultrasonography in 343 ventilated infants with severe respiratory distress syndrome (RDS) following instillation of single or multiple doses of a natural porcine surfactant (Curosurf). In 148/343 infants (43%) ICH was diagnosed (grade I or II: 22%, grade III or IV: 21%). In 26 cases (8%) ICH was present on the ultrasound scan prior to surfactant instillation at a median age of 6 h. Incidence and severity of ICH was similar after single- or multiple-dose surfactant treatment. Using a logistic regression model the following risk factors predictive of ICH were defined: low birth weight, allocation to certain hospitals, vaginal delivery, Apgar score < or = 6, rectal temperature on admission < or = 36 degrees C, primary anaemia, acidosis prior to treatment, RDS grade IV in pre-treatment chest films and poor response to surfactant treatment. CONCLUSION: Our study provides supportive evidence that multiple doses of Curosurf do not increase the risk for ICH as compared to single-dose administration.     

Congenital diaphragmatic hernia: experience with preoperative stabilization and delayed surgery without ECMO and inhaled nitric oxide

Despite many advances in the management of congenital diaphragmatic hernia (CDH), the condition carries a mortality rate of 40-50% usually consequent to pulmonary hypoplasia and/or persistent pulmonary hypertension. Several centers have reported improved survival with preoperative stabilization and delayed surgery, which is now an accepted method of management. This is a retrospective analysis of all neonates with respiratory distress at birth due to CDH who were treated at our institution with neither extracorporeal membrane oxygenation nor nitric oxide being used. The medical records of all neonates with CDH and respiratory distress at birth who were treated at this institution from August 1, 1992 through March 1, 1997 were reviewed. There were 21 patients, 11 male and 10 female. There were 17 full-term and 4 premature infants; two premature infants at 30 and 34 weeks' gestation were not resuscitated because of severe associated congenital anomalies. Surgery was performed from 5 to 144 hr (mean 45 hr) in 18 infants. One infant died during preoperative stabilization from severe pulmonary hypoplasia and pulmonary hypertension and one infant died postoperatively from the same conditions. Seventeen of 19 infants (89.5%) survived and were discharged home. Three infants (17.6%) who failed to thrive due to severe gastroesophageal reflux (GER) required fundoplication. Eleven infants (64.7%) who had sepsis proven by blood culture responded satisfactorily to appropriate antibiotics. Preoperative stabilization and delayed surgery has been a satisfactory form of management in our series. The significant complication was sepsis, which must be addressed.     

Developmental patterns of heart rate and variability in prematurely-born infants with apnea of prematurity

At equivalent post-conceptional ages, prematurely-born infants have higher heart rates and reduced heart rate variability, relative to full-term neonates. Premature birth might exert long-lasting effects on central and peripheral mechanisms that control cardiovascular activity. We assessed development of heart rate and heart rate variability in symptomatic preterm infants up to 6 months of age. Fifty 6.5-h evening recordings of EKG and breathing were obtained from prematurely-born infants (gestational ages: 24-35 weeks). Cardiac R-R intervals were captured with a resolution of +/- 0.5 msec. One-min epochs were selected from three periods of regular respiration in recordings from premature infants and 72 recordings of full-term infants at comparable post-conceptional ages. Mean heart rate and heart rate variability were determined for each recording. At 40 weeks post-conception, prematurely-born infants with apnea of prematurity showed higher heart rates and reduced heart rate variability than did full-term neonates. These differences between premature and full-term infants persisted throughout the next 6 months in those infants born prior to 30 weeks gestation, and in those infants born at 30-35 weeks who experienced respiratory distress syndrome (RDS) during the neonatal period. The findings suggest that premature delivery, or complications thereof, exerts long-lasting effects on cardiac control.     

Effect of surfactant replacement therapy on the outcome of premature infants with respiratory distress syndrome

Lung surfactant replacement has been tested clinically in recent years. In this study the outcome of 31 premature infants with moderate to severe neonatal respiratory distress syndrome (RDS) treated with surfactant was compared to that of 74 prematures with RDS treated conventionally by positive pressure ventilation and supportive care. The groups were well matched for gestational age, birthweight, sex, and Apgar scores at 1 and 5 min. Surfactant treatment resulted in a significant decrease in mortality--from 36.6% in the untreated group to 12.9% in the surfactant-treated group (P < 0.04). This improvement in survival was seen also in prematures with a birthweight < 1,000 g; in the untreated group mortality was 57.6% compared to 23.5% in the treated group (P < 0.05). The incidence of pneumothorax was lower in the treated group--42% vs. 13% (P < 0.01). Surfactant treatment resulted in a trend of more survivors without bronchopulmonary dysplasia or intraventricular hemorrhage, even though surfactant therapy did not change the incidence of either.     

Interleukin 8 and granulocyte elastase in the tracheobronchial aspirate of infants without respiratory distress syndrome or intrauterine infection and development of chronic lung disease

To elucidate the mechanism of the development of chronic lung disease (CLD) in infants without respiratory distress syndrome or intra-uterine infection, we serially measured the concentrations of interleukin 8 (IL-8) and granulocyte elastase alpha 1 proteinase inhibitor complex (E-alpha 1 PI) and elastase activity in the tracheobronchial aspirate of very low birth weight infants without respiratory distress syndrome or intra-uterine infection until day 28. IL-8 concentration and elastase activity between day 21 and 28 in infants who developed CLD later were significantly higher compared with those in infants who did not develop CLD. E-alpha 1 PI concentration between day 25 and 28 in infants who developed CLD later was significantly higher compared with those in infants who did not develop CLD. The area under the curve of the IL-8 and E-alpha 1 PI concentrations and elastase activity between day 1 and day 28 in infants with CLD was significantly higher than those in infants without CLD. These data suggest that the lung tissue injury caused by the enzymes from neutrophils accumulated and activated by IL-8 also play an important role in the development of this type of CLD.     

Morbidity and mortality in low-birth-weight infants (1,000 g, or less (author's transl)

50 low-birth-weight infants (1,000 g. or less) admitted to an Intensive Care Unit from January 1972 up to December 1974 are evaluated. Obstetrical data maturity and morbidity are compared in order to investigate factors that might predispose survival of these infants. Significant differences in gestational age, birth weight and maturity have been encountered. Mortality rate increases with a low Apgar score at one and five minutes, a low hematocrit an admission, early appearance of apnea, respiratory distress, when ressuscitation was required, need for assisted ventilation and septicemia. Among the factors that improve the rate of survival are: being small for gestational age, early rupture of membranes and temperature on admission above 35.5 degrees (axillary). Problems most frequently encountered were respiratory distress, apnea, infection and metabolic disturbances. Mortality rate was 76%, lowered to 50% among the small for gestational age group. The main causes of death were sepsis, severe hypoxia and intracraneal hemorrhage.     

Early onset group B streptococcal disease: clinical, roentgenographic, and pathologic features

Thirty-one neonates with early onset of serious group B streptococcal infections were observed in a four-year period. The mortality was 52%. Premature infants with clinical signs of respiratory distress syndrome were at highest risk of death; clinical signs of RDS were typical until apnea, shock, respiratory failure, and worsening of the radiographic pattern unexpectedly intervened. Pathologic material from infants with radiographic evidence either of RDS or of pneumonia showed both typical hyaline membrane disease and pneumonia in most instances. Factors which may be helpful in recognizing premature infants at risk for GBS disease in the much larger group of premature infants with uncomplicated RDS include: history of artificial, premature, or prolonged rupture of membranes; localized pulmonary infiltrates on chest roentgenogram; low absolute neutrophil count; and an unusually rapid progression of RDS.     

Neonatal urinary uric acid/creatinine [correction of ceratinine] ratio as an additional marker of perinatal asphyxia

The diagnosis and evaluation of perinatal asphyxia can be problematic and objective means of assessing its severity are lacking. To study the validity of urinary uric acid as a marker of the degree of perinatal asphyxia, the ratio of urinary uric acid to creatinine (UA/Cr) in urine specimens obtained after birth was measured in two groups of infants. Eighteen term infants with Apgar scores < or = 5 at 5 min and/or an umbilical cord blood pH < or = 7.2, and a base deficit > or = 12 meq/l were compared to 50 healthy controls. The severity of the perinatal asphyxia was determined by using an ASPHYXIA SCORE. The UA/Cr was higher in the asphyxiated group when compared to controls. (2.06 +/- 1.12, vs. 0.64 +/- 0.48; P < 0.001). Within the perinatal asphyxia group, a significant correlation was found between the UA/Cr ratio and the asphyxia score. (r = 0.86, P < 0.01). CONCLUSION: Infants with perinatal asphyxia have a significantly higher urinary UA/Cr ratio. This may be used as an indicator of the severity of perinatal asphyxia.     

Importance of pre- and perinatal risk factors in respiratory distress syndrome of premature infants. A logical regression analysis of 1100 cases

BACKGROUND: Respiratory distress syndrome (RDS) due to surfactant deficiency remains a cause of considerable mortality in the neonatal period. METHODS: In a retrospective study we analysed the records of 1109 premature newborns with a birth weight below 1500 g that were treated on our unit. RDS was assumed if the infants needed mechanical ventilation with oxygen supplementation and the typical radiological signs were present on chest x-ray. RESULTS: No changes in the incidence of RDS were found during the period of observation. Below 29 weeks gestational age 90% of infants suffered from RDS (55% severe RDS grade III or IV). The incidence was 75% (grade III or IV: 32%) for infants born at 29 and 30 weeks, 48% (grade III or IV: 15%) at 31 and 32 weeks and 33% (grade III or IV: 6%) for neonates born at 33 weeks of gestation. Using a logistic regression analysis model the following parameters were found to increase the risk for RDS significantly (p < 0.05): no prenatal steroid treatment, Cesarean section, male gender, APGAR at 5 min < 7, metabolic acidosis (base excess < or = -6 mval) and rectal temperature < 36 degrees C on admission. Following gestosis, insufficiency of the placenta and premature rupture of membranes a decrease in the incidence of RDS was observed. CONCLUSION: We conclude that although some risk factors for RDS will be difficult to exclude (e.g. maternal disease, gender) the incidence and severity of RDS can be reduced by measures like maternal antenatal steroid treatment. Perinatal asphyxia (low APGAR values and/or acidosis) and hypothermia should be avoided, as these conditions increase the relative risk for developing RDS.     

Prevention of neonatal respiratory distress syndrome through the administration of prednisolone in the fetal period

The clinical effectiveness of antenatal prednisolone medication (prednisolone hemisuccinate) for the prophylaxis of idiopathic respiratory distress syndrome (IRDS) was studied in 114 premature infants with a gestational age between 28 and 36 weeks. There was a statistically significant difference (chi2 - test, p less than 0,01) between the frequency of IRDS in this group and in another one consisting of 137 premature babies with a nearly identical distribution of gestational age, whose mothers did not get prednisolone before delivery. It could be shown that the time interval between medical induction and delivery should not exceed 2 weeks, since the effect decreases with time. At present prednisolone medication during the fetal period may serve as useful prophylactic measure for IRDS in cases of premature birth. As there are a lot of contraindication against prednisolone and as we do know very much about side effects, it seems necessary to seek for other, less dangerous inductors.     

Repetitive conundrums of centromere structure and function

BACKGROUND: Adult participants in randomized controlled trials often have better outcomes than patients who are eligible but not enrolled. OBJECTIVE: To examine whether newborn infants who were allocated to placebo in an investigational drug trial had better outcomes than infants who were eligible but not randomized (eligible NR). Study design: During a randomized controlled trial of antithrombin therapy in premature infants with respiratory distress syndrome, data were collected prospectively on all 76 infants in the eligible NR group. Study outcomes were compared with those of all 61 infants who were randomized to placebo. The same exogenous surfactant was used in all patients. RESULTS: In the placebo group the mean (SD) birth weight was 1201 (314) g, mean (SD) gestational age was 28.8 (2.3) weeks, and 51% were male. In infants in the eligible NR group, mean (SD) birth weight was 1141 (262) g, mean (SD) gestational age was 28.3 (2. 3) weeks, and 58% were male; 57% of infants in both groups had been exposed to steroids before birth. The median duration of mechanical ventilation was reduced from 6.2 days in the eligible NR group to 4. 8 days in the placebo group (P =.008). There was also a trend toward less frequent and less severe intraventricular hemorrhage in trial participants. CONCLUSIONS: These data are consistent with the hypothesis that sick newborn infants may benefit from participation in a randomized controlled trial.     

Experience in a neonatal intensive care unit affects pain response

OBJECTIVE: To determine the effect of being in the neonatal intensive care unit (NICU) on pain responses in infants of 32 weeks' postconceptual age (PCA). DESIGN: A cross-sectional comparative design was used. SETTING: Two level III NICUs, each in metropolitan, university teaching hospitals. PATIENTS: Infants of 32 weeks' PCA born within the past 4 days (the newly born group; n = 53) were compared with infants of the same PCA who had been born 4 weeks earlier (the earlier-born group: n = 36) and had spent that time in an NICU. OUTCOME MEASURES: Heart rate, oxygen saturation levels, and facial actions were used as outcomes in a between-group repeated measures analysis of variance across the heel stick procedure. Background variables of Apgar, weight at birth and data collection, severity of illness, age group, and total number of invasive procedures were entered into a stepwise regression. RESULTS: The two groups responded differently to the heel stick: the earlier-born infants had less behavioral manifestations of pain than the newly born infants. The number of invasive procedures was the primary factor that explained those behavioral differences, with Apgar as a second explanatory factor. The earlier-born infants had higher heart rates and lower oxygen saturation than the newly born infants before as well as during the procedure. These physiological differences were explained by the perinatal factors of age at birth and birth weight. CONCLUSION: Preterm infants who spend PCA weeks 28 through 32 in an NICU are less mature in their pain response than newborn premature infants of 32 weeks' PCA. Greater frequency of invasive procedures is associated with behavioral immaturity, whereas birth factors are associated with physiological immaturity.     

The use of nasal CPAP in newborns with respiratory distress syndrome

The efficiency of applying continuous positive airway pressure (CPAP) by the nasal route was retrospectively nalyzed in 32 newborns with RDS (23 uncomplicated HMD with additional cardiac or pulmonary complications and 7 RDS of non-hyaline membrane etiology) who underwent nasal CPAP treatment at the Kinderspital Zurich from 1972--1974. 16 of the 23 infants with uncomplicated HMD were successfully treated with CPAP. They showed a significant rise in PaO2 as well as a significant drop in respiratory frequency during nasal CPAP application, the PaCO2 did not change significantly. The remaining 7 infants in this group (7/23) had to be intubated and mechanically ventilated owing to a persistent high FIO2 (4 infants), technical difficulties (1) or nasal hypersecretion (2). Two of these 23 infants died, one of meningitis, one of cerebral hemorrhage. The two infants with HMD and additional cardiac or pulmonary complications and 3 of 7 infants with RDS of non-hyaline membrane etiology had to be intubated and mechanically ventilated after failure of nasal CPAP. All 9 infants in these two groups survived. The nasal CPAP system as described is a simple, inexpensive and effective method of applying CPTPP in newborns with uncomplicated HMD, except radiological stage IV. In HMD with additional cardiac or pulmonary complications and in RDS of non-hyaline membrane etiology the results of nasal CPAP treatment were not convincing.