Mark C. Mammel

Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial

Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%). Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia.

Dexamethasone was compared with placebo in a double-blind, crossover, randomised study of infants with severe bronchopulmonary dysplasia who had required mechanical ventilation for at least four weeks, despite treatment with diuretics, methylxanthines, bronchodilators, fluid restriction, nutritional supplementation, and ligation of the patent ductus arteriosus when indicated. Gestational age ranged from 27 to 33 weeks and birth weight from 800 to 1730 g. Patients received dexamethasone (0 . 5 mg/kg/day) or normal saline for the first 3 days, then treatment was crossed over for the next 3 days. The study was terminated when sequential analysis showed that all six patients had improved during dexamethasone therapy. Significant improvements were seen in ventilator-determined respiratory rate, peak inspiratory pressure, fractional inspired oxygen concentration, and alveolar arterial oxygen gradients (p less than 0 . 05). Although dexamethasone hastened weaning from mechanical ventilation, infection occurred in a substantial proportion of patients.

Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: A multicenter controlled trial

To determine whether a single prophylactic dose of synthetic surfactant would reduce mortality and morbidity rates, we performed a randomized, controlled trial of Exosurf Neonatal at 19 hospitals in the United States. The Exosurf preparation (5 ml/kg) was instilled into the endotracheal tube of premature infants weighing 700 to 1100 gm during mechanical ventilation, as soon as practical after birth. Control infants were treated with air (5 ml/kg). Dose administration was performed in secrecy by clinicians who did not reveal for 2 years what they had instilled. A total of 222 infants received air and 224 received the synthetic surfactant; 36 infants with congenital pneumonia or malformations were excluded from the primary efficacy analysis. By the age of 28 days, there were 44 deaths in the air group and 27 deaths in the surfactant group (p = 0.022). By the age of 1 year after term there were 61 deaths in the air group and 35 deaths in the surfactant group (p = 0.002). Although there was no reduction in the incidence of respiratory distress syndrome, a significant reduction in the number of deaths attributed to respiratory distress syndrome, a significant reduction in the incidence of pulmonary air leaks, and significantly lower requirements for oxygen and mean airway pressure indicated that lung disease was less severe in the Exosurf-treated infants. There were no significant differences in the incidence of complications such as bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, and infection. The results indicate that a single prophylactic dose of Exosurf, in high-risk premature infants treated soon after birth, reduces the number of deaths from respiratory distress syndrome and the overall mortality rate.

Observational Study of Humidified High-Flow Nasal Cannula Compared with Nasal Continuous Positive Airway Pressure

OBJECTIVES To conduct an in vitro evaluation of a humidified high-flow nasal cannula (HFNC) system at different flows, cannula sizes, and air leaks and also an in vivo analysis of mean end-expiratory esophageal pressure (EEEP) from nasal continuous positive airway pressure at 6 cm H(2)O (NCPAP+6) versus HFNC. STUDY DESIGN In the in vitro study, we measured HFNC system pressure and flow, with varying degrees of leak and with and without the use of a pressure-limiting valve. In the in vivo study, we measured EEEP in 15 newborns on NCPAP+6 and then on HFNC at 6 L/minute, with flow decreased by 1 L/minute every 30 minutes. Heart rate, respiratory rate, fraction of inspired oxygen, arterial oxygen saturation, respiratory distress syndrome score, and EEEP were recorded for each intervention. Data analysis was done using repeated-measures analysis of variance and linear regression. RESULTS In the in vitro study, in the absence of leaks, the pressures were limited by the pressure-limiting valve only at flows > or = 2 L/minute. With leaks of 30% and 50%, delivered pressures were always < 3 cm H(2)O. In the in vivo study, respiratory rate increased from baseline (NCPAP+6) as flow decreased (P < .02). Intrapatient and interpatient coefficients of variation were always high. CONCLUSIONS A pressure-limiting valve is necessary in a HFNC system. Although mean EEEP levels were similar in NCPAP+6 and HFNC, tachypnea developed as flow diminished. This system apparently cannot predict EEEP, because of interpatient and intrapatient variation.

Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome.

OBJECTIVE To evaluate the effect of prolonged partial liquid ventilation with perflubron (partial liquid ventilation), using conventional and high-frequency ventilatory techniques, on gas exchange, hemodynamics, and lung pathology in an animal model of lung injury. DESIGN Prospective, randomized, controlled study. SETTING Animal laboratory of the Infant Pulmonary Research Center, Childrens Health Care-St. Paul. SUBJECTS Thirty-six newborn piglets. INTERVENTIONS We studied newborn piglets with lung injury induced by saline lavage. Animals were randomized into one of five treatment groups: a) conventional gas ventilation (n = 8); b) partial liquid ventilation with conventional ventilation (n = 7); c) partial liquid ventilation with high-frequency jet ventilation (n = 7); d) partial liquid ventilation with high-frequency oscillation (n = 7); and e) partial liquid ventilation with high-frequency flow interruption (n = 7). After induction of lung injury, all partial liquid ventilation animals received intratracheal perflubron to approximate functional residual capacity. After 30 mins of stabilization, animals randomized to high-frequency ventilation were changed to their respective high-frequency modes. Hemodynamics and blood gases were measured before and after lung injury, after perflubron administration, and then every 4 hrs for 20 hrs. Histopathologic evaluation was carried out using semiquantitative scoring and computer-assisted morphometric analysis on pulmonary tissue from animals surviving at least 16 hrs. MEASUREMENTS AND MAIN RESULTS All animals developed acidosis and hypoxemia after lung injury. Oxygenation significantly (p < .001) improved after perflubron administration in all partial liquid ventilation groups. After 4 hrs, oxygenation was similar in all ventilator groups. The partial liquid ventilation-jet ventilation group had the highest pH; intergroup differences were seen at 16 and 20 hrs (p < .05). The partial liquid ventilation-oscillation group required higher mean airway pressure; intergroup differences were significant at 4 and 8 hrs (p < .05). Aortic pressures, central venous pressures, and heart rates were not different at any time point. Survival rate was significantly lower in the partial liquid ventilation-flow interruption group (p < .05). All partial liquid ventilation-treated animals had less lung injury compared with gas-ventilated animals by both histologic and morphometric analysis (p < .05). The lower lobes of all partial liquid ventilation-treated animals demonstrated less damage than the upper lobes, although scores reached significance (p < .05) only in the partial liquid ventilation-conventional ventilation animals. CONCLUSIONS In this animal model, partial liquid ventilation using conventional or high-frequency ventilation provided rapid and sustained improvements in oxygenation without adverse hemodynamic consequences. Animals treated with partial liquid ventilation-flow interruption had a significantly decreased survival rate vs. animals treated with the other studied techniques. Histopathologic and morphometric analysis showed significantly less injury in the lower lobes of lungs from animals treated with partial liquid ventilation. High-frequency ventilation techniques did not further improve pathologic outcome.

Tracheobronchial histopathology associated with high-frequency jet ventilation.

We compared the tracheobronchial histopathology seen after conventional mechanical ventilation (CMV) and high-frequency jet ventilation (HFJV) in 44 adult cats. Two different HFJV humidity systems were examined: one used entrained mist alone, and the other infused 3 ml/kgh of 0.45% NaCl directly into the jet stream. HFJV produced more tracheal damage than CMV. This damage occurred at the endotracheal tube tip. The pattern of injury was acute inflammation, with erosion, necrosis, and infiltration of polymorphonuclear (PMN) leukocytes. The HFJV humidity system using entrained mist alone produced more damage than the HFJV infusion-pump humidity system. HFJV also produced more luminal mucus at all airway levels. Lower airways had different injury patterns. After 16 h, CMV produced more histopathology in the carina and main-stem bronchi. Here, the injuries were losses of surface cilia, losses of epithelial goblet cells, and inflammation. The dissimilar histologic injury patterns seen with 2 different forms of mechanical ventilation suggest different mechanisms of injury.

Partial liquid ventilation : A comparison using conventional and high-frequency techniques in an animal model of acute respiratory failure

OBJECTIVE To test the hypothesis that high-frequency ventilation (HFV), when compared with conventional techniques, enhances respiratory gas exchange during partial liquid ventilation (PLV). DESIGN A four-period crossover design. SETTING Animal research laboratory of Childrens Health Care-St. Paul. SUBJECTS Thirty-two newborn piglets, weighing 1.40 +/- 0.39 kg. INTERVENTIONS Animals were divided into four groups of eight animals: a) PLV with high-frequency jet ventilation; b) PLV with jet ventilation using a background intermittent mandatory ventilation (IMV) rate; c) PLV with high-frequency oscillation; or d) PLV with high-frequency flow interruption using a background IMV rate. After anesthesia, paralysis, and tracheotomy, a normal saline wash procedure produced lung injury. Perfluorocarbon was then instilled via the endotracheal tube in an amount estimated to represent functional residual capacity. Animals received randomly either PLV using conventional techniques or PLV using the selected HFV technique as initial treatment. Then, animals were crossed over to the alternative treatment at equal mean airway pressure, as measured at the endotracheal tube tip. This sequence was repeated for a total of four crossover periods, such that all animals were treated twice with PLV using conventional techniques and twice with PLV using HFV. MEASUREMENTS AND MAIN RESULTS We measured airway pressures at the endotracheal tube tip, aortic and central venous blood pressures, arterial blood gases, and respiratory system mechanics at baseline, after induction of lung injury, and at specified intervals throughout the experiment. Measurements were made before and 15 mins after crossovers, then ventilators were adjusted to normalize gas exchange. Measurements were again made 30 mins later, at the end of the treatment period. All types of PLV provided adequate gas exchange. Only PLV using jet ventilation with IMV produced gas exchange equal to that seen during PLV using conventional techniques at equivalent mean airway pressure. By the end of the treatment periods, only PLV using high-frequency oscillation continued to require higher airway pressure than PLV using conventional techniques for equivalent gas exchange. CONCLUSIONS Gas exchange was not enhanced during PLV-HFV. Application of HFV with PLV provides no clear acute physiologic advantages to PLV using more conventional techniques.

Tracheostomy for Infants Requiring Prolonged Mechanical Ventilation: 10 Years’ Experience

BACKGROUND: Despite advances in care of critically ill neonates, extended mechanical ventilation and tracheostomy are sometimes required. Few studies focus on complications and clinical outcomes. Our aim was to provide long-term outcomes for a cohort of infants who required tracheostomy. METHODS: This study is a retrospective review of 165 infants born between January 1, 2000 and December 31, 2010 who required tracheostomy and ventilator support. Children with complex congenital heart disease were excluded. RESULTS: Median gestational age was 27 weeks (range 22–43), and birth weight was 820 g (range 360–4860). The number of male (53.9%) and female (46.1%) infants was similar (P = .312). Infants were divided into 2 groups based on birth weight ≤1000 g (A) and >1000 g (B). Group A: 87 (57.6%) infants; group B 64 (42.4%). Overall tracheostomy rate was 6.9% (87/1345) for group A versus 0.9% (64/6818) for B (P <.001). Group A had a longer time from intubation to positive pressure ventilation independence, 505 days (range 62–1287) vs 372 days (range 15–1270; P = .011). Infants who had >1 reason for tracheostomy comprised 78.8% of the sample; 69.1% of infants were discharged on ventilators. Birth weight did not affect time from tracheostomy to decannulation (P = .323). More group A infants were decannulated (P = .023). laryngotracheal reconstruction rate was 35.8%. Five-year survival was 89%. Group B had higher mortality (P = .033). 64.2% of infants had developmental delays; 74.2% had ≥2 comorbidities. CONCLUSIONS: Tracheostomy rates were higher for extremely low birth weight infants than previously reported rates for all infants. Decannulation rates and laryngotracheal reconstruction rates were consistent with previous studies. Survival rates were high, but developmental delay and comorbidities were frequent.

Necrotizing tracheobronchitis: A complication of high-frequency ventilation

The tracheobronchial histopathologic findings in eight neonates who died after treatment with high-frequency jet ventilation (HFJV) were compared with those in eight similar infants who died after treatment with conventional mechanical ventilation. The HFJV and conventionally treated groups were matched as closely as possible for birth weight, gestational age, and duration of mechanical ventilation. A 4-point, nine-variable histologic scoring system was used to grade tissue changes in the trachea, carina, and mainstem bronchi. The patients who received HFJV had significantly more histologic damage in their tracheas, carinas, and right and left mainstem bronchi. At all levels of the airway examined, HFJV was associated with more inflammation, greater losses of ciliated epithelium, and more mucus within the lumen of the airway than was conventional mechanical ventilation.

Randomized Controlled Trial of Volume-Targeted Synchronized Ventilation and Conventional Intermittent Mandatory Ventilation Following Initial Exogenous Surfactant Therapy

We set out to evaluate the impact of volume‐targeted synchronized ventilation and conventional intermittent mandatory ventilation (IMV) on the early physiologic response to surfactant replacement therapy in neonates with respiratory distress syndrome (RDS). We hypothesized that volume‐targeted, patient‐triggered synchronized ventilation would stabilize minute ventilation at a lower respiratory rate than that seen during volume‐targeted IMV, and that synchronization would improve oxygenation and decrease variation in measured tidal volume (Vt). This was a prospective, randomized study of 30 hospitalized neonates with RDS. Infants were randomly assigned to volume‐targeted ventilation using IMV (n = 10), synchronized IMV (SIMV; n = 10), or assist/control ventilation (A/C; n = 10) after meeting eligibility requirements and before initial surfactant treatment. Following measurements of arterial blood gases and cardiovascular and respiratory parameters, infants received surfactant. Infants were studied for 6 hr following surfactant treatment.