Donald M. Null

Ventilatory management of infant baboons with hyaline membrane disease: The use of high frequency ventilation

Abstract: We tested the hypothesis that high frequency oscillatory ventilation (HFOV) would result in decreased pulmonary barotrauma in infants with hyaline membrane disease by comparing HFOV at 10 Hz to conventional positive pressure ventilation with continual distending airway pressure (PPV/PEEP) in premature baboons with hyaline membrane disease. Nineteen baboon fetuses were randomized to one of two treatment groups, delivered at 140 ± 2 days, and, after stabilization and instrumentation of PPV/PEEP, placed in their respective ventilator group. Animals on conventional ventilation were managed by adjustment of tidal volume and frequency (to 1 Hz) to keep PaCO2 below 55 and by adjustment of the mean airway pressure. One of the “HFOV” group died of cardiovascular complications before going on HFOV and was eliminated from data analysis. The remaining HFOV baboons survived the 11-day experimental period without evidence of airleak. Six of the 11 prematures treated with PPV/PEEP developed pulmonary interstitial emphysema and/or pneumothorax and five of the animals died within 48 h. The intergroup differences in airleak were significant (p < 0.05). Mean airway pressure (measured at the proximal airway) was higher initially with HFOV but then was lowered more rapidly than in the PPV/PEEP animals. The arterial to alveolar oxygen ratio rose and the FIO2 could be lowered more rapidly with HFOV than with conventional ventilation. These differences reached significance by 20 h. After 60 h there were no significant differences between HFOV and the PPV/PEEP survivors. HFOV resulted in more uniform saccular expansion, higher arterial to alveolar oxygen ratio, less oxygen exposure, and decreased acute barotrauma when compared to PPV/PEEP. Although initially mean airway pressure was in the HFOV animals this was not associated with measurable baroinjury. These data support the efficacy of HFOV in the treatment of prematures with hyaline membrane disease.

A baboon model of bronchopulmonary dysplasia. II. Pathologic features

Abstract A light microscopic (LM), transmission electron microscopic (TEM), and scanning electron microscopic (SEM) study was performed on the lungs from seven baboons delivered by cesarean section prematurely (75% of full gestation) and one at full term. Six of the seven premature baboons pursued a clinical course typical of human hyaline membrane disease (HMD) and/or bronchopulmonary dysplasia (BPD). All the animals were supported with mechanical ventilation and exposed to continuous high levels of inspired oxygen. Three animals died early (⩽3 days) of complications and two demonstrated typical light and electron microscopic lesions of hyaline membrane disease. Three baboons survived ⩾ 8 days and developed pathologically confirmed bronchopulmonary dysplasia, characterized by an altered inflation pattern of atelectasis and overdistension/“emphysema,” bronchial and bronchiolar lesions of necrosis, regenerative hyperplastic and/or squamous metaplastic changes, and peribronchiolar fibrosis and early alveolar wall fibrosis. A striking finding was a hyperplastic/obliterative respiratory bronchiolar lesion, most frequently seen in the atelectatic areas. The lungs of these animals lacked pores of Kohn; a feature shared by a study group of untreated baboons with gestation ages of 109 to 180 days. It is suggested that the lack of collateral ventilation, plus the striking hyperplastic-obliterative airway lesion might explain the characteristic feature of atelectasis. The histopathologic features of this model coincide with with those of BPD in the human neonate, with the exception of the hypertensive vascular changes, which may be a time-related lesion. The pathologic findings further support the premise that the premature baboon will be a very useful model in which the primary etiologic consideration of oxygen toxicity and barotrauma can be separated as to their roles in the causation of bronchopulmonary dysplasia.

A baboon model of bronchopulmonary dysplasia: I. Clinical features

Abstract Investigation in bronchopulmonary dysplasia (BPD) has been seriously hampered by the lack of a suitable animal model. The consistent development of BPD in preterm baboons ( Papio cynocephalus ) with hyaline membrane disease (HMD) who were treated with 95–100% inspired oxygen and supported with mechanical ventilation for more than 1 week is reported. One term (173 days) and nine preterm (134–147 days) pregnancies were delivered by cesarean section with birth weights 495–988 g. Amniotic fluid lecithin: sphingomyelin (L/S) ratios ranged from 0.47 to 1.00. The six animals with L/S ratios ⩽ 0.62 developed HMD. The clinical and radiologic course was indistinguishable from HMD in preterm humans. HMD was confirmed pathologically in two animals dying acutely. One of the remaining four was supported with supplemental oxygen as needed and remains a long-term survivor of HMD. The other three were maintained in 95–100% oxygen. A clinical and radiographic picture similar to that of human BPD developed in each and was pathologically confirmed. The preterm baboon appears to be a suitable animal model for investigation of the etiology, pathophysiology, prevention, therapy, and long-term sequelae of HMD and BPD.

High-frequency oscillatory ventilation Versus intermittent mandatory ventilation : early hemodynamic effects in the premature baboon with hyaline membrane disease

ABSTRACT: We studied the hemodynamic consequences during the first 24 h of life in premature baboons (140 d) with hyaline membrane disease that were treated with high-frequency oscillatory ventilation (HFOV) or conventional intermittent mandatory ventilation (IMV). Cardiac output and organ blood flow were measured at three time-points using the radiolabeled microsphere technique. Seven of seven HFOV and six of eight IMV animals survived the 24-h period. By design, initial mean airway pressure (Paw) was higher in the HFOV group (p < 0.01). HFOV Paw was progressively reduced during the study period because of improving oxygenation as measured by the arterial to alveolar oxygen ratio. In contrast, it was necessary to increase Paw in the IMV animals to maintain the arterial to alveolar oxygen ratio. By 23 h, the IMV group required higher Paw than the HFOV group (p < 0.05) and had a lower arterial to alveolar oxygen ratio (p < 0.05). We found no significant differences in left ventricular output, effective systemic flow, organ blood flow, or central venous pressure between the two groups at 3, 8, or 23 h. The HFOV strategy used in our study resulted in significant improvement in oxygenation during the initial 24 h of treatment without adverse effect on left ventricular output, cerebral blood flow, or central venous pressure. We conclude that when appropriate changes in Paw are made during HFOV in response to improvement in arterial oxgenation and changes in lung inflation as assessed by chest radiographs HFOV can be achieved without depressing cardiovascular dynamics more than during conventional therapy with IMV.

Pulmonary interstitial emphysema treated by high-frequency oscillatory ventilation

Twenty-seven low birth weight infants who developed pulmonary interstitial emphysema (PIE) and respiratory failure while on conventional ventilation were treated with high-frequency oscillatory ventilation (HFOV). The mean birth weight was 1.2 kg (range 0.55 to 2) with gestational age of 28 wk (range 25 to 34). Ten patients died, six of whom had documented sepsis with shock and were therefore excluded from analysis. All patients showed initial improvement on HFOV. Surviving patients showed continued improvement in oxygenation and ventilation at increasingly lower fraction of inspired oxygen and proximal airway pressure with resolution of PIE, while nonsurvivors progressively developed chronic respiratory insufficiency with continued PIE from which recovery was not possible. Overall survival in nonseptic patients was 80% (16 of 20). We found HFOV to be effective in the treatment of PIE and hypothesieze that interstitial airleak is decreased during HFOV because adequate ventilation is provided at lower peak distal airway pressures.

High-frequency ventilation compared to conventional positive-pressure ventilation in the treatment of hyaline membrane disease in primates.

High-frequency ventilation (HFV) has been suggested as an alternative to conventional positive-pressure ventilation (PPV) in the treatment of infants with hyaline membrane disease (HMD). Using a previously validated primate model of HMD, 15 baboon fetuses were delivered at 75% of gestation and randomly assigned to 1 of 3 ventilator treatment groups: (a) PPV, (b) HFV delivered by an oscillator (HFO), or (c) HFV delivered by a flow interrupter (HFFI). All animals had clinical and radiographic evidence of HMD. At 96 h of life, all animals were sacrificed and clinical and pathologic findings were analyzed. During the first 10 h of the experiment, the HFO animals required higher mean proximal airway pressures than either the HFFI or PPV groups. However, both the HFFI and HFO animals had higher PaO2/PAO2 ratios than the PPV controls, suggesting earlier saccular recruitment. Thus, HFV is as effective as PPV in the treatment of HMD in baboons. Whether it will decrease the risk of bron-chopulmonary dysplasia is not known.

Extracorporeal membrane oxygenation and high-frequency oscillatory ventilation: potential therapeutic relationships

Eighteen neonates 33 to 42 wk gestational age with severe respiratory failure were referred for extracorporeal membrane oxygenation (ECMO). Sixteen ultimately met the ECMO criteria, of whom 15 were first offered high-frequency oscillatory ventilation (HFOV). Seven responded to HFOV alone and did not require ECMO treatment. Eight of the nine remaining patients were placed on ECMO support with HOFV. Infants who responded to HFOV alone tended to have pneumonia more than meconium aspiration, to be smaller and more immature, to have higher Apgar scores, and to have suffered severe hypoxia (alveolar-arterial oxygen pressure difference over 600 torr) for less time than the ECMO group. Although patient numbers are small, a trend is noted which favors HFOV treatment alone in terms of the duration of HFOV, the total duration of assisted ventilation, the rapidity with which extubation was accomplished, and the length of hospital stay.

Pulmonary interstitial emphysema in the premature baboon with hyaline membrane disease.

During experiments designed to develop an appropriate ventilatory strategy for high-frequency ventilation (HFV) in the premature baboon with hyaline membrane disease (HMD), we observed the development of pulmonary interstitial emphysema (PIE). Four study groups of 5 animals each received positive-pressure ventilation and positive end-expiratory pressure (PPV/PEEP) or HFV and 1 of 3 sighing techniques. Pathologically, all animals ventilated with PPV/PEEP or HFV with a carefully controlled intermittent sigh developed dilatation of the distal conducting airway and alveolar duct, with poorly expanded pulmonary saccules. The imposition of a sigh with inappropriate timing or excessive volume ruptured the dilated airway walls and caused interstitial air to accumulate. This was evident from the location of striking dilation of the distal airways and pseudocysts in areas of atelectasis. Thus, early in the course of HMD when saccular aeration is minimal, the pathogenesis of PIE is related to airway rather than alveolar rupture.

A comparison of ventilation strategies for the use of high-frequency oscillatory ventilation in the treatment of hyaline membrane disease

To assess the efficacy of high frequency oscillatory ventilation (HFOV) in the management of infants with hyaline membrane disease (HMD), we compared two HFOV strategies with conventional positive pressure ventilation with positive end expiratory pressure (PPV) for 24 h in premature baboons (140 d gestation). Three out of 14 PPV, five out of five HFOV‐E (begun at birth; 15 Hz; I:E 1:2), and none of 10 HFOV‐L (begun after 3 h PPV; 10 Hz; I:E 1:2) were killed at 24 h for morphologic examination. Physiologic (Paw, Pa/AO2, IO2, B. P., pulse, blood gases) data on all animals in each group were assessed at each 3 h interval and over time. Intergroup differences in radiographs at 0 and 24 h and in morphology were quantitatively assessed by comparison with a panel of standards. All animals had radiographic HMD. Initial Paw was set higher with HFOV‐E (16.8) than PPV or HFOV‐L (14.1, 14.1). PPV baboons required increasing Paw to maintain constant Pa/AO2. Six out of 14 PPV animals developed airleak and three out of three had morphologic HMD. In contrast Pa/AO2 was higher in both HFOV groups at lower Paw by 24 h. None of 15 HFOV animals developed airleak. HFOV‐E lungs had dramatic differences in morphology with uniform saccular opening and decreased edema and hyaline membranes compared to PPV. HFOV‐L had less dramatic effects because of lower Paw and delayed application. Early use of HFOV at a high Paw favorably alters the course of HMD. Unless closely monitored, this strategy results in lung overinflation which may adversely affect venous return and cardiac output.

Cardiac performance in ECMO candidates: Echocardiographic predictors for ECMO☆

Twenty-one neonates with severe respiratory failure, who met criteria in this center for extracorporeal membrane oxygenation (ECMO), underwent echocardiographic examinations to assess the role of cardiac dysfunction in determining the need for ECMO. The echocardiographic indexes of function included peak aortic and pulmonary flow velocity, aortic and pulmonary acceleration, shortening fraction, velocity of circumferential fiber shortening, right ventricular output, and left ventricular output. Patients were offered a staged treatment protocol using high-frequency oscillatory ventilation (HFOV), followed by ECMO if failing HFOV rescue. Nine patients demonstrated progressive deterioration and required ECMO (group 1); 12 patients recovered without ECMO (group 2). There were no significant intergroup differences in AaDO2, age, weight, gestational age, inotropic support, mean airway pressure, systemic blood pressure, or arterial blood gas parameters. Group 1 had significantly lower pulmonary and aortic peak flow velocities, lower pulmonary acceleration, lower shortening fraction, and lower velocity of circumferential fiber shortening (P less than .05). We found that values for peak pulmonary velocity less than 0.70 m/s with pulmonary acceleration less than 14 m/s2 would predict the need for ECMO in 7 of 9 group 1 patients and recovery without ECMO in 11 of 12 group 2 patients (P less than .01, Fishers Exact test). We conclude that on initial echocardiographic evaluation, cardiac performance was impaired in those patients who subsequently required ECMO compared with a group of patients with similar severity in gas exchange who recovered without ECMO. We speculate that echocardiographic assessment of cardiac performance in ECMO candidates may prove useful in prediction of the subsequent need for ECMO or expedient transfer to an ECMO center.