[Physiological basis for the use of muscarine antagonists in bronchopulmonary dysplasia]. / Bases physiologiques de l'utilisation des antagonistes muscariniques dans les dysplasies bronchopulmonaires.

The rationale for the use of muscarinic antagonists in bronchopulmonary dysplasia (BPD) is based on the physiology and pharmacology of airway smooth muscle, the pathology of BPD, and the response of infants with BPD to bronchodilators, in vivo and in vitro studies of airway smooth muscle of newborn animals and humans indicate that vagal efferent airway innervation and/or muscarinic receptors are functional at birth, as well as early in gestation. Current concepts regarding muscarinic receptor subtypes suggest that M3 receptors mediate airway smooth muscle contraction, M2 receptors are autoinhibitory and limit vagally-mediated bronchoconstriction, and M1 receptors may play a facilitatory role in ganglionic transmission. Muscarinic receptor subtypes appear to be functionally expressed at birth but may undergo developmental regulation. Infants with BPD have an elevated pulmonary resistance that is accompanied by hypertrophy of airway smooth muscle, b2-agonists cause bronchodilation in BPD as does atropine in infants recovering from severe BPD. The synthetic congener of atropine, ipratropium bromide (IPB) causes bronchodilation in ventilator-dependent infants with BPD in a dose-dependent fashion. Nebulized IPB causes a decrease in respiratory resistance that reaches a maximum of 20% at 175 mg. The bronchodilation seen with muscarinic antagonists suggests that part of the elevated resistance associated with BPD is due to increased muscarinic tone, presumably vagal in origin. When IPB is combined with salbutamol (0.04 mg) the response is increased in magnitude and duration; reaching a slightly larger decreases in resistance (26%) that is now accompanied by an increase in compliance (20%).(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilator pattern influences neutrophil influx and activation in atelectasis-prone rabbit lung.

Both ventilator pattern and neutrophil activation influence lung injury in adult respiratory distress syndrome (ARDS). We therefore questioned whether ventilator pattern independently affects neutrophil accumulation and function in early ARDS. Thirty-five New Zealand White rabbits were anesthetized, paralyzed, and prepared using sterile techniques. Fifteen surfactant-depleted animals were randomized and ventilated for 4 h using high-frequency oscillatory ventilation (HFO) at 15 Hz with an inspired O2 fraction = 1.0 and arterial PO2 (PaO2) > 400 Torr (a pattern known to reverse atelectasis) or conventional mechanical ventilation (CMV) with PaO2 = 80-100 Torr (a pattern with some atelectasis despite positive end-expiratory pressure). Eight normal animals on CMV with PaO2 > 400 Torr served as a reference group (NorCMV). NorCMV animals progressively increased circulating polymorphonuclear neutrophil (PMN) numbers and had minor pressure-volume curve alterations but no other significant changes. Lavaged CMV animals developed the characteristic gas exchange and marked pressure-volume curve abnormalities of ARDS. Circulating PMNs remained constant but developed decreased chemotactic activity, whereas lung neutrophil numbers increased significantly (P = 0.0002) and had substantially enhanced chemiluminescence (P = 0.0003 vs. NorCMV animals). Although lavaged HFO animals accumulated an intermediate number of lung neutrophils (lung myeloperoxidase > NorCMV animals; P = 0.003), the chemiluminescence and chemotaxis of these PMNs were the same as in cells from NorCMV animals. We concluded that both the degree of neutrophil activation and lung injury can be minimized by preventing cyclic alveolar/airway expansion and collapse in the surfactant-deficient lung by use of appropriate ventilator patterns.

Sustained inflations improve respiratory compliance during high-frequency oscillatory ventilation but not during large tidal volume positive-pressure ventilation in rabbits.

OBJECTIVE: To determine whether volume recruitment maneuvers that induce significant lung reexpansion during high-frequency oscillatory ventilation are also of value during conventional positive-pressure ventilation. DESIGN: Crossover comparison of volume recruitment maneuvers administered during high-frequency oscillatory ventilation and positive-pressure ventilation in normal and surfactant-deficient adult rabbits. SETTING: Laboratory. SUBJECTS: Nineteen adult New Zealand white rabbits (weight 2.3 to 3.3 kg). METHODS: Respiratory system compliance was measured plethysmographically before and after sustained inflations in six normal and five saline-lavaged anesthetized rabbits, using both ventilators over a range of mean and end-expiratory pressures. RESULTS: Under conditions where sustained inflations during high-frequency oscillatory ventilation at 15 Hz increased respiratory system compliance 50 +/- 28%, sustained inflations during conventional positive-pressure ventilation at a rate of 30 to 40 breaths/min and tidal volumes of 14 to 17 mL/kg did not change respiratory system compliance (mean change 3 +/- 9%). Sustained inflations during conventional positive-pressure ventilation could not be made effective by increasing the positive end-expiratory pressure level to equal the mean pressure during high-frequency oscillatory ventilation. Sustained inflations on conventional positive-pressure ventilation remained ineffective up to positive end-expiratory pressure levels of 17.5 cm H2O. In lavaged rabbits, sustained inflations increased respiratory system compliance 49 +/- 14% during high-frequency oscillatory ventilation and 0 +/- 3% during conventional positive-pressure ventilation. Sustained inflations increased compliance significantly during conventional positive-pressure ventilation only when ventilating with tidal volumes of 7 mL/kg and low end-expiratory pressure. CONCLUSIONS: Active recruitment of lung volume during high-frequency oscillatory ventilation appears necessary, because small pressure/volume cycles adequate to support high-frequency gas transport are not able to reexpand atelectatic lung units without the aid of a sustained inflation. We conclude that volume recruitment maneuvers improve respiratory system compliance substantially during high-frequency oscillatory ventilation at 15 Hz, but these maneuvers offer potential risk and no benefit during conventional positive-pressure ventilation with large tidal volumes or when using smaller tidal volumes and high levels of positive end-expiratory pressure.

Optimizing alveolar expansion prolongs the effectiveness of exogenous surfactant therapy in the adult rabbit.

We evaluated four ventilator patterns after the administration of 80 mg/kg bovine lipid extract surfactant (LES) to anesthetized, paralyzed, saline-lavaged New Zealand white rabbits. Two ventilator types were compared: high frequency oscillatory ventilation (HFO) versus conventional mechanical ventilation (CMV), each at high (HI) and low (LO) end-expiratory lung volumes (EELV); n = 6, each group; treatment duration = 4 h. Target PaO2 ranges were > 350 mm Hg for groups with high EELV (i.e., HFO-HI and CMV-HI) and 70 to 100 mm Hg for those with low EELV (i.e., HFO-LO and CMV-LO). Ventilator pressures were limited to < or = 39/9 cm H2O in the CMV-HI group. Five of six CMV-HI-treated animals did not maintain target PaO2 levels. Both ventilator type and strategy influenced outcome significantly. Animals managed with HFO had higher mean arterial pressures (p = 0.004), lower mean airway pressures (Paw) (p < 0.00008) and HCO3- requirements (p < 0.02), larger inflation (p = 0.003) and deflation (p < 0.00001) respiratory system volumes at 10 cm inflation pressure, and higher lung lamellar body (p = 0.0006) and lavage fluid (p = 0.003) phospholipid quantities than did CMV-treated animals. The deflation P-V curve (p = 0.0004), lamellar body (p < 0.00001) and lavage fluid (p = 0.0002) phospholipid levels were superior after the high EELV strategy. We conclude that ventilator pattern strongly influences exogenous surfactant efficacy. Benefits arise from keeping EELV high enough to prevent atelectasis and using small (approximately 2 ml/kg) tidal volumes to prevent overdistension.(ABSTRACT TRUNCATED AT 250 WORDS)

The association between preterm newborn hypotension and hypoxemia and outcome during the first year.

Ninety-eight newborn infants, less than 34 weeks at birth, were studied to examine the relationship between newborn hypotension and hypoxemia and brain damage. Heart rate, blood pressure and oxygen tension were recorded continuously during the 96 h following delivery. Outcome measures included neuropathology in children who died, and motor and cognitive development at one year corrected age in children who survived. There were 22 children with a minor and 27 with a major abnormal outcome. There was a relationship between newborn hypotension, newborn hypoxemia and low birth weight, and a major abnormal outcome. The probability of a major abnormal outcome increased from 8% in newborns with no hypotension or hypoxemia, to 53% in children with both hypotension and hypoxemia. These findings support the contention that combinations of sustained newborn hypotension and hypoxemia are important factors in the development of brain damage, accounting for a major abnormal outcome.

Volume recruitment maneuvers are less deleterious than persistent low lung volumes in the atelectasis-prone rabbit lung during high-frequency oscillation.

OBJECTIVES: To test whether the pulmonary risk of repeated volume recruitment is greater or less than the risk associated with unreversed atelectasis during 6 hrs of high-frequency oscillatory ventilation in the atelectasis-prone rabbit lung. DESIGN: Prospective, controlled, randomized comparison over 6 hrs of ventilator management. SETTING: Laboratory. SUBJECTS: Twenty-eight adult New Zealand white male rabbits (weight 2.3 to 2.8 kg). BACKGROUND: Controversy exists over whether high-frequency oscillatory ventilation should be used with volume recruitment maneuvers in the atelectasis-prone lung, or be used at low mean and peak pressures without volume recruitment to avoid the risks of even transient pulmonary overdistention. Potential risks and benefits accompany both alternatives. INTERVENTIONS: We evaluated the pulmonary effects of three high-frequency oscillatory ventilation protocols in anesthetized rabbits made surfactant deficient by saline lavage, using animals ventilated with conventional positive-pressure ventilation with positive end-expiratory pressure as a reference group; n = 5 in each group. The three high-frequency oscillatory ventilation groups were ventilated for 6 hrs at 15 Hz (900 breaths/min), FIO2 = 1.0. The repeated stretch group received 15-sec sustained inflations at 30 cm H2O mean airway pressure every 20 mins, with maintenance mean airway pressure sufficient to keep PaO2 > 350 torr (46.7 kPa). The repeated deflation group was maintained at levels that produced PaO2 70 to 120 torr (9.3 to 16 kPa), with the endotracheal tube opened to atmospheric pressure for 15 secs every 20 mins. Animals in the repeated stretch after deflations group were managed as in the repeated stretch protocol but each sustained inflation was preceded by a 15-sec deflation to functional residual capacity. The conventional positive-pressure ventilation group was ventilated at rates of 30 to 100 breaths/min, keeping PaO2 70 to 120 torr (9.3 to 16 kPa). End-points included terminal functional residual capacity and a compliance index computed from respiratory system pressure-volume curves. MEASUREMENTS AND MAIN RESULTS: After 6 hrs of ventilation, respiratory system compliance in the repeated stretch group had returned to control values (1.35 +/- 0.18 [SD] mL/kg/cm H2O). Respiratory system compliance was significantly less than this number in both the repeated deflation (0.89 +/- 0.08) and repeated stretch after deflations (1.24 +/- 0.22) groups (p < .05). Respiratory system compliance after 3 hrs of conventional positive-pressure ventilation decreased to 0.34 +/- 0.10 mL/kg/cm H2O. Functional residual capacity changes paralleled these changes of respiratory system compliance. CONCLUSIONS: These data demonstrate that the potential pulmonary risk of repeated lung stretch during volume recruitment is significantly less than the damage arising from the avoidance of such maneuvers in lungs in which alveolar recruitment is possible. We conclude that sustained inflations during high-frequency oscillatory ventilation produce the benefits of increased oxygenation for a given mean airway pressure plus decreased progression of lung injury.

Middle cerebral artery blood flow velocity in the newborn following delivery.

Ninety-five normally grown term and preterm newborns were examined to determine the means and prediction limits of cerebral blood flow velocity following delivery and to examine the relationship of systemic blood pressure to cerebral blood flow velocity. Doppler blood flow velocity was observed during the four days following delivery. Continuous measures of blood pressure and heart rate were recorded concurrently. Mean peak systolic and end diastolic blood flow velocity immediately following delivery was 43.2 and 9.3 cm/sec for term newborn, and 31.8 and 3.3 cm/sec for preterm newborn. During the 24 h following delivery there was no change of peak systolic blood flow velocity but a two to three fold increase of end diastolic blood flow velocity in the term and preterm newborn. The reference limits for peak systolic and end diastolic blood flow velocity provide criteria to define abnormal increases and decreases of blood flow velocity. During the 24 h following delivery, increasing diastolic blood pressure was associated with increasing end diastolic blood flow velocity independent of birth weight and time following delivery. Also there was a significant correlation between systemic pressure pulsatile index and middle cerebral artery blood flow velocity pulsatile index. Thus systemic blood pressure pulsatility must be recognized as distinct from other intracerebral influences on cerebral blood flow velocity regulation in the newborn.

Dexamethasone therapy for bronchopulmonary dysplasia: improved respiratory mechanics without adrenal suppression.

The purpose of the present study was to examine the pattern of changes in respiratory system mechanics induced by dexamethasone (Dex) in infants with bronchopulmonary dysplasia (BPD) and to determine whether dosages that produce these changes induce adrenal suppression. We examined mechanics in seven ventilator-dependent premature infants (age, 33 +/- 4.8 days) with BPD, before and daily during Dex therapy. Dex (0.5 mg/kg/day) was given intravenously for 7 days unless complications necessitated early termination. Respiratory system resistance (Rrs) and compliance (Crs) were measured by the passive expiratory flow-volume technique during the course of dexamethasone therapy or until extubation. Adrenocorticotrophic hormone (ACTH) stimulation tests were done at baseline and following Dex therapy to evaluate adrenal function. Dex therapy caused a 77 +/- 18% increase in Crs (from 0.97 +/- 0.09 SEM mL/cmH2O to 1.6 +/- 0.16 mL/cmH2O; P less than 0.025) and a 33 +/- 5% decrease in Rrs (from 0.20 +/- 0.02 cmH2O/mL/s to 0.14 +/- 0.01 cmH2O/mL/s; P less than 0.01). Concurrently, ventilator rate, mean airway pressure, and FIO2 all decreased significantly (P less than 0.025). Extubation occurred later in infants with the lowest Crs and highest Rrs at baseline. At extubation, all Crs values were greater than 1.33 mL/cmH2O and Rrs values were less than 0.15 cmH2O/mL/s. Systolic blood pressure increased from 61 +/- 6.3 mmHg to 84 +/- 17 mmHg, 72-96 h after the start of Dex (P less than 0.025). There were no episodes of culture-positive sepsis. Neither basal nor ACTH-stimulated levels of cortisol were suppressed as a result of Dex therapy (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotension and hypoxemia in the preterm newborn during the four days following delivery identify infants at risk of echosonographically demonstrable cerebral lesions.

This prospective study of 130 preterm newborns at less than 34 weeks gestational age has examined the predictive value of abnormalities in continuously recorded newborn blood pressure, heart rate, and oxygen tension during the 4 d following delivery for echosonographically demonstrable cerebral lesions (EDCL) identified in the infant by six months corrected age. EDCL consisting of intraventricular hemorrhage, ventriculomegaly, or hyperechoic parenchymal lesions in the brain were identified in 44 preterm newborns (34%). The incidence of EDCL in preterm newborns with no hypotension or hypoxemia was 13%. The incidence of EDCL was significantly increased in preterm newborns with either hypotension or hypoxemia. The probability of EDCL exceeded 50% when the total exposure to either hypotension or hypoxemia during the 4 d exceeded 50 mmHg-hours, or when newborn hypotension and hypoxemia occurred concurrently. No relationship to hypertension, bradycardia, or tachycardia was detected. These findings indicate that hypotension and hypoxemia in the preterm newborn during the 4 d following delivery are useful risk markers of EDCL.

Blood pressure and heart rate of the preterm newborn following delivery.

Thirty-five preterm newborns were studied to determine the mean blood pressure and heart rate of preterm newborns less than 1500 gm and greater than or equal to 1500 gm at birth. Systemic blood pressure increased and heart rate decreased with increasing maturity at birth. Both systemic blood pressure and heart rate increased during the four days following delivery. The 95% prediction limits of stable preterm newborns less than 1500 gm and greater than or equal to 1500 gm at birth are useful criteria to define hypertension and hypotension, as well as tachycardia and bradycardia.

Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia.

Although the muscarinic antagonist Ipratropium bromide is used clinically as a bronchodilator in infants ventilated because of bronchopulmonary dysplasia (BPD), no studies have compared the response or efficacy of different dosages or its effectiveness in combination with beta-adrenergic agonists. We measured the response of respiratory system mechanics in 10 ventilated infants (25 +/- 2 days of age) to 75, 125, and 175 micrograms ipratropium bromide (IB), 125 micrograms IB plus 0.04 mg salbutamol (SAL), 175 micrograms IB plus 0.04 mg SAL, and saline vehicle, delivered via nebulizer into the ventilator circuit. Respiratory system resistance (Rrs) and compliance (Crs) were measured by the passive flow-volume technique. Rrs and Crs were measured before and at 1 to 2 h and at 4 h after delivery of the five drug dosages or saline. All six studies were completed within a 72-h period. Saline had no significant effect on mechanics. Significant responses to ipratropium alone were seen only after 175 micrograms where Rrs decreased 20 +/- 3% (SEM) (p less than 0.05) at 1 to 2 h and 16 +/- 5% (p less than 0.05) at 4 h. After 125 micrograms IB + SAL and 175 micrograms IB + SAL, Rrs was significantly decreased both at 1 to 2 h and at 4 h, and Crs was significantly increased 20 +/- 6% and 20 +/- 4%, respectively, at 1 to 2 h. The greatest decrease in Rrs (26 +/- 6%) was seen 1 to 2 h after 175 micrograms IB + salbutamol.(ABSTRACT TRUNCATED AT 250 WORDS)

A clinical comparison of indices of pulmonary gas exchange with changes in the inspired oxygen concentration.

Several indices have been introduced as convenient alternatives to calculation of the physiological shunt fraction (Qs/QT) for the assessment of pulmonary gas exchange. These include: the arterial-alveolar oxygen tension ratio (a/APO2), the arterial oxygen tension-inspired oxygen concentration ratio (PaO2/FIO2), the respiratory index (RI), [A-a)DO2/PaO2) and the alveolar-arterial oxygen tension difference [A-a)Do2). These indices are in use clinically despite the fact that they may not accurately predict gas exchange in situations where FIO2, Qs/QT or arterial-venous oxygen content is changing. The clinical stability of each of these indices, relative to the behaviour of the physiological shunt, was therefore investigated prospectively in ten mechanically ventilated postoperative adults as FIO2 was varied from 0.30 to 1.00. None of the indices studied reliably reflected the behaviour of the physiological shunt. As FIO2 was increased incrementally from 0.30 to 1.00, 42 to 55 per cent of the measured changes in these indices were opposite in direction to the corresponding changes in the physiological shunt. The maximum magnitudes of the opposite changes were substantial; 24 and 22 per cent for the a/APO2 and PaO2/FIO2 ratio respectively, 67 per cent for the RI and 101 per cent for the (A-a)DO2. We conclude that the use of any of these indices for clinical assessment of a patient's gas exchange defect when FIO2 is varying can be substantially misleading.

Lung volume maintenance prevents lung injury during high frequency oscillatory ventilation in surfactant-deficient rabbits.

Controversy exists whether high frequency oscillatory ventilation with an active expiratory phase (HFO-A) should be used at low ventilator pressures or high alveolar volumes to minimize lung injury in the atelectasis-prone lung. We therefore ventilated 20 anesthetized, tracheostomized rabbits made surfactant-deficient by lung lavage in 1 of 3 ways: HFO-A at a high lung volume (HFO-A/HI), HFO-A at a low lung volume (HFO-A/LO), or conventional mechanical ventilation (CMV); all received 100% oxygen for 7 h. We examined oxygenation, lung mechanics, and lung pathology. Arterial oxygenation in the HFO-A/HI rabbits was kept greater than 350 mm Hg. Mean lung volume above FRC in these animals was 23.4 ml/kg. In rabbits ventilated with HFO-A/LO and CMV, arterial oxygen tensions were 70 to 100 mm Hg. Mean lung volumes were 7.8 and 4.3 ml/kg, respectively. Total respiratory system pressure-volume curves (P-V curves) showed no change from baseline in the HFO-A/HI group after 7 h of ventilation. The low lung volume groups (HFO-A/LO and CMV) showed a diminution in hysteresis of their P-V curves, lower total respiratory system compliance, more hyaline membranes and severe airway epithelial damage. (All changes significant with p less than 0.05). We conclude that maintenance of alveolar volume is a key mechanism in the prevention of lung injury during mechanical ventilation of the atelectasis-prone lung. For optimal outcome using high frequency oscillatory ventilation, alveoli must be actively reexpanded and then kept expanded using appropriate mean airway pressures.

Lung volume recruitment during high-frequency oscillation in atelectasis-prone rabbits.

In diffuse lung injury, optimal oxygenation occurs with high-frequency oscillatory ventilation (HFO-A, where A is active expiratory phase) when sustained inflations (SI) are applied periodically to recruit lung volume. Theoretically pulsed pressures may be safer and more effective than static pressures for reexpanding alveoli. We compared the increases in lung volume and arterial PO2 (PaO2) induced by 30-s increases in mean airway pressure in six New Zealand White rabbits made atelectasis prone by saline lavage plus 1 h of conventional ventilation. Pulsatile SI's (HFO-A left on during increase in mean pressure) of delta PSI = 5, 10, and 15 cmH2O and static SI's (HFO-A off during SI) of delta PSI = 5, 10, 15, and 20 cmH2O were delivered in random order. Lungs were ventilated at 15 Hz, inspired fractional concentration of O2 = 1.0, and mean airway pressure 15-20 cmH2O between test periods and deflated to functional residual capacity before each SI to standardize volume history. With both maneuvers, increases in lung volume and PaO2 induced by SI's were proportional to the magnitude of the SI (P less than 0.001) in all cases. Pulsatile SI's consistently increased lung volume and PaO2 more than static SI's having the same delta PSI (P less than 0.005) such that any given target PaO2 or change in volume (delta V) was achieved at 5 cmH2O less mean pressure with the pulsatile maneuver. Respiratory system compliance increased after both types of SI. Oxygenation and lung volume changes at 5 min were related with r = 0.58 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

High-frequency oscillatory ventilation in premature infants with respiratory failure: a preliminary report.

High-frequency ventilation has been used successfully to manage life-threatening complications in premature infants with lung disease. Here we report a preliminary assessment of the efficacy and safety of high-frequency oscillatory ventilation-(HFO-A, A = active expiratory phase) when used as a primary ventilator in 11 infants of 24-34 weeks gestation who required ventilatory support. HFO-A was initiated after no more than 5.5 hr of conventional mechanical ventilation (CMV). HFO-A at 15 Hz was used for 12-203 hr following a protocol designed for rapid reduction of FI02 requirements. CO2 elimination was easily achieved in all infants. Oxygenation was satisfactory, except in one infant with congenital pneumonia. There were four deaths during HFO-A: two pulmonary (one congenital pneumonia; one pulmonary hemorrhage) and two nonpulmonary. The HFO-A protocol utilized lung volume recruitment maneuvers plus mean airway pressures (MAwP) greater than those generally used early in the course of CMV. Therefore, in a subset of infants less than or equal to 29 weeks' gestation with respiratory distress syndrome (RDS), ventilator pressures and gas exchange were compared in infants treated with either HFO-A or CMV. Maximum MAwP levels were reached earlier in six infants on HFO-A (5.2 +/- 2.5 hr; mean +/- SD) than in a comparable group of 9 CMV-treated infants (36 +/- 1 hr). This earlier use of high MAwP lowered the FI02 to less than 0.4 by 18.9 +/- 11 hr with HFO-A as compared with 64 +/- 6 hr using CMV, without any evidence of an increase in pulmonary complications. There were 17 complications in the nine CMV-treated infants; and four in the six HFO-A treated ones. We conclude that HFO-A, instituted early and used with a protocol designed for early reduction in FI02 requirements, demonstrates sufficient efficacy and safety to warrant further clinical trials in the routine management of infant RDS.