Thomas A. Hazinski

Experimental Effects of Chloral Hydrate on Ventilatory Response to Hypoxia and Hypercarbia

Summary: The effect of chloral hydrate (CH)-induced sleep on inspiratory drive has not been systematically assessed. To determine the effects of CH on the ventilatory responses to hypercarbia and to hypoxia, nine unanesthetized adult rabbits with chronic tracheostomy were studied. We compared awake ventilatory measurements before CH to non-REM sleep assessments at 30, 60, 90, and 120 min after administration of 250 mg/kg of CH. There were no significant differences between any of these assessment intervals for respiratory rate, PACO2, PAO2 tidal volume (VT), minute volume, Ti/Ttot, or VTi. Hypercarbic ventilatory response slopes were not diminished at any of the CH-sleep intervals compared to the awake mean slope. In addition, the ventilatory response to hypoxia at PAO2 = 70 mm Hg (V70) and the hypoxic response slope demonstrated no significant decrease at any of the CH-sleep intervals. In summary, absence of any significant decrease in either hypercarbic or hypoxic ventilatory response after CH administration indicates absence of any CH effect on chemical inspiratory drive.Speculation: Sedation with chloral hydrate is an acceptable means of facilitating sleep for clinical assessments of chemical inspiratory drive. Chloral hydrate may also be the preferred drug whenever a sedative-hypnotic agent is necessary in patients with precarious pulmonary status or marginal central ventilatory drive.

Vitamin E does not prevent oxygen-induced lung injury in newborn lambs.

Summary: In newborn lambs, lung vascular permeability to protein increases after 3 days of continuous oxygen breathing. We studied six unanesthetized lambs that were less than 1 month old to see if intramuscular administration of vitamin E, an antioxidant, would prevent or lessen the severity of this oxygen-induced lung injury. To assess lung fluid balance, we measured pulmonary arterial and left atrial pressures, lung lymph flow, and concentrations of protein in lymph and plasma of lambs that received intramuscularly vitamin E, 20 mg/kg body weight, for 2 days before the experiment and then daily as they breathed pure oxygen. Despite a 10-fold increase in the plasma concentration of vitamin E (2.5 ± 0.4 μg/ml to 24.4 ± 2.9 μg/ml), pulmonary microvascular permeability to protein increased in all of the lambs within 3 days of sustained hyperoxia: lung lymph flow tripled, the concentration of protein in lymph increased, and the ratio of the albumin concentration to the globulin concentration in lymph, relative to that in plasma, decreased. Vascular pressures did not change significantly during the course of oxygen breathing. In four lambs, we injected [125I]-albumin into the right atrium and determined the time for specific activity in lymph to reach one-half that of plasma (half-equilibration). The time averaged 146 ± 21 min before oxygen breathing and 46 ± 7 min after 3 days to oxygen. These data provide clearcut evidence that severe endothelial injury occurred. All six lambs died of respiratory failure after 4 days or less in oxygen. Extra-vascular lung water per g of dry lung tissue was significantly greater in these lambs than in control lambs (5.88 ± 0.46 versus 4.72 ± 0.14).These results show that sustained hyperoxia increased trans-vascular movement of fluid and protein into the pulmonary inter-stitium and caused edema. The outcome of these studies was almost identical to that of previous experiments to which lambs continuously breathed oxygen but did not receive vitamin E. We conclude that vitamin E was not effective to protecting the lungs from microvascular injury.Speculation: These results suggest that administration of vitamin E to animals that are not deficient in vitamin E does not protect them from oxygen-induced lung injury.

Furosemide decreases ventilation in young rabbits

To test the hypothesis that furosemide would cause metabolic alkalosis and thus alveolar hypoventilation, normal rabbit pups were given either furosemide (4 mg/kg/day) or saline solution for the first 8 to 10 days of life. Pups given furosemide developed primary metabolic alkalosis and reduced ventilation, which resulted in secondary respiratory acidosis. Lung compliance was improved by furosemide, and the ventilatory response to CO2 was unaffected. KCl injection in alkalotic pups increased ventilation and decreased pH. The data show that conventional doses of furosemide can (1) cause metabolic alkalosis and reduce ventilation; (2) increase the PaCO2, which reflects changes in acid-base status and not changes in lung function; and (3) increase lung compliance, perhaps by decreasing lung water. When these effects occur in infants with chronic lung disease, the beneficial effect of furosemide may be obscured.

Effects of asphyxia on lung fluid balance in baby lambs.

The purpose of this study was to assess the effects of combined hypoxia and hypercapnia and of severe asphyxia on lung water balance and protein transport in newborn lambs. We studied ten 2-4-wk-old anesthetized lambs which were mechanically ventilated first with air for 2-3 h, then with 10-12% oxygen in nitrogen for 2-4 h, and then with 10-12% oxygen and 10-12% carbon dioxide in nitrogen for 2-4 h. Next we stopped their breathing for 1-2 min to produce severe asphyxia, after which we followed their recovery in air for 2-4 h. In 5 of the 10 lambs we intravenously injected radioactive albumin and measured its turnover time between plasma and lymph during the baseline period and after recovery from asphyxia. During alveolar hypoxia alone, mean pulmonary arterial pressure increased 60% and lung lymph flow increased 74%, whereas lymph protein concentration decreased from 3.47 +/- 0.13 to 2.83 +/- 0.15 g/dl. Cardiac output, left atrial pressure, and plasma protein concentration did not change. When carbon dioxide was added to the inspired gas mixture, pulmonary arterial pressure increased 22%, cardiac output increased 13%, lung lymph flow increased 33%, and lymph protein concentration decreased from 2.83 +/- 0.15 to 2.41 +/- 0.13 g/dl. Left atrial pressure and plasma protein concentration did not change. After 60-90 s of induced asphyxia, vascular pressures and lung lymph flow rapidly returned to values the same as those obtained during the baseline period. The turnover time for radioactive albumin between plasma and lymph was the same between the baseline and recovery periods (185 +/- 16 vs. 179 +/- 12 min). The ratio of albumin to globulin in lymph relative to the same ratio in plasma did not change during any phase of these experiments. Five lambs killed after recovery from asphyxia had significantly less blood and extravascular water in their lungs than control lambs had. We conclude that in the newborn lamb both alveolar hypoxia and alveolar hypoxia with hypercapnia increase lung lymph flow by increasing filtration pressure in the microcirculation, but neither hypoxia with hypercapnia nor brief severe asphyxia alters the protein permeability of the pulmonary microcirculation.

Increased sweat chloride levels associated with prostaglandin E1 infusion.

5. Hung W, Wright JC, Finkelstein JW, Blizzard RM: Salivary:serum ratios of I TM in cretinism. J Clin Endocrinol Metab 22:1151, 1962. 6. Spencer RP, Karimeddini MK: Decreased salivary gland accumulation of pertecbnetate in neonatal hypothyroidism. J Nucl Med 22:96, 1981. 7. McKusick VA: Mendelian inheritance in man, ed 6. Baltimore, 1983, Johns Hopkins University Press, p 663. 8. Stanbury JB, Chapman EM: Congenital hypothyroidism with goitre. Lancet 1:1162, 1960. 9. Gilboa Y, Ber A, Lewitus Z, Hasenfratz J, Tikva P: Goitrous myxedema due to .iodide trapping defect. Arch Intern Med 112:212, 1963. 10. Wolff J, Thompson RH, Robbins J: Congenital goitrous cretinism due to the absence of iodide-concentrating ability. J Clin Endocrinol Metab 24:699, 1964.

Estimation of ventilatory response to carbon dioxide in newborn infants using skin surface blood gas electrodes

Using only skin surface blood gas measurements, we calculated the ventilatory response to inhaled carbon dioxide from changes in skin surface PCO2 (PSCO2). This new method is based on the fact that if CO2 elimination is nearly constant, the change in alveolar ventilation from one steady state level to another is inversely proportional to the change in PSCO2. From this we derived a ventilatory ratio (VR) for 0%, 2%, and 4% CO2 breathing. A ventilatory response slope is then calculated from the three VR values, and is similar to a standard CO2 response slope. We serially studied 20 infants (28 to 40 weeks gestation) 2 to 9 weeks of age. Ten infants had serious apnea, ten did not. The infants breathed each test gas for 8 to 10 minutes during quiet sleep with skin surface electrodes attached. Infants with apnea were studied before and after apneic spells resolved. We found that apneic infants had a significantly reduced VR slope compared with that in the nonapneic infants, regardless of age. When apnea disappeared, the ventilatory ratio slope always increased into the range measured in nonapneic infants. In nonapneic infants the ventilatory ratio slope significantly increased with postnatal age. We conclude that infants with serious apnea have a reduced ventilatory response to CO2 and that the resolution of apnea is associated with the development of a normal CO2 response.

F2-ISOPROSTANES (F2I) IN TRACHEOBRONCHIAL ASPIRATE FLUID (TBAF) INDICATE ASSOCIATION BETWEEN INCREASED FIO2 AND LIPID PEROXIDATION IN THE LUNGS OF PREMATURE INFANTS. |[utrif]| 1957

F 2 -ISOPROSTANES (F 2 I) IN TRACHEOBRONCHIAL ASPIRATE FLUID (TBAF) INDICATE ASSOCIATION BETWEEN INCREASED FIO 2 AND LIPID PEROXIDATION IN THE LUNGS OF PREMATURE INFANTS. ▴ 1957

Lung fluid balance in hypoxic lambs

Summary: In spontaneously breathing newborn lambs, alveolar hypoxia increases lung microvascular pressure, which causes lung lymph flow to increase and the concentration of protein in lymph to decrease. To see if this response derives from hypoxia itself rather than from the change in breathing pattern that occurs during hypoxia, we measured lung vascular pressures, pleural pressure, cardiac output, and lung lymph flow in 12 anesthetized lambs that were ventilated at a fixed rate and tidal volume, first with air, then with 10-14% O2 in nitrogen. Alveolar hypoxia did not affect pleural pressure, but pulmonary arterial pressure increased from 19 to 32 torr, lung lymph flow increased from 2.20 to 3.83 ml/h and lymph protein concentration decreased from 3.4 to 2.8 g/dl. To be certain that the increased lymph flow associated with hypoxia is not simply the result of an acute release of fluid from the lungs and to assess the effects of carbon dioxide on lymph flow during hypoxia, we next studied six unanesthetized lambs kept hypoxic for a total of 12 h. After a 2-4-h period in air the lambs breathed 9-11% O2 in nitrogen for 2-4 h, then 8-11% O2 and 3-5% CO2 in nitrogen for 8-10 h. In these lambs we injected intravenously radioactive albumin and measured its uptake in lymph to see if sustained hypoxia alters microvascular permeability to protein in the lungs. In these experiments pulmonary arterial pressure increased from 17 to 37 torr, lung lymph flow increased from 1.74 to 3.28 ml/h, and lymph protein concentration decreased from 3.8 to 3.1 g/dl during hypoxia. Addition of CO2 to the inspired gas did not affect steady state lung lymph flow. Lymph flow remained elevated throughout the 12 h of alveolar hypoxia, and postmortem lung water determinations were not different from those of controls (4.65 ± 0.28 versus 4.72 ± 0.14 g/g dry bloodless lung). The time required for radioactive albumin to equilibrate in lymph at one-half the specific activity of plasma was no different before and during hypoxia (130 ± 7 versus 125 ± 11 min). We conclude that in the newborn lamb, alveolar hypoxia increases transvascular fluid filtration by increasing microvascular hydraulic pressure without altering microvascular permeability to protein. This response is independent of changes in pleural pressure or inspired carbon dioxide.

F 2 Isoprostanes (F 2 I) in Tracheobronchial Aspirate (TBA) Within 24 Hours After Birth Predict Bronchopulmonary Dysplasia (BPD) ♦ 1631

F 2 Isoprostanes (F 2 I) in Tracheobronchial Aspirate (TBA) Within 24 Hours After Birth Predict Bronchopulmonary Dysplasia (BPD) ♦ 1631

INCIDENCE OF HYPERTENSION IN OXYGEN-DEPENDENT INFANTS WITH BPD. † 1811

Systemic hypertension is said to occur in up to 50% of oxygen-dependent infants with BPD, and to be linked to the severity of pulmonary disease and/or to the use of certain drugs. To ascertain the current incidence of hypertension in such infants, we reviewed the records of all oxygen-dependent infants who attended our BPD Follow-up program from October 1995 through December 1996. Infants were evaluated every 1-4 weeks until supplemental oxygen therapy and other drugs had been discontinued for at least 1 month. Systolic blood pressure was obtained during each visit by the same individual using an automated oscillometric method; blood pressure was not recorded if the infant was uncooperative. The blood pressure of each infant was compared with published norms (Horan, Pediatrics 79:1, 1987). We defined hypertension as a systolic blood pressure > 95%ile for post-conceptional age on more than one occasion. As suggested by the Blood Pressure Task Force, we also identified those infants with high-normal blood pressure as those infants whose blood pressure was between the 90th and the 95th%iles on more than one occasion. We evaluated 132 blood pressures in 40 consecutive infants with BPD, 26 males and 14 females. Their birth weight averaged 1133±683 g (range: 480-4140) and gestational age was 28±4 weeks (range: 23-41). They were discharged from the NICU at 11±5 weeks of age and followed for an average of 22±18 wks (Range: 3-75). None of the infants was noted to be hypertensive in the NICU or at NICU discharge. Of the 40 infants, 2 (1 male, 1 female) had hypertension and 2 (1 male, 1 female) had high-normal blood pressure. In both males, the elevation in blood pressure was transient and resolved without therapy within 8 weeks of onset. One female had sustained hypertension and the other female had sustained high-normal blood pressure. For the entire group, if BP was compared to chronologic age instead of post-conceptional age, only one female of the 40 infants could be classified as hypertensive and one male had high-normal blood pressure. In the entire group, BP was not associated with BPD severity, renal or cardiovascular disease or the use of oxygen, diuretics, bronchodilators or corticosteroids. We conclude that, contrary to previous reports, hypertension occurs in less than 5% of oxygen-dependent infants with BPD and when it occurs, is unrelated to drugs or disease severity.