The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial.

OBJECTIVE: To determine whether indomethacin tocolysis in preterm labour is associated with a better perinatal outcome than placebo. DESIGN: A randomised placebo-controlled trial. SETTING: Two university teaching hospitals with level three neonatal intensive care units. POPULATION: Women in preterm labour with intact membranes between 23 and 30 weeks of gestation. METHODS: Random allocation to tocolysis with indomethacin (50 mg followed by 25 mg 6 hourly for 48 hours) or placebo in a double-blind fashion. MAIN OUTCOME MEASURES: The primary outcome, perinatal mortality or severe neonatal morbidity, was defined as perinatal death, necrotising enterocolitis, bronchopulmonary dysplasia, intraventricular haemorrhage or peri-ventricular leucomalacia. Data were analysed using odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Between March 1995 and February 1996, 34 women (39 babies) were recruited. The baseline characteristics of the two groups were similar. No patient was lost to follow up. In the indomethacin group, gestation was prolonged by > 48 hours in 13/16 (81%) of women vs 10/18 (56%) in the placebo group. The incidence of perinatal mortality or severe neonatal morbidity was not significantly different between the groups, but occurred in twice as many babies in the indomethacin group as in the placebo group--6/19 (32%) vs 3/20 (15%) OR (95% CI) 2.62 (0.44-18.8). There was one perinatal death, of a baby delivered at 24 weeks of gestation. This occurred in the indomethacin group. CONCLUSION: There is no evidence that indomethacin tocolysis is beneficial, and further trials are needed to assess the impact of indomethacin tocolysis in preterm labour.

Concordance and precision of dual X-ray absorptiometry with a 10 s scan.

Development of dual energy X-ray absorptiometry (DXA) scanners with multidetector array technology has resulted in greatly shortened scanning times. The Hologic QDR-4500 includes an ultrafast (10 s) "turbo" scan mode recommended by the manufacturer for fast screening studies or as an aid to positioning the patient prior to scanning using the normal fast (30 s), medium (1 min) or high definition (2 min) modes. The suitability of the turbo mode for use in routine clinical studies was assessed by examining the concordance of bone mineral density (BMD) measurements obtained in this mode with measurements obtained using the three normal scanning modes. Studies in 151 female patients showed statistically significant discrepancies in four out of the six scan sites studied with systematic differences of 2.9% and 3.1% being observed for the posteroanterior (PA) spine and intertrochanteric region of the hip, respectively. In vivo precision for the 10 s scan found by performing duplicate measurements on 37 patients had a coefficient of variation of 1.3% for PA spine and 2.5% for femoral neck BMD. An investigation of the dependence of precision on body mass index (BMI) shows that the precision of spine and hip BMD was adversely affected with increasing BMI but the trend was statistically significant only in the spine. It was concluded that turbo mode scans are acceptable for routine clinical studies of the spine and hip but should not be used for longitudinal studies or patients with BMI greater than 30 kg m-2.

Sequential changes in pulmonary epithelial permeability after birth in term and preterm rabbits.

We assessed sequential changes in the permeability properties of the pulmonary epithelium in spontaneously breathing, newborn term (30 days of gestation) and preterm (28 days) rabbit pups, using the rate of pulmonary clearance of 99mTc-DTPA (MW = 492) as an index of permeability. In term rabbits, clearance was faster at 1 h of age than at hourly timepoints thereafter (p < 0.05). In preterm rabbits, clearance rates measured from 1 to 5 h after birth were not quite significantly different (p = 0.0519) although the trend to slower clearance with increasing time after birth was significant. When term and preterm rabbits were compared, clearance was similar at 1 h after birth but was faster at both 2 and 3 h in the preterm rabbits (p < 0.05). Pulmonary epithelial permeability appears to be increased in the immediate postnatal period and the duration of increased permeability is longer in preterm rabbits. Because lung water content at birth is greater in the preterm rabbits, we speculate that the permeability changes may be associated with clearance of fetal lung liquid.

Tibial hemimelia and tetralogy of Fallot associated with first trimester exposure to amantadine.

Although amantadine hydrochloride has been extensively used for the prevention of influenza A2, few data exist regarding its safety in pregnancy. We report the outcome of a pregnancy during which the mother was treated with amantadine in the first trimester. The infant, born at 29 weeks gestation, has tetralogy of Fallot and tibial hemimelia. Follow-up of the four prospective cases known to date to the Motherisk Program in Toronto did not identify any abnormalities.

99mTc-DTPA clearance in preterm lambs. Effect of surfactant therapy and ventilation.

Surfactant therapy and high-frequency oscillatory ventilation (HFO) may minimize damage to the pulmonary epithelium of surfactant-deficient newborns. Using pulmonary clearance of insufflated, aerosolized 99mTc-DTPA (molecular weight 492) as an index of lung epithelial permeability, we examined the effects of 300 mg bovine lipid extract surfactant (S) administered at birth to preterm lambs ventilated by either HFO or conventional mechanical ventilation (CMV). Four groups of lambs, delivered by cesarean section at 129 to 133 days of gestation, were studied: (1) HFO + S, (2) CMV + S, (3) HFO, and (4) CMV. 99mTc-DTPA clearance was assessed at 2, 4, and 5.5 h after birth. Surfactant treatment improved oxygenation and lung pressure-volume relationships, with oxygenation best maintained by the combination of HFO + S. All groups had similar biexponential clearance curves at the three time points, however, and there was no significant difference in the mean rates of clearance (k) between the four groups at 2 h (k = 6.03 +/- 0.60 [SEM], 7.04 +/- 1.46, 5.67 +/- 0.91, and 7.23 +/- 0.97 %/min for Groups 1, 2, 3, and 4, respectively), 4 h (k = 6.95 +/- 0.77, 5.60 +/- 0.51, 6.39 +/- 0.64, and 6.78 +/- 1.71 %/min), and 5.5 h (k = 7.43 +/- 0.78, 6.08 +/- 0.80, 7.86 +/- 0.90, and 7.95 +/- 0.66 %/min). These data suggest that neither surfactant nor HFO significantly alters pulmonary epithelial permeability to a small radiolabeled molecule in preterm lambs.

Fibrinogen depletion and control of permeability in oleic acid lung injury.

To determine if the biphasic pulmonary clearance of aerosolized 99mTc diethylene penta acetate (99mTc-DTPA) observed in oleic acid lung injury represents acute epithelial damage followed by sealing as a result of intra-alveolar fibrin deposition, we examined the effect of fibrinogen depletion. 99mTc-DTPA clearance was assessed in three groups of rabbits: Group 1, normal fibrinogen + oleic acid injury; Group 2, fibrinogen-depleted + oleic acid injury; Group 3, fibrinogen-depleted with no oleic acid injury. In Group 3 animals with no lung injury, the 99mTc-DTPA clearance rate, expressed as k, the percent decrease in thoracic radioactivity, was similar to that previously reported for healthy rabbits (k = 1.16 +/- 0.57%/min, mean +/- SD). Oleic acid administration to Groups 1 and 2 resulted in significantly faster clearance rates, with identical biphasic curves in all animals, irrespective of fibrinogen status. There were no significant differences between either the initial fast phase (k, Group 1 = 5.26 +/- 1.83%/min, Group 2 = 5.70 +/- 1.77%/min) or the subsequent slow phase (k, Group 1 = 1.67 +/- 0.63%/min, Group 2 = 1.57 +/- 0.55%/min, p greater than 0.05). On histologic examination, Groups 1 and 2 showed greater cellular interstitial infiltrate, alveolar edema, and hemorrhage than did Group 3. Fibrinogen depletion plus oleic acid injury resulted in greater alveolar cellular exudate, edema, and hemorrhage than did either oleic acid or fibrinogen depletion alone. We conclude that fibrinogen is not necessary to produce biphasic 99mTc-DTPA clearance in oleic acid lung injury.

Effect of increased surface tension and assisted ventilation on 99mTc-DTPA clearance.

Experiments were performed to determine the effects of conventional mechanical ventilation (CMV) and high-frequency oscillation (HFO) on the clearance of technetium-99m-labeled diethylenetriamine pentaacetate (99mTc-DTPA) from lungs with altered surface tension properties. A submicronic aerosol of 99mTc-DTPA was insufflated into the lungs of anesthetized, tracheotomized rabbits before and 1 h after the administration of the aerosolized detergent dioctyl sodium sulfosuccinate (OT). Rabbits were ventilated by one of four methods: 1) spontaneous breathing; 2) CMV at 12 cmH2O mean airway pressure (MAP); 3) HFO at 12 cmH2O MAP; 4) HFO at 16 cmH2O MAP. Administration of OT resulted in decreased arterial PO2 (PaO2), increased lung wet-to-dry weight ratios, and abnormal lung pressure-volume relationships, compatible with increased surface tension. 99mTc-DTPA clearance was accelerated after OT in all groups. The post-OT rate of clearance (k) was significantly faster (P less than 0.05) in the CMV at 12 cmH2O MAP [k = 7.57 +/- 0.71%/min (SE)] and HFO at 16 cmH2O MAP (k = 6.92 +/- 0.61%/min) groups than in the spontaneously breathing (k = 4.32 +/- 0.55%/min) and HFO at 12 cmH2O MAP (4.68 +/- 0.63%/min) groups. The clearance curves were biexponential in the former two groups. We conclude that pulmonary clearance of 99mTc-DTPA is accelerated in high surface tension pulmonary edema, and this effect is enhanced by both conventional ventilation and HFO at high mean airway pressure.

Pulmonary haemodynamics during exercise after low and high doses of acetylsalicylic acid in sheep.

Despite comparable increases in cardiac output there is a greater reduction in pulmonary vascular resistance (PVR) in sheep during exercise than in dog or man. The mechanism for this marked reduction in PVR in sheep is unknown. To assess the role of arachidonic acid metabolites in producing this low PVR we measured the effect of intravenous acetylsalicylic acid (ASA, 10 mg/kg) on PVR at rest and during exercise in sheep. ASA caused a slight rise in resting PVR (p less than 0.05), but did not affect the exercise-induced decrease in PVR. High-dose ASA (100 mg/kg), presumably sufficient to block the lipoxygenase pathway produced the same responses as low-dose ASA which should only block the cyclo-oxygenase pathway. Products of the cyclo-oxygenase and lipoxygenase pathways which include vasodilator prostaglandins, have only a minor role in maintaining low pulmonary vascular resistance at rest and have no demonstrable role in the reduced PVR that occurs during exercise in sheep.

Measurement of pulmonary clearance of radioaerosol using a portable sodium iodide probe.

To determine whether a portable sodium iodide (NaI) probe could provide a valid measure of the pulmonary half-life (T1/2) of aerosolized technetium-99m-diethylenetriaminepentaacetate (99mTc-DTPA, mol wt = 492) in small chests, we measured pulmonary clearance in rabbits using a gamma-scintillation camera and the portable probe. In 10 experiments the lungs of New Zealand White rabbits were insufflated with aerosolized 99mTc-DTPA (0.6 mum aerodynamic mass median diameter) and then simultaneously imaged with the gamma-camera and the probe positioned over the upper right lung. In an additional 12 experiments, alveolar-capillary membrane permeability was increased by either intratracheal instillation of 0.1 N hydrochloric acid (HCl) or intravenous injection of 100 mg/kg of oleic acid. All animals tolerated the procedure. There was a significant decrease in pulmonary T1/2 in both the HCl group (53.4 +/- 10.4 min, mean +/- SE) and the oleic acid group (14.7 +/- 2.3 min) when compared with control (127.5 +/- 18.1 min). When we compared the T 1/2 of the right lung determined by the gamma-camera with that measured by the probe, the correlation coefficient was 0.95. Potential nonpulmonary contributions to thoracic radioactivity were not significant. We conclude that a portable NaI probe is a valid means of determining T 1/2 of 99mTc-DTPA in small chests when compared with a gamma-camera and can detect increases in the permeability of the alveolar-capillary membrane to small solutes.

Pulmonary epithelial permeability in hyaline-membrane disease.

Neonatal hyaline-membrane disease is complicated by pulmonary edema, yet left atrial pressures are normal. Alveolar-capillary-membrane permeability may therefore be increased. To assess pulmonary epithelial permeability, we measured the pulmonary clearance and half-life of aerosolized 99mTc-diethylenetriamine pentacetate (99mTc-DTPA) on 31 occasions in 15 intubated premature infants with hyaline-membrane disease. Three infants with respiratory failure due to other diseases were studied on four occasions. All studies of infants with hyaline-membrane disease that were performed in the first 72 hours of life demonstrated a biphasic clearance curve with a rapid-phase half-life of 1.6 +/- 0.6 minutes (mean +/- S.D.). As these infants recovered, the curve became monophasic with a half-life of 56.0 +/- 32.1 minutes. Two infants remained dependent on oxygen and ventilator support and had persistent biphasic curves with a rapid-phase half-life of 1.5 +/- 0.7 minutes. All infants without hyaline-membrane disease had monophasic curves with a half-life of 65.4 +/- 33.6 minutes. Using a similar technique, we observed that newborn lambs and piglets have a monophasic pulmonary clearance of 99mTc-DTPA (114 +/- 59 minutes in lambs and 52.5 +/- 16.3 minutes in piglets). We conclude that the lungs of neonates with hyaline-membrane disease are abnormally permeable to small solutes and that this abnormality persists in infants with subsequent chronic lung disease.

Effects of exercise on lung lymph flow in sheep and goats during normoxia and hypoxia.

Vigorous exercise causes a marked increase in cardiac output with only a minimal increase in measureable pulmonary vascular pressures. These changes in pulmonary hemodynamics should affect lung water and solute movement. On nine occasions, we measured the effect of normoxic exercise on lung lymph flow in four sheep and two goats with chronic lymph fistulas (wt = 15-25 kg). In addition, lymph flow was also measured on five occasions in sheep during exercise at reduced barometric pressures (430 and 380 mmHg). During normobaria, the animals ran at 3-5 km/h with 0-10% elevation of the treadmill for 15 to 85 min. Exercise on average caused a 100% increase in cardiac output, a 140% increase in lung lymph flow, and a slight but significant reduction in lymph to plasma concentration ratio (l/p) for total protein and albumin (mol wt = 70,000). There was a significant linear correlation between lymph flow and cardiac output (r = 0.87, P less than 0.01). There was no change in l/p for IgG (mol wt = 150,000) or IgM (mol wt = 900,000) and no significant change in mean pulmonary arterial (Ppa) or mean left atrial (Pla) pressures. Transition from normobaria to hypobaria caused an increase in Ppa but no change in Pla, cardiac output, or lymph flow. Exercise during hypobaria caused increases in lymph flow that were qualitatively similar to changes observed during normobaric exercise: there was a 60% increase in cardiac output, a 90% increase in lymph flow, and an 11% reduction in l/p for total protein. There was no change in l/p for albumin, IgG, or IgM, and no further change in Ppa. The increased lymph flow during normoxic and hypobaric exercise is best explained by an increase in pulmonary vascular surface area for fluid and protein exchange. Our results suggest that the normal ovine lung has the potential to nearly triple the amount of perfused microvascular surface area. This speculation is relevant to the interpretation of lymph flow data from other experiments.

Fulminating haemophilus influenzae b meningitis.

Haemophilus influenzae type b (HIb) is the most common cause of bacterial meningitis in children with a mortality rate ranging from 1.6% to 14%. Most patients have a 2-3 day history of symptoms prior to admission. A few have fulminating disease with rapid neurological deterioration. Review of 191 cases of HIb meningitis revealed a mortality rate of 2.1% but all who died had fulminating meningitis (FM). Four of six patients with FM died. FM patients had symptoms for less than 24 hours before rapid neurological deterioration with increased ICP, seizures, coma and/or respiratory arrest. Review of 10 FM cases revealed that on admission, 5 had hypotension, 3 had thrombocytopenia, and 8 had coma. Typical CSF changes were seen in only 7. All fatal cases died within 24 hours. Brain swelling and tonsillar herniation were found at autopsy. SDS-PAGE outer membrane protein subtyping did not show one "killer strain". Animal and autopsy data suggest that diminished CSF outflow and cerebral edema contribute to increased ICP. To improve survival of FM patients, initial treatment must (1) decrease ICP below levels impairing cerebral perfusion, (2) maintain adequate ventilation and blood pressure, and include (3) LP when stable, (4) antibiotics, and (5) close monitoring. Utilizing these principles, two FM patients survived without major sequelae.

Effect of high-frequency oscillation on lung lymph flow.

We investigated the effect of high-frequency oscillation (HFO) on lung lymphatic function under normal conditions and when lung lymph flow was increased by air microembolization. In six experiments, sheep and goats with chronic lung lymph fistulas and vascular catheters were anesthetized, paralyzed, intubated, and ventilated according to the following protocol: 1) intermittent positive-pressure ventilation (IPPV) for 1 h, 2) HFO with a frequency of 15 Hz and an estimated tidal volume of 1-2 ml/kg for 1-2 h, and 3) IPPV for 0.5 h. Ventilator settings were adjusted to maintain arterial Po2 above 100 Torr and a normal arterial Pco2. Vascular, esophageal, and mean airway pressures were monitored continuously. Lymph flow and cardiac output were recorded every 15 min. With this protocol, there were no changes in pulmonary vascular or esophageal pressures, and lymph flow remained stable throughout the experiment. In an additional five experiments, air microemboli were infused for approximately 30 min during HFO. Left atrial pressure was unchanged and lymph flow tripled. This response was qualitatively and quantitatively similar to that previously reported for unanesthetized spontaneously breathing sheep. We conclude that HFO does not impair lymphatic function under resting conditions and that lymphatics retain their ability to increase water and protein clearance during HFO.