Breathing pattern, CO2 elimination and the absence of exhaled NO in freely diving Weddell seals.

UNLABELLED: Weddell seals undergo lung collapse during dives below 50 m depth. In order to explore the physiological mechanisms contributing to restoring lung volume and gas exchange after surfacing, we studied ventilatory parameters in three Weddell seals between dives from an isolated ice hole on McMurdo Sound, Antarctica. METHODS: Lung volumes and CO(2) elimination were investigated using a pneumotachograph, infrared gas analysis, and nitrogen washout. Thoracic circumference was determined with a strain gauge. Exhaled nitric oxide was measured using chemiluminescence. RESULTS: Breathing of Weddell seals was characterized by an apneustic pattern with end-inspiratory pauses with functional residual capacity at the end of inspiration. Respiratory flow rate and tidal volume peaked within the first 3 min after surfacing. Lung volume reductions before and increases after diving were approximately 20% of the lung volume at rest. Thoracic circumference changed by less than 2% during diving. The excess CO(2) eliminated after dives correlated closely with the duration of the preceding dive. Nitric oxide was not present in the expired gas. CONCLUSION: Our data suggest that most of the changes in lung volume during diving result from compression and decompression of the gas remaining in the respiratory tract. Cranial shifts of the diaphragm and translocation of blood into the thorax rather than a reduction of thoracic circumference appear to compensate for lung collapse. The time to normalise gas exchange after surfacing was mainly determined by the accumulation of CO(2) during the dive. These findings underline the remarkable adaptations of the Weddell seal for restoring lung volume and gas exchange after diving.

Do antenatal corticosteroids help in the setting of preterm rupture of membranes?

OBJECTIVE: It is now accepted that corticosteroid administration before preterm delivery reduces neonatal mortality and morbidity. However, corticosteroid use in the setting of rupture of membranes remains controversial. STUDY DESIGN: We reviewed data from the first and largest randomized trial in this area and included them in a new meta-analysis. RESULTS: Data from 318 women with rupture of membranes in the Auckland Trial showed that there was a trend toward reduction of the risk of respiratory distress syndrome with corticosteroids but that this trend did not reach statistical significance. There was little effect on the risks of neonatal death, intraventricular hemorrhage, and fetal, neonatal, or maternal infection. Combined data from 15 controlled trials involving >1400 women with rupture of membranes confirmed that corticosteroids reduce the risks of respiratory distress syndrome (relative risk, 0.56; 95% confidence interval, 0.46-0.70), intraventricular hemorrhage (relative risk, 0.47; 95% confidence interval, 0.31-0.70), and necrotizing enterocolitis (relative risk, 0.21; 95% confidence interval, 0.05-0.82). They also may reduce the risk of neonatal death (relative risk, 0.68; 95% confidence interval, 0.43-1.07). They do not appear to increase the risk of infection in either mother (relative risk, 0.86; 95% confidence interval, 0.61-1.20) or baby (relative risk, 1.05; 95% confidence interval, 0.66-1.68). The duration of rupture of membranes does not alter these outcomes. CONCLUSION: The available data indicate that corticosteroid administration is beneficial in the setting of rupture of membranes. In our opinion further trials to address this question cannot be justified.

Splenic contraction, catecholamine release, and blood volume redistribution during diving in the Weddell seal.

The spleen of the Weddell seal (Leptonychotes weddelli) may contract and inject red blood cells (RBCs) into the peripheral circulation during diving, but evidence for this hypothesis is indirect. Accordingly, we measured splenic dimensions by ultrasonography, plasma catecholamine concentrations, hemoglobin concentration, and hematocrit in five Weddell seals before and after intravenous epinephrine during halothane anesthesia and while awake at the surface after voluntary dives. Spleen size was reduced immediately after epinephrine injection or after the seal surfaced. Within the first 2 min after the seal surfaced, cephalocaudal splenic length was 71 +/- 2% (mean +/- SD; P < 0.05) and splenic thickness was 71 +/- 4% (P < 0.05) of the maximal resting values. Splenic size increased (half-time = 6-9 min) after the seal surfaced and was inversely correlated with plasma epinephrine and norepinephrine concentrations. Hemoglobin concentration increased from 17.5 +/- 5.3 g/dl (measured during general anesthesia) to 21.9 +/- 3.7 g/dl (measured in the first 2 min after surfacing). At these same times, the hematocrit increased from 44 +/- 12 to 55 +/- 8%. These values decreased (half-time = 12-16 min) after the seal surfaced. We estimate 20.1 liters of RBCs were sequestered at rest, presumably in the spleen, and released either on epinephrine injection or during diving. Catecholamine release and splenic contraction appear to be an integral part of the voluntary diving response of Weddell seals.

Changes in thoracic dimensions induced by breathing movements in fetal sheep.

The dimensions of the three major axes of the thorax (longitudinal, transverse and antero-posterior) were monitored in utero from the ultrasonic transit-time between pairs of piezo-electric transducers chronically implanted at opposite sides of the thorax in five fetal sheep at 119-122 days of gestation; tracheal and vascular catheters and diaphragmatic EMG electrodes were also implanted. To measure thoracic length, ultrasound transducers were implanted on the diaphragm and over the upper sternum and manubrium sterni. A pair was implanted on opposite sides of the chest to measure thoracic width, and another pair was implanted over the lower thoracic spine and lower sternum (antero-posterior dimension). The width of the thorax either decreased (mean 0.6 +/- 0.2 mm) or increased (mean 0.7 +/- 0.1 mm) during fetal breathing movements (FBM). The depth of the thorax (antero-posterior dimension) usually decreased (mean 0.9 +/- 0.1 mm) during FBM. The distance between the upper sternum and the diaphragm decreased by 1.0 +/- 0.1 mm (left side) and 1.6 +/- 0.3 mm (right side) during inspiratory efforts. The distance between the upper thorax and a fixed point on the lower thoracic spine decreased by a similar amount. Overall, fetal thoracic dimensions changed by 1-3%. The largest changes measured, and the most surprising, were reductions, rather than increases, in the separation between the dome of the diaphragm and the upper thorax; this suggests that, during inspiratory efforts, the upper thorax moves caudally by a greater distance than the diaphragm. FBM induce complex and variable changes in thoracic dimensions; these are likely to induce small alterations in the shape of the lungs that may act as a stimulus to lung growth.

Hormonal regulatory adjustments during voluntary diving in Weddell seals.

Subadult male Weddell seals were instrumented with microcomputer-based backpacks and were then monitored during voluntary diving and recovery periods in McMurdo Sound, Antarctica. Depth and duration of diving, swim speed, and dive pattern were routinely monitored. An indwelling venous catheter was used to collect plasma samples at various time periods before and following diving episodes, so that changes in plasma concentrations of hormones and of metabolites could be measured. Adrenergic and nitroxidergic regulatory effects were assessed indirectly by measuring concentration changes in catecholamine and cyclic guanosine monophosphate (cGMP), respectively. The studies found that (i), except for dives of less than several minutes, epinephrine and norepinephrine both increased as a function of diving duration, then rapidly decreased during recovery (with a half time of about 10 min), (ii) that the changes in catecholamine concentrations correlated with splenic contraction and an increase in circulating red blood cell mass (hematocrit), (iii) that the changes in catecholamines, especially [epinephrine], were inversely related to insulin/glucagon ratios, which mediated a postdiving hyperglycemia, and (iv) that in long dives (but not short ones) the changes in catecholamines correlated with increasing reliance on anaerobic metabolism, indicated by increased plasma lactate concentrations. These diving-catecholamine relationships during voluntary diving at sea were similar to those observed during enforced submergence (simulated diving) under controlled laboratory conditions. At the end of diving, even while catecholamine concentrations were still high, many of the above effects were rapidly reversed and the reversal appeared to correlate with accelerated nitric oxide production, indirectly indicated by increased plasma cGMP concentrations. Taken together, the data led to the hypothesis of important adrenergic regulation of the diving response in seals, with rapid reversal at the end of diving and during recovery being regulated by nitroxidergic mechanisms.

Myoglobin saturation in free-diving Weddell seals.

Although the consumption of myoglobin-bound O2 (MbO2) stores in seal muscles has been demonstrated in seal muscles during laboratory simulations of diving, this may not be a feature of normal field diving in which measurements of heart rate and lactate production show marked differences from the profound diving response induced by forced immersion. To evaluate the consumption of muscle MbO2 stores during unrestrained diving, we developed a submersible dual-wavelength laser near-infrared spectrophotometer capable of measuring MbO2 saturation in swimming muscle. The probe was implanted on the surface of the latissimus dorsi of five subadult male Weddell seals (Leptonychotes weddelli) released into a captive breathing hole near Ross Island, Antarctica. Four seals had a monotonic decline of muscle O2 saturation during free diving to depths up to 300 m with median slopes of -5.12 +/- 4.37 and -2.54 +/- 1.95%/min for dives lasting < 17 and > 17 min, respectively. There was no correlation between the power consumed by swimming and the desaturation rate. Two seals had occasional partial muscle resaturations late in dives, indicating transfer of O2 from circulating blood to muscle myoglobin. Weddell seals partially consume their MbO2 stores during unrestrained free diving.

Ultrasonic heating of the brain of the fetal sheep in utero.

The fetal sheep was used as a model to determine the extent of ultrasound-induced heating of brain tissue in procedures involving pulsed Doppler examination of fetal intracranial arteries. Temperature measurements were recorded in late-gestation fetuses insonated in utero. The centre frequency was 3.5 MHz and a pulse repetition rate of 6 to 10 kHz produced a power output of 0.6 or 2 W. The brain was insonated in the near field of a focussed beam where the -6-dB beam width was 1.7 cm for the 0.6-W transducers and 1.2 cm for the 2-W transducers. Mean (standard error) maximal temperature increases of 3.0 degrees C (0.3) and 12.5 degrees C (1.3), respectively, were recorded in dead fetuses. The mean values obtained in normally perfused living fetuses were lower by 43% and 30%, respectively, showing that vascular perfusion substantially limited ultrasonic heating in sheep fetal brain tissue. There were no changes in blood flow to the heated brain tissue as measured using radiolabelled microspheres.

Thyrotrophin-releasing hormone (TRH) and lung maturation.

Clinical trials of thyrotrophin-releasing hormone (TRH) in conjunction with antepartum glucocorticoid treatment in the prevention of respiratory distress syndrome is based on experimental evidence that fetal lung maturation is accelerated by exposure to raised concentrations of triiodothyronine (T3) in fetal plasma. Studies of fetal rat and rabbit lung in vitro show an inconsistent increase in surfactant synthesis in response to T3 and potentiation of the response to corticosteroid. Experiments with fetal rodents in vivo are difficult to interpret because of confounding effects of the procedures and the responses to T3 are variable. In fetal sheep, very high concentrations of T3 are without effect on lung maturation. These observations suggest that the action of TRH on the lung may be mediated at least in part by one of the numerous, non-hormonal pathways known to be stimulated by TRH, particularly the autonomic nervous system. Experiments in rats and sheep lend support to this possibility. It is concluded that available evidence is inadequate to determine the mechanism of action of TRH.

A randomized, controlled trial of antepartum thyrotropin-releasing hormone and betamethasone in the prevention of respiratory disease in preterm infants.

OBJECTIVE: The objective was to investigate whether the addition of thyrotropin-releasing hormone to antepartum betamethasone further reduces the incidence of respiratory disease in preterm infants. STUDY DESIGN: A randomized, placebo-controlled, double-blind trial of antepartum thyrotropin-releasing hormone (400 micrograms given intravenously four times) and betamethasone (5 mg given intramuscularly four times) was conducted in 378 mothers likely to be delivered between 24 and 32.6 weeks' gestation. Statistical analysis was by relative risk, chi 2, t tests, and multiple logistic regression analysis. RESULTS: Four hundred five live-born infants were delivered. In infants without lethal abnormalities delivered between 24 hours and 10 days from entry (n = 175) the incidence of respiratory distress syndrome was reduced from 52% to 31% (relative risk 0.61, 95% confidence interval 0.41 to 0.89) and that of severe respiratory distress syndrome from 42% to 20% (relative risk 0.48, 95% confidence interval 0.29 to 0.78) in the placebo and thyrotropin-releasing hormone groups, respectively. The number of deaths fell from 14 to one (relative risk 0.08, 95% confidence interval 0.01 to 0.63). The incidence of chronic lung disease was not significantly different, but that of an adverse outcome (chronic lung disease or death by 36 weeks' gestation) fell from 29% in the placebo group to 16% with thyrotropin-releasing hormone (relative risk 0.55, 95% confidence interval 0.31 to 0.99). CONCLUSION: The addition of thyrotropin-releasing hormone to antepartum glucocorticoid treatment reduces the incidence of respiratory distress syndrome and improves survival in preterm infants.

The role of cortisol in preparing the fetus for birth.

The glucocorticoids, cortisol and corticosterone, have a unique function in the fetus in inducing a wide range of enzymes before birth that have little or no function during fetal life but on which survival after birth is dependent. The loss of the placenta at birth deprives the fetus of a source of oxygen, glucose and heat (among many other things) for which alternatives must be available immediately if survival is to be assured. In anticipation of these needs several organs undergo maturational changes in late pregnancy aimed at meeting these requirements. The lungs mature structurally and functionally, becoming distensible and capable of coping with high surface tension when air enters the alveoli with the first breath. In the liver, glycogen accumulates and gluconeogenesis is initiated to meet the demands for glucose until feeding begins. There is an increase in the production of tri-iodothyronine and catecholamines in preparation for the sharp increase in metabolic rate and thermogenesis associated with breathing and the cold environment. All these dramatic maturational events are regulated by cortisol as are numerous others in most organ systems that contribute to neonatal well-being but on which survival is less dependent. Pharmacological manipulation of these systems before birth has made a substantial contribution to improving human health.

Pulsed ultrasound and electrocortical activity in fetal sheep.

The aim of this study was to determine if low intensity ultrasound affects electrocortical activity in chronically instrumented fetal sheep. A 3.5-MHz transducer was attached to each fetal skull (n = 9) and activated periodically to emit pulses of 5.8 microseconds duration at a repetition rate of 2 kHz generating a power output of 60 mW. The power supply was activated in 30-s bursts every 180 s but random electronic switching energized the transducer with 50% of bursts. On average, 175 bursts of ultrasound were delivered to the fetus over 19.5 h. Blinded analysis of continuous recordings of electrocortical activity showed it to be unaffected by the ultrasound exposures. Therefore, it is unlikely that ultrasonic examination of human fetuses will affect normal cyclical electrocortical activity.

Concentrations, metabolic clearance rates, production rates and plasma binding of cortisol in Antarctic phocid seals.

We have reported previously that plasma of the Weddell seal, a member of the phocid family, contains a very high concentration of cortisol. The present study was undertaken to determine whether high cortisol levels were common to seals in the Antarctic environment, or to other phocidae, and to determine the mechanism of the hypercortisolaemia. High levels of cortisol (0.82-2.38 mumol/l) were found in 4 phocidae (Weddell, crabeater, leopard and Southern elephant seals), whereas levels in a member of the otariid family (Antarctic fur seal) were similar to human values. Metabolic clearance rates (MCR) and production rates (PR) of cortisol were determined in the field in Weddell (N = 1), crabeater (N = 3) and leopard (N = 3) seals following bolus injections of [3H] cortisol. The MCR and PR did not differ between the three phocids, but whereas the MCR of 410-590 1/day was twice that of human values, the PR of 460-1180 mumol.m-2 x d-1 was up to 40-fold greater. The binding capacity of corticosteroid-binding globulin (CBG) was equal to or greater than the plasma concentrations of cortisol, resulting in relatively low concentrations of free cortisol. We conclude that hypercortisolaemia is maintained in phocid seals mainly by a high production rate--the highest (corrected for surface area) reported in any species. The relatively low cortisol levels in otariid seals studied in the same environment suggest that the high PR in phocidae is unrelated to the harsh climatic conditions, but may be part of their adaptation for diving to extreme depths.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiphospholipid antibodies in pregnancy: prevalence and clinical associations.

OBJECTIVE: To determine prevalence, clinical association and predictive power of antiphospholipid antibodies in pregnancy. DESIGN: To test for the presence of anticardiolipin antibodies and lupus anticoagulant in order to confirm prevalence data which imply that each antibody has the same clinical significance. A detailed obstetric history and the outcome measures were obtained from each patient in the study. SETTING: National Women's Hospital, Auckland, New Zealand. SUBJECTS: Nine hundred and thirty-three consecutively booked pregnant women. MAIN OUTCOME MEASURES: Prevalence of auto-antibodies; perinatal morbidity and mortality; incidence of pre-eclampsia, growth retardation and fetal distress. RESULTS: Nine women (1.0%) had anticardiolipin antibodies, 11 (1.2%) had lupus anticoagulant and two had both antibodies. The fetal mortality rate for women with antibodies was 167/1000. Pre-eclampsia occurred significantly more often in women with auto-antibodies. CONCLUSION: The presence of antiphospholipid antibodies is frequently associated with adverse pregnancy outcome (9/18 pregnancies). High titre anticardiolipin antibodies carry a poor prognosis.

Sympathectomy and beta-adrenergic blockade during lung maturation stimulated by TRH and cortisol in fetal sheep.

To test whether beta-adrenergic mechanisms and the sympathetic nervous system are involved in the synergistic action of thyrotropin-releasing hormone (TRH) and cortisol on lung maturation, fetal sheep (n = 32) were infused from 121 to 128 days of gestation with saline, TRH + cortisol, TRH + cortisol + beta-adrenergic blocker, or TRH + cortisol after chemical sympathectomy with 6-hydroxydopamine. TRH + cortisol increased lung distensibility and stability and alveolar concentrations of saturated phosphatidylcholine two- to threefold over control fetuses. beta-Adrenergic blockade prevented the increase in distensibility in response to TRH + cortisol. Sympathectomy did not impair the increase in distensibility and stability in response to TRH + cortisol but inhibited the increase in alveolar total phospholipids. Tissue concentrations of saturated phosphatidylcholine increased in TRH + cortisol-treated fetuses after either sympathectomy or beta-adrenergic blockade. We concluded that during lung maturation by TRH + cortisol 1) sympathetic mechanisms are requisite for surfactant release, 2) nonneurogenic beta-adrenergic mechanisms are requisite for the maturation of the mechanical properties of the lung and 3) stimulation of surfactant synthesis is independent of beta-adrenergic action and the sympathetic nervous system.

The influence of oligohydramnios on thoracic dimensions of fetal sheep.

Oligohydramnios frequently leads to lung hypoplasia in the fetus, but the underlying mechanisms are incompletely understood. Our aim was to determine the effects of oligohydramnios on the dimensions of the fetal thorax. Using pairs of implanted ultrasound transducers in 6 fetal sheep, we measured 4 thoracic dimensions (transverse, anterior-posterior, manubrium to left and right hand sides of the diaphragmatic dome) for 2 control days, 3 days of amniotic and allantoic fluid drainage (oligohydramnios), and 2 days after the return of drained fluids. The effect of oligohydramnios, which began at 121-2 days of gestation (term being c.145 days), on each dimension was quantified daily as the difference between the measured value and the value predicted from the growth of that dimension over the study period. Oligohydramnios led, within 48 hours, to significant reductions in the transverse dimension (5.9-6.1%) and in the distance between the manubrium and the dome of the diaphragm (1.7-2.2%). There was no change in the anterior-posterior dimension. We conclude that oligohydramnios causes alterations, within 48 hours, in the dimensions of the fetal thorax which can be reversed, at least partially, by re-expansion of the fluid sacs. These changes, which are expected to produce reductions in thoracic volume, may, if prolonged, lead to lung hypoplasia.