Early activation of inflammation and clotting in the preterm lamb with neonatal RDS: comparison of conventional ventilation and high frequency oscillatory ventilation.

In neonatal respiratory distress syndrome activation of inflammation and clotting is demonstrated. High frequency oscillatory ventilation (HFOV) is considered to be less damaging to the human preterm lung, resulting in less activation of inflammation and clotting compared with conventional ventilation (CV). To assess the sequence of events of activation of inflammation and clotting and to compare the impact of HFOV to CV, we ventilated preterm lambs delivered by cesarean section at 132 d gestational age (term 145 d) for 8 h by CV (n = 10) or HFOV (n = 11). Fifteen minutes after birth and at 2-h intervals thereafter blood samples, from umbilical catheters, were analyzed for AP50 (complement activation), number of polymorphonuclear leukocytes, beta-glucuronidase, platelet function, activated partial thromboplastin time, thrombin time and thrombin inhibition, and bronchoalveolar lavage fluid was analyzed for elastase, thrombin and protein. We found complement activation, low number of polymorphonuclear leukocytes and high levels of beta-glucuronidase already at 15 min after birth. Within 2 to 4 h after birth platelet function deteriorated, activated partial thromboplastin time prolonged, and thrombin inhibition decreased. Activation of inflammation and clotting in the lungs was demonstrated by increased levels of elastase and thrombin in bronchoalveolar lavage fluid. In the HFOV group, AP50 remained significantly higher than in the CV group, reflecting less complement activation, and platelet function analysis remained significantly lower, reflecting better platelet function. We conclude that systemic activation of inflammation can be found in the ventilated preterm lamb with respiratory distress syndrome within 15 min after birth. Afterward, or due to activation of inflammation, clotting is activated. HFOV possibly attenuates activation of inflammation.

Renal and cerebral responses to hypoxemia in the ovine fetus.

Mild to moderate hypoxemia without major changes in pH and pCO(2) does not reduce fetal renal blood flow and fetal urine production rate. Other factors such as acidemia, hypercapnia or changes in lung liquid production or fetal swallowing are candidates for the reduced amniotic fluid in the growth retarded fetus. Mild hypoxemia influences the fetal brain development in that the migration of PKC immunoreactive cells is delayed after a period of 48 h of hypoxemia. This could be due to the fact that under these circumstances the expected compensatory increase in fetal cerebral blood flow was only significant 1 h after the onset of hypoxemia. Further research on the final position of the hippocampal neurons in term lambs, subjected to fetal mild hypoxemia, can give more information on the effects of hypoxemia on the fetal brain.

Daily rhythms in renal blood flow and urine production rate in the near-term sheep fetus.

Daily rhythmicity of renal blood flow (RBF) and urine flow (UF) was studied in fetal sheep between 121-125 d of gestation. Fetal arterial blood pressure, heart rate, UF, and right RBF were measured continuously for 24-h periods in 10 sheep. Rhythmic variations during a 24-h period were found for all variables studied. The rhythms of arterial blood pressure and heart rate were highly correlated, whereas an inverse correlation was found between arterial blood pressure with RBF and between arterial blood pressure with UF. These findings indicate that fetal RBF is not blood pressure dependent. Furthermore, fetal UF appears not to be mediated by pressure-dependent diuresis.

Renal responses to prolonged (48 h) hypoxemia without acidemia in the late-gestation ovine fetus.

The effect of sustained moderate hypoxia on renal blood flow and renal function was studied in the ovine fetus (123-129 days). The experiments consisted of 48 h of isocapnic hypoxia, not resulting in acidemia, but sufficient to produce redistribution of blood flow in favor of the brain at the expense of the carcass. Hypoxemia was induced by maternal nitrogen inhalation. Fetal arterial O(2) saturation and arterial O(2) pressure (Pa(O(2))) decreased from, respectively, 50.6 +/- 3.0% and 17.2 +/- 0.9 mmHg during control to 36.4 +/- 2.7% and 13.4 +/- 0.7 mmHg on the first and to 32.2 +/- 2. 2% and 12.4 +/- 0.7 mmHg on the second day of hypoxemia. Fetal renal blood flow and urine production rate were continuously measured using ultrasonic flow transducers. Fetal renal blood flow increased during hypoxemia from 11.8 +/- 1.6 to 15.6 +/- 1.8 ml/min and remained elevated throughout the 48-h hypoxemia period (P < 0.01). Renal blood flow was inversely correlated with fetal Pa(O(2)) (r is -0.69, P < 0.0001). Fetal urine production rate, glomerular filtration rate, filtration factor, osmotic clearance, and free water clearance did not significantly change from control values during hypoxemia or recovery. We conclude that hypoxemia without acidemia results in an immediate and considerable increase in fetal renal blood flow, which remains elevated for the entire hypoxemic period.

Delayed neuronal migration of protein kinase Cgamma immunoreactive cells in hippocampal CA1 area after 48 h of moderate hypoxemia in the near term ovine fetus.

The brain is uniquely sensitive to disturbances in energy and oxygen supply, particularly during the early stage of life. Since hypoxemia can indirectly activate the intracellular messenger protein kinase C (PKC), we studied the PKCgamma-immunoreaction in the fetal hippocampal CA1 region of naive (n=4), instrumented control (n=7), and instrumented hypoxemic fetuses (n=14), at a mean gestational age of 127 days. Forty-eight hours of mild to moderate hypoxemia, were followed by a 48-h recovery period. Hypoxemia resulted in an increase in carotid blood flow (137% of control), and a shift towards a higher percentage of high-voltage electrocortical activity. After recovery, the fetal brain was fixated by perfusion of both carotid arteries, sectioned and immunostained for PKCgamma. The distribution of PKCgamma-immunoreactive cells was significantly changed after 48 h of hypoxemia in that the migration of cells (from the ventricular region towards the stratum pyramidale) was delayed (p<0.01) compared to naive and instrumented control animals. In contrast to the distribution, the relative total optical density of PKCgamma-ir cells and fibres in the CA1 hippocampal area was not significant different between the animal groups. We conclude that hypoxemia delayed migration of PKCgamma-ir cells, without neuronal degeneration.

Urine production rate and renal blood flow in the near-term ovine fetus are not related to high and low voltage electrocortical activity.

Studies in both the human and ovine near-term fetus have identified the clustering of physiologic and behavioral parameters into states. In a recent study in the human fetus a considerable decrease was found in fetal urine production during non-rapid eye movement (non-REM) compared with REM sleep. Whether this decrease was caused by decreased renal blood flow or changes in urine concentration is not known. This prompted us to investigate the relation between fetal urine production rate and electrocortical activity in the near-term ovine fetus. We hypothesized that in the ovine fetus urine production and renal blood flow during REM [comparable to low voltage electrocortical activity (LV ECoG)] would be lower than during non-REM [(high voltage (HV) ECoG)]. In eight fetal sheep between 123 and 127 d of gestation (term 147 d), ECoG, renal blood flow, urine flow, and urine osmolality were measured continuously for 6 h on 2 consecutive days. Data were analyzed into HV ECoG and LV ECoG whereafter urine flow, urine osmolality, and renal blood flow data were averaged per state. We found no significant differences in urine flow, urine osmolality, or renal blood flow between the two behavioral states in the ovine fetus. Because these data are in sharp contrast to those found in the human fetus, we conclude that the observed dissimilarities in renal responses between the human and sheep fetus add to the already known differences in behavioral states between the two species.