Nathan Wasserstrum

Indomethacin in the treatment of premature labor. Effects on the fetal ductus arteriosus.

Indomethacin is a potent agent in the treatment of premature labor, but its use has been limited because of concern about its constrictive effects on the fetal ductus arteriosus. To study these effects we used serial fetal echocardiography in 13 pregnant women in premature labor who received indomethacin according to three different dose schedules, ranging from 100 to 175 mg per day, for a maximum of 72 hours. The gestational ages of the fetuses ranged from 26.5 to 31.0 weeks. The detection of ductal constriction in 7 of the 14 fetuses by echocardiography led to the discontinuation of indomethacin. Three fetuses also had tricuspid regurgitation. There was no statistically significant difference between the mean (+/- SEM) gestational age of the fetuses with ductal constriction and that of those without constriction (29.3 +/- 0.59 and 28.4 +/- 0.52, respectively). There was no relation between serum indomethacin levels in the mothers and ductal constriction. In all seven fetuses affected, ductal constriction had resolved by the time they were restudied 24 hours after the discontinuation of indomethacin. Persistent fetal circulation was not detected in any of the 11 neonates studied after delivery. Indomethacin used to treat premature labor appears to cause transient constriction of the ductus arteriosus in some fetuses, even after short-term use.

Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement

Maternal hypothyroidism may be associated with a variety of pregnancy complications.

The oxygen consumption/oxygen delivery curve in severe preeclampsia: Evidence for a fixed oxygen extraction state

OBJECTIVE Increased total body oxygen consumption requirements are usually met by increased oxygen delivery and increased oxygen extraction. In certain conditions (e.g., adult respiratory distress syndrome) the ability to increase oxygen extraction is lost, and any increase in oxygen consumption depends on increased oxygen delivery. The objective of this study was to investigate the oxygen delivery/oxygen consumption relationship in severe preeclampsia. STUDY DESIGN Thirty-two patients with severe preeclampsia (blood pressure > 160/110 mm Hg; 3 to 4+ proteinuria) were monitored with a pulmonary artery catheter. Baseline oxygen consumption and delivery in a group without volume expansion or pharmacologic vasodilatation were compared with those in a group who had received a magnesium sulfate infusion. RESULTS Oxygen consumption, oxygen delivery, arterial-venous-oxygen difference, and the oxygen extraction ratio were low when compared to that for normal 32 to 38 week pregnancy. The oxygen extraction ratio, defined as the ratio of oxygen consumption to oxygen delivery, was abnormally low for pregnancy, especially considering the low oxygen delivery levels in these patients. Oxygen consumption was dependent on oxygen delivery over the entire range of values seen. CONCLUSIONS Severe preeclampsia is associated with an abnormality of tissue oxygen extraction, as evidenced by a low and unresponsive oxygen extraction ratio. Oxygen consumption increases proportionately with increases in oxygen delivery without reaching an oxygen delivery-independent state. Even at high oxygen delivery levels the oxygen consumption in preeclamptic patients is still abnormally low for pregnancy.

Barorefiex function in normal pregnancy

The sinoaortic baroreflex is one of the primary mechanisms that regulates blood pressure. Decreased baroreflex sensitivity has been reported in preeclampsia. We sought to determine whether pregnancy altered baroreflex sensitivity. From a radial artery catheter, heart rate and mean arterial pressure were recorded continuously onto a polygraph. The ratio of change in heart rate produced per unit of change in mean arterial pressure was calculated as an index of baroreflex sensitivity. Mean arterial pressure responses to incremental infusions of phenylephrine (0.4 to 2.0 micrograms/kg/min) were measured in the same patients at term (n = 9, 38.0 +/- 0.3 weeks) and again 6 to 8 weeks postpartum (n = 7). The results indicated (1) higher baroreflex sensitivity in pregnancy than in the postpartum period (0.9 vs 0.5 beats/min/mm Hg) (p less than 0.007); (2) attenuated vascular responsiveness to alpha-adrenergic stimulation in pregnancy (p less than 0.05); (3) a relationship between vascular responsiveness and baroreflex sensitivity. We conclude that pregnancy is associated with an increase in baroreflex sensitivity and that the attenuated response to phenylephrine is, at least in part, a result of increased baroreflex sensitivity.

Nitroprusside in preeclampsia. Circulatory distress and paradoxical bradycardia.

In severe preeclampsia, short-term peripartum management of hypertension with hydralazine is complicated by relatively prolonged hypotensive episodes, resulting in fetal distress. We hypothesized that nitroprussides rapid onset and brief antihypertensive action would permit more controlled blood pressure reduction. Nitroprusside was infused into 10 invasively monitored subjects until mean arterial pressure either 1) was gradually reduced 10-20% or 2) fell abruptly. Subjects fell into two groups, defined by whether the hypotensive effect of nitroprusside was accompanied by a fall in heart rate (group A, n = 1) or a rise (group B, n=2). Group B showed the expected sinoaortic baroreceptor reflex elevations in heart rate (+17 ±6 beats/min) in response to moderate falls in mean arterial pressure (‐32±9 mm Hg) elicited by moderate doses (1.03±0.23 /tg/kg/min). However in group A, steep reductions in mean arterial pressure (‐75±22 mm Hg, p<0.0001), significantly greater than in group B (p<0.05), occurred at much lower doses (0.35±0.23 /ig/kg/min;/?<0.05) and were accompanied by falls in heart rate (-21±7 beats/min). The apparently paradoxical falls in heart rate and extreme hypotensive responses in group A indicate severe circulatory compromise, corresponding to the cardiac and vasomotor depression that characterizes severe hemorrhage and other forms of acute/severe hypovolemic hypotension. This hemodynamic pattern represents a cardiopulmonary baroreceptor reflex presumably related to the Bezold-Jarisch reflex. The appearance of this pattern in the present study probably reflects the imposition of nitroprussides prominent venous dilator action on the relatively reduced blood volume that generally characterizes severe preeclampsia.

Contractile effect of endothelin in human placental veins: Role of endothelium prostaglandins and thromboxane

OBJECTIVE The aim was to study the effects of endothelin-1 on human placental veins and the role of cyclooxygenase products as mediators of these effects. STUDY DESIGN Rings of placental veins with and without endothelium were suspended in organ chambers filled with physiologic salt solution. After a period of stabilization at optimal basal tension, isometric tensions in the control group were recorded at increasing concentrations of endothelin-1 (10(-10) to 10(-7) mol/L). Rings in the experimental groups were treated with either indomethacin (cyclooxygenase inhibitor, 10(-5) mol/L), dazoxiben (thromboxane synthetase inhibitor, 10(-4) mol/L), or SQ29548 (thromboxane receptor antagonist, 10(-6) mol/L) before addition of endothelin-1. To demonstrate the presence of functional thromboxane receptors in the rings, contractile responses to U-46619 (10(-9) to 10(-6) mol/L), a thromboxane A2 analog were measured. The effectiveness of SQ29548 blockade was tested in rings treated with SQ29548 (10(-6) mol/L) before addition of U-46619. The concentration-response curves of the treated and control groups were compared with the Student paired t test. RESULTS Endothelin-1 in doses of 10(-10) to 10(-7) mol/L caused concentration-dependent contraction of placental veins. Indomethacin significantly reduced the response of veins with endothelium to low endothelin-1 concentrations (10(-9.5) to 10(-9) mol/L), (p < 0.05). However, it had no effect at higher endothelin-1 concentrations or in vessels without endothelium. The presence of functional thromboxane A2 receptors was confirmed by the vasoconstrictor effect of U-46619 and its blockade by treatment with SQ29548. Neither SQ29548 nor the thromboxane A2 synthesis inhibitor dazoxiben significantly influenced the response to endothelin-1. CONCLUSIONS These results demonstrated that endothelin-1 is a potent vasoconstrictor in the human placental vein. Although functional thromboxane A2 receptors exist in this vessel, endothelin-1s action is independent of thromboxane A2. Prostaglandins may mediate part of the endothelin-1-induced placental vasoconstriction. However, endothelin-1 acts primarily by a direct effect on vascular smooth muscle cells.

Acute Volume Expansion with Colloid Increases Oxygen Delivery and Consumption but Does Not Improve the Oxygen Extraction in Severe Preeclampsia

The objective of this study was to determine the effect of volume expansion with colloid on oxygen consumption (VO2), oxygen delivery (DO2) and the oxygen extraction ratio in patients with severe preeclampsia. The study was prospective and descriptive and took place in the tertiary care labor and delivery unit in a university hospital. Fourteen women with severe preeclampsia who received a pulmonary artery catheter and radial arterial line to monitor their hemodynamic and respiratory status took part in the study. Patients who had received prior medication or volume expansion were excluded. The intervention employed was acute volume expansion, using colloidal solutions (Dextran 70 or Haemaccel) to elevate the pulmonary capillary wedge pressure (PCWP) > 12 mm Hg, and this was followed by repeat measurements. The main outcome measures were PCWP, mean pulmonary artery pressure, cardiac output, systemic vascular resistance, VO2, DO2, and oxygen extraction. The VO2 and DO2 (but not oxygen extraction) increased...

Experimental hypertension in pregnant sheep

Abstract Experimental renal hypertension, with use of the one-kidney, one-clip model, was produced in nine pregnant ewes who were then studied during the last one third of gestation. The animals were chronically instrumented for the recording of arterial pressure, heart rate, and cardiac output; blood volume was determined weekly. The studies were carried out in four phases; a control period of 2 weeks, a surgery period of 1 week, a constriction or hypertensive period, and a postpartum period of 2 weeks. We detected no significant changes in heart rate or cardiac output during any phase of the study. The arterial pressure significantly increased during the constriction and postpartum phases (p