Glucocorticoid administration to women at risk of preterm delivery to accelerate fetal lung maturation has become standard practice. Antenatal glucocorticoids decrease the incidence of intraventricular haemorrhage as well as accelerating fetal lung maturation. Little is known regarding side effects on fetal cerebral function. Cortisol and synthetic glucocorticoids such as betamethasone increase fetal blood pressure and femoral vascular resistance in sheep. We determined the effects of antenatal glucocorticoid administration on cerebral blood flow (CBF) in fetal sheep. Vehicle (n= 8) or betamethasone (n= 8) was infused over 48 h via the jugular vein of chronically instrumented fetal sheep at 128 days gestation (term 146 days). The betamethasone infusion rate was that previously shown to produce fetal plasma betamethasone concentrations similar to human umbilical vein concentrations during antenatal glucocorticoid therapy. Regional CBF was measured in 10 brain regions, using coloured microspheres, before and 24 and 48 h after onset of treatment, and during hypercapnic challenges performed before and 48 h after onset of betamethasone exposure. Betamethasone exposure decreased CBF in all brain regions measured except the hippocampus after 24 h of infusion (P < 0·05). The CBF decrease was most pronounced in the thalamus and hindbrain (45–50 % decrease) and least pronounced in the cortical regions (35–40 % decrease). It was mediated by an increase in cerebral vascular resistance (CVR, P < 0·05) and led to a decrease in oxygen delivery to subcortical and hindbrain structures of 30–40 %, to 8·6 ± 1·1 ml (100 g)−1 min−1, and 40–45 %, to 11·0 ± 1·6 ml 100 g−1 min−1, respectively (P < 0·05). After 48 h of betamethasone treatment, the reduction in CBF was diminished to about 25–30 %, but was still significant in comparison to vehicle‐treated fetuses in all brain regions except three of the five measured cortical regions (P < 0·05). CVR and oxygen delivery were unchanged in comparison to values at 24 h of treatment. The CBF increase in response to hypercapnia was diminished (P < 0·05). These observations demonstrate for the first time that glucocorticoids exert major vasoconstrictor effects on fetal CBF. This mechanism may protect the fetus against intraventricular haemorrhage both at rest and when the fetus is challenged. Betamethasone exposure decreased the hypercapnia‐induced increase in CBF (P < 0·05) due to decreased cerebral vasodilatation (P < 0.05).
Therapeutic hypothermia may alter the required dosage of analgesics and sedatives, but no data are available on the effects of mild hypothermia on plasma fentanyl concentration during continuous, long-term administration. We therefore assessed in a porcine model the effect of prolonged hypothermia on plasma fentanyl concentration during 33 h of continuous fentanyl administration. Seven female piglets (weight: 11.8 +/- 1.1 kg) were anesthetized by IV fentanyl (15 microg . kg(-1) . h(-1)) and midazolam (1.0 mg . kg(-1) . h(-1)). After preparation and stabilization (12 h), the animals were cooled to a core temperature of 31.6 degrees +/- 0.2 degrees C for 6 h and were then rewarmed and kept normothermic at 37.7 degrees +/- 0.3 degrees C for 6 more hours. Plasma fentanyl concentrations were measured by radioimmunoassay, cardiac index by thermodilution, and blood flows of the kidney, spleen, pancreas, stomach, gut, and hepatic artery by a colored microspheres technique. Furthermore, in an additional 4 pigs, temperature dependency of hepatic microsomal cytochrome P450 3A4 (CYP3A4) was determined in vitro by ethylmorphine N-demethylation. Plasma fentanyl concentration increased by 25% +/- 11% (P < 0.05) during hypothermia and remained increased for at least 6 h after rewarming. Hypothermia reduced the cardiac index (41% +/- 15%, P < 0.05), as well as all organ blood flows except the hepatic artery. A strong temperature dependency of CYP3A4 was found (P < 0.01). Mild hypothermia induced a distribution and/or elimination-dependent increase in plasma fentanyl concentration which remained increased for several hours after rewarming. Consequently, a prolonged increase of the plasma fentanyl concentration should be anticipated for appropriate control of the analgesia/sedatives during and early after therapeutic hypothermia.
To examine the effects of intrauterine growth restriction on nephron number, renal circulation, and renal excretory functions in newborns, studies were conducted on 1-day-old anaesthetized piglets, divided into normal weight (n = 6) and intrauterine growth restricted (n = 6) piglets. Renal blood flow was measured by coloured microspheres, glomerular filtration rate was measured by inulin clearance, and osmotic clearance and fractional sodium excretion were calculated. In addition, an estimation of the nephron number was performed by counting representative glomerular numbers in microscopic sections. Newborn intrauterine growth restricted piglets exhibited a reduced glomerular filtration rate and osmotic clearance (P < 0.05), whereas renal blood flow and the filtration fraction as well as fractional sodium excretion were similar in normal weight and intrauterine growth restricted piglets. The nephron number was markedly reduced in intrauterine growth restricted piglets even if the nephron number was related to body weight (P < 0.01). There was a positive correlation between nephron number and glomerular filtration rate (r = 0.69, P < 0.05). Reduced glomerular filtration rate of newborn intrauterine growth restricted piglets is associated with a reduced nephron number. Thus, at birth, compensatory response of renal function due to nephron deficit does not exist in intrauterine growth restricted piglets.
Summary:Studies documenting the cerebral hemodynamic consequences of selective brain hypothermia (SBH) have yielded conflicting data. Therefore, the authors have studied the effect of SBH on the relation of cerebral blood flow (CBF) and CMRO 2 in the forebrain of pigs. Selective brain hypothermia was induced in seven juvenile pigs by bicarotid perfusion of the head with extracorporally cooled blood. Cooling and stepwise rewarming of the brain to a T brain of 38°C, 25°C, 30°C, and 38°C at normothermic T trunk (38°C) decreased CBF from 71 ± 12 mL 100 g −1 min −1 at normothermia to 26 ± 3 mL 100 g −1 min −1 and 40 ± 12 mL 100 g −1 min −1 at a T brain of 25°C and 30°C, respectively. The decrease of CMRO 2 during cooling of the brain to a T brain of 25°C resulted in a mean Q 10 of 2.8. The ratio between CBF and CMRO 2 was increased at a T brain of 25°C indicating a change in coupling of flow and metabolism. Despite this change, regional perfusion remained coupled to regional temperatures during deep cerebral hypothermia. The data demonstrate that SBH decreases CBF and oxygen metabolism to a degree comparable with the cerebrovascular and metabolic effects of systemic hypothermia. The authors conclude that, irrespective of a change in coupling of blood flow and metabolism during deep cerebral hypothermia, cerebral metabolism is a main determinant of CBF during SBH. Key Words: Selective brain hypothermia-Cerebral flowmetabolism coupling-Microspheres-Pig.There is considerable evidence that hypothermia is a useful intrainsult and postinsult treatment modality for brain injury caused by hypoxia-ischemia, trauma, or neonatal asphyxia (Dietrich, 1992, Gunn et al., 1998bWass et al., 1996). Moreover, systemic hypothermia is routinely used during cardiopulmonary bypass in cardiovascular surgery (McCullough et al., 1999;Jonas, 1998). Because systemic hypothermia causes potentially hazardous side effects (for review see Schubert, 1995), selective brain hypothermia (SBH) is being looked at more intensively with respect to feasibility and cerebroprotective effects (Gunn et al., 1997;Kuluz et al., 1992;Schwartz et al., 1996b).Hypothermic cerebral protection is mediated in part by a reduction of cerebral metabolism (Lanier, 1995). Numerous animal and human studies have shown that systemic hypothermia decreases cerebral blood flow (CBF) and CMRO 2 (Greeley et al., 1993;Michenfelder et al., 1991). However, very few studies have addressed the cerebrovascular and cerebral metabolic responses to SBH. Currently there is no study documenting the physiologic effects of SBH on CMRO 2 and, consequently, on the coupling of CBF and CMRO 2 . Furthermore, investigations documenting the hemodynamic consequences of SBH have reported seemingly conflicting data on the cerebrovascular effects of SBH. A single study in rats has shown that external head cooling results in an increase of CBF (Kuluz et al., 1993). Based on this study it has been concluded that the method of cooling (systemic vs. selective) may be a key factor in determining the cerebral he...
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