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Departments of 1 Physiology2 Paediatrics3 The Liggins Institute, The University of Auckland, Auckland, New Zealand
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(Received 20 February 2005;
accepted after revision 4 March 2005; first published online 8 March 2005)
Corresponding author L. Bennet: Department of Physiology, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Email: l.bennet{at}auckland.ac.nz
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Introduction |
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Consistent with this proposal, the ACTH and cortisol responses of preterm fetuses (before 120 days gestation) to moderate hypoxia (Akagi & Challis, 1990b; Matsuda et al. 1992), brief umbilical cord occlusion (Green et al. 2000) or hypotension (Rose et al. 1978, 1981) were markedly less than those reported in the late gestation fetus (Rose et al. 1978, 1981; Jackson et al. 1989; Akagi & Challis, 1990b; Richardson et al. 1996; Carmichael et al. 1997; Unno et al. 1997; Fraser et al. 2001; Gardner et al. 2001). Strikingly, although some studies in preterm fetuses have reported a rise in ACTH, albeit to lower peak levels than in late gestation, they found no rise in cortisol levels (Rose et al. 1981; Akagi & Challis, 1990b; Green et al. 2000). For example, at 112–116 days gestation, Green et al. (2000) found a significant rise in ACTH levels, but no increase in cortisol levels after either the first or seventh episode of a series of 90 s umbilical cord occlusions repeated at an interval of 30 min. These data suggested that it is the adrenocortical response to ACTH that is immature in the preterm fetus (Rose et al. 1982; Green et al. 2000), possibly due to reduced expression of the adrenal ACTH receptor (Fraser et al. 2001). It is hypothesized that this apparent profound adrenocortical immaturity compromises the ability of the preterm fetus to maintain homeostasis during hypoxic stress, contributing to hypotension and other morbidity after birth (Bolt et al. 2002; Ng et al. 2004). This has important implications, since severe hypoxia is more common in infants born prematurely than at term (Low, 2004), and frequently occurs before the onset of labour (Low et al. 2003).
However, an important methodological issue for studies of hypoxic stress is that preterm fetuses have a much greater anaerobic capacity and lower aerobic requirements than at term (Dawes et al. 1959; Mott, 1961; Shelley, 1964). These considerations led us to hypothesize that previous experiments in the preterm fetus using mild or brief hypoxic insults may not have been sufficient to elicit a near-maximal HPA response, and that responses comparable with that seen at term could be elicited by a severe insult. We therefore examined the time course of changes in the HPA axis after severe asphyxia in the preterm fetus at 70% of gestation (term is 147 days gestation), equivalent to the human fetus of 28–30 weeks of gestation (McIntosh et al. 1979).
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Methods |
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All procedures were approved by the Animal Ethics Committee of The University of Auckland. Groups of Suffolk ewes were time mated (three days) with Romney rams in a ratio of 5:1 at fortnightly intervals. The ewes were individually identified by ear tags. Ewes who did not conceive after 48 h with the ram were not re-bred. Pregnancy was confirmed by ultrasound at 40 days. Fifteen singleton fetal sheep were instrumented at 97–99 days of gestation (term is 147 days) as previously described (Bennet et al. 1999). Food, but not water was withdrawn 18 h before surgery. Ewes were given 5 ml of Streptocin (procaine penicillin, 250 000 IU) and dihydrostreptomycin (250 mg ml–1; Stockguard Laboratories Ltd, Hamilton, New Zealand) intramuscularly for prophylaxis 30 min prior to the start of surgery. Anaesthesia was induced by I.V. injection of Alfaxan (alphaxalone, 3 mg kg–1; Jurox, Rutherford, NSW, Australia), and general anaesthesia maintained using 2–3% halothane in O2. Ewes were intubated, and the depth of anaesthesia, maternal heart rate and respiration were constantly monitored by trained anaesthetic staff.
Using sterile techniques, catheters were placed in the left fetal femoral artery and vein, right brachial artery, and the amniotic sac. An ultrasound blood flow probe (size 2R; Transonic Systems Inc., Ithaca, NY, USA) was placed around the right femoral artery to measure femoral blood flow (FBF). A stainless-steel electrode (Cooner Wire, Chatsworth, CA, USA) was placed across the fetal chest to measure the fetal electrocardiogram (ECG). An inflatable silicone occluder was placed around the umbilical cord of all fetuses (In Vivo Metric, Healdsburg, CA, USA; Bennet et al. 2000; Quaedackers et al. 2004a). All fetal leads were exteriorized through the maternal flank and a maternal long saphenous vein was catheterized to provide access for postoperative care. After surgery, all exteriorized catheters and leads were kept in an enclosed Perspex box suspended from the side of the Ewe's metabolic cage. Antibiotics (gentamicin, 80 mg; Pharmacia and Upjohn, Rydalmere, NSW, Australia) were administered into the amniotic sac prior to closure of the uterus.
Postoperatively all sheep were housed in separate metabolic cages with access to water and food ad libitum, together in a temperature-controlled room (16 ± 1°C, humidity 50 ± 10%) with a 12 h:12 h light:dark cycle. A period of 4–6 days postoperative recovery was allowed before experiments commenced, during which time antibiotics were administered to the ewe daily for four days I.V. (benzylpenicillin sodium, 600 mg; Novartis Ltd, Auckland, New Zealand, and gentamicin, 80 mg). Fetal catheters were maintained patent by continuous infusion of heparinized saline (20 U ml–1 at 0.15 ml h–1) and the maternal catheter maintained by daily flushing.
Experimental design
Experiments were conducted at 103–104 days gestation (70% of gestation). Fetal arterial and venous pressures, corrected for maternal movement by subtraction of amniotic fluid pressure, FBF and fetal heart rate (FHR) derived from the fetal ECG were recorded continuously from 12 h before occlusion to 72 h after occlusion. Data were stored to disk by custom software for off-line analysis (Labview for Windows; National Instruments Ltd, Austin, TX, USA). Fetuses were randomly assigned to the sham control (n = 7) or the asphyxia group (n = 8). Fetal asphyxia was induced by rapid inflation of the umbilical cord occluder for 25 min with sterile saline of a defined volume known to completely inflate the occluder and totally compress the umbilical cord, as determined in pilot experiments with a Transonic flow probe placed around an umbilical vein (Bennet et al. 1999). The duration of occlusion was chosen as one that we have previously reported to represent an acute, severe, near-terminal insult but which could be survived without postasphyxial cardiac support (Bennet et al. 2000; Quaedackers et al. 2004a,b). Successful occlusion was confirmed by observation of a rapid onset of bradycardia with a rise in mean arterial pressure (MAP), and by pH and blood gas measurements.
Fetal arterial blood samples were taken from the brachial catheter at 15 min prior to umbilical cord occlusion or sham occlusion, 5 and 20 min during occlusion or sham occlusion and 2, 4, 6, 10, 24, 48 and 72 h after occlusion or sham occlusion for determination of blood gases, acid–base balance (Ciba-Corning Diagnostics 845 blood gas analyser and co-oximeter; East Walpole, MA, USA) and for glucose and lactate determination (YSI model 2300; Yellow Springs Instruments, Yellow Springs, OH, USA). Blood samples (1 ml) were collected at the same times (except for 5 min of occlusion), transferred immediately to chilled test tubes and centrifuged at 4°C for 15 min (1811 g). Plasma was stored at –20°C for subsequent adrenocorticotrophic hormone (ACTH) and cortisol assay. After the last blood sample, ewes and fetuses were killed by an intravenous overdose of pentobarbitone sodium (9 g) to the ewe (Pentobarb 300; Chemstock International, Christchurch, New Zealand).
Hormone analysis
Fetal plasma ACTH and cortisol levels were measured using specific radioimmunoassays (RIA) established and validated for ovine plasma (Fraser et al. 1997). Total immunoreactive cortisol concentrations were determined in triplicate after extraction with diethyl ether by an in-house RIA validated for use with maternal and fetal ovine plasma. The antiserum to cortisol was raised in rabbits against Cortisol-3-O-carboxymethyl-oxime-bovine serum albumin (Cortisol 3-CMO: BSA) and was used at a final dilution of 1:19 200. The cross-reactivity of the antiserum at 50% binding with other relevant steroid-related compounds was 3.3% 11-deoxycortisol, 0.18% cortisone, 0.5% corticosterone, 0.015% progesterone and 0.002% 11
-hydroxyprogesterone. No detectable cross-reactivity was observed for 17-hydroxypregnenolone, pregnanediol, 21-deoxycortisone, aldosterone, cholesterol or dexamethasone. The lower limit of detection was 10 pg per tube (0.13 ng ml–1); samples containing < 0.13 ng ml–1 were given this value for the purposes of analysis. The intra- and interassay coefficients of variations were 3.68 and 3.97%, respectively, at the cortisol concentrations determined in plasma.
Immunoreactive concentrations of ACTH were measured in duplicate using a commercially available 125I RIA kit (24130, DiaSorin, Stillwater, MN, USA) previously validated for use with both fetal and maternal ovine plasma. The intra-assay and interassay coefficients of variation were 9.7 and 12.8%, respectively. The mean sensitivity of the ACTH assay was 9.7 pg ml–1; samples containing < 9.7 pg ml–1 were given this value for analysis.
Data analysis and statistics
Off-line analysis of the physiological data was performed using customized Labview programs (Labview, National Instruments, Austin, TX, USA). The effect of asphyxia was evaluated by analysis of variance (ANOVA; SPSS v10, SPSS Inc., Chicago, IL, USA). Femoral vascular resistance (FVR) was calculated using the formula (mean arterial pressure – mean venous pressure)/absolute femoral artery blood flow (mmHg min ml–1). The baseline period was taken as the mean of the 12 h before occlusion. Differences between groups were determined by analysis of variance, adjusted using baseline levels as a covariate (ANCOVA). Where a significant effect of treatment group or an interaction between time and group was found, post hoc comparisons were undertaken using the least significant difference test. The within-subjects relationship between fetal mean arterial blood pressure and cortisol levels after asphyxia was examined using the method of Bland & Altman (1995). Statistical significance was accepted at P < 0.05. Data are presented as means ± S.E.M.
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Results |
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Twenty-five minutes of umbilical cord occlusion was associated with marked fetal hypoxia, hypercapnia and mixed respiratory and metabolic acidosis (Table 1), which resolved after release of occlusion.
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There were no significant baseline differences between the sham and asphyxia groups in any parameter measured. At the onset of cord occlusion there was a rapid fall in FHR, with a sustained bradycardia throughout the period of occlusion (nadir at the end of occlusion 57.4 ± 3.8 beats min–1 versus sham 188.9 ± 3.3 beats min–1, P < 0.05; Fig. 1). Following the end of occlusion FHR rapidly increased to a peak of 235.4 ± 5.4 beats min–1 at 8 min postocclusion (P < 0.001) before returning to baseline values by 1 h. MAP was initially elevated at the onset of occlusion (peaking at 4 min of occlusion at 57.0 ± 1.0 mmHg versus 37.3 ± 0.2 mmHg in sham controls, P < 0.001, Fig. 1). MAP then fell, to a nadir of 10.3 ± 0.6 mmHg, P < 0.05 (Fig. 1). Following the end of occlusion MAP rapidly recovered, with an initial transient period of hypertension (peaking at 8 min at 49.9 ± 2.7 mmHg, P < 0.05) before falling slightly, but remaining elevated through the first hour (P < 0.05).
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Fetal cardiovascular responses after release of cord occlusion
Following reperfusion, there was an initial rapid recovery of FHR with a brief overshoot tachycardia followed by a return to baseline values, although there was a trend for FHR to be elevated initially. FHR then fell and was significantly suppressed compared with the sham group between 42 and 66 h after occlusion (Fig. 2). In contrast, MAP was significantly elevated overall during the first 36 h after occlusion (P < 0.05, ANOVA; Fig. 2), maximal in the first 3 h. FBF was profoundly reduced throughout the entire recovery period compared with the sham group (P < 0.05; Fig. 2), while FVR was increased throughout recovery (P < 0.05; Fig. 2). There was a marked increase in FVR in the first 3 h after release of occlusion, corresponding with the early increase in MAP. FVR then transiently fell for a few hours (although it remained above values in the sham group), rose to a second peak between 18 and 24 h, then progressively fell, and was only mildly increased compared to sham control group levels in the final 24 h of the study.
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There were no significant baseline differences in ACTH or cortisol levels between the sham and asphyxia groups. After 20 min of cord occlusion there was a significant rise in plasma concentrations of both ACTH (P < 0.05, ANOVA) and cortisol (P < 0.05). Following reperfusion, plasma ACTH levels peaked between 2 and 4 h in the asphyxia group and returned to control values at 24 h (Fig. 3, top panel). Plasma cortisol levels remained significantly elevated after the end of occlusion compared to the sham control group until 72 h after occlusion (P < 0.05; Fig. 3, bottom panel). There was a modest correlation between fetal cortisol levels and fetal mean arterial blood pressure in the 72 h after umbilical cord occlusion (r2 = 0.15, P = 0.05, within-subjects regression analysis).
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Discussion |
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Activation of the HPA axis is a well-characterized response to stresses such as hypoxia (Jackson et al. 1989; Richardson et al. 1996; Carmichael et al. 1997; Unno et al. 1997; Fraser et al. 2001) and hypotension (Rose et al. 1978) in the near-term and term fetus and neonate. Comparison with studies in earlier gestation are complicated by the many-fold lower basal cortisol levels seen in the preterm fetus (Challis & Brooks, 1989); however, with some caution, the relative rise in cortisol may be used as an index suggesting broadly equivalent physiological significance. On this basis, a four- to 10-fold rise in cortisol levels during hypoxic stress has been observed in near-term fetal sheep (Jackson et al. 1989; Unno et al. 1997; Gardner et al. 2001), whereas no rise in cortisol was found following brief cord occlusion or moderate hypoxaemia or hypotension in preterm fetuses (Rose et al. 1981; Akagi & Challis, 1990a; Green et al. 2000).
Results from other types of study, however, have raised contradictory evidence. For example, although basal cortisol levels are low in the preterm ovine fetus, the fetal pituitary is highly responsive both to endogenous stimuli such as infusion of corticotrophin releasing hormone and to exogenous stimuli such as exteriorization and haemorrhage (McFarlane et al. 1995). However, these studies did not examine the adrenal responses.
In the present study, when the preterm fetus was exposed to a more severe challenge, the ACTH and cortisol responses were far more pronounced than in previous studies of the preterm fetus that used inhalational hypoxia (Richardson et al. 1996) or intermittent short umbilical cord occlusion (Green et al. 2000). It is likely that the apparent discrepancy between the present findings and previous reports is related to the far greater anaerobic tolerance of the preterm fetus (Mott, 1961), with higher cardiac glycogen levels than at term (Shelley, 1964) This means that the preterm fetus can survive far more prolonged intervals of severe asphyxia than at term (George et al. 2004). Thus, one reason for the attenuated HPA response in previous studies of hypoxia or shorter periods of asphyxia might be simply that, in effect, the insults were only mild or even subthreshold stimuli for the preterm fetus.
It is interesting that in a previous study of short (90 s) umbilical cord occlusions in preterm fetuses, which were approximately 10 days older than in the present study and presumably correspondingly more mature, there was a significant rise in ACTH but not cortisol levels on the first day of occlusions (Green et al. 2000). After 4 days of continued occlusions in that study, however, a small (2.8-fold) postocclusion rise in cortisol levels was found. This suggests that a critical duration of stimulation is required to trigger the cortisol response of the preterm fetus. Consistent with this hypothesis, at 105–112 days gestation in the fetal sheep, an infusion of ACTH was associated with only a three-fold rise in fetal cortisol levels after 3 h, but 28-fold after 24 h (Carter et al. 1998).
The acute cardiovascular responses in the present study also contrast with previous studies of moderate hypoxia. Such studies suggested that the preterm fetus does not reduce peripheral blood flow during hypoxia (Iwamoto et al. 1989) and during partial cord compression cannot increase arterial blood pressure (Iwamoto et al. 1991), i.e. that the ability to centralize circulation in response to a hypoxic challenge is immature. In contrast, and consistent with previous studies of the renal responses to asphyxia at this gestational age (Quaedackers et al. 2004b), we found marked initial hypertension during complete umbilical cord occlusion associated with an initial, actively mediated fall in FBF, as shown by the very rapid and large increase in vascular resistance in the first 6 min after the start of umbilical cord occlusion. In the near-term fetus the initial vasoconstriction during asphyxia is primarily mediated by sympathetic neural activity (Jensen & Lang, 1992) and possibly augmented by release of stress hormones such as arginine vasopressin and renin–angiotensin system (RAS) activation (Raff et al. 1991; Giussani et al. 1994b; Rosnes et al. 1998); limited data suggest that this also occurs in preterm fetuses (Cheung, 1992; Lumbers et al. 2001). Finally, the rise in circulating cortisol demonstrated in the present study may also help to support initial hypertension, as discussed below.
The degree of peripheral vasoconstriction observed initially during occlusion in the present study is similar to that measured using the microsphere technique in the near-term fetus (Jensen et al. 1987). This response is believed to be an important adaptive mechanism acting to redistribute combined ventricular output from non-essential or ‘peripheral’ organs to essential organs such as the heart, brain and adrenals (Hanson, 1988). The present data provide further evidence that this initial cardiovascular defence response is ‘mature’ in the preterm fetus (Gunn et al. 2001). However, consistent with studies in the near-term fetus, this initial adaptation was rapidly lost, leading to partial peripheral reperfusion, followed by a nearly pressure-passive fall in parallel with the secondary fall in arterial blood pressure (Jensen et al. 1987; Jensen & Lang, 1992). The failure of redistribution of combined ventricular output during asphyxia is not simply a function of maturation, since the response is seen at all ages examined thus far, but the mechanisms that mediate this loss of peripheral vascular tone are unknown. Furthermore, it is not unique to the femoral vascular bed, with similar responses being seen in the gut and kidney (Quaedackers et al. 2004a,b). Potentially, loss of vasoconstriction could reflect loss of sympathetic activity. However, this seems improbable given that circulating catecholamines increase markedly during prolonged asphyxia (Gu et al. 1985). Similarly, it does not reflect loss of adrenal activity since, in the present study, cortisol levels were high at the end of the period of cord occlusion. Thus these data suggest that some additional factor, such as severe local tissue acidosis, actively inhibits femoral vascular tone during prolonged asphyxia.
The initial HPA axis response during hypoxia in our study suggests an ACTH-driven rise in cortisol levels, with a rapid rise in both hormones. There is some evidence that the fetal lung can also secrete ACTH during stress, but since the lung clears ACTH at higher concentrations, it is unlikely to be a factor in the present study (Cudd & Wood, 1995). Maternal cortisol can cross the placenta (Wood & Rudolph, 1984). However, the major increase in fetal cortisol levels in the present study occurred during the interval of complete occlusion of the umbilical cord, suggesting that a maternal contribution is improbable.
Later in recovery there was a marked dissociation between fetal ACTH and cortisol levels, with significantly elevated cortisol values at 24 and 48 h in the asphyxia group, while ACTH concentrations were not different from sham control levels. This suggests the possibility of an ACTH-independent adrenal response in that phase, as previously proposed (Gagnon et al. 1997). Furthermore, there are data indicating that carotid sinus denervation delays the rise in cortisol levels but not ACTH concentrations (Giussani et al. 1994a), suggesting the possibility of partial neural control of cortisol release. However, it might potentially reflect slower clearance of cortisol, although there are few data on relative clearance rates in the preterm fetus. Alternatively, the delayed fall in cortisol levels may simply reflect local adrenal cortisol upregulation which is slower to resolve. Tangalakis et al. (1990), for example, have shown that in preterm fetal sheep at a very similar gestational age to the present study, an infusion of ACTH induced an increase in the width of the adrenal cortex and in the levels of mRNA for key steroidogenic enzymes.
The physiological importance of the sustained elevation of fetal cortisol in the recovery period is unknown. As recently demonstrated, sympathetic nervous system activation is the major mediator of the peripheral vasoconstriction and mild increase in MAP after asphyxia in preterm fetal sheep (Quaedackers et al. 2004a). The correlation between fetal MAP during the 3 day recovery period with cortisol levels in the present study suggests that the adrenocortical response also has a role in sustaining blood pressure during recovery. This is consistent with the observation that exogenous infusions of cortisol increase fetal arterial blood pressure (Tangalakis et al. 1992; Forhead et al. 2000a; Hegarty et al. 2000; Forhead & Fowden, 2004). The sustained increase in femoral vascular resistance, which had not fully resolved after 72 h, is similar to that which we have reported in other vascular beds at this age (Quaedackers et al. 2004a,b). It may be speculated that increased resistance across all peripheral vascular beds is necessary to help support blood pressure because of transiently impaired cardiac contractility secondary to reversible cardiac injury (Barberi et al. 1999; Gunn et al. 2000).
The mechanisms of the effect of cortisol on blood pressure remain unclear. Glucocorticoids have direct cardiac effects, mediated by augmented coupling of the ß-adrenoreceptors to cellular postreceptor signal transduction (Bian et al. 1993) and, of particular interest, potentially by augmented sympathetic responses (Chan et al. 1991; Segar et al. 2001). Consistent with this suggestion, Padbury et al. (1995) have shown that neonatal lambs which had received antenatal betamethasone had significantly elevated blood pressure, cardiac output and cardiac contractility, despite similar preload (as assessed by left ventricular end-diastolic pressure). In part this may be due to a significant increase in ß-adrenergic receptor-dependent myocardial cyclic adenosine monophosphate generation (Stein et al. 1993). Furthermore, synthetic glucocorticoid administration is associated with increased vascular resistance (Derks et al. 1997; Fletcher et al. 2000; Schwab et al. 2000). Finally, there is evidence in late gestation that hypercortisolaemia leads to activation of the fetal RAS (Forhead et al. 2000b; Zimmermann et al. 2003). However, the initial rise in blood pressure was independent of the RAS (Forhead & Fowden, 2004) and we have previously reported that, in the present model, renin levels are reduced during recovery from asphyxia (Quaedackers et al. 2004b).
Conclusions
Profound asphyxia in the preterm fetus led to a very large relative increase in ACTH and cortisol levels during asphyxia, which was comparable with near-term responses, followed by sustained elevation that gradually resolved between 24 and 72 h. These data do not support the concept that there is a phase of adrenocortical underresponsiveness in the preterm fetus. Rather they suggest that the greater anaerobic tolerance of the preterm fetus, compared with the near-term fetus, means that its full range of responses is only activated by more severe insults. The correlation between cortisol levels following severe asphyxia and fetal MAP suggests that, at least in part, the prolonged adrenocortical response may help to sustain fetal blood pressure during a critical period of recovery.
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P < 0.01, 
P < 0.001 compared to sham controls.
) and the asphyxia group (•) from 12 h before occlusion until 72 h after release of occlusion 