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Ann Thorac Surg 2008;85:1719-1727. doi:10.1016/j.athoracsur.2008.01.096
© 2008 The Society of Thoracic Surgeons
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Original Articles: Pediatric Cardiac

Fetal Stress Response to Fetal Cardiac Surgery

Christopher T. Lam, BSa, Samar Sharma, BSa, R. Scott Baker, BSa,b, Jerri Hilshorst, CCPa, John Lombardi, CCPa, Kenneth E. Clark, PhDb, Pirooz Eghtesady, MD, PhDa,b,*

a Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
b Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio

Accepted for publication January 28, 2008.

* Address correspondence to Dr Eghtesady, Division of Cardiothoracic Surgery, Cincinnati Children's Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3032 (Email: pirooz.eghtesady{at}cchmc.org).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: A deleterious fetal stress response, although not fully elucidated, may account for poor outcomes after experimental fetal cardiac surgery. We set out to characterize this fetal stress response and its potential role in placental dysfunction.

Methods: Fifteen ovine fetuses at gestational day 100 to 114 were placed on extracorporeal support for 30 minutes and were then followed 2 hours after cardiopulmonary bypass. Fetal plasma samples were analyzed for vasopressin, cortisol, and β-endorphin levels, and correlated to fetal hemodynamics and placental gas exchange.

Results: Unique temporal patterns of response were seen in release of the three stress hormones. Vasopressin demonstrated the most profound and early response followed by cortisol and β-endorphin, the latter continuing to rise in the post-bypass period. A sharp rise in fetal mean arterial pressure and placental vascular resistance strongly correlated with rising vasopressin levels. Post-bypass deterioration of fetal gas exchange and hemodynamics correlated with the ensuing rise in cortisol and β-endorphin. Rising fetal lactate levels correlated with elevations in all three stress hormones.

Conclusions: Fetal cardiopulmonary bypass leads to a profound, early rise in vasopressin concentrations that strongly correlates with placental dysfunction after fetal bypass. Vasopressin may play an important mechanistic role in pathogenesis of this placental dysfunction.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The American Heart Association reports that approximately 40,000 children in the United States are born with congenital heart defects every year. Many of these are effectively corrected through surgical intervention after birth. A few defects, however, continue to be associated with significant morbidity and mortality. There is increasing evidence that some of these defects may benefit from fetal interventions, including fetal cardiac surgery [1–3]. Previous studies have demonstrated the feasibility for fetal cardiopulmonary bypass.

Placental dysfunction after cardiopulmonary bypass, however, remains the Achilles' heel of experimental fetal cardiac surgery [4–7]. This placental dysfunction presents as an increase in placental vascular resistance (PVR) and associated deterioration in fetal gas exchange [6, 8, 9]. Bypass-induced inflammation and an inappropriate fetal stress response to bypass have been implicated in this pathophysiology [8, 10, 11]. As a result of the idea that perhaps the fetal adrenocortical axis is not capable of mounting an adequate response, steroid supplementation has been attempted during fetal cardiopulmonary bypass with limited success [9]. Similarly, attempting to curtail the stress response through administration of analgesics directly into the fetal central nervous system has been tried with some efficacy [8, 10, 11]. A better understanding of the fetal stress response and its underlying mechanism(s) would allow for perhaps a targeted approach to abrogate the inappropriate responses. Many investigators have shown that the fetus can mount a response to noxious stimuli such as hypoxia or "needling" (as would occur with fetal transfusion through hepatic puncture) by increasing key fetal stress hormones, such as vasopressin and β-endorphin [12–14].

These critical mediators of the fetal stress response have not been defined in the setting of experimental fetal cardiac surgery. Unique to this milieu is that stressors related to general fetal surgery (hysterotomy, fetal manipulation) are compounded by those related to cardiac surgery (sternotomy, cannulation of great vessels) and the associated need for extracorporeal circulation. Defining the role and contribution of each of these components could help substantially in identifying measures aimed at reducing fetal stress.

In this regard, defining the changes in the hormone vasopressin is of great interest, as this peptide has potent vasoconstrictive properties. Furthermore, prior data have shown that vasopressin is the primary mediator of the "brain-sparing" response in the fetus [15], which is physiologically quite analogous to previously reported circulatory redistribution seen with experimental fetal cardiac surgery [7, 8]. In both, blood is "transiently" diverted to vital organs such as the brain, heart, and adrenal glands, but away from the body and the placenta. For this reason, we investigated the fetal stress response to surgical manipulation and extracorporeal circulation, with particular emphasis on vasopressin as a crucial player in the associated increased in PVR.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Surgical Procedure
Nineteen singleton and twin pregnant ewes from 100 to 114 days of gestation were studied (term, approximately 148 days). Fifteen fetuses underwent 30 minutes of extracorporeal circulatory support including 3 that had sternotomy and were followed 2 hours after bypass. These were compared with 4 equally instrumented control animals that did not undergo extracorporeal circulatory support. Surgical preparation and fetal cardiopulmonary bypass were performed as previously described by our group [16, 17]. Briefly, ewes were fasted for 24 hours before sedation with ketamine and diazepam, intubated endotracheally, and placed on 2% isoflurane and oxygen. Ewes received 0.3 mg Buprenex (Reckitt and Colman, Richmond, VA) intramuscularly and penicillin G. Catheters were placed in the ewe's femoral artery and vein for measurement of blood gases and delivery of intravenous fluids, respectively. After midline laparotomy and minor hysterotomy, catheters were placed in the fetal femoral artery for blood gas measurements, blood sampling, and pressure monitoring. Through the same hysterotomy, an umbilical flow probe (4 to 6 mm, Transonic Systems, Ithaca, NY) was placed to measure placental blood flow. Placental vascular resistance was calculated as previously described [18].

Fetal Cardiopulmonary Bypass
Using methods we have previously described [16, 17, 19], fetal cannulation was performed using 10F to 12F Bio-Medicus venous cannula in the jugular vein, and a 6F to 8F Bio-Medicus (Medtronic, Minneapolis, MN) arterial cannula in the carotid artery. Three animals received a sternotomy to compare the effects of more severe stress response from the sternotomy as reported previously [8, 16]. Hemodynamic values were continuously recorded using a PowerLab data acquisition system, (AD Instruments, Colorado Springs, CO). Cardiopulmonary bypass was conducted with a roller pump system, using normothermia, vacuum-assisted venous drainage, a Baby-RX reservoir (Terumo, Somerset, NJ), a heat exchanger, placenta as sole oxygenator, and blood prime derived from another adult ewe [17, 20]. Cardiopulmonary bypass lasted 30 minutes with a target flow rate of 200 to 250 mL · min–1 · kg–1 based on our prior studies [17], and fetuses were followed for 2 hours after bypass. Ewes and fetuses were euthanized for autopsy measurement of fetal morphometrics and confirmation of catheter positions. All procedures were performed in accordance with Institutional Animal Care and Use Committee–approved procedures in an Association for Assessment and Accreditation of Laboratory Animal Care–approved facility.

Blood Sampling Regimen
Maternal and fetal arterial blood gases were collected (0.3 mL) immediately on gaining arterial access, just before cardiopulmonary bypass, at 30 minutes on bypass, and 30 and 120 minutes after bypass. Blood gases were measured with an i-STAT clinical analyzer, (i-STAT Corp, Windsor, NJ). Maternal and fetal lactate values were measured with a YSI 2300-STAT analyzer, (YSI Corp, Yellow Springs, OH).

Fetal blood samples (4 mL) for immunoassay were collected using the same regimen as for blood gases listed above. Because fetuses need to be well heparinized (activated clotting time approximately 400 seconds) before and during cardiopulmonary bypass, blood samples were collected into lithium heparin–coated tubes (Monovettes; Sarstedt, Newton, NC) rather than EDTA tubes, immediately placed on ice, and then centrifuged at 1,500g at 4°C for 15 minutes. Fetal plasma was aliquoted into 0.5 and 1.0 mL samples and frozen at –20°C until assay.

Immunoassay Measurements
All stress hormones were assayed using commercially available enzyme-linked immunosorbent assay kits that cross react with sheep proteins. Assay results were read with a Multiskan-EX microplate reader (Thermo EC, Waltham, MA) using Ascent software (Thermo EC, Waltham, MA). All samples were assayed in duplicate and mean values reported.

The vasopressin assay (Assay Designs, Ann Arbor, MI) had a sensitivity of 3.5 pg/mL with intraassay and interassay coefficients of variation of 5.9% to 10.6% and 6.0% to 8.5%, respectively. β-Endorphin (Phoenix Pharmaceuticals, Burlingame, CA) had a sensitivity of 0.7 ng/mL with intraassay and interassay coefficients of variation of 5% or less and 14% or less, respectively. β-Endorphin plasma samples were concentrated 10:1 to ensure values would fall within the range of the assay. The cortisol assay (Oxford Biomedical Research, Rochester Hills, MI) has a sensitivity of 0.1 ng/mL with intraassay and interassay coefficients of variation of 10% or less.

Statistical Analysis
The data were analyzed using type III analysis of variance tests for between-group and in-group differences and least significant difference post-hoc analysis between baseline and other time points, with significance declared at a probability value of 0.05 or less. Correlation coefficients (R 2 values) were determined using best-fit regression lines with mean values of stress hormones at each time point compared with corresponding means of fetal arterial blood gas and hemodynamic values. We defined strong correlations as correlation coefficients from 0.7 to 1.0, medium correlations as correlation coefficients from 0.4 to less than 0.7, and weak correlations as correlation coefficients less than 0.4. Values are given as mean ± standard deviation. Software packages SPSS 15.0 (SPSS, Inc, Chicago, IL) and Excel 2003 (Microsoft Corp, Redmond, WA) were used for data analysis.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Placental Gas Exchange
Fetal arterial blood gas values with the conduct of fetal cardiopulmonary bypass are shown in Table 1. As reported previously [4, 7, 10, 19, 20], fetal cardiopulmonary bypass leads to significant fetal respiratory acidosis with time, as evidenced by progressive decrease in arterial pH (p ≤ 0.05) and increase in arterial partial pressure of carbon dioxide (p ≤ 0.01). Conversely fetal arterial partial pressure of oxygen was stable until the post-bypass period, when it began to decline, typifying the late hypoxia observed with fetal cardiopulmonary bypass. Concentrations of fetal plasma lactate rose significantly and steadily with each successive measurement throughout the entire protocol (p ≤ 0.01). Although all 15 fetuses were successfully weaned off cardiopulmonary bypass, during the post-bypass period, 1 fetus succumbed by 30 minutes, 2 by 60 minutes, and 2 by 120 minutes. Fourteen fetuses of the 19 survived the entire protocol (74% survival).


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  		Table 1 Fetal Blood Gases and Lactate Concentrations Before, During, and After Cardiopulmonary Bypass, and In-Group Analysis of Variance With Least Significant Difference Post-Hoc Analysis a
 
Fetal Hemodynamics
Fetal mean arterial pressure (MAP) increased acutely and profoundly (in-group analysis of variance, p = 0.0009) from 36 ± 5 to 62 ± 17 mm Hg with onset of fetal cardiopulmonary bypass, peaking within 3 minutes (70% rise; p < 0.01; Fig 1A). Fetal MAP remained elevated throughout the entire 30 minutes of cardiopulmonary bypass for every time point compared with baseline (p ≤ 0.01 by post-hoc analysis). Fetal MAP quickly returned to baseline levels with cessation of fetal cardiopulmonary bypass (37 ± 10 mm Hg; p < 0.001 versus 30 minutes on bypass) and declined by 120 minutes after bypass. Fetal hemodynamics did not change in the sham-operated group.


Figure 1
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  		Fig 1. Values displayed are mean ± standard deviation. The initial 10 minutes of cardiopulmonary bypass are displayed minute by minute to show acute changes with onset of bypass. (A) Fetal mean arterial pressure rapidly increases over prebypass values within the first minute, peaking at 3 minutes and remaining profoundly elevated throughout the bypass period, *p ≤ 0.001. Mean arterial pressure dropped abruptly to prebypass levels with cessation of bypass and remained lower compared with bypass (#p ≤ 0.01 versus bypass). (B) Umbilical blood flow reached a significant and sustained increase by 15 minutes of bypass (*p ≤ 0.01), returning to baseline after bypass cessation, and remaining lower than during the final 15 minutes of bypass levels thereafter (#p ≤ 0.01). (C) Although umbilical vascular resistance appears to rise markedly during bypass, owing to considerable individual variation no significant events were noted (in-group analysis of variance, p = 0.853). Hemodynamic variables for sham bypass animals did not change (data not shown).

 
Individual umbilical blood flow responses to the onset of fetal cardiopulmonary bypass were highly variable, initially trending downward before displaying a significant and sustained increase by 15 minutes on bypass (31%; p < 0.01; Fig 1B). With termination of cardiopulmonary bypass, umbilical blood flow returned to prebypass values within 15 minutes and was lower than baseline by 120 minutes. Umbilical blood flow at 90 and 120 minutes after cardiopulmonary bypass were lower than those during the final 15 minutes on bypass (p ≤ 0.05). Similarly, individual PVR responses to fetal cardiopulmonary bypass were highly variable, trending higher during the cardiopulmonary bypass period (9%7 ± 136% at 4 minutes on bypass; Fig 1C). After cardiopulmonary bypass, PVR returned to prebypass levels.

Fetal Stress Hormones
Fetal plasma concentrations of vasopressin increased more than 600% during the prebypass period (p = 0.024; Table 2, Fig 2). This rise continued during cardiopulmonary bypass, peaking at 30 minutes on bypass. Fetal vasopressin levels then began a gradual decline, being elevated by only more than 500% at 30 minutes after bypass, and then declining further by 120 minutes after bypass. The 3 fetuses exposed to sternotomy displayed the same pattern as those without sternotomy and are included with the cardiopulmonary bypass group (p > 0.70 by analysis of variance). As expected, a similar prebypass rise in vasopressin levels occurred in the sham-operated group, peaking at 30 minutes after sham cardiopulmonary bypass (p = 0.071; Table 2). However, it should also be noted that sham control levels are not subject to the dilutional influence of priming volume during cardiopulmonary bypass with maternal vasopressin levels of approximately 3 pg/mL [15], and therefore preclude accurate group comparison during fetal extracorporeal circulatory support and after cardiopulmonary bypass.


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  		Table 2 Fetal Plasma Concentrations of Stress Hormones Before, During, and After Cardiopulmonary Bypass or Sham Treatment, and In-Group Analysis of Variance with Least Significant Difference Post-Hoc Analysis a
 

Figure 2
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  		Fig 2. Fetal stress hormone levels represented as percent change from baseline for vasopressin (open bars, dotted line), β-endorphin (striped bars, solid line), and cortisol (solid bars, dashed line), significances noted in Table 2. Note the dramatic, early rise of vasopressin (prebypass) compared with the later, sustained rise in β-endorphin and cortisol (trend lines added to depict temporal differences). Cortisol also peaked on bypass like vasopressin, but in contrast remained relatively stable after bypass. β-Endorphin levels continued to rise throughout, peaking at 120 minutes after bypass. (Hyst. = hysterotomy.)

 
Similarly, fetal cortisol increased before cardiopulmonary bypass (250%; p = 0.017; Table 2, Fig 2), rising further during cardiopulmonary bypass and cresting by 30 minutes on bypass (>375%; p = 0.001). Like vasopressin, cortisol levels, although still elevated (in-group analysis of variance, p = 0.022), began to plateau after cardiopulmonary bypass.

In contrast, fetal β-endorphin levels increased to more than 180% of prebypass levels by 30 minutes after cardiopulmonary bypass (p = 0.019; Table 2, Fig 2). Further, unlike vasopressin and cortisol, β-endorphin concentrations continued to climb (in-group analysis of variance, p = 0.005), reaching 275% by 120 minutes after cardiopulmonary bypass (p = 0.002).

Physiologic Correlations
Increasing vasopressin and cortisol values correlated with increasing fetal MAP (Fig 3A, 3C), whereas β-endorphin values negatively correlated with fetal MAP (Fig 3B). Increasing vasopressin and cortisol values also correlated strongly with increasing PVR (R 2 > 0.66; Fig 4A, 4C), whereas increased β-endorphin values correlated with decreased PVR (Fig 4B). Lower vasopressin and cortisol levels correlated with improved fetal pH, ie, inverse correlation (R 2 = 0.4328 and 0.4999, respectively, not shown), whereas increased vasopressin and cortisol levels correlated with higher arterial partial pressures of carbon dioxide (R 2 = 0.4502 and 0.5365, respectively, not shown). Stress hormones and arterial partial pressure of oxygen did not correlate. Elevated vasopressin and cortisol both robustly correlated with increased lactate levels (R 2 > 0.70; Fig 5A, 5C), as did increased β-endorphin values although not as strongly (Fig 5B).


Figure 3
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  		Fig 3. Regression lines of best fit were plotted for mean arterial pressure (mm Hg) against corresponding stress hormone levels. Note increasing vasopressin (A) and cortisol (C) levels correlated with a higher mean arterial pressure, whereas lower β-endorphin (B) levels correlated with higher mean arterial pressure.

 

Figure 4
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  		Fig 4. Regression lines of best fit were plotted for placental vascular resistance against corresponding stress hormone levels. Note the strong correlations for increasing vasopressin (A) and cortisol (C), and lower β-endorphin (B) levels, correlated with increased placental vascular resistance.

 

Figure 5
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  		Fig 5. Regression lines of best fit were plotted for lactate against corresponding stress hormone levels. Note the consistently strong correlations between vasopressin (A), β-endorphin (B), and cortisol (C) levels with lactate levels.

 
Vasopressin Index of Fetal Well-Being
As noted before, individual responses of animals can be somewhat variable, with some animals being quite stable for prolonged periods, while others have more rapid deterioration despite being exposed to identical experimental protocols. For this reason, we created three groups based on length of postbypass fetal survival and fetal metabolic response to surgery and cardiopulmonary bypass to examine vasopressin as a marker of fetal well-being. A ranking of "poor" indicated early postbypass fetal demise, "fair" indicated postbypass survival with profound metabolic deterioration, and "good" indicated survival with minimal metabolic change (Fig 6). Because vasopressin is believed to be a general marker of stress and we wanted to validate this assumption, animals were ranked into the preceding categories without consideration for treatment status (sham, bypass, or bypass with sternotomy). Based on this ranking assessment, pH, arterial partial pressure of carbon dioxide, and lactate all deteriorate in separate and distinct patterns among groups with regard to time and index grouping (p < 0.001; Fig 6A–6C, Table 3) and in conjunction with distinct and separate patterns of vasopressin levels by grouping (p = 0.05; Fig 6D, Table 3). Of note, elevated vasopressin levels do not persist as the condition of the fetus deteriorates, but rather appear to signify impending demise. All fetuses that went on to have hemodynamic and metabolic deterioration reached vasopressin levels greater than 100 pg/mL. In contrast, none of the animals that had vasopressin levels less than or equal to 90 pg/mL suffered any adverse consequences. Therefore, on the basis of high vasopressin levels (>100 pg/mL), it appears possible to assess and predict fetal well-being or perhaps impending demise.


Figure 6
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  		Fig 6. Individual fetuses were ranked for condition according to metabolic status and fetal survival after bypass. Rankings were good (squares with solid line, n = 5), fair (circles with dashed line, n = 6), or poor (triangles with dotted line, n = 4). Three sham-operated fetuses resided in the good group and 1 in the fair group. Fetal rankings yielded clear pH (A), arterial partial pressure of carbon dioxide (PCO 2; B), lactate (C), and vasopressin (D) level differences by group (p ≤ 0.05; Table 3) for each by multiple regression type III analysis of variance analysis. Significant within group differences are @p ≤ 0.05 by post hoc analysis versus hysterotomy (Hyst.) in Good condition animals, +p ≤ 0.05 versus hysterotomy in Fair condition, and *p ≤ 0.05 versus before bypass in Poor condition animals and further illustrate the differences in variable trajectories for each group. Taken together, these data suggest vasopressin could be used to assess and indicate fetal well-being.

 

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  		Table 3 Multiple Regression Type III Analysis of Variance Analysis of Select Fetal Arterial Blood Gases and Vasopressin Values, Among Condition Type, Effect of Time, and Condition and Effect of Time a
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This report demonstrates that fetal vasopressin and β-endorphin levels rise dramatically with conduct of fetal surgery and extracorporeal circulation, and also documents the temporal phases of stress hormones vasopressin, β-endorphin, and cortisol during the course of experimental fetal cardiac surgery in the immature fetus. Our results also suggest that a dramatic rise in the potent vasoconstrictor vasopressin strongly correlates with the associated rise in PVR and the deteriorations in fetal gas exchange seen with fetal cardiopulmonary bypass. Lastly, our data suggest that very high vasopressin levels (>100 pg/mL) are a strong indicator of actual fetal condition and potentially an early marker of impending fetal deterioration and perhaps demise when other metabolic indicators appear less concerning.

Two prior reports had specifically evaluated changes in fetal serum cortisol concentrations with fetal cardiopulmonary bypass and noted mild to moderate increases [10, 11]. Those studies, however, were conducted in older, more mature fetuses (approximately 130 days' gestation) than reported here. Clinical translation of fetal cardiac surgery requires experimentation in the appropriate gestational age fetuses equivalent to human gestation of 21 to 29 weeks inasmuch as significant physiologic changes occur in the uteroplacental unit during gestation [21]. Further, prior studies used steroid administration or hemodiafiltration, which could have influenced the fetal stress response or hormone concentrations. Indeed, some had advocated treating the fetus with higher doses of steroids after fetal cardiopulmonary bypass, assuming that the fetus is not capable of mounting an adequate response [8, 10]. Our findings would suggest otherwise, perhaps explaining the lack of a significant response to fetal steroid supplementation. Steroid use in this setting must also be carefully considered in light of mounting evidence for their detrimental effects on developing fetal organs [22–24].

Physiologic responses observed during fetal cardiopulmonary bypass can be broken down into three distinct phases. The early phase is notable for a marked rise in fetal MAP (mentioned in prior studies [4], but notably absent in others [7, 10]) and accompanied by a variable response in umbilical blood flow and PVR. A second or plateau phase occurs during the remainder of cardiopulmonary bypass in which elevated but stable fetal MAP is accompanied by rising umbilical blood flow, PVR, and fetal hypercapnia. In the final or third phase, which begins after termination of fetal cardiopulmonary bypass, there is an immediate decline in fetal MAP and umbilical blood flow (and continued rise in PVR), followed by worsening fetal hypercarbia, lactic acidosis, and lastly fetal hypoxia, the last portending imminent fetal death [4, 6–11, 17, 19].

The temporal pattern in the fetal stress response we observed correlates with the preceding sequence of physiologic events. We noted an early and profound increase in vasopressin concentrations (>600%), followed by a rise in cortisol and β-endorphin, the latter continuing to rise in the postbypass period. Further, the high levels of vasopressin in the prebypass and bypass phase correlated strongly to the early elevations of fetal MAP and PVR. Not surprisingly, all three stress hormones displayed moderate correlations with expected trends in fetal pH, arterial partial pressure of carbon dioxide, and lactic acidosis. No correlations to fetal arterial partial pressure of oxygen were noted mainly because fetal hypoxia is a late and terminal event in these animals. The temporal sequence of stress hormone elevations seen in our study is similar to prior reports using other fetal stimuli (eg, fetal needling for transfusion) [14, 25, 26] and is suggestive of differential mechanisms responsible for their release. For instance, we observed declining fetal arterial partial pressure of oxygen along with the continued rise in β-endorphin, which is known to elevate in response to hypoxia [26]. The magnitude and duration of their collective responses also suggest that the immature fetus has not developed adequate control over their regulatory mechanisms.

The profound rise in vasopressin seen in our study has significant implications for characteristic rise in PVR and associated placental dysfunction observed with experimental fetal cardiac surgery. Vasopressin is a nanopeptide hormone and neurotransmitter synthesized in the hypothalamus and stored in the posterior pituitary. Vasopressin is believed to be the primary mediator of the fetal stress response and its brain-sparing effect [27]. The brain-sparing effect is a well-described fetal adaptive mechanism that consists of preferential redistribution of fetal circulation to the brain, heart, and the adrenal glands [27]. Interestingly, prior investigators have also shown that experimental fetal cardiac surgery is associated with a preferential redistribution of fetal circulation away from the body (and the placenta) to the brain, heart, and the adrenal glands [7, 8]. The redistribution seen after fetal surgery and exposure to extracorporeal circulation, however, is more severe and persistent in comparison to the reported brain-sparing response.

Our results suggest that the stress response is initiated early on during surgery and, indeed, may portend subsequent outcome. As such, it is conceivable that some of the detrimental aspects of prior fetal cardiopulmonary bypass studies may have had little to do with exposure to extracorporeal circulation but rather to the overall stress of the experimental surgical protocol. It is of interest that in our studies, sternotomy did not appear to compound or exacerbate the overall stress induced by other aspects of fetal cardiac surgery. Future studies may show that early inhibition of fetal stress response could perhaps dramatically improve outcomes and prevent the rise in PVR.

Our findings of elevated vasopressin levels are consistent with prior reports involving other types of fetal insults such as hypoxia or hemorrhage [12, 28]. The magnitude of the response observed by us (approximately 90 pg/mL among healthy animals and >100 pg/mL among the sick animals), however, is orders of magnitude greater than previously reported (approximately 1 pg/mL). Vasopressin has a known strong vasoconstrictive effect on the placental vasculature [12,15, 29]. Also, a substantial rise in fetal MAP has been previously reported by Gibson and Lumbers [30] with high-dose fetal infusion of vasopressin. It is conceivable, therefore, that the persistent circulatory changes seen in the fetus after cardiopulmonary bypass stem in part from the excessive release of vasopressin. Of note, however, the elevated vasopressin levels do not remain as such as the condition of the fetus deteriorates, reflecting either exhaustion or suppression of the release mechanism.

In the sheep placenta, mRNAs for the vasopressin receptor types V1a (mediates vasoconstriction) and V2 (mediates fluid reabsorption) are equivalently expressed at 100 days of gestation [31]; however, vasopressin itself is not produced in the placenta. We and others have also noted that after cardiopulmonary bypass the fetus often needs and may benefit from significant volume resuscitation [32, 33], perhaps reflecting changes in fetal fluid reabsorption secondary to the circulating vasopressin. Further evaluation of expression of vasopressin receptors in the placenta is warranted along with potential use of vasopressin antagonists to further elucidate potential mechanisms involved.

Of final note, the responses seen in this study were seen despite the implementation of anesthetic and analgesic regimen as used currently during clinical open fetal surgery. We had previously investigated the potential use of high-dose fentanyl, as in clinical neonatal cardiac surgery, for ameliorating the fetal stress response [34]. Paradoxically, we found that high-dose fentanyl, as used in clinical practice, is indeed detrimental to the placenta and the placental circulation, a finding corroborated by Fisk and colleagues [35]. Therefore, further studies and alternative approaches are warranted to adequately suppress the fetal stress response before successful clinical application of fetal cardiac surgery.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The authors gratefully acknowledge the technical assistance of Mr. Robert Ferguson and Anoop Brar, PhD, for insightful discussions and input, Mr. Robert Giulitto and Hoxworth Blood Center for donation of blood collection supplies, and Jodie Duffy, PhD, for use of the microplate reader. Our research is supported by grants from the American Heart Association National Scientist Development Grant (0535292N), Children's Heart Foundation of Chicago, Children's Heart Association of Cincinnati, and the Cincinnati Children's Hospital Research Foundation Translational Research Initiative.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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