|Year : 2008 | Volume
| Issue : 4 | Page : 152-158
Fetal cardiac surgery - Hype or holy grail?
Vadiyala Mohan Reddy, Ashok Muralidaran
Pediatric Cardiac Surgery, Stanford University Medical Center, Stanford, California; and Maimonides University Medical Center, New York, USA
|Date of Web Publication||17-Jun-2010|
Vadiyala Mohan Reddy
300 Pasteur Drive, Falk Bldg.CVRB 650-723-0190
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Reddy VM, Muralidaran A. Fetal cardiac surgery - Hype or holy grail?. Heart Views 2008;9:152-8
There is little doubt that certain congenital heart diseases progress adversely in utero generating abnormal flow patterns that compromise cardiac function by impairing normal chamber growth and maturation. What has been elusive so far is the consistent means to intervene early enough to reverse, if possible, or halt the progression of such lesions so as to provide a near normal heart or at least the opportunity for a postnatal two-ventricle repair. While a minimalistic approach is certainly preferable as has been attempted for the Hypoplastic Left Heart Syndrome (HLHS) with fetal balloon valvuloplasties  , a case for open fetal cardiac surgery does exist for lesions like the Ebstein's anomaly or pulmonary atresia or for removal of endocardial fibroelastosis (EFE) in the setting of HLHS. And it is here that new paradigms have to be set and old ones readjusted to suit the needs of the myriad components of the fetal-maternal unit.
| Historical Perspective|| |
Standing on the proverbial shoulders of giants, much of the progress in fetal surgery has been offshoots of very elegant studies done by Dr.Rudolph and other investigators on fetal lambs. We now better understand the fundamental hemodynamics and physiology of the fetal-maternal unit and its response to various factors that it is likely to be exposed to during surgical manipulations. These studies paved the way for the eventual launch of fetal surgery as a specialty  . With fetal echocardiography providing an excellent picture of the structural and functional abnormalities in early gestation  , the natural next step was to explore the safest ways and means to tackle the problem at the earliest possible time point. We will cover the early years in the journey from 1978 through '95 in this historical section.
| Animal Models of Congenital Heart Disease|| |
An intrauterine lamb model of LV inflow and outflow obstruction was created by Rudolph et al with characterization of the consequences on flow and chamber dimensions that resembled HLHS and severe congenital aortic stenosis respectively  . This was followed by fetal lamb models of simulated creation and repair of pulmonary and aortic stenosis by Turley et al in 1982 and another group in '87 , . More invasive cardiac procedures entailed the need for successful fetal extracorporeal circulation and methods of myocardial preservation, stimulating a flurry of research in the field.
| Fetal Cardiopulmonary Bypass|| |
The earliest attempts to address the twin problems was in 1991 by Hawkins et al who placed fetal lambs on cardiopulmonary bypass at hypothermia and normothermia, and administered cold crystalloid cardioplegia.  These studies revealed the emergence of placental insufficiency as an added problem, which remains a formidable barrier till date. The placental dysfunction arising from increased vascular resistance manifested as reduced oxygenation and impaired ventilation leading to fetal acidosis, myocardial depression and death minutes after bypass.
The early 1990s witnessed studies designed to better comprehend the nature of the placental hemodynamics and studies attempting to circumvent the placental dysfunction with the fetus on cardiopulmonary bypass. Verrier and Vlahakes provide a succinct review of the developments in fetal cardiac bypass of those times in an interesting 1992 article  .
| Understanding the Placental Hemodynamics|| |
Assad, Lee and Hanley placed the isolated in situ lamb placenta on bypass [Figure 1] and studied the placental vascular resistance and compliance to varying flow rates, quantified the large capacitance of the placental vessels and calculated the precise perfusion rates and pressures required to create and hence avoid increased placental vascular resistance , . It was apparent that a high flow rate was required during bypass to sustain placental function and as a corollary, low umbilical flow rates induced placental dysfunction. These inferences were independently validated by Bradley, Hanley and associates who documented redistribution of blood away from the placenta during fetal bypass causing dysfunction  , and by Hawkins and co-workers who demonstrated improved placental function with higher bypass flow rates  . Since higher flows were limited by cannula sizes used on the fetal heart, Fenton, Heinemann and Hanley inquired the possibility of excluding the placenta from the bypass circuit and hence provide adequate systemic perfusion with lower flow rates and with an oxygenator in the circuit  .
| The Humoral aspect of Placental Dysfunction|| |
Apart from hemodynamic factors, studies also revealed a humoral component to placental insufficiency. Sabik, Assad and Hanley speculated on the role of vasoconstrictive prostaglandins and demonstrated the beneficial role of indomethacin and high-dose steroid administration in preserving placental blood flow during fetal bypass , . Fenton, Heinemann and Hanley also hypothesized the role of the fetal stress response with catecholamine release in response to anesthesia and surgical stress in causing decreased placental perfusion  . In this study, ketamine anesthesia was shown to be inferior in preserving placental blood flow when compared with total spinal anesthesia in lamb fetuses on bypass. Using the combination of indomethacin and spinal anesthesia, Fenton and colleagues placed fetal lambs (80% gestation) on bypass, returned them to the uterus after weaning from the pump and followed to term, achieving 80% survival among singleton fetuses  .
Certain caveats exist regarding the possible application of the two pharmacological strategies mentioned above to the human context. While Indomethacin is detrimental to certain vascular beds, notably of the kidneys, there is a legitimate concern regarding the fetal use of steroids in causing premature closure of the ductus arteriosus and venosus. While the fetal stress response study used spinal anesthesia, it was not compared to narcotics that are used in preterm and term neonates, due to the lack of opioid receptors in sheep.
| The Current Era|| |
As of 1996 unanswered questions prevailed on preventing placental dysfunction applicable to a primate model and on issues regarding myocardial preservation during cardiopulmonary bypass. This section encompasses the advances that have occurred in the past decade.
| Understanding the Bypass Circuit|| |
Maternal blood prime and exposure of fetal blood to the large extracorporeal surface area of the circuit were concerns addressed by early studies in this period. The conventional fetal bypass circuits had a volume of about 150 ml which were filled with crystalloids, maternal blood or a combination of both. Large crystalloid volumes caused fetal hemodilution and maternal blood in amounts sufficient to replace the fetal blood volume, especially in small fetuses, may impair fetal tissue and placental oxygenation  .
That the extracorporeal circuit triggered a systemic inflammatory reaction by the activation of complement and eicosanoids in adults and children was well established by that time , . This was also shown by Reddy et al in the fetal setting in a study that revealed significantly elevated IL-6 levels post bypass  . Our group also tested a novel In-Line axial flow pump [Figure 2], the Hemopump, that minimized extracorporeal surface area and used no priming volume and demonstrated significantly higher placental flow and reduced placental resistance during and after bypass compared to a conventional circuit [Figure 3]  . This pump was also used on long term studies of fetal survival to term post bypass and proved the technical feasibility of such an undertaking  .
In further studies comparing the Hemopump with the conventional roller pump, they found significantly increased neutrophil degranulation accompanying placental dysfunction in the fetuses on roller pumps further underscoring the necessity to minimize extracorporeal surface area during fetal bypass  . The pump however, suffered the drawback of being overly simplistic and lacking the mechanism to deal with inadvertent air embolism. Lombarti et al, in a recent study used a similar miniaturized circuit with a centrifugal pump for placing immature fetal sheep on bypass  . The same group had earlier published a study with vacuum assisted venous drainage for enhancing bypass flows to offset placental dysfunction  .
| Focus on the Endothelium|| |
Champsaur and co-workers evaluated the various beneficial effects of a pulsatile flow during fetal lamb bypass as opposed to the conventional continuous flow obtained with roller pumps. Their first study was published in 1994 with subsequent studies in '97 and 2000. In their earliest study, they documented higher pump flows and placental flow with decreased systemic vascular resistance in the pulsatile pump group  .
A salutary role for shear stress in inducing the release of Nitric Oxide was postulated as the reason behind the beneficial effects of pulsatility in better preserving placental flow during bypass  . The group further demonstrated higher endothelin-1 levels and plasma renin concentration in fetuses on continuous flow bypass as opposed to the pulsatile flow fetuses suggesting a major role for endothelial dysfunction mediated by the renin-angiotensin system in placental insufficiency  .
Reddy et al provided further evidence for endothelial dysfunction as an etiological factor for placental insufficiency by documenting selective impairment of endothelial-dependent vasodilation post bypass in the lamb fetus, linking it to a combination of decreased nitric oxide levels and elevated circulating endothelin-1 levels acting via vasoconstrictive endothelin-A receptors  .
| Fetal Myocardial Protection|| |
The fetal myocardial ultrastructure differs substantially from that of the mature myocardium spawning significant differences in fetal cardiac function. A reduced concentration of sarcomeres per unit mass of myocardium results in the decreased ventricular compliance observed in fetal hearts  . The fetal cardiac myocyte also has a reduced sarcoplasmic reticular content, with depreciated calcium storage and transport capacity  . These factors necessitate tailoring the myocardial protection strategies to the fetal context.
To this end Malhotra et al compared the efficacy of cardioplegia solutions with varying calcium concentrations in preserving myocardial function on an isolated fetal sheep heart preparation  . They documented improved post-ischemia recovery and better preservation of myocardial function with solutions that had a reduced calcium concentration as opposed to normocalcemic or hypercalcemic cardioplegia preparations. In another study with a similar preparation, the group documented no difference in post-arrest cardiac function between normothermic fibrillation and hypothermic normocalcemic cardioplegia  . The latter study was performed to circumvent the theoretical difficulty of maintaining fetal hypothermia in utero.
| Ongoing Research and Future Directions|| |
It is a truism that fetal cardiac surgery endured many teething troubles some of which still persist, and progress has been pretty incremental. As has been obvious so far, almost all the work has been on lamb fetuses, and it is common knowledge to any researcher in the field as to how resilient the sheep uterus is to any manipulation. All the principles gleaned in all these years of research have to be prudently applied to primate models before their ultimate translation to human benefit. The first such primate model was reported by Ikai et al where they demonstrated the technical feasibility of placing baboon fetuses that are less than 1000 grams on bypass, and discerned the beneficial effects of isoflurane anesthesia over fentanyl and midazolam in causing adequate uterine relaxation  .
Eghtesady and colleagues in a recent inventive study reported maternal hemodynamic response to fetal cardiac bypass in sheep  . They noted significant subsidence in uterine arterial flow independent of the overall maternal hemodynamic status but associated with specific events during fetal bypass correlating with worsening fetal blood gases. This study certainly adds a new dimension to the parameters that contribute to success in fetal cardiac surgery. This group has also recently published the role of vasopressin  and perturbations in the Nitric Oxide pathway in placental dysfunction following ovine fetal bypass  .
Currently in our lab we are working on isolated fetal heart models to better address the cardioplegia issue, have placental perfusion studies planned to better comprehend the microvasculature and are actively working toward bettering the techniques of fetal bypass in lamb fetuses.
In as yet unpublished studies, we have attempted to include a membrane oxygenator in the circuit to maintain physiological levels of paO2 and paCO2 during bypass and have found some benefit in delaying hemodynamic deterioration in the post-bypass fetus. Our studies have also correlated post-bypass thromboxane B2 levels with reduced umbilical flows and are investigating the use of thromboxane antagonists to overcome this phenomenon.
Using the isolated rabbit fetal heart Langendorff model, we are currently investigating the effects of crystalloid and blood cardioplegia at varying temperatures and pressures on fetal myocardial protection. Preliminary studies have revealed warm crystalloid cardioplegia at low pressure as being more cardioprotective compared to cold temperatures and higher pressures
To summarize, there is yet a silver bullet to address the issues of placental dysfunction, myocardial preservation and uterine perfusion. Future studies leavened with a molecular perspective will catalyze a more fundamental understanding of the factors involved. Until then, complex questions in fetal cardiac surgery remain relevant.
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[Figure 1], [Figure 2], [Figure 3]