Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model.

Focal tumor ablation with ethanol could provide benefits in low-resource settings because of its low overall cost, minimal imaging technology requirements, and acceptable clinical outcomes. Unfortunately, ethanol ablation is not commonly utilized because of a lack of predictability of the ablation zone, caused by inefficient retention of ethanol at the injection site. To create a predictable zone of ablation, we have developed a polymer-assisted ablation method using ethyl cellulose (EC) mixed with ethanol. EC is ethanol-soluble and water-insoluble, allowing for EC-ethanol to be injected as a liquid and precipitate into a solid, occluding the leakage of ethanol upon contact with tissue. The aims of this study were to compare the 1) safety, 2) release kinetics, 3) spatial distribution, 4) necrotic volume, and 5) overall survival of EC-ethanol to conventional ethanol ablation in a murine breast tumor model. Non-target tissue damage was monitored through localized adverse events recording, ethanol release kinetics with Raman spectroscopy, injectate distribution with in vivo imaging, target-tissue necrosis with NADH-diaphorase staining, and overall survival by proxy of tumor growth. EC-ethanol exhibited decreased localized adverse events, a slowing of the release rate of ethanol, more compact injection zones, 5-fold increase in target-tissue necrosis, and longer overall survival rates compared to the same volume of pure ethanol. A single 150 µL dose of 6% EC-ethanol achieved a similar survival probability rates to six daily 50 µL doses of pure ethanol used to simulate a slow-release of ethanol over 6 days. Taken together, these results demonstrate that EC-ethanol is safer and more effective than ethanol alone for ablating tumors.

A novel speculum-free imaging strategy for visualization of the internal female lower reproductive system.

Fear of the speculum and feelings of vulnerability during the gynecologic exams are two of the biggest barriers to cervical cancer screening for women. To address these barriers, we have developed a novel, low-cost tool called the Callascope to reimagine the gynecological exam, enabling clinician and self-imaging of the cervix without the need for a speculum. The Callascope contains a 2 megapixel camera and contrast agent spray mechanism housed within a form factor designed to eliminate the need for a speculum during contrast agent administration and image capture. Preliminary bench testing for comparison of the Callascope camera to a $20,000 high-end colposcope demonstrated that the Callascope camera meets visual requirements for cervical imaging. Bench testing of the spray mechanism demonstrates that the contrast agent delivery enables satisfactory administration and cervix coverage. Clinical studies performed at Duke University Medical Center, Durham, USA and in Greater Accra Regional Hospital, Accra, Ghana assessed (1) the Callascope's ability to visualize the cervix compared to the standard-of-care speculum exam, (2) the feasibility and willingness of women to use the Callascope for self-exams, and (3) the feasibility and willingness of clinicians and their patients to use the Callascope for clinician-based examinations. Cervix visualization was comparable between the Callascope and speculum (83% or 44/53 women vs. 100%) when performed by a clinician. Visualization was achieved in 95% (21/22) of women who used the Callascope for self-imaging. Post-exam surveys indicated that participants preferred the Callascope to a speculum-based exam. Our results indicate the Callascope is a viable option for clinician-based and self-exam speculum-free cervical imaging.Clinical study registration ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/record/ NCT00900575, Pan African Clinical Trial Registry (PACTR) https://www.pactr.org/ PACTR201905806116817.

Understanding Factors Governing Distribution Volume of Ethyl Cellulose-Ethanol to Optimize Ablative Therapy in the Liver.

OBJECTIVE: Ethanol ablation, the injection of ethanol to induce necrosis, was originally used to treat hepatocellular carcinoma, with survival rates comparable to surgery. However, efficacy is limited due to leakage into surrounding tissue. To reduce leakage, we previously reported incorporating ethyl cellulose (EC) with ethanol as this mixture forms a gel when injected into tissue. To further develop EC-ethanol injection as an ablative therapy, the present study evaluates the extent to which salient injection parameters govern the injected fluid distribution. METHODS: Utilizing ex vivo swine liver, injection parameters (infusion rate, EC%, infusion volume) were examined with fluorescein added to each solution. After injection, tissue samples were frozen, sectioned, and imaged. RESULTS: While leakage was higher for ethanol and 3%EC-ethanol at a rate of 10 mL/hr compared to 1 mL/hr, leakage remained low for 6%EC-ethanol regardless of infusion rate. The impact of infusion volume and pressure were also investigated first in tissue-mimicking surrogates and then in tissue. Results indicated that there is a critical infusion pressure beyond which crack formation occurs leading to fluid leakage. At a rate of 10 mL/hr, a volume of 50 µL remained below the critical pressure. CONCLUSIONS: Although increasing the infusion rate increases stress on the tissue and the risk of crack formation, injections of 6%EC-ethanol were localized regardless of infusion rate. To further limit leakage, multiple low-volume infusions may be employed. SIGNIFICANCE: These results, and the experimental framework developed to obtain them, can inform optimizing EC-ethanol to treat a range of medical conditions.

Development of Algorithms for Automated Detection of Cervical Pre-Cancers With a Low-Cost, Point-of-Care, Pocket Colposcope.

GOAL: In this paper, we propose methods for (1) automatic feature extraction and classification for acetic acid and Lugol's iodine cervigrams and (2) methods for combining features/diagnosis of different contrasts in cervigrams for improved performance. METHODS: We developed algorithms to pre-process pathology-labeled cervigrams and extract simple but powerful color and textural-based features. The features were used to train a support vector machine model to classify cervigrams based on corresponding pathology for visual inspection with acetic acid, visual inspection with Lugol's iodine, and a combination of the two contrasts. RESULTS: The proposed framework achieved a sensitivity, specificity, and accuracy of 81.3%, 78.6%, and 80.0%, respectively, when used to distinguish cervical intraepithelial neoplasia (CIN+) relative to normal and benign tissues. This is superior to the average values achieved by three expert physicians on the same data set for discriminating normal/benign cases from CIN+ (77% sensitivity, 51% specificity, and 63% accuracy). CONCLUSION: The results suggest that utilizing simple color- and textural-based features from visual inspection with acetic acid and visual inspection with Lugol's iodine images may provide unbiased automation of cervigrams. SIGNIFICANCE: This would enable automated, expert-level diagnosis of cervical pre-cancer at the point of care.

An integrated strategy for improving contrast, durability, and portability of a Pocket Colposcope for cervical cancer screening and diagnosis.

INTRODUCTION: We have previously developed a portable Pocket Colposcope for cervical cancer screening in resource-limited settings. In this manuscript we report two different strategies (cross-polarization and an integrated reflector) to improve image contrast levels achieved with the Pocket Colposcope and evaluate the merits of each strategy compared to a standard-of-care digital colposcope. The desired outcomes included reduced specular reflection (glare), increased illumination beam pattern uniformity, and reduced electrical power budget. In addition, anti-fogging and waterproofing features were incorporated to prevent the Pocket Colposcope from fogging in the vaginal canal and to enable rapid disinfection by submersion in chemical agents. METHODS: Cross-polarization (Generation 3 Pocket Colposcope) and a new reflector design (Generation 4 Pocket Colposcope) were used to reduce glare and improve contrast. The reflector design (including the angle and height of the reflector sidewalls) was optimized through ray-tracing simulations. Both systems were characterized with a series of bench tests to assess specular reflection, beam pattern uniformity, and image contrast. A pilot clinical study was conducted to compare the Generation 3 and 4 Pocket Colposcopes to a standard-of-care colposcope (Leisegang Optik 2). Specifically, paired images of cervices were collected from the standard-of-care colposcope and either the Generation 3 (n = 24 patients) or the Generation 4 (n = 32 patients) Pocket Colposcopes. The paired images were blinded by device, randomized, and sent to an expert physician who provided a diagnosis for each image. Corresponding pathology was obtained for all image pairs. The primary outcome measures were the level of agreement (%) and κ (kappa) statistic between the standard-of-care colposcope and each Pocket Colposcope (Generation 3 and Generation 4). RESULTS: Both generations of Pocket Colposcope had significantly higher image contrast when compared to the standard-of-care colposcope. The addition of anti-fog and waterproofing features to the Generation 3 and 4 Pocket Colposcope did not impact image quality based on qualitative and quantitative metrics. The level of agreement between the Generation 3 Pocket Colposcope and the standard-of-care colposcope was 75.0% (kappa = 0.4000, p = 0.0028, n = 24). This closely matched the level of agreement between the Generation 4 Pocket Colposcope and the standard-of-care colposcope which was also 75.0% (kappa = 0.4941, p = 0.0024, n = 32). CONCLUSION: Our results indicate that the Generation 3 and 4 Pocket Colposcopes perform comparably to the standard-of-care colposcope, with the added benefit of being low-cost and waterproof, which is ideal for use in resource-limited settings. Additionally, the reflector significantly reduces the electrical requirements of the Generation 4 Pocket Colposcope enhancing portability without altering performance compared to the Generation 3 system.

International Image Concordance Study to Compare a Point-of-Care Tampon Colposcope With a Standard-of-Care Colposcope.

OBJECTIVE: Barriers to cervical cancer screening in low-resource settings include lack of accessible, high-quality services, high cost, and the need for multiple visits. To address these challenges, we developed a low-cost, intravaginal, optical cervical imaging device, the point-of-care tampon (POCkeT) colposcope and evaluated whether its performance is comparable with a standard-of-care colposcope. MATERIALS AND METHODS: There were 2 protocols, which included 44 and 18 patients. For the first protocol, white-light cervical images were collected in vivo, blinded by device, and sent electronically to 8 physicians from high-, middle-, and low-income countries. For the second protocol, green-light images were also collected and sent electronically to the highest performing physician from the first protocol who has experience in both a high- and low-income country. For each image, physicians completed a survey assessing cervix characteristics and severity of precancerous lesions. Corresponding pathology was obtained for all image pairs. RESULTS: For the first protocol, average percent agreement between devices was 70% across all physicians. The POCkeT and standard-of-care colposcope images had 37% and 51% agreement with pathology for high-grade squamous intraepithelial lesions (HSILs), respectively. Investigation of HSIL POCkeT images revealed decreased visibility of vascularization and lack of contrast in lesion margins. After changes were made for the second protocol, the 2 devices achieved similar agreement to pathology for HSIL lesions (55%). CONCLUSIONS: Based on the exploratory study, physician interpretation of cervix images acquired using a portable, low-cost POCkeT colposcope was comparable to a standard-of-care colposcope.

Design of a Novel Low Cost Point of Care Tampon (POCkeT) Colposcope for Use in Resource Limited Settings.

INTRODUCTION: Current guidelines by WHO for cervical cancer screening in low- and middle-income countries involves visual inspection with acetic acid (VIA) of the cervix, followed by treatment during the same visit or a subsequent visit with cryotherapy if a suspicious lesion is found. Implementation of these guidelines is hampered by a lack of: trained health workers, reliable technology, and access to screening facilities. A low cost ultra-portable Point of Care Tampon based digital colposcope (POCkeT Colposcope) for use at the community level setting, which has the unique form factor of a tampon, can be inserted into the vagina to capture images of the cervix, which are on par with that of a state of the art colposcope, at a fraction of the cost. A repository of images to be compiled that can be used to empower front line workers to become more effective through virtual dynamic training. By task shifting to the community setting, this technology could potentially provide significantly greater cervical screening access to where the most vulnerable women live. The POCkeT Colposcope's concentric LED ring provides comparable white and green field illumination at a fraction of the electrical power required in commercial colposcopes. Evaluation with standard optical imaging targets to assess the POCkeT Colposcope against the state of the art digital colposcope and other VIAM technologies. RESULTS: Our POCkeT Colposcope has comparable resolving power, color reproduction accuracy, minimal lens distortion, and illumination when compared to commercially available colposcopes. In vitro and pilot in vivo imaging results are promising with our POCkeT Colposcope capturing comparable quality images to commercial systems. CONCLUSION: The POCkeT Colposcope is capable of capturing images suitable for cervical lesion analysis. Our portable low cost system could potentially increase access to cervical cancer screening in limited resource settings through task shifting to community health workers.

Using a low-sodium, high-potassium salt substitute to reduce blood pressure among Tibetans with high blood pressure: a patient-blinded randomized controlled trial.

OBJECTIVES: To evaluate the effects of a low-sodium and high-potassium salt-substitute on lowering blood pressure (BP) among Tibetans living at high altitude (4300 meters). METHOD: The study was a patient-blinded randomized controlled trial conducted between February and May 2009 in Dangxiong County, Tibetan Autonomous Region, China. A total of 282 Tibetans aged 40 or older with known hypertension (systolic BP≥140 mmHg) were recruited and randomized to intervention (salt-substitute, 65% sodium chloride, 25% potassium chloride and 10% magnesium sulfate) or control (100% sodium chloride) in a 1: 1 allocation ratio with three months' supply. Primary outcome was defined as the change in BP levels measured from baseline to followed-up with an automated sphygmomanometer. Per protocol (PP) and intention to treat (ITT) analyses were conducted. RESULTS: After the three months' intervention period, the net reduction in SBP/DBP in the intervention group in comparison to the control group was -8.2/-3.4 mmHg (all p<0.05) in PP analysis, after adjusting for baseline BP and other variables. ITT analysis showed the net reduction in SBP/DBP at -7.6/-3.5 mmHg with multiple imputations (all p<0.05). Furthermore, the whole distribution of blood pressure showed an overall decline in SBP/DBP and the proportion of patients with BP under control (SBP/DBP<140 mmHg) was significantly higher in salt-substitute group in comparison to the regular salt group (19.2% vs. 8.8%, p = 0.027). CONCLUSION: Low sodium high potassium salt-substitute is effective in lowering both systolic and diastolic blood pressure and offers a simple, low-cost approach for hypertension control among Tibetans in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT01429246.

Can electronic sphygmomanometers be used for measurement of blood pressure at high altitudes?

OBJECTIVE: Validated automated oscillometric sphygmomanometers have been recommended by clinical guidelines to replace mercury sphygmomanometers. No studies have been conducted to evaluate whether these validated devices designed for use at normal altitude are also suitable at high altitudes. METHODS: In Dangxiong County in Tibet, 4300 m above sea level, two trained cardiologists used standardized protocols to measure the blood pressure (BP) of 129 adults aged between 19 and 69 years three times in a quiet room. The electronic sphygmomanometer was connected to the mercury sphygmomanometer by a 'Y,' or a three-way air-control valve, and the electronic device providing the pressure. This allowed simultaneous and blinded BP measurements with both instruments. RESULTS: The mean systolic BP measured by the electronic sphygmomanometer (124.67 ± 20.39 mmHg) was significantly higher than the BP reported by the mercury device (118.91 ± 20.56 mmHg; P < 0.001), whereas the diastolic BP measured by electronic (76.54 ± 12.63 mmHg) and mercury (76.95 ± 13.86 mmHg) sphygmomanometers showed no significant difference (P = 0.228). There was a strong linear relationship between readings from the two instruments, with correlation coefficients for systolic and diastolic BP of 0.97 and 0.96, respectively. Bland-Altman plots showed a general consistency between the two instruments for both systolic and diastolic BP. The systolic BP values, calibrated by subtracting the mean difference, were not inferior to those obtained from linear regression equations. CONCLUSION: This first explorative study conducted at a high altitude demonstrated that the electronic sphygmomanometer can provide an accurate direct measurement of diastolic BP; however, a simple calibration is required for systolic BP.

Changes in fetal ovine metabolism and oxygen delivery with fetal bypass.

Since the 1980s, attempts at experimental fetal cardiac bypass for the purpose of correcting severe congenital heart defects in the womb have been hampered by deterioration of placental function. This placental pathophysiology in turn affects transplacental transport of nutrients and gas exchange. To date, the effects of bypass on fetal metabolism and oxygen delivery have not been studied. Nine Suffolk sheep fetuses from 109-121 days gestation were instrumented and placed on fetal bypass for 30 min and followed postbypass for 2 h. Blood gases, glucose, and lactate were serially measured in the fetal arterial and umbilical venous circulations throughout the procedure. Insulin and glucagon levels were serially measured by immunoassay in fetal plasma. Fetal-placental hemodynamics were measured continuously. The expression of glycogen content was examined in fetal liver. Oxygen delivery to the fetus and fetal oxygen consumption were significantly deranged after the conduct of bypass (in-group ANOVA (P = 0.001) and overall contrast (P = 0.072) with planned contrast (P < 0.05) for delivery and consumption, respectively). There were significant alterations in fetal glucose metabolism in the postbypass period; however, insulin and glucagon levels did not change. Fetal liver glycogen content appeared lower after bypass. This is the first report documenting fetal metabolic dysregulation that occurs in response to the conduct of fetal bypass. The significant alterations in fetal oxygen and glucose delivery coupled with hepatic glycogen depletion complicate and impede fetal recovery. These initial findings warrant further investigation of interventions to restore metabolic and hemodynamic homeostasis after fetal bypass.

Myocardial function after fetal cardiac bypass in an ovine model.

OBJECTIVE: Fetal cardiac surgery might improve the prognosis of certain complex congenital heart defects that have significant associated mortality and morbidity in utero or after birth. An important step in translating fetal cardiac surgery is identifying potential mechanisms leading to myocardial dysfunction after bypass. The hypothesis was that fetal cardiac bypass results in myocardial dysfunction, possibly because of perturbation of calcium cycling and contractile proteins. METHODS: Midterm sheep fetuses (n = 6) underwent 30 minutes of cardiac bypass and 120 minutes of monitoring after bypass. Sonomicrometric and pressure catheters inserted in the left and right ventricles measured myocardial function. Cardiac contractile and calcium cycling proteins, along with calpain, were analyzed by means of immunoblotting. RESULTS: Preload recruitable stroke work (slope of the regression line) was reduced at 120 minutes after bypass (right ventricle: baseline vs 120 minutes after bypass, 38.6 ± 6.8 vs 20.4 ± 4.8 [P = .01]; left ventricle: 37 ± 7.3 vs 20.6 ± 3.9, respectively [P = .01]). Tau (in milliseconds), a measure of diastolic relaxation, was increased in both ventricles (right ventricle: baseline vs 120 minutes after bypass, 32.7 ± 4.5 vs 67.8 ± 9.4 [P < .01]); left ventricle: 26.1 ± 3.2 vs 63.2 ± 11.2, respectively [P = .01]). Cardiac output was lower and end-diastolic pressures were higher in the right ventricle, but not in the left ventricle, after bypass compared with baseline values. Right ventricular troponin I was degraded by increased calpain activity, and protein levels of sarco(endo)plasmic reticulum calcium ATPase were reduced in both ventricles. CONCLUSIONS: Fetal cardiac bypass was associated with myocardial dysfunction and disruption of calcium cycling and contractile proteins. Minimizing myocardial dysfunction after cardiac bypass is important for successful fetal surgery to repair complex congenital heart defects.

Application of near-infrared spectroscopy during fetal cardiac surgery.

BACKGROUND: Near-infrared spectroscopy (NIRS) has been shown to provide reliable noninvasive monitoring of regional oxygenation in a variety of clinical settings. We set out to test its feasibility as a monitor of fetal and placental oxygenation during fetal cardiac surgery. MATERIALS AND METHODS: Six ovine fetuses from 98-110 ds gestation were placed on fetal bypass for 30 min and followed post-bypass for 2 h. A NIRS probe (MI INVOS 5100B; Somanetics, Troy, MI) was placed on the pregnant uterine horn during and after fetal surgery. NIRS values were compared with blood gas values obtained by direct sampling from umbilical circulation. RESULTS: NIRS values positively correlated with umbilical venous oxygen saturation (R(2)=0.891, P<0.01) and partial oxygen pressure values (R(2)=0.810, P<0.01). NIRS values also correlated to a lesser extent with umbilical venous pH and pCO(2), and fetal arterial pH, pO(2), and oxygen saturation. CONCLUSIONS: This is the first report of application of NIRS in the setting of fetal surgery. NIRS permits noninvasive assessment of placental oxygen saturation and pO(2). This technology is a simple and useful tool for real-time monitoring of oxygen delivery to the fetus during maternal-fetal cardiac interventions and of overall well-being of the fetal-placental unit.

Fetal right ventricular myocardial function is better preserved by fibrillatory arrest during fetal cardiac bypass.

BACKGROUND: Protection and preservation of fetal myocardial function are important for successful fetal intracardiac repair. Our objective was to determine fetal biventricular cardiac performance after two cardiac-arrest techniques. METHODS: Three groups of midterm ovine fetuses underwent 90-minute bypass. A control group (no arrest shams, n = 3), and two groups that included 20 minutes of arrest, using fibrillatory (n = 3) or blood cardioplegia (n = 3), were compared. Blood cardioplegia consisted of 4:1 cold blood to crystalloid solution induction every 10 minutes, followed by a warm shot terminal dose before clamp removal. Myocardial function variables from biventricular intracardiac pressure catheters, and 3-axes cardiac sonomicrometry, fetal hemodynamics, and arterial blood gases were continuously recorded. Fetal myocardium was collected for troponin-I analysis at 90 minutes. Statistical analysis was by two-way analysis of variance for repeated measures. RESULTS: Compared with sham, right ventricular myocardial contractility was reduced with plegia but not fibrillation at 90 minutes after arrest: dP/dt max (511 ± 347 vs 1208 ± 239, p < 0.01) and preload-recruitable stroke work (7.2 ± 8.5 vs 32.3 ± 14.6, p < 0.01). Right ventricular end diastolic pressure-volume relationship (ventricular stiffness) worsened by 90 minutes for plegia vs fibrillation (0.84 ± 0.18 vs 0.25 ± 0.16, p < 0.05). There were no differences in left ventricle performance between groups. Fetal heart rate increased in shams by 30 minutes after arrest compared with both arrest groups (p < 0.05). Right ventricular troponin-I degradation increased with plegia, but not fibrillation, compared with sham (p < 0.05). CONCLUSIONS: In vivo, fetal right ventricular contractile function deteriorates with a common blood-plegia regimen. Fibrillatory arrest better preserves right ventricular function, the dominant ventricle in fetal life, for short arrest periods.

Dynamic fluid shifts induced by fetal bypass.

OBJECTIVE: Fluid shifts have been suggested to occur with fetal bypass. The degree or mechanisms behind these volume changes (or location) have not been defined. We characterized the preceding and correlated the findings to plasma vasopressin concentrations, the critical peptide of osmoregulation. METHODS: Seventeen ovine fetuses (105-111 days' gestation) were started on bypass and followed 2 hours after bypass. Hemodynamics and volume replacements needed to maintain minimum reservoir volume during bypass and normal physiologic parameters after bypass were recorded. Serial blood samples were collected to assess gas exchange and vasopressin levels. Changes in total tissue water content were measured for several organs and the placenta. Plasma volume, fluid shifts, and osmolarity were calculated. RESULTS: Hematocrit values decreased by 15 minutes of bypass to 28% from 33% and then increased to 34% by 120 minutes after bypass, corresponding to a decreased fetal plasma volume of 79 to 72 mL/kg by 120 minutes after bypass. The majority of volume shifts (approximately 100 mL/kg) occurred during bypass, but additional volume replacements were required after bypass to maintain normal hemodynamics, resulting in overall losses of 0.8 mL x kg(-1) x min(-1). Losses were not accounted for by placental or organ edema. Vasopressin levels increased dramatically with bypass (39-51.5 pg/mL) and were strongly predicted by increased fetal plasma volumes (R(2) = 0.90), whereas osmolarity was not significantly associated with plasma volumes. CONCLUSION: Fetal bypass leads to significant fluid shifts that correlate strongly with increasing vasopressin levels (but not changes in osmolarity). The placenta is not the primary site of volume loss. Rehydration of the fetus is necessary after bypass.

Fetal stress response to fetal cardiac surgery.

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 beta-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 beta-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 beta-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.

A simple solution is "prime" for fetal cardiopulmonary bypass.

Worsening fetal gas exchange is the hallmark of frequently observed placental dysfunction after fetal bypass. Several factors influence this pathophysiology, but the optimal prime constituents for fetal bypass have yet to be defined. Calcium and sodium bicarbonate are frequently added to prime solutions for adjustments toward physiologic values. We examined whether similar manipulations are warranted with fetal bypass. Ovine fetuses (n = 10) at 104-110 days' gestation were placed on bypass for 30 minutes. Calcium chloride and sodium bicarbonate were added to adjust prime ionized calcium and pH. Fetal hemodynamics and arterial blood gases were collected immediately before, and 15 and 30 minutes on bypass. Statistical significance was determined by Student's t test and best fit correlations. Calcium addition negatively correlated with fetal pH (R >or= 0.63) and po2 (R >or= 0.41), and displayed a robust positive correlation with pco2 (R = 0.88) during bypass. Similarly, bicarbonate addition revealed correlations for pco2 (R >or= 0.70) and po2 (R >or= 0.57), with a strong negative correlation to umbilical blood flow (R >or= 0.75). Calcium addition to the prime adversely affects fetal gas exchange worsening acidosis during fetal bypass. Bicarbonate addition to the prime is also detrimental to the fetus resulting in greater CO2 production and impaired hemodynamics.

Vacuum-assisted venous drainage during fetal cardiopulmonary bypass.

Fetal bypass presents several perfusion challenges, including the need for high arterial flow rates using flexible arterial and small venous cannulae. We hypothesized that vacuum-assisted venous drainage (VAVD) would improve drainage and allow perfusion at higher flow rates which are thought to prevent placental dysfunction induced by fetal bypass. We conducted bypass for 60 minutes in 14 fetal lambs (90-105 days gestation; approximately 1-1.5 kg) using a roller pump and various angled venous cannulae (8-12 Fr). VAVD at -20 mm Hg or -40 mm Hg was compared with gravity drainage. Average flow using gravity drainage was 139 ml/kg/min; after VAVD, we achieved average flows of 285 ml/kg/min (range, 109-481 ml/kg/min). VAVD at -40 mm Hg caused right atrial trauma in four fetuses; no injury was seen at -20 mm Hg. Venous air entrainment during repair of the injuries did not result in any apparent air embolism. Spontaneous pulmonary hemorrhage occurred in two fetuses at the highest flows (> or = 400 ml/kg/min). In all but one case, termination of bypass was followed by placental dysfunction within 120 minutes. VAVD can be safely applied during fetal bypass provided pressures are kept < or = -20 mm Hg. However, the achieved higher flow rates do not prevent postbypass placental dysfunction and may indeed be detrimental to the fetus.