John Lombardi

Bosentan prevents hypoxia-reoxygenation–induced pulmonary hypertension and improves pulmonary function

BACKGROUND Acute hypoxia results in increased pulmonary vascular resistance. Despite reoxygenation, pulmonary vascular resistance remains elevated and pulmonary function is altered. Endothelin-1 might contribute to hypoxia-reoxygenation-induced pulmonary hypertension and to reoxygenation injury by stimulating leukocytes. This study was carried out using an established model of hypoxia and reoxygenation to determine whether endothelin-1 blockade with Bosentan could prevent hypoxia-reoxygenation-induced pulmonary hypertension and reoxygenation injury. METHODS Twenty neonatal piglets underwent 90 minutes of hypoxia, 60 minutes of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery. Control animals (n = 12) received no drug treatment, whereas the treatment group (n = 8) received the endothelin-1 receptor antagonist, Bosentan, throughout hypoxia. RESULTS In controls, pulmonary vascular resistance increased during hypoxia to 491% of baseline and remained elevated after reoxygenation; however in the Bosentan group, it increased to only 160% of baseline by end-hypoxia, then decreased to 76% at end-recovery. Arterial endothelin-1 levels in controls increased to 591% of baseline after reoxygenation. Arterial nitrite levels decreased during hypoxia in controls but were maintained in the Bosentan group. Consequently, animals in the Bosentan group had better postreoxygenation pulmonary vascular resistance, A-a gradient, and airway resistance along with lower myeloperoxidase levels than controls. CONCLUSIONS Acute hypoxia and postreoxygenation pulmonary hypertension was attenuated by Bosentan, which maintained nitric oxide levels during hypoxia, decreased leukocyte-mediated injury, and improved pulmonary function.

Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation

BACKGROUND Reoxygenation of hypoxic myocardium during repair of congenital heart defects results in poor ventricular function and cellular injury. Endothelin-1 (ET-1), a potent vasoconstrictor that increases during hypoxia, may suppress myocardial function and activate leukocytes. The objective was to determine whether administration of an endothelin receptor antagonist could improve ventricular function and decrease cardiac injury after hypoxia and reoxygenation. METHODS Fourteen piglets underwent 90 minutes of ventilator hypoxia, 1 hour of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery (controls). Nine additional animals received an infusion of Bosentan, an ET(A/B) receptor antagonist, (5 mg/kg per hour) during hypoxia and reoxygenation. RESULTS Right and left ventricular dP/dt in controls decreased to 78% and 52% of baseline, respectively, after recovery (p < 0.05). In contrast, Bosentan-treated animals had complete preservation of RV dP/dt and less depression of LV dP/dt. Bosentan reduced the hypoxia and reoxygenation-induced elevation of ET-1 and iNOS mRNA at the end of recovery (p < 0.05). Bosentan-treated animals had diminished myocardial myeloperoxidase activity and lipid peroxidation compared with controls (p < 0.05). Myocardial apoptotic index, elevated by hypoxia and reoxygenation, was lower in the Bosentan-treated animals (p < 0.05). CONCLUSIONS Endothelin-1 receptor antagonism improved functional recovery and decreased leukocyte-mediated injury after reoxygenation. The reduction in cardiac cell death might also improve long-term outcome after reoxygenation injury.

Cardiopulmonary bypass in the immature fetus through novel use of a mini-centrifugal pump

The concept that the natural history of certain heart defects could be positively modified through in utero intervention has stimulated extensive research in fetal cardiac intervention and surgery since the early 1980s. Since the management of certain defects would require the use of cardiopulmonary support, extensive studies have been directed toward the application of a variety of perfusion circuits. The unique features of the fetal patient have directed the focus of many of these designs toward miniaturization of components and minimization of prime volume. Large extracorporeal surface contact areas and prime volumes have been identified as potential contributors to a frequently observed placental dysfunction following fetal cardiopulmonary bypass (CPB). We set out to develop means of CPB using a centrifugal micro-system that would not require supplemental prime volume. We describe the unique application of an adult right heart assist device, primarily used for ‘off-pump’ coronary revascularization for fetal cardiopulmonary support. Finally, while previous fetal experiments have used late-gestation mature fetuses, we studied more immature fetuses of mid-gestation, relevant to current clinical attempts in fetal therapy.

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 (R2 ≥ 0.63) and po2 (R2 ≥ 0.41), and displayed a robust positive correlation with pco2 (R2 = 0.88) during bypass. Similarly, bicarbonate addition revealed correlations for pco2 (R2 ≥ 0.70) and po2 (R2 ≥ 0.57), with a strong negative correlation to umbilical blood flow (R2 ≥ 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.

Accuracy of the Spectrum Medical M4 and Terumo CDI 500 compared to the Radiometer ABL90 FLEX benchtop blood analyzer

The benchtop blood analyzer is the gold standard for blood oxygen saturation (SO2) and hemoglobin (Hb) analysis. However, the benchtop analyzer only provides values at a given point in time. In the field of cardiovascular perfusion and the practice of cardiopulmonary bypass (CPB), continuous measurement of SvO2 and hemoglobin values have become commonplace. Two devices currently available which monitor these values are the Terumo CDI 500 and Spectrum Medical M4. A retrospective study was conducted to examine the accuracy of the M4 technology and the CDI 500 as they compare to each other and the ABL90 FLEX, a benchtop blood gas analyzer. The data revealed the magnitude of mean differences were small, even when significant. However, the 95% Limits of Agreement were too large for either device to allow substitution of the CDI 500 and M4 hemoglobin or SvO2 values for ABL90 values. As recommended by the manufacturers, the CDI 500 and M4 should only be used as a trending device.