John W. McGillicuddy

Extracorporeal Life Support for Severe Acute Respiratory Distress Syndrome in Adults

Objective:Severe acute respiratory distress syndrome (ARDS) is associated with a high level of mortality. Extracorporeal life support (ECLS) during severe ARDS maintains oxygen and carbon dioxide gas exchange while providing an optimal environment for recovery of pulmonary function. Since 1989, we have used a protocol-driven algorithm for treatment of severe ARDS, which includes the use of ECLS when standard therapy fails. The objective of this study was to evaluate our experience with ECLS in adult patients with severe ARDS with respect to mortality and morbidity. Methods:We reviewed our complete experience with ELCS in adults from January 1, 1989, through December 31, 2003. Severe ARDS was defined as acute onset pulmonary failure, with bilateral infiltrates on chest x-ray, and PaO2/fraction of inspired oxygen (FiO2) ratio ≤100 or A-aDO2 >600 mm Hg despite maximal ventilator settings. The indication for ECLS was acute severe ARDS unresponsive to optimal conventional treatment. The technique of ECLS included veno-venous or veno-arterial vascular access, lung “rest” at low FiO2 and inspiratory pressure, minimal anticoagulation, and optimization of systemic oxygen delivery. Results:During the study period, ECLS was used for 405 adult patients age 17 or older. Of these 405 patients, 255 were placed on ECLS for severe ARDS refractory to all other treatment. Sixty-seven percent were weaned off ECLS, and 52% survived to hospital discharge. Multivariate logistic regression analysis identified the following pre-ELCS variables as significant independent predictors of survival: (1) age (P = 0.01); (2) gender (P = 0.048); (3) pH ≤7.10 (P = 0.01); (4) PaO2/FiO2 ratio (P = 0.03); and (5) days of mechanical ventilation (P < 0.001). None of the patients who survived required permanent mechanical ventilation or supplemental oxygen therapy. Conclusion:Extracorporeal life support for severe ARDS in adults is a successful therapeutic option in those patients who do not respond to conventional mechanical ventilator strategies.

Large animal model of chronic pulmonary hypertension.

A large animal model is needed to study artificial lung attachment in a setting simulating chronic lung disease with significant pulmonary hypertension (PH). This study sought to create a sheep model that develops significant PH within 60 days with a low rate of mortality. Sephadex beads were injected in the pulmonary circulation of sheep every other day for 60 days at doses of 0.5, 0.75, and 1 g (n = 10, 10, 7). Mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were obtained every 2 weeks. In the 0.5, 0.75, and 1-g groups, 90, 70, and 14.3% of sheep completed the study, respectively, with the remainder experiencing heart failure. By the 60th day, pulmonary vascular resistance had increased (p < 0.01) from 0.89 ± 0.3 to 3.2 ± 0.9 mm Hg/(L/min) and from 0.9 ± 0.3 to 4.3 ± 3.2 mm Hg/(L/min) in the 0.5 and 0.75-g groups, respectively. Significant right ventricular hypertrophy was observed in the 0.75-g group but not in the 0.5-g group. Data from the 1-g group were insufficient for analysis due to high mortality. Thus, the 0.5 and 0.75-g groups generate significant PH, but the 0.75-g group is a better model of chronic PH in lung disease due to the development of right ventricular hypertrophy.

Effect of Artificial Lung Compliance on in Vivo Pulmonary System Hemodynamics

This study examined the effect of artificial lung compliance (C) on pulmonary system (PS) impedance and right ventricular function during in-series attachment of the MC3 Biolung in adult sheep. Compliances, C, of 0–20 ml/mm Hg were tested at the Biolung inlet. Results indicate the PS 0th harmonic input impedance modulus was not affected by C. The PS first harmonic input impedance modulus (Z1) was 10.9 ± 3.2 mm Hg/(l/min) at C = 0 ml/mm Hg and minimized to 2.41 ± 0.79 mm Hg/(l/min) at C ≥ 0.5 ml/mm Hg. Cardiac output was 58% ± 10% of its pre-Biolung attachment, baseline value at C = 0 ml/mm Hg and was maximized to an average of 75% ± 11% at C ≥ 0.5 ml/mm Hg. The left ventricular lateral-to-anteroposterior axis length ratio, which decreases with leftward septal shift, increased with C from 0.52 ± 0.12 at C = 0 ml/mm Hg to 0.76 ± 0.06 at C = 5 ml/mm Hg (p < 0.05), but decreased slightly with C at C > 5 ml/mm Hg. Therefore, the ideal C for right ventricular function is at least 0.5 ml/mm Hg and may be as high as 5 ml/mm Hg to minimize septal shift.

In vitro fluid mechanical effects of thoracic artificial lung compliance.

This in vitro study sought to determine what compliance minimizes thoracic artificial lung impedance and pump power output. A pulsatile pump drove 3.0 cP glycerol through a circuit consisting of an MC3 Biolung® preceded by a piston-cylinder (PC, n = 5) chamber with a variable compliance or a polyurethane (n = 4) chamber with a fixed, yet pressure-dependent, compliance. Each chamber was tested at flow rates of 1.8, 3.0, and 5.0 l/min and heart rates of 60, 75, and 100 bpm. Compliances, C, from 0-20 ml/mm Hg were tested in the PC chamber. Instantaneous pump outlet flow and pressure were acquired for determination of device zeroth and first harmonic input impedance, Z0 and Z1, and pump steady and pulsatile output powers, Ps and Pp. PC chamber results indicate that Z0, Z1, Ps, and Pp were minimized at C > 1, 5, 0.5, and 4 ml/mm Hg, respectively. This suggests that C should be 1 ml/mm Hg at minimum and ideally 5 ml/mm Hg. The polyurethane chamber was statistically similar to the PC chamber at C = 1 ml/mm Hg when comparing Z0 and Ps, but was statistically inferior when comparing Z1 and Pp. The polyurethane compliance chamber, therefore, should be redesigned with greater compliance.

Cytolytic Induction Therapy Improves Clinical Outcomes in African-american Kidney Transplant Recipients

Objective: Determine the impact of cytolytic versus IL-2 receptor antibody (IL-2RA) induction on acute rejection, graft loss and death in African-American (AA) kidney transplant (KTX) recipients. Background: AAs are underrepresented in clinical trials in transplantation; thus, there is controversy regarding the optimal choice of perioperative antibody induction in KTX to improve outcomes. Methods: National cohort study using US transplant registry data from January 1, 2000 to December 31, 2009 in adult solitary AA KTX recipients, with at least 5 years of follow-up. Multivariable logistic and Cox regression were utilized to assess the outcomes of acute rejection, graft loss, and mortality, with interaction terms to assess effect modification. Results: Twenty-five thousand eighty-four adult AAs receiving solitary KTX were included, 16,927 (67.5%) received cytolytic induction and 8157 (32.5%) received IL-2RA induction. After adjustment for recipient sociodemographics, donor, and transplant characteristics, the use of cytolytic induction therapy reduced the risk of acute rejection by 32% (OR 0.68, 0.62–0.75), graft loss by 9% (HR 0.91, 0.86–0.97), and death by 12% (HR 0.88, 0.83–0.94). There were a number of significant effect modifiers, including public insurance, panel reactive antibody, delayed graft function, and steroid withdrawal; in these groups, cytolytic induction substantially improved clinical outcomes. Conclusions: These data demonstrate that cytolytic induction therapy, as compared with IL-2RA, reduces the risk of rejection, graft loss, and death in adult AA KTX recipients, particularly in those who are sensitized, receive public insurance, develop delayed graft function, or undergo steroid withdrawal.

Development of the MC3 BioLung/spl trade/

MC3 has previously developed a total artificial lung that can supply full pulmonary support, while imparting the appropriate impedance characteristics to allow perfusion by the right ventricle. To date, the MC3 device has been tested in healthy and sick animals, demonstrating both performance and improved survival. This article describes the engineering design and preliminary testing of the next generation of the MC3 device, called the BioLung/spl trade/. The design goals were to decrease the overall device size and remove areas of blood flow stasis in the fiber bundle to improve gas exchange efficiency and minimize thrombus formation. Based on CFD analysis and bench-top pressure-flow and gas exchange performance, we successfully decreased the fiber surface area 24%, while maintaining the oxygen transfer rates, and lowered the pressure drop by 10% to 40%. Animal studies without anticoagulation demonstrated that the new design removed the formation of thrombosis in the collection gap region between the fiber bundle and device housing, and decreased the amount of micro thrombi visible in the fiber bundle. Although these results are preliminary, they strongly suggest that the BioLung/spl trade/ design will be a significant step towards moving the MC3 artificial lung technology to clinical application.