Sarah R. Garlick

The Effects of Hormone Resuscitation on Cardiac Function and Hemodynamics in a Porcine Brain-Dead Organ Donor Model

We compared the effects of hormone resuscitation (HR) with a norepinephrine‐based protocol on cardiac function, hemodynamics and need for vasopressor support after brain death in a porcine model. Following brain death induction, animals were treated with norepinephrine and fluids for 3 h. In the following 3 h, they continued on norepinephrine and fluids (control) or received additional HR (triiodothyronine, methylprednisolone, vasopressin, insulin). Data were collected pre‐brain death, 3 and 6 h post‐brain death. At 6 h, median norepinephrine use was higher in controls (0.563 vs. 0 μg/kg/min; p < 0.005), with 6/8 HR animals weaned off norepinephrine compared with 0/9 controls. Mean arterial pressure was higher in HR animals at 6 h (74 ± 17 vs. 54 ± 14 mmHg; p < 0.05). Cardiac contractility was also significantly higher in HR animals at 6 h (stroke work index 1.777 vs. 1.494). After collection of 6 h data, all animals were placed on the same low dose of norepinephrine. At 6.25 h, HR animals had higher stroke work (3540 ± 1083 vs. 1536 ± 702 mL.mmHg; p < 0.005), stroke volume (37.2 ± 8.2 vs. 21.5 ± 9.8 mL; p < 0.01) and cardiac output (5.8 ± 1.4 vs. 3.2 ± 1.2 L/min; p < 0.005). HR in a porcine model of brain death reduces norepinephrine requirements, and improves hemodynamics and cardiac function. These results support the use of HR in the management of the brain‐dead donor.

Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation.

Background. Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury. Methods. A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively. Results. The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001). Conclusions. Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.

The preload recruitable stroke work relationship as a measure of left ventricular contractile dysfunction in porcine cardiac allografts

OBJECTIVE Paradoxically, it has been reported that after 1.5-4 h of hypothermic ischaemic preservation there is complete recovery of contractile function in canine cardiac allografts, as assessed by the preload recruitable stroke work (PRSW) relationship. This raises questions about the suitability of the canine heart as a model for preservation research and the PRSW relationship as an end-point. The aim of the present study was to evaluate the PRSW relationship as an index of left ventricular contractility in porcine cardiac allografts. METHODS Eighteen orthotopic heart transplants were performed in inbred Westran pigs. Brain death was induced in the donor pigs 1 h prior to explantation. The donor hearts were arrested with extracellular cardioplegia, which was stored in ice prior to administration. On explantation, the donor hearts were immersed in cardioplegia and stored in ice. The donor hearts were subjected to either 4 (IT4, n = 6), 6 (IT6, n = 9) or 14 (IT14, n = 3) h of ischaemia. Post-transplant, all hearts were supported with dobutamine (10 mcg/kg per min). The PRSW relationship was derived from pressure-volume loops obtained by epicardial sonomicrometry and transmyocardial micromanometry. Multiple linear regression was used to describe and compare the PRSW relationship before brain death in the donor and after weaning from bypass in the recipient. RESULTS Eleven hearts were weaned successfully from cardiopulmonary bypass: IT4 100% (6/6), IT6 56% (5/9) and IT14 0% (0/3) (IT4 versus IT14: P = 0.012). Analysis of the PRSW relationship revealed a reduction in contractility in both the IT4 and IT6 groups (both P < 0.0001), but a greater reduction in the IT6 group (P < 0.0001). Notably, the volume-axis intercept of the PRSW relationship was found to be a better discriminator of post-preservation contractile dysfunction than the slope of the PRSW relationship. CONCLUSIONS The porcine hearts susceptibility to ischaemic injury makes it ideal for evaluating the effect of different preservation strategies on contractile recovery. The PRSW relationship can be used to evaluate the differences in contractile recovery, though the nature of the effect of ischaemic preservation necessitates analysis by multiple linear regression.

The initial rate of troponin I release post-reperfusion reflects the effectiveness of myocardial protection during cardiac allograft preservation

OBJECTIVE To determine if the initial rate of troponin I release post-reperfusion reflects the effectiveness of myocardial protection during cardiac allograft preservation. METHODS A porcine model of orthotopic heart transplantation was used. Data from two control groups (CON(4) and CON(14)) and two treatment groups (CAR(4) and CAR(14)) were analysed. Hearts in CON(4) (n=6) and CAR(4) (n=6) were subjected to 4 h of ischaemia while hearts in CON(14) (n=3) and CAR(14) (n=6) were subjected to 14 h of ischaemia. All hearts were arrested and stored in the same extracellular preservation solution. Both donor and recipient animals in the CAR(4) and CAR(14) groups received a single intravenous dose of cariporide (2 mg/kg), prior to explantation and reperfusion, respectively. RESULTS Mean (SEM) plasma troponin I levels (microg/ml) 3 h post-reperfusion were: CON(4) 210+/-52, CAR(4) 68+/-21, CON(14) 633+/-177, CAR(14) 346+/-93. On multiple linear regression analysis, the rate of troponin I release over the first 3 h post-reperfusion was significantly lower in hearts stored for 4 h compared to hearts stored for 14 h (P<0.0001) and in hearts treated with cariporide compared to control hearts (P=0.0017). Early graft function was superior in hearts treated with cariporide, when compared to control hearts stored for the same period of time. All of the CAR(14) hearts could be weaned from cardiopulmonary bypass whereas none of the CON(14) could be weaned (6/6 vs. 0/3; P=0.012). While all hearts stored for 4 h could be weaned, contractility, as measured by the preload recruitable stroke work (PRSW) relationship, was significantly better preserved in CAR(4) hearts than in CON(4) hearts (P<0.0001). CONCLUSIONS The initial rate of troponin I release post-reperfusion is determined by the duration of cardiac allograft ischaemia. Altering the myocardial preservation strategy can reduce the rate of release. Such reductions are associated with improvements in early graft function. These findings validate the initial rate of troponin I release post-reperfusion as an end-point when comparing cardiac allograft preservation strategies. In addition, the present study provides indirect evidence that troponin I degradation during ischaemia-reperfusion is related to the accumulation of intracellular calcium.

Sodium-hydrogen exchanger inhibition, pharmacologic ischemic preconditioning, or both for extended cardiac allograft preservation1

Background. The aim of this study was to determine the efficacy of cariporide (a sodium-hydrogen exchanger inhibitor), BMS180448 (a pharmacologic ischemic preconditioning agent), and the combination thereof, as adjuvant therapies for extended cardiac allograft preservation. Methods. A porcine model of donor brain death and orthotopic heart transplantation was used. All hearts were arrested and stored for 14 hr in an extracellular preservation solution. Control hearts (CON; n=3) did not receive any additional treatment. Treated hearts received BMS180448 alone (BMS; n=3), cariporide alone (CAR; n=6), or both BMS180448 and cariporide (B+C; n=6). Donors of BMS180448-treated hearts received 2 mg/kg, 15 min before explantation. Donors and recipients of cariporide-treated hearts received 2 mg/kg, 15 min before explantation and reperfusion, respectively. Results. The CON and BMS arms of the study were terminated after three transplantations because initial results in these groups were poor. Significantly, none of the control hearts could be weaned successfully from bypass, whereas all of the treated hearts were weaned successfully (CAR vs. CON and B+C vs. CON:P =0.012). The rate of troponin I release during the first 3 hr after reperfusion was significantly lower in CAR (P =0.0180) and B+C (P =0.0154) recipients than in CON recipients. Mean plasma troponin I levels (&mgr;g/mL) 3 hr after reperfusion were as follows: CON 633±177, BMS 576±110, CAR 346±93, and B+C 296±97. Conclusion. In this porcine model of extended cardiac allograft preservation, cariporide was more effective than BMS180448 as an adjuvant to our usual preservation solution. There was no additional benefit from the combination of the two therapies.