Michael K. Pasque

Metabolic intervention to affect myocardial recovery following ischemia

Myocardial recovery during reperfusion following ischemia is critical to patient survival in a broad spectrum of clinical settings. Myocardial functional recovery following ischemia correlates well with recovery of myocardial adenosine triphosphate (ATP). Adenoslne triphosphate recovery is uniformly incomplete during reperfusion following moderate ischemk injury and is therefore subject to manipulation by metabolic intervention. By definition ATP recovery is limited either by (1) energy availability and application in the phosphorylation of adenosine monophosphate (AMP) to ATP or (2) availability of AMP for this conversion. Experimental data suggest that substrate energy and the mechanisms required for its application in the creation of high energy phosphate bonds (AMP conversion to ATP) are more than adequate during reperfusion following moderate ischemic injury. Adenosine monophosphate availability, however, Is Inadequate following ischemia due to loss of diffusable adenine nucleotide purine metabolites. These purine precursors are necessary to fuel adenine nucleotide salvage pathways. Metabolic interventions that enhance AMP recovery rather than those that improve substrate energy availability during reperfusion are therefore recommended. The mechanisms of various metabolic interventions are discussed in this framework along with the rationale for or against their clinical application.

The Effect of PEEP on Left Ventricular Diastolic Dimensions and Systolic Performance Following Myocardial Revascularization

To quantitate the alterations in left ventricular (LV) dimensions and performance at successive levels of positive end-expiratory pressure (PEEP), 16 patients undergoing coronary artery bypass grafting (CABG) underwent instrumentation with ultrasonic dimension transducers to measure the minor-axis diameter of the left ventricle. Matched micromanometers were placed to measure intracavitary LV pressure and intrathoracic pressure. LV pressure and dimension data were recorded and computer analyzed during continuous positive-pressure ventilation at 0, 5, 10, and 15 cm H2O of PEEP 4 to 8 hours postoperatively. Preload was determined by the end-diastolic minor-axis diameter, cardiac output was measured by thermodilution, and indices of LV contractility assessed included the maximal velocity of minor-axis shortening and the slope of the end-systolic pressure-diameter relationship. PEEP produced a progressive increase in intrathoracic pressure associated with a fall in cardiac output; this was associated with a decrease in LV end-diastolic diameter and no significant change in the maximal velocity of minor-axis shortening or the slope of the end-systolic pressure-diameter relationship. Our results indicate that PEEP of 10 cm H2O or greater will produce a significant fall in cardiac output in patients following CABG, due to a decrease in preload rather than impaired LV contractility.

Assessment of the intrinsic contractile status of the heart during sepsis by myocardial pressure-dimension analysis.

The effect of sepsis on the intrinsic contractile status of the myocardium is best examined in the awake, closed-chest animal with intact circulation because anesthesia, open thoracotomy, and circulatory support are all known to affect hemodynamics. To fulfill these criteria, 18 adult dogs were chronically studied in the awake state after instrumentation with left ventricular high-fidelity pressure catheters and ultrasonic dimension transducers to measure left ventricular transmural pressure and minor axis dimension. This allowed computer assessment of the left ventricular end-systolic pressure-dimension relationship in the control state and at intervals following cecal ligation in one group of dogs. A second group of control animals was studied over variable time intervals without cecal ligation to evaluate the temporal stability and reproducibility of the animal model and the end-systolic pressure-dimension relationship. Evaluation of contractility by use of the end-systolic pressure-dimension relationship was essential because this relationship is a sensitive indicator of the intrinsic myocardial contractile state while remaining insensitive to the wide swings in preload and afterload that are commonly seen in sepsis. In the control group of dogs, the temporal consistency and stability of the end-systolic pressure-dimension relationship in this model was confirmed; no significant changes in the slope and dimension-axis intercept were demonstrated over the study interval. In the septic group of dogs, however, the intrinsic myocardial contractility significantly deteriorated as the mean slope of the end-systolic pressure-dimension relationship (mmHg/mm) decreased from 16.87 ± 0.85 to 12.79 ± 1.67 over 120 hours following cecal ligation. Intrinsic contractility of the heart during sepsis was therefore isolated for the first time from the widely variant loading conditions seen during sepsis by pressure-dimension analyses in the chronically instrumented, awake, closed-chest canine with intact circulation.

The Influence of Time on the Response to Dopamine after Coronary Artery Bypass Grafting: Assessment of Left Ventricular Performance and Contractility Using Pressure/Dimension Analyses

Pressure and dimension analyses were used to quantitate the changing cardiac response to dopamine over a 24-hour interval after coronary artery bypass grafting (CABG). Ultrasonic dimension transducers were utilized to measure the minor-axis diameter of the left ventricle, and matched micromanometers were inserted to measure intracavitary left ventricular pressure and intrathoracic pressure. Pressure and dimension data were recorded and analysed by computer during dopamine infusion at 0, 2.5, 5.0, and 10.0 micrograms per kilogram per minute, at periods designated as early (2 to 4 hours after CABG) and late (18 to 24 hours after CABG). Myocardial contractile responses to dopamine (peak velocity of minor-axis shortening, maximal excursion) were similar at each dose in the early and late studies. However, overall hydraulic performance, as reflected by cardiac outputs and the areas of the pressure/diameter work loops, had augmented late dose responses. This study suggests a major change in the relationship between the heart and peripheral control mechanisms that may partially explain diminishing inotropic requirements over time, in addition to the generally accepted occurrence of improvement in contractile state and functional reserve following cardiac operation.

Effects of Delay in Administration of Potassium Cardioplegia to the Isolated Rat Heart

Ischemic injury to the heart in the period between aortic cross-clamping and administration of cardioplegic solution was evaluated in the normothermic rat heart model. After isolation and control perfusion with oxygenated Krebs-Henseleit bicarbonate buffer, the hearts were given lactated Ringers cardioplegic solution (30 mEq of K+ per liter) for 2 minutes at three different intervals following aortic clamping: no delay, 2-minute delay, and 5-minute delay. Thereafter, the hearts were left unperfused and the time to initiation of ischemic contracture was recorded. Adenosine triphosphate (ATP) and creatine phosphate levels were measured in all groups prior to and at the conclusion of cardioplegia administration. A 2-minute delay in the administration of cardioplegic solution resulted in significantly lower (p less than 0.001) ATP levels that were restored after 2 minutes of cardioplegia administration. Contracture times were not significantly altered. A 5-minute delay resulted in significantly shorter (p less than 0.001) contracture times and significantly lower (p less than 0.001) ATP levels that were not restored to preischemic levels by 2 minutes of cardioplegia administration. The fate of the myocardium may be insensitive to events that occur during the earliest moments of ischemia provided that rapid administration of oxygenated potassium cardioplegia follows the ischemic period and restores preischemic high-energy phosphate stores. However, there is a critical ischemic time during the initial interval before cardioplegia that is associated with an impaired ability of the myocardium to tolerate subsequent ischemia.

Anesthesia-Induced Myocardial Depression: Quantitation of Effects on Systolic and Diastolic Function

The effect of general anesthesia induced with halothane and nitrous oxide on left ventricular (LV) contractility and diastolic mechanics was directly assessed in the chronically instrumented canine model. Seven dogs were instrumented with ultrasonic dimension transducers to measure LV diameter and micromanometers to measure LV transmural pressure. Contractility was assessed by the slope (EES) of the end-systolic pressure-diameter relationship PES = EES (LES - LD). Diastolic compliance was assessed by fitting end-diastolic pressure-dimension data to the exponential P = alpha (e beta epsilon L-1), where alpha and beta are nonlinear elastic coefficients. A new index (ID20) that identifies the dose of anesthetic necessary to depress the inotropic state by 20% was calculated to be 0.63% for halothane. Contractility was progressively decreased by halothane, with EES falling from 10.1 +/- 0.6 at control to 6.7 +/- 0.4 at 1% halothane and to 4.2 +/- 0.5 at 2% halothane (p less than 0.05 at each halothane level). However, similar levels of halothane did not significantly alter alpha and beta, nor did they significantly shift the exponential diastolic compliance curve from control. Seven patients who underwent coronary artery bypass grafting conducted under narcotic anesthesia showed a similar halothane-induced depression of contractility; 0.5% halothane decreased EES from 11.5 +/- 2.0 to 8.0 +/- 2.4 (p less than 0.01). Use of ID20 allows reclassification of anesthetic agents in accord with their myocardial depressant effects, which with halothane appears to be caused by decreased inotropism without alterations in diastolic chamber mechanics.