Paul M. Heerdt

Chronic Unloading by Left Ventricular Assist Device Reverses Contractile Dysfunction and Alters Gene Expression in End-Stage Heart Failure

BackgroundLeft ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca2+ transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca2+ handling. Methods and ResultsThe isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca2+-ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na+-Ca2+ exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca2+ uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca2+ uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts. ConclusionsLVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca2+ cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.

Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome

Barth syndrome is an X‐linked cardiac and skeletal mitochondrial myopathy. Barth syndrome may be due to lipid alterations because the product of the mutated gene is homologous to phospholipid acyltransferases. Here we document that a single mitochondrial phospholipid species, tetralinoleoyl‐cardiolipin, was lacking in the skeletal muscle (n = 2), right ventricle (n = 2), left ventricle (n = 2), and platelets (n = 6) of 8 children with Barth syndrome. Tetralinoleoyl‐cardiolipin is specifically enriched in normal skeletal muscle and the normal heart. These findings support the notion that Barth syndrome is caused by alterations of mitochondrial lipids.

Isoflurane pretreatment ameliorates postischemic neurologic dysfunction and preserves hippocampal Ca2+/calmodulin-dependent protein kinase in a canine cardiac arrest model.

BackgroundInhalational anesthetics are neuroprotective in rat models of global ischemia. To determine whether isoflurane at a clinically relevant concentration is neuroprotective in a canine model of cardiac arrest, we measured neurologic function and hippocampal Ca2+/calmodulin-dependent protein kinase II (CaMKII) content 20 h after cardiac arrest. MethodsWe tested the neuroprotective effect of 30 min of 1.5% isoflurane exposure before 8 min of global ischemia induced with ventricular fibrillation. Animals were randomized to four groups: control, isoflurane–control, ischemia, and isoflurane–ischemia. After resuscitation and 20 h of intensive care, each animal’s neurologic deficit score was determined by two blinded evaluators. The hippocampal content of CaMKII, determined by immunoblotting, was measured by an individual blinded to the treatment groups. CaMKII activity was measured in samples from the cortex, hippocampus, and striatum of animals in each group. ResultsIsoflurane–ischemic animals had a median neurologic deficit score of 22.6% compared with 43.8% for the ischemic animals (P < 0.05). Hippocampal levels of the &bgr;-subunit of CaMKII (CaMKII&bgr;) were relatively preserved in isoflurane–ischemic animals (68 ± 4% of control) compared with ischemic animals (48 ± 2% of control;P < 0.001), although both groups were statistically significantly lower than control (P < 0.001 ischemia vs. control and P < 0.05 isoflurane–ischemia vs. control). ConclusionsIsoflurane is an effective neuroprotective drug in a canine cardiac arrest model in terms of both functional and biochemical criteria.

Disparity of isoflurane effects on left and right ventricular afterload and hydraulic power generation in swine

The interaction between myocardial and vascular effects of anesthetics has a potential impact on how these drugs influence performance of the heart.Most studies have focused on volatile anesthetic effects on the left ventricle (LV) and systemic circulation. Whether the right ventricle (RV) and pulmonary circulation respond in a similar fashion, however, is unclear. In the present study, we therefore examined the dose-related effects of isoflurane on LV and RV contractility and total afterload and related changes to simultaneous effects on the hydraulic power generated by each chamber. Two groups of swine were studied: one received no additional treatment before isoflurane (ISO, n = 6), and the other received hexamethonium, atropine, and propranolol to produce autonomic blockade before isoflurane administration (ISO+AB, n = 4). For each experiment, measurements were made of RV and LV regional segment lengths and pressures, along with proximal aortic and pulmonary arterial (PA) blood flow and pressure during the administration of 0, 0.5, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC) isoflurane. Contractility was assessed by calculating the regional preload recruitable stroke work slope (PRSW). Afterload was characterized in both nonpulsatile and pulsatile terms by calculating aortic input impedance magnitude (Z). From these data, total arterial resistance (R), characteristic impedance (Z (C)), and vascular compliance (C) were determined with reference to a three-element Windkessel model of the circulation. Additionally, steady-state (WSS), oscillatory (WOS), and total (WT) hydraulic power output of each ventricle was calculated. In the ISO group, isoflurane produced a nearly threefold greater decrease of peak systolic pressure in the LV than in the RV, yet the dose-related decrease of regional PRSW was virtually the same in both chambers. In the aorta, isoflurane produced a maximal 25% reduction in R at 1.0 MAC and doubled C without a significant change in ZC. Alternatively, PA R was increased from baseline at 1.0 and 1.5 MAC, whereas ZC was increased from all other values at 1.5 MAC. PA C was not altered by isoflurane. In ISO+AB pigs, PA ZC at baseline was higher than that evident in ISO animals but was not altered by isoflurane. In contrast, baseline aortic R was lower in ISO+AB pigs but was still modestly reduced by 1.0 MAC isoflurane. In ISO animals, WT and WSS from both ventricles demonstrated dose-related decreases, but the reductions in LV WT and WSS were greater than those for the RV at all doses. Accordingly, the power requirement per unit flow decreased for the LV but remained constant for the RV. WOS for both ventricles was also reduced by isoflurane. However, the LV WOS to WT ratio increased, which indicates that more power was lost to the system by pulsation. In contrast, reductions in RV WT and W (OS) were nearly parallel at all isoflurane doses, and the WOS to WT ratio was unchanged. In the ISO+AB group, isoflurane-induced alterations in LV and RV power characteristics were similar to those in the ISO group. These data indicate that, despite similar effects on biventricular contractility, isoflurane exerts qualitatively different effects on RV and LV afterload, in part via alteration in autonomic nervous activity, that influence the distribution of power output between steady-state and pulsatile components. Implications: In this study, we examined the effects of isoflurane on cardiac performance in swine and found that, although the drug depresses contraction of both the left and right ventricles similarly, it has different effects on forces that oppose the ejection of blood. These findings demonstrate that the two interdependent pumps that comprise the heart can be influenced differently by anesthetic drugs. (Anesth Analg 1998;87:511-21)

Rapid Chemical Antagonism of Neuromuscular Blockade by L-Cysteine Adduction to and Inactivation of the Olefinic (Double-bonded) Isoquinolinium Diester Compounds Gantacurium (AV430A), CW 002, and CW 011

Background:The ultra–short-acting neuromuscular blocker gantacurium is chemically degraded in vitro by rapid adduction of l-cysteine to its central olefinic double bond. Preliminary data have suggested that exogenous (intravenous) l-cysteine abolishes gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have been synthesized to undergo slower l-cysteine adduction, yielding intermediate duration. l-Cysteine adduction to and antagonism of these novel agents is further defined herein. Methods:Comparative reaction half-time for l-cysteine adduction in vitro of the three compounds was determined by high-performance liquid chromatography. ED95 for twitch inhibition in monkeys under isoflurane was calculated, and duration at ∼4–5× ED95 was correlated with reaction half-time for adduction. Speed of l-cysteine antagonism was contrasted with anticholinesterase reversal. Potencies of CW 002 and its adduction product were compared to provide a basis for l-cysteine antagonism. Results:Rate of l-cysteine adduction in vitro (reaction half-time) was 11.4 and 13.7 min for CW 002 and CW 011 versus 0.2 min for gantacurium, and was inversely related to duration of block (P < 0.0001). CW 002 and CW 011 were 3× longer acting than gantacurium (28.1 and 33.3 min vs. 10.4 min), but only half the duration of cisatracurium. The adduct of CW 002 was ∼70× less potent than CW 002. l-Cysteine (10–50 mg/kg intravenously) given 1 min after approximately 4–5× ED95 doses of all the three compounds abolished block within 2–3 min. Conclusions:l-Cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous l-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time.

Noninvasive cardiac output monitoring with bioreactance as an alternative to invasive instrumentation for preclinical drug evaluation in beagles

INTRODUCTION Non-invasive measurement of cardiac output (CO) using bioreactance signals (NICOM) was recently validated in swine and human adults. The present study was designed to test the hypothesis that NICOM flow measurements can accurately measure CO and detect acute drug-induced changes in aortic blood flow (AoQ)≥10% in beagles. METHODS Data from 5 anesthetized, open chest beagles used for preclinical screening of novel neuromuscular blocking drugs were analyzed for the study. AoQ was measured beat-to-beat with a probe on the aortic root and averaged over 30s intervals. NICOM CO measurements were simultaneously obtained every 30s. NICOM precision (random variation) and accuracy relative to AoQ were assessed from individual segments of steady-state data. The ability of NICOM to detect acute alterations in AoQ≥10% was determined from other segments with dynamic change. RESULTS 516 simultaneous CO measurements between 826 and 2436 mL/min were analyzed. Steady-state measurements (20% of the dataset) revealed an average AoQ-NICOM difference (bias) of 63±38 mL/min, a percent error of 6.1%, and a NICOM precision of 6.1%. Within the acute change dataset, 21/23 events reflecting a ≥10% change in beat-to-beat AoQ were detected by the NICOM (sensitivity of 0.91). In none of 10 instances where drug or fluid injection altered AoQ<10% did the NICOM indicate a change (specificity of 1.0). DISCUSSION Continuous, non-invasive measurement of CO by bioreactance provides data that satisfactorily approximates invasive measurement of aortic blood flow in beagles. In addition, despite a 30s interval between measurements, the NICOM appears to have sufficient fidelity to detect and quantify acute, drug-induced changes in CO. These data suggest that the NICOM may represent an alternative to open chest instrumentation for CO measurement in preclinical drug evaluation studies.

The dose-dependent effects of halothane on right ventricular contraction pattern and regional inotropy in swine.

The right ventricle (RV) is comprised of two embryologically distinct units, the inflow and outflow tracts, which normally contract sequentially and differ in the magnitude of increased inotropy during sympathetic nervous stimulation.The present study examined the dose-response effects of halothane on the RV contraction pattern and regional contractility in seven openchest pigs instrumented for measurement of inflow and outflow tract pressures and segment lengths. The RV contraction pattern was evaluated by comparing the phase of inflow and outflow tract shortening, and regional contractility was determined by calculation of preload recruitable stroke work (PRSW) slope. Using this methodology, an inflow-outflow tract contraction phase difference of -27 degrees (inflow tract shortened earlier) was evident at baseline, but was abolished by 1.0 and 1.5 minimum alveolar anesthetic concentration (MAC) halothane; PRSW slope of both the inflow and outflow tracts, however, demonstrated similar dose-related change. To determine whether alterations in cardiac sympathovagal balance played a role in the RV response to halothane, an additional four animals were studied after pretreatment with hexamethonium, propranolol, and atropine. In these animals, there was no difference in the regional contraction phase either at baseline or during halothane administration, and dose-related depression of PRSW by halothane was again similar in both regions. However, when halothane effects on regional PRSW in animals with autonomic blockade were compared to those of neurally intact animals, a 20% greater depression of outflow tract PRSW by 0.5 MAC halothane was evident. This study demonstrates that halothane abolishes the normal sequential pattern of RV contraction without exerting markedly variant negative inotropic effects within different regions of the RV, and provides evidence to suggest that alterations in cardiac sympathovagal balance may contribute to the effect of halothane on RV contraction dynamics. (Anesth Analg 1996;82:1152-8)

Bivalirudin utilization in cardiac surgery: shifting anticoagulation from indirect to direct thrombin inhibition

PurposeBivalirudin use for anticoagulating patients undergoing cardiac surgery, particularly those with or at risk for heparin-induced thrombocytopenia, has expanded over the past several years. The purpose of this review is to provide a summary of the following: the differences between indirect and direct thrombin inhibition, unfractionated heparin’s limitations (i.e., heparin-induced thrombocytopenia), bivalirudin’s pharmacology, recent cardiac surgery trials comparing bivalirudin and unfractionated heparin as anticoagulants, the growing role of bivalirudin-mediated anticoagulation for various surgical procedures, and the potential of bivalirudin-mediated vascular graft patency.SourceA systematic search of the English literature was performed using PubMed from the United States National Library of Medicine. Pertinent articles from 1992-2010 were obtained from this search, and their reference lists were used to retrieve additional relevant articles.Principal findingsIn small studies in the cardiac surgery arena, bivalirudin has demonstrated a similar safety and efficacy profile compared with unfractionated heparin. Bivalirudin’s role as an anticoagulant in various cardiac surgical procedures (i.e., heart transplant) and vascular surgical procedures is growing and reviewed. Additionally, the molecular basis for the potential for bivalirudin-mediated improvement in vascular graft patency after coronary artery bypass graft procedures is discussed.ConclusionAlthough bivalirudin is not approved for cardiac surgery in the United States, it can be used in this setting in Canada as an anticoagulant in patients with heparin-induced thrombocytopenia provided the cardiac anesthesiologist is knowledgeable about potential complications from its use and knows how to manage or mitigate their incidence appropriately. During cardiopulmonary bypass, bivalirudin anticoagulation protocols must be thoroughly followed to attain optimal clinical outcomes. Additionally, further studies with bivalirudin are needed to determine the best monitoring modality and dosing regimen.RésuméObjectifL’utilisation de la bivalirudine chez les patients sous anticoagulants devant subir une chirurgie cardiaque, et plus particulièrement chez ceux qui présentent une thrombocytopénie induite par l’héparine ou qui en courent le risque, s’est répandue au cours des dernières années. Cet article de synthèse offre un aperçu des différences entre l’inhibition indirecte et l’inhibition directe de la thrombine, des limitations de l’héparine non fractionnée (p. ex. la thrombocytopénie induite par l’héparine), de la pharmacologie de la bivalirudine, de récentes études en chirurgie cardiaque comparant la bivalirudine et l’héparine non fractionnée en tant qu’anticoagulants, du rôle croissant de l’anticoagulation facilitée par la bivalirudine lors de diverses interventions chirurgicales et du potentiel d’amélioration facilitée par la bivalirudine de la perméabilité du greffon vasculaire.SourceUne recherche systématique de la littérature rédigée en anglais a été effectuée sur PubMed à partir de la United States National Library of Medicine et a permis d’obtenir des articles pertinents datés de 1992 à 2010. Les listes de références de ces articles ont ensuite été utilisées pour accéder à d’autres articles pertinents.Constatations principalesDans le cadre d’études de faible envergure, la bivalirudine a démontré un profil d’innocuité et d’efficacité similaire à celui de l’héparine non fractionnée lors d’une chirurgie cardiaque. Le rôle de la bivalirudine en tant qu’anticoagulant utilisé lors de diverses interventions chirurgicales cardiaques (p. ex. transplantation cardiaque) et vasculaires prend de l’ampleur et est de plus en plus étudié. Nous présentons également les mécanismes au niveau moléculaire qui sous-tendent le potentiel d’amélioration facilitée par la bivalirudine de la perméabilité du greffon vasculaire après une chirurgie de pontage aorto-coronarien.ConclusionBien que la bivalirudine ne soit pas approuvée pour la chirurgie cardiaque aux États-Unis, elle peut être utilisée comme anticoagulant au Canada chez les patients présentant une thrombocytopénie induite par l’héparine, pourvu que l’anesthésiologiste cardiaque connaisse les complications pouvant résulter de son utilisation et soit en mesure de les gérer ou de limiter leur incidence. Les protocoles d’anticoagulation par la bivalirudine lors d’une circulation extra-corporelle doivent être strictement respectés afin d’obtenir les meilleurs résultats cliniques possibles. En outre, on doit encore étudier la bivalirudine en vue de déterminer les modalités de monitorage et les schémas posologiques les plus efficaces.

Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430A) in dogs.

BackgroundThis investigation determined the cardiopulmonary side effects of a novel nondepolarizing neuromuscular blocking drug with an ultrashort duration of action in anesthetized male beagles. MethodsThe ED95 for GW280430A was first determined in four animals. These data were then used to guide bolus dosing in multiples of ED95 in six dogs instrumented for hemodynamic measurements as well as inspiratory pressure and pulmonary compliance. Cardiopulmonary data were compared before and after the conclusion of a 60- to 90-min GW280430A infusion and in response to subsequent incremental bolus dosing starting with 3.125 × ED95. An adverse response was regarded as an alteration of 10% or greater in any variable. Arterial blood was obtained for histamine analysis before and 1 min after each dose. ResultsThe ED95 of GW280430A was 0.064 ± 0.01 mg/kg, and stable neuromuscular blockade was maintained with infusion of 0.012 ± 0.002 mg · kg−1 · min−1. With the exception of a late 14% increase in heart rate, there were no cardiopulmonary changes during infusion. Bolus dosing produced no cardiopulmonary change until a decrease in mean arterial pressure was elicited in four of six dogs at 25 × ED95. This response was modest, transient, and associated with a concomitant increase in plasma histamine concentration. There were no accompanying changes indicative of direct myocardial depression, pulmonary vasoconstriction, or bronchospasm. ConclusionsThese data indicate that GW280430 does not produce demonstrable cardiovascular effects in the anesthetized dog until doses far in excess of the ED95 are administered as a bolus.

Practice patterns in choice of left double-lumen tube size for thoracic surgery.

BACKGROUND:Some anesthesiologists choose smaller than body size-appropriate left sided double-lumen tubes (DLTs) (“down-size“) for lung isolation in an attempt to limit the risk of airway trauma. There are few data on the effects of DLT size on intraoperative outcome measures. METHODS:In 300 adults undergoing thoracic surgery requiring lung isolation, we conducted a prospective pilot study to evaluate whether the use of 35 FR DLT, regardless of gender and/or height (care standard of two investigators), was associated with a similar incidence of intraoperative hypoxemia, lung isolation failure, or need for DLT repositioning during surgery (noninferiority) than with the conventional goal of inserting the largest possible DLT (care standard of two other investigators). DLT insertion position was immediately confirmed with fiberoptic bronchoscopy after direct laryngoscopic placement and after lateral positioning. RESULTS:The combined incidence of transient hypoxemia, inadequate lung isolation, or need for DLT repositioning during surgery did not differ among patients receiving 35, 37, or 39 FR DLT, regardless of gender or height. Despite the high frequency of 35 FR DLT use, 2% of patients required further down-sizing due to the inability to introduce the DLT into the left mainstem bronchus or when no inflation of the bronchial cuff was needed for lung isolation. CONCLUSIONS:Under the conditions of this pilot study, the use of smaller than conventionally sized DLT was not associated with any differences in clinical intraoperative outcomes.