John D. Madigan

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.

Reversal by Vasopressin of Intractable Hypotension in the Late Phase of Hemorrhagic Shock

BACKGROUND Hypovolemic shock of marked severity and duration may progress to cardiovascular collapse unresponsive to volume replacement and drug intervention. On the basis of clinical observations, we investigated the action of vasopressin in an animal model of this condition. METHODS AND RESULTS In 7 dogs, prolonged hemorrhagic shock (mean arterial pressure [MAP] of approximately 40 mm Hg) was induced by exsanguination into a reservoir. After approximately 30 minutes, progressive reinfusion was needed to maintain MAP at approximately 40 mm Hg, and by approximately 1 hour, despite complete restoration of blood volume, the administration of norepinephrine approximately 3 micrograms . kg(-1). min(-1) was required to maintain this pressure. At this moment, administration of vasopressin 1 to 4 mU. kg(-1). min(-1) increased MAP from 39+/-6 to 128+/-9 mm Hg (P<0.001), primarily because of peripheral vasoconstriction. In 3 dogs subjected to similar prolonged hemorrhagic shock, angiotensin II 180 ng. kg(-1). min(-1) had only a marginal effect on MAP (45+/-12 to 49+/-15 mm Hg). Plasma vasopressin was markedly elevated during acute hemorrhage but fell from 319+/-66 to 29+/-9 pg/mL before administration of vasopressin (P<0.01). CONCLUSIONS Vasopressin is a uniquely effective pressor in the irreversible phase of hemorrhagic shock unresponsive to volume replacement and catecholamine vasopressors. Vasopressin deficiency may contribute to the pathogenesis of this condition.

Surgical Management of the Patient with an Implanted Cardiac Device: Implications of Electromagnetic Interference

OBJECTIVE To identify the sources of electromagnetic interference (EMI) that may alter the performance of implanted cardiac devices and develop strategies to minimize their effects on patient hemodynamic status. SUMMARY BACKGROUND DATA Since the development of the sensing demand pacemaker, EMI in the clinical setting has concerned physicians treating patients with such devices. Implanted cardiovertor defibrillators (ICDs) and ventricular assist devices (VADs) can also be affected by EMI. METHODS All known sources of interference to pacemakers, ICDs, and VADs were evaluated and preventative strategies were devised. RESULTS All devices should be thoroughly evaluated before and after surgery to make sure that its function has not been permanently damaged or changed. If electrocautery is to be used, pacemakers should be placed in a triggered or asynchronous mode; ICDs should have arrhythmia detection suspended before surgery. If defibrillation is to be used, the current flow between the paddles should be kept as far away from and perpendicular to the lead system as possible. Both pacemakers and ICDs should be properly shielded if magnetic resonance imaging, positron emission tomography, or radiation therapy is to be used. The effect of EMI on VADs depends on the model. Magnetic resonance imaging adversely affects all VADs except the Abiomed VAD, and therefore its use should be avoided in this population of patients. CONCLUSIONS The patient with an implanted cardiac device can safely undergo surgery as long as certain precautions are taken.

A double-blind randomized trial: prophylactic vasopressin reduces hypotension after cardiopulmonary bypass

BACKGROUND Inhibition of angiotensin-converting enzyme (ACE) predisposes patients to vasodilatory hypotension after cardiopulmonary bypass (CPB). This hypotension has been correlated with arginine vasopressin deficiency and can be corrected by its replacement. In patients receiving ACE inhibition, we investigated whether initiation of vasopressin before CPB would diminish post-CPB hypotension and catecholamine use by avoiding vasopressin deficiency. METHODS Cardiac surgical patients on ACE inhibitor therapy were randomized to receive vasopressin (0.03 U/min) (n = 13) or an equal volume of normal saline (n = 14) starting 20 minutes before CPB. RESULTS Vasopressin did not change pre-CPB mean arterial pressure or pulmonary artery pressure. After CPB, the vasopressin group had a lower peak norepinephrine dose than the placebo group (4.6 +/- 2.5 versus 7.3 +/- 3.5 microg/min, p = 0.03), a shorter period on catecholamines (5 +/- 6 versus 11 +/- 7 hours, p = 0.03), fewer hypotensive episodes (1 +/- 1 versus 4 +/- 2, p < 0.01), and a shorter intensive care unit length of stay (1.2 +/- 0.4 versus 2.1 +/- 1.4 days, p = 0.03). CONCLUSIONS In this cohort, prophylactic administration of vasopressin, at a dose without a vasopressor effect pre-CPB, reduced post-CPB hypotension and vasoconstrictor requirements, and was associated with a shorter intensive care unit stay.

Retinoic acid suppresses intimal hyperplasia and prevents vessel remodeling following arterial injury

Vitamin A and its derivatives (retinoids) are capable of inhibiting vascular smooth muscle cell proliferation in vitro. The present study examines the effect of two retinoids, all-trans retinoic acid and 13-cis retinoic acid, on intimal hyperplasia following arterial injury. After receiving varying doses of all-trans retinoic acid or 13-cis retinoic acid, 78 male Sprague-Dawley rats underwent standard balloon catheter denudation of the left common carotid artery. Morphometric analysis and immunohistochemistry for proliferating cell nuclear antigen was performed at early and late time points. Intimal/medial ratios were reduced in a dose-dependent fashion for animals treated with all-trans retinoic acid (P = 0.001) and 13-cis retinoic acid (P = 0.004). Proliferating cell nuclear antigen labeling indices were reduced after treatment with all-trans retinoic acid and 13-cis retinoic acid at early time points post-injury. At a dose of 10 mg/kg, both all-trans retinoic acid and 13-cis retinoic acid inhibited vessel remodeling as measured by increases in luminal diameter (P < 0.05) and external elastic lamina (P < 0.05). Retinoids are an attractive clinical option for the treatment of restenosis following angioplasty and arterial surgery.

Selective anticoagulation with active site blocked factor IXa in synthetic patch vascular repair results in decreased blood loss and operative time.

Heparin has been the mainstay of anti thrombic therapy in arterial repair procedures. With increasing use of synthetic patch angioplasty (polytetrafluoroethylene [PTFE] or Dacron, Medical Products, Flagstaff, AZ) to improve long-term patency and limit aneurysmal dilation, however, the use of heparin has been associated with excessive needle hole bleeding, resulting in time delay in the operating room to achieve hemostasis, as well as clinically significant blood loss. Because of the multiple sites of action of heparin in the coagulation cascade, both intravascular (desired effect) and extravascular (untoward side effect) hemostasis are impaired. The authors therefore tested the hypothesis that selective inhibition of intravascular coagulation, without significant impairment of extravascular hemostasis, would prevent clotting intraluminally while preserving hemostasis at the suture line of the patch graft. The unique position of factor IX/IXa in the coagulation cascade renders its inhibition an ideal target in this setting. The authors prepared active site blocked factor IXa (IXai) using dansyl-Glu-Gly-Arg chloromethylketone, and tested this hypothesis in a New Zealand rabbit aortotomy model with PTFE patch closure using either heparin (25 IU/

Mechanical Unloading With a Miniature In-Line Axial Flow Pump as an Alternative to Cardiopulmonary Bypass

Cardiopulmonary bypass (CPB) causes a well described systemic inflammatory response. To avoid these potential detrimental effects, coronary artery bypass grafting (CABG) has been attempted off CPB on the beating heart. With the use of a left ventricular (LV) assist device during CABG, the heart can be made flaccid with β-blockade, and the systemic circulation can continue to be supported. The hemodynamic and hematologic consequences of left heart bypass with a miniature axial flow pump were studied in a sheep CABG model.

A Technique of Stapled Gastrojejunostomy for Open Gastric Bypass Results in Increased Wound Complication-Rate

Background: Gastric bypass may be facilitated by a stapled gastrojejunostomy.This study compared two different techniques for performing this critical anastomosis in open surgery. Methods: 67 consecutive patients were retrospectively studied for weight loss, hospital length of stay, anastomotic stricture, wound complication, and incisional hernia. 49 patients had a two layer handsutured gastrojejunostomy over a 34 Fr bougie via a laparotomy (sutured). 18 patients had a stapled gastrojejunostomy using the technique of Wittgrove and Clark via a laparotomy (stapled). All patients received prophylactic intravenous antibiotics preoperatively. Results: Initial BMI, % of excess weight lost at 6 weeks and 6 months, and hospital length of stay were not statistically different between the groups. However, the rate of wound complication and incisional hernia rate were significantly higher in the stapled group when compared to the sutured group (p<0.01). Conclusions: Based on these data we suggest that the technique of Wittgrove and Clark for performing the gastrojejunostomy should not be used in open gastric bypass as it results in increased rates of wound complication and incisional hernia.

Restoration of renal function in shock by perfusion of the renal artery with venous blood: A counterintuitive approach

ObjectiveAcute renal failure (ARF) in low-flow states may be reversed by increasing renal perfusion. When hemodynamics are maximized, renal perfusion can only be improved by shunting a higher proportion of cardiac output to the kidney; however, in low-flow states, this reduces already compromised systemic pressure and perfusion to other organs. Increasing perfusion using venous blood (VB) would be an attractive option because decreased systemic pressure and perfusion to other organs could be avoided. However, it is not known whether VB can provide adequate oxygen delivery to restore or maintain renal function. We studied whether antegrade VB perfusion of the kidney via the renal artery would restore urine output (UO) and glomerular filtration rate (GFR) in hypoperfused ARF. DesignShock was induced in six dogs via a hemorrhagic protocol resulting in a systolic blood pressure of 50–70 mm Hg, a mixed venous oxygen saturation of 25% to 40%, and a UO <10% of baseline. After 60 mins of shock, the left renal artery was cannulated under fluoroscopy and perfused at pressures of 100–150 mm Hg for 30 mins with VB drawn from the vena cava and delivered by an extracorporeal pump system. The right kidneys were controls and remained hypoperfused. ResultsAll VB-perfused kidneys recovered renal function after a sustained period of shock and marked oliguria: UO from 0.7 ± 1.6 mL/hr to 101 ± 58 mL/hr (p < .01); GFR from approximately 0 to 70.3 ± 55 mL/min (p = .04). The control kidneys’ UO (0.7 ± 1.6 mL/hr) and GFR (0 mL/min) remained unchanged throughout the study. The experimental kidneys were able to extract oxygen from VB (O2 saturation, 31 ± 7% to 16 ± 4%;p = .01). ConclusionWhen flow is controlled, kidneys in hypoperfused ARF can extract sufficient oxygen from antegrade VB perfusion to restore renal function (UO and GFR).