Howard R. Levin

Vasopressin Deficiency Contributes to the Vasodilation of Septic Shock

BACKGROUND The hypotension of septic shock is due to systemic vasodilation. On the basis of a clinical observation, we investigated the possibility that a deficiency in vasopressin contributes to the vasodilation of septic shock. METHODS AND RESULTS In 19 patients with vasodilatory septic shock (systolic arterial pressure [SAP] of 92 +/- 2 mm Hg [mean +/- SE], cardiac output [CO] of 6.8 +/- 0.7 L/min) who were receiving catecholamines, plasma vasopressin averaged 3.1 +/- 1.0 pg/mL. In 12 patients with cardiogenic shock (SAP, 99 +/- 7 mm Hg; CO, 3.5 +/- 0.9 L/min) who were also receiving catecholamines, it averaged 22.7 +/- 2.2 pg/mL (P < .001). A constant infusion of exogenous vasopressin to 2 patients with septic shock resulted in the expected plasma concentration, indicating that catabolism of vasopressin is not increased in this condition. Although vasopressin is a weak pressor in normal subjects, its administration at 0.04 U/min to 10 patients with septic shock who were receiving catecholamines increased arterial pressure (systolic/diastolic) from 92/52 to 146/66 mm Hg (P < .001/P < .05) due to peripheral vasoconstriction (systemic vascular resistance increased from 644 to 1187 dyne.s/cm5; P < .001). Furthermore, in 6 patients with septic shock who were receiving vasopressin as the sole pressor, vasopressin withdrawal resulted in hypotension (SAP, 83 +/- 3 mm Hg), and vasopressin administration at 0.01 U/min, which resulted in a plasma concentration (approximately 30 pg/mL) expected for the level of hypotension, increased SAP from 83 to 115 mm Hg (P < .01). CONCLUSIONS Vasopressin plasma levels are inappropriately low in vasodilatory shock, most likely because of impaired baroreflex-mediated secretion. The deficiency in vasopressin contributes to the hypotension of vasodilatory septic shock.

Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading.

BACKGROUND Ventricular dilation, indexed by marked shifts toward larger volumes of the end-diastolic pressure-volume relation (EDPVR), has been considered to represent an irreversible aspect of ventricular remodeling in end-stage heart failure. However, we hypothesized that such dilation could be reversed with sufficient hemodynamic unloading, such as can be provided by a left ventricular assist device (LVAD). METHODS AND RESULTS The EDPVRs of hearts from seven patients with end-stage idiopathic cardiomyopathy and comparable baseline hemodynamics were measured ex vivo at the time of cardiac transplantation; these were compared with EDPVRs from three normal human hearts that were technically unsuitable for transplantation. Four of the patients received optimal medical therapy; three of the patients, who deteriorated on optimal therapy, underwent LVAD support for approximately 4 months. Compared with the normal hearts, EDPVRs of hearts from medically treated patients were shifted toward markedly larger volumes. In contrast, EDPVRs of hearts from LVAD patients were similar to those of normal hearts. CONCLUSIONS Chronic hemodynamic unloading of sufficient magnitude and duration can result in reversal of chamber enlargement and normalization of cardiac structure as indexed by the EDPVR, both important aspects of remodeling, even in the most advanced stages of heart failure.

Double-Blind, Placebo-Controlled Study of the Long-term Efficacy of Carvedilol in Patients With Severe Chronic Heart Failure

BACKGROUND Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. METHODS AND RESULTS We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16 +/- 0.01 and a mean maximal oxygen consumption of 13.6 +/- 0.6 mL.kg-1.min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n = 33) or matching placebo (n = 16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P = .005) and stroke volume index (P = .010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P = .003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P = .002), functional class (P = .013), and submaximal exercise tolerance (P = .006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P = .028), but carvedilol-treated patients had more dizziness and advanced heart block. CONCLUSIONS Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Ecg amplifier and cardiac pacemaker for use during magnetic resonance imaging

A device for monitoring a patient or pacing a patient is disclosed which can safely operate in a MRI system. The device uses unique RF filtering and shielding to attenuate voltages on the leads resulting from the high frequency RF signals produced in the MRI. The device is uniquely shielded to prevent induced currents from disrupting the amplifying and processing electronics. The device uses an optional secondary low pass or band reject filter to eliminate interference from the MRIs gradient magnetic field. The device uses optional inductors placed close to electrodes to limit RF currents through the electrodes. Several embodiments of the RF filter are taught which depend on the number of sensing leads, whether the leads are shielded, whether the RF filter is contained in the electronic shielded housing or whether single or multistage filtering is employed. The device may operate as an extended ECG monitor or may be an implantable MRI safe pacemaker.

Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system

ObjectiveThis nonrandomized study using concurrent controls was performed to determine whether the HeartMate implantable pneumatic (IP) left ventricular assist system (LVAS) could provide sufficient hemodynamic support to allow rehabilitation of severely debilitated transplant candidates and to evaluate whether such support reduced mortality before and after transplantation. MethodsOutcomes of 75 LVAS patients were compared with outcomes of 33 control patients (not treated with an LVAS) at 17 centers in the United States. All patients were transplant candidates who met the following hemodynamic criteria: pulmonary capillary wedge pressure ≥ 20 mm Hg with a systolic blood pressure ≤ 80 mm Hg or a cardiac index ≤ 2.0 L/minute/m2. In addition, none of the patients met predetermined exclusion criteria. ResultsMore LVAS patients than control patients survived to transplantation: 53 (71%) versus 12 (36%) (p = 0.001); and more LVAS patients were alive at 1 year: 48 (91%) versus 8 (67%) (p = 0.0001). The time to transplantation was longer in the group supported with the LVAS (average, 76 days; range, <1–344 days) than in the control group (average, 12 days; range, 1–72 days). In the LVAS group, the average pump index (2.77 L/minute/m2) throughout support was 50% greater than the corresponding cardiac index (1.86 L/minute/m2) at implantation (p = 0.0001). In addition, 58% of LVAS patients with renal dysfunction survived, compared with 16% of the control patients (p < 0.001). ConclusionsThe LVAS provided adequate hemodynamic support and was effective in rehabilitating patients based on improved renal, hepatic, and physical capacity assessments over time. In the LVAS

Reverse Remodeling From Cardiomyoplasty in Human Heart Failure External Constraint Versus Active Assist

BACKGROUND Cardiomyoplasty (CM) is a novel surgical therapy for dilated cardiomyopathy. In this procedure, the latissimus dorsi muscle is wrapped around the heart and chronically paced synchronously with ventricular systole. While studies have found symptomatic improvement from this therapy, the mechanisms by which CM confers benefit remain uncertain. This study sought to better define these mechanisms by means of serial pressure-volume relation analysis. METHODS AND RESULTS Serial pressure-volume studies were performed by the conductance catheter method in three patients (total to date) with dilated cardiomyopathy (New York Heart Association class III) who underwent CM. Data were measured at baseline (before surgery) and at 6 and 12 months after CM. Chronic left ventricular (LV) systolic and diastolic changes induced by CM were evaluated with the stimulator in its stable pacing mode (every other beat) and after temporarily suspending pacing. CM-stimulated beats were compared with pacing-off beats to evaluate active systolic assist effects of CM. In each patient, CM resulted in a chronic lowering of cardiac end-diastolic volume and an increased ejection fraction. Most notably, the end-systolic pressure-volume relation shifted leftward, consistent with reversal of chronic chamber remodeling. In contrast, the diastolic pressure-volume relation was minimally altered, and the loops shifted down along the same baseline relation. These marked chronic changes in LV function measurable with CM stimulation off contrasted to only minor acute effects observed when the muscle wrap was activated. This suggests that the benefit of CM derived less from active systolic assist than from remodeling, perhaps because of an external elastic constraint. CONCLUSIONS These data, while limited to a small number of patients, suggest that CM can reverse remodeling of the dilated failing heart. While systolic squeezing assist effects of CM may play a role in some patients, our study found that this was not required to achieve substantial benefits from the procedure. We speculate that CM may act more passively, like an elastic girdle around the heart, to help reverse chamber remodeling.

Determinants of blood flow to vital organs during cardiopulmonary resuscitation in dogs.

Whether blood flow during cardiopulmonary resuscitation (CPR) results from intrathoracic pressure fluctuations or direct cardiac compression remains controversial. From modeling considerations, blood flow due to intrathoracic pressure fluctuations should be insensitive to compression rate over a wide range, but dependent on the applied force and compression duration. If direct compression of the heart plays a major role, however, flow should be dependent on compression rate and force, but above a threshold, insensitive to compression duration. These differences in hemodynamics produced by changes in rate and duration form a basis for determining whether blood flow during CPR results from intrathoracic pressure fluctuations or from direct cardiac compression. Manual CPR was studied in eight anesthetized, 21 to 32 kg dogs after induction of ventricular fibrillation. There was no surgical manipulation of the chest. Myocardial and cerebral blood flows were determined with radioactive microspheres. At nearly constant peak sternal force (378 to 426 newtons), flow was significantly increased when the duration of compression was increased from 14 +/- 1% to 46 +/- 3% of the cycle at a rate of 60/min. Flow was unchanged, however, after an increase in rate from 60 to 150/min at constant compression duration. The hemodynamics of manual CPR were next compared with those produced by vest inflation with simultaneous ventilation (vest CPR) in eight other dogs. Vest CPR changed intrathoracic pressure without direct cardiac compression, since sternal displacement was less than 0.8 cm. At a rate of 150/min, with similar duration and right atrial peak pressure, manual and vest CPR produced similar flow and perfusion pressures. Finally, the hemodynamics of manual CPR were compared with the hemodynamics of direct cardiac compression after thoracotomy. Cardiac deformation was measured and held nearly constant during changes in rate and duration. As opposed to changes accompanying manual CPR, there was no change in perfusion pressures when duration was increased from 15% to 45% of the cycle at a constant rate of 60/min. There was, however, a significant increase in perfusion pressures when rate was increased from 60 to 150/min at a constant duration of 45%. Thus, vital organ perfusion pressures and flow during manual external chest compression are dependent on the duration of compression, but not on rates of 60 or 150/min. These data are similar to those observed for vest CPR, where intrathoracic pressure is manipulated without sternal displacement, but opposite of those observed for direct cardiac compression.(ABSTRACT TRUNCATED AT 400 WORDS)

Randomized, Double-Blind Trial of Inhaled Nitric Oxide in LVAD Recipients With Pulmonary Hypertension

BACKGROUND Pulmonary vascular resistance is often elevated in patients with congestive heart failure, and in those undergoing left ventricular assist device (LVAD) insertion, it may precipitate right ventricular failure and hemodynamic collapse. Because the effectiveness of inotropic and vasodilatory agents is limited by systemic effects, right ventricular assist devices are often required. Inhaled nitric oxide (NO) is an effective, specific pulmonary vasodilator that has been used successfully in the management of pulmonary hypertension. METHODS Eleven of 23 patients undergoing LVAD insertion met criteria for elevated pulmonary vascular resistance on weaning from cardiopulmonary bypass (mean pulmonary artery pressure > 25 mm Hg and LVAD flow rate < 2.5 L x min[-1] x m[-2]) and were randomized to receive either inhaled NO at 20 ppm (n = 6) or nitrogen (n = 5). Patients not manifesting a clinical response after 15 minutes were given the alternative agent. RESULTS Hemodynamics for the group at randomization were as follows: mean arterial pressure, 72 +/- 6 mm Hg; mean pulmonary artery pressure, 32 +/- 4 mm Hg; and LVAD flow, 2.0 +/- 0.3 L x min(-1) x m(-2). Patients receiving inhaled NO exhibited significant reductions in mean pulmonary artery pressure and increases in LVAD flow, whereas none of the patients receiving nitrogen showed hemodynamic improvement. Further, when the nitrogen group was subsequently given inhaled NO, significant hemodynamic improvements ensued. There were no significant changes in mean arterial pressure in either group. CONCLUSIONS Inhaled NO induces significant reductions in mean pulmonary artery pressure and increases in LVAD flow in LVAD recipients with elevated pulmonary vascular resistance. We conclude that inhaled NO is a useful intraoperative adjunct in patients undergoing LVAD insertion in whom pulmonary hypertension limits device filling and output.

A Preliminary Study of Cardiopulmonary Resuscitation by Circumferential Compression of the Chest with Use of a Pneumatic Vest

BACKGROUND More than 300,000 people die each year of cardiac arrest. Studies have shown that raising vascular pressures during cardiopulmonary resuscitation (CPR) can improve survival and that vascular pressures can be raised by increasing intrathoracic pressure. METHODS To produce periodic increases in intrathoracic pressure, we developed a pneumatically cycled circumferential thoracic vest system and compared the results of the use of this system in CPR (vest CPR) with those of manual CPR. In phase 1 of the study, aortic and right-atrial pressures were measured during both vest CPR (60 inflations per minute) and manual CPR in 15 patients in whom a mean (+/- SD) of 42 +/- 16 minutes of initial manual CPR had been unsuccessful. Vest CPR was also carried out on 14 other patients in whom pressure measurements were not made. In phase 2 of the study, short-term survival was assessed in 34 additional patients randomly assigned to undergo vest CPR (17 patients) or continued manual CPR (17 patients) after initial manual CPR (duration, 11 +/- 4 minutes) had been unsuccessful. RESULTS In phase 1 of the study, vest CPR increased the peak aortic pressure from 78 +/- 26 mm Hg to 138 +/- 28 mm Hg (P < 0.001) and the coronary perfusion pressure from 15 +/- 8 mm Hg to 23 +/- 11 mm Hg (P < 0.003). Despite prolonged unsuccessful manual CPR, spontaneous circulation returned with vest CPR in 4 of the 29 patients. In phase 2 of the study, spontaneous circulation returned in 8 of the 17 patients who underwent vest CPR as compared with only 3 of the 17 patients who received continued manual CPR (P = 0.14). More patients in the vest-CPR group than in the manual-CPR group were alive 6 hours after attempted resuscitation (6 of 17 vs. 1 of 17) and 24 hours after attempted resuscitation (3 of 17 vs. 1 of 17), but none survived to leave the hospital. CONCLUSIONS In this preliminary study, vest CPR, despite its late application, successfully increased aortic pressure and coronary perfusion pressure, and there was an insignificant trend toward a greater likelihood of the return of spontaneous circulation with vest CPR than with continued manual CPR. The effect of vest CPR on survival, however, is currently unknown and will require further study.

Screening Scale Predicts Patients Successfully Receiving Long-term Implantable Left Ventricular Assist Devices

BACKGROUND Although use of long-term implantable left ventricular assist devices (LVAD) is becoming more popular, further reduction of the mortality rate accompanying device insertion through improved patient selection would make this alternative even more appealing. We sought to develop a scoring system that was based on criteria obtainable at the time of evaluation and predictive of successful early outcome and simple to apply. METHODS AND RESULTS Patients (n = 56) undergoing LVAD insertion between 1990 and 1994 were screened for easily obtainable preoperative risk factors. To test the association between survival and each risk factor, a chi 2 analysis was performed, and relative risks were estimated. Oliguria, ventilator dependence, elevated central venous pressure, elevated prothrombin time, and reoperation stats had low probability values and high estimated relative risks. On the basis of these relations, a risk factor-selection scale (RFSS) (range, 0 to 10) was developed by computing appropriate weights for each risk factor. The distribution of patients for each scale score reveal that with RFSS > or = 5, most device recipients will die (P < .001). The average RFSS (+/- SD) of survivors (n = 42) was 2.45 +/- 1.73 compared with 5.43 +/- 2.85 in nonsurvivors (n = 14) (P < .0001). Univariate logistical regression was also significant (score statistic, 16.2; df = 1; P = .001). CONCLUSIONS The RFSS is simple, easy to apply, and statistically valid. Physicians could use the scale as a starting point in discussing the suitability for LVAD implantation in a specific patient and as a basis for comparing patient outcomes.