PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.

BACKGROUND: Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. METHODS: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. RESULTS: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. DISCUSSION: Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.

BACKGROUND: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery. While there is solid evidence for the treatment of other cardiovascular diseases of acute onset, treatment strategies in haemodynamic instability due to CS and LCOS remains less robustly supported by the given scientific literature. Therefore, we have analysed the current body of evidence for the treatment of CS or LCOS with inotropic and/or vasodilating agents. This is the second update of a Cochrane review originally published in 2014. OBJECTIVES: Assessment of efficacy and safety of cardiac care with positive inotropic agents and vasodilator agents in CS or LCOS due to AMI, HF or after cardiac surgery. SEARCH METHODS: We conducted a search in CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in October 2019. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) enrolling patients with AMI, HF or cardiac surgery complicated by CS or LCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to Cochrane standards. MAIN RESULTS: We identified 19 eligible studies including 2385 individuals (mean or median age range 56 to 73 years) and three ongoing studies. We categorised studies into 11 comparisons, all against standard cardiac care and additional other drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo; enoximone versus dobutamine, piroximone or epinephrine-nitroglycerine; epinephrine versus norepinephrine or norepinephrine-dobutamine; dopexamine versus dopamine; milrinone versus dobutamine and dopamine-milrinone versus dopamine-dobutamine. All trials were published in peer-reviewed journals, and analyses were done by the intention-to-treat (ITT) principle. Eighteen of 19 trials were small with only a few included participants. An acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements occurred in nine of 19 trials. In general, confidence in the results of analysed studies was reduced due to relevant study limitations (risk of bias), imprecision or indirectness. Domains of concern, which showed a high risk in more than 50% of included studies, encompassed performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. All comparisons revealed uncertainty on the effect of inotropic/vasodilating drugs on all-cause mortality with a low to very low quality of evidence. In detail, the findings were: levosimendan versus dobutamine (short-term mortality: RR 0.60, 95% CI 0.36 to 1.03; participants = 1701; low-quality evidence; long-term mortality: RR 0.84, 95% CI 0.63 to 1.13; participants = 1591; low-quality evidence); levosimendan versus placebo (short-term mortality: no data available; long-term mortality: RR 0.55, 95% CI 0.16 to 1.90; participants = 55; very low-quality evidence); levosimendan versus enoximone (short-term mortality: RR 0.50, 0.22 to 1.14; participants = 32; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine-dobutamine (short-term mortality: RR 1.25; 95% CI 0.41 to 3.77; participants = 30; very low-quality evidence; long-term mortality: no data available); dopexamine versus dopamine (short-term mortality: no deaths in either intervention arm; participants = 70; very low-quality evidence; long-term mortality: no data available); enoximone versus dobutamine (short-term mortality RR 0.21; 95% CI 0.01 to 4.11; participants = 27; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine (short-term mortality: RR 1.81, 0.89 to 3.68; participants = 57; very low-quality evidence; long-term mortality: no data available); and dopamine-milrinone versus dopamine-dobutamine (short-term mortality: RR 1.0, 95% CI 0.34 to 2.93; participants = 20; very low-quality evidence; long-term mortality: no data available). No information regarding all-cause mortality were available for the comparisons milrinone versus dobutamine, enoximone versus piroximone and enoximone versus epinephrine-nitroglycerine. AUTHORS' CONCLUSIONS: At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS. Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS.

Primary intra-aortic balloon support versus inotropes for decompensated heart failure and low output: a randomised trial.

AIMS: The haemodynamic effects of primary implantation of an intra-aortic balloon pump (IABP) versus inotropes in decompensated heart failure and low output (DHF-LO), but without an acute coronary syndrome, have not been investigated. We therefore aimed to investigate the effect of primary IABP implantation as compared to inotropes on haemodynamics in DHF-LO with no acute ischaemia. METHODS AND RESULTS: Patients (n=32) with DHF-LO despite IV diuretics were randomised to primary 50 mL IABP or inotropes (INO: enoximone or dobutamine). The primary endpoint was the improvement of organ perfusion assessed by ∆ mixed-venous oxygen saturation (SvO2) at 3 hours; secondary endpoints included ∆ cardiac power output (CPO), NT-proBNP proportional change, cumulative fluid balance and ∆ dyspnoea severity score, all at 48 hours. Data are presented as median (IQR). Patients were 60 (48-69) years old and 72% were male. Baseline SvO2 was 44 (39-53)%. ∆SvO2 was higher in the IABP group (+17 [+9; +24] vs. +5 [+2; +9]%, p<0.05). IABP patients had a higher ∆CPO, a greater relative reduction in NT-proBNP, a more negative cumulative fluid balance, and a greater reduction in dyspnoea severity score. There were no IABP-related serious adverse events (SAEs). Thirty-day mortality was 23% (IABP) vs. 44% (INO). CONCLUSIONS: Primary circulatory support by IABP showed a significant increase in improved organ perfusion assessed by SvO2.

Preliminary results of the Multicenter Observational Study with Enoximone in Cardiac surgery (MOSEC).

BACKGROUND: Perioperative administration of Enoximone has been shown to improve hemodynamics, organ function, and inflammatory response. Aim of the present study was to evaluate the effects of Enoximone after on-pump cardiac surgery. METHODS: A protocol for a multicenter observational study was reviewed and approved by local ethic committee. This preliminary report involves the first 29 patients enrolled, in whom Enoximone was perioperatively administered in the context of on-pump cardiac surgery. All patients enrolled were propensity-matched 1:1 with controls not receiving Enoximone, renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. RESULTS: After propensity matching, the two cohorts of patients receiving Enoximone or not did not show any significant differences among baseline characteristics. Patients receiving Enoximone showed a progressive improvement of eGFR at each time-point of follow-up: roughly +4.3, +10.0, and +12.3 mL/min/1.73 m2 on postoperative days 2, 7, and 30; respectively. Consistently, maximum difference versus baseline was +12.6 mL/min/1.73 m2 (or +19.3%) among Enoximone patients vs +3.3 mL/min/1.73 m2 (or +4.4%) among controls (p = 0.02). Multivariable regression analysis (R2-adjusted 0.47) showed only age (ß -0.53; p = 0.01), preoperative eGFR (ß -0.39; p = 0.02), diabetes (ß 2.1; p = 0.01), cardio-pulmonary bypass duration (ß 0.08; p = 0.05), and Enoximone administration (ß -0.74; p = 0.05) to be independently correlated with delta eGFR variation on day 30. CONCLUSION: These preliminary results show that perioperative Enoximone administration improved renal function in patients undergoing on-pump cardiac surgery. Further studies are needed to confirm these findings.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.

BACKGROUND: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are life-threatening conditions. While there is a broad body of evidence for the treatment of people with acute coronary syndrome under stable haemodynamic conditions, the treatment strategies for people who become haemodynamically unstable or develop CS remain less clear. We have therefore summarised here the evidence on the treatment of people with CS or LCOS with different inotropic agents and vasodilative drugs. This is the first update of a Cochrane review originally published in 2014. OBJECTIVES: To assess efficacy and safety of cardiac care with positive inotropic agents and vasodilator strategies in people with CS or LCOS due to AMI, HF or cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in June 2017. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine-dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo.All trials were published in peer-reviewed journals, and analysis was done by the intention-to-treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events.Levosimendan may reduce short-term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low-quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short-term survival benefit with levosimendan vs. dobutamine is not confirmed on long-term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low-quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low-quality evidence).All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short-term mortality with very low-quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine-dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in-hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants). AUTHORS' CONCLUSIONS: Apart from low quality of evidence data suggesting a short-term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug-based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS.Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well-designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal-directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support.

A pathophysiological role of PDE3 in allergic airway inflammation.

Phosphodiesterase 3 (PDE3) and PDE4 regulate levels of cyclic AMP, which are critical in various cell types involved in allergic airway inflammation. Although PDE4 inhibition attenuates allergic airway inflammation, reported side effects preclude its application as an antiasthma drug in humans. Case reports showed that enoximone, which is a smooth muscle relaxant that inhibits PDE3, is beneficial and lifesaving in status asthmaticus and is well tolerated. However, clinical observations also showed antiinflammatory effects of PDE3 inhibition. In this study, we investigated the role of PDE3 in a house dust mite-driven (HDM-driven) allergic airway inflammation (AAI) model that is characterized by T helper 2 cell activation, eosinophilia, and reduced mucosal barrier function. Compared with wild-type (WT) littermates, mice with a targeted deletion of the PDE3A or PDE3B gene showed significantly reduced HDM-driven AAI. Therapeutic intervention in WT mice showed that all hallmarks of HDM-driven AAI were abrogated by the PDE3 inhibitors enoximone and milrinone. Importantly, we found that enoximone also reduced the upregulation of the CD11b integrin on mouse and human eosinophils in vitro, which is crucial for their recruitment during allergic inflammation. This study provides evidence for a hitherto unknown antiinflammatory role of PDE3 inhibition in allergic airway inflammation and offers a potentially novel treatment approach.

Use of enoximone in management of anaphylaxis complicated by labetalol use.

A 42-year-old woman with end-stage renal failure was admitted to the intensive care unit following resuscitation from a pulseless electrical activity cardiac arrest after intravenous piperacillin/tazobactam. Persistent bradycardia and hypotension, unresponsive to epinephrine and norepinephrine, were suspected to have been exacerbated by chronic labetalol therapy for resistant arterial hypertension. As an alternative, the non-adrenergic inotrope, enoximone, was started. This, combined with thrombolysis for possible pulmonary embolism, heralded significant haemodynamic improvement, allowing weaning from inotropic support. A clear CT pulmonary angiogram 2 days post-arrest and significantly raised mast cell tryptase levels confirmed anaphylaxis rather than pulmonary embolism as the precipitating cause. We believe this to be the first case report of phosphodiesterase-III inhibitor use in the management of anaphylaxis complicated by α/ß-blockade, and discuss the mechanism behind this effect and comparison with the more commonly reported use of glucagon.

Influence of levosimendan on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery.

OBJECTIVES: Levosimendan is an inotropic drug with organ-protective properties due to its activation of mitochondrial K(ATP) channels. This prospective, randomized, double-blind, placebo-controlled study investigated whether administration of levosimendan prior to cardiopulmonary bypass could reduce organ dysfunction and influence subsequent secondary endpoints. PATIENTS AND METHODS: Patients with left ventricular ejection fraction <30% scheduled for elective coronary artery bypass surgery (with or without valve surgery) received either levosimendan (12.5 mg, 0.1 µg kg(-1) per min; n = 17) or placebo (n = 16) central venous infusion, immediately after anaesthesia induction, as add-on medication to a goal-orientated treatment algorithm. RESULTS: A total of 33 patients completed the study. There were no statistically significant differences in Sequential Organ Failure Assessment scores, survival, haemodynamic parameters, time to extubation, time in intensive care unit, need for haemodialysis or health-related quality-of-life at 6 months post operation. The levosimendan group compared with the placebo group had significantly lower use of epinephrine (35% versus 81%) and nitroglycerine (6% versus 44%) 24 h postoperation, and significantly less frequent serious adverse events (13% versus 47%). CONCLUSIONS: These preliminary results show that timely perioperative levosimendan treatment is feasible, has a favourable safety profile safe and may help to prevent low cardiac output syndrome. However, organ function was not preserved. Further studies, using larger sample sizes, are required.

Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome.

BACKGROUND: The recently published German-Austrian S3 Guideline for the treatment of infarct related cardiogenic shock (CS) revealed a lack of evidence for all recommended therapeutic measures. OBJECTIVES: To determine the effects in terms of efficacy, efficiency and safety of cardiac care with inotropic agents and vasodilator strategies versus placebo or against each other for haemodynamic stabilisation following surgical treatment, interventional therapy (angioplasty, stent implantation) and conservative treatment (that is no revascularization) on mortality and morbidity in patients with acute myocardial infarction (AMI) complicated by CS or low cardiac output syndrome (LCOS). SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), EMBASE (Ovid) and ISI Web of Science, registers of ongoing trials and proceedings of conferences in January 2013. Reference lists were scanned and experts in the field were contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials in patients with AMI complicated by CS or LCOS. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the published protocol. All trials were analysed individually. Hazard ratios (HRs) and odds ratios with 95% confidence intervals (CI) were extracted but not pooled because of high heterogeneity between the control group interventions. MAIN RESULTS: Four eligible, very small studies were identified from a total of 4065 references. Three trials with high overall risk of bias compared levosimendan to standard treatment (enoximone or dobutamine) or placebo. Data from a total of 63 participants were included in our comparisons, 31 were treated with levosimendan and 32 served as controls. Levosimendan showed an imprecise survival benefit in comparison with enoximone based on a very small trial with 32 participants (HR 0.33; 95% CI 0.11 to 0.97). Results from the other similarly small trials were too imprecise to provide any meaningful information about the effect of levosimendan in comparison with dobutamine or placebo. Only small differences in haemodynamics, length of hospital stay and the frequency of major adverse cardiac events or adverse events overall were found between study groups.Only one small randomised controlled trial with three participants was found for vasodilator strategies (nitric oxide gas versus placebo) in AMI complicated by CS or LCOS. This study was too small to draw any conclusions on the effects on our key outcomes. AUTHORS' CONCLUSIONS: At present there are no robust and convincing data to support a distinct inotropic or vasodilator drug based therapy as a superior solution to reduce mortality in haemodynamically unstable patients with CS or low cardiac output complicating AMI.

Weaning from inotropic support and concomitant beta-blocker therapy in severely ill heart failure patients: take the time in order to improve prognosis.

AIMS: Beta-blockers improve the prognosis in heart failure (HF), but their introduction may seem impossible in patients dependent on inotropic support. However, many of these patients can be titrated on beta-blockers, but there is little evidence of successful clinical strategies. METHODS AND RESULTS: We analysed the records of inotropy-dependent patients referred for assessment for heart transplantation. Thirty-six patients (45%) could not be weaned (NW) and underwent left ventricular assist device (LVAD) implantation or transplantation, or died. However, 44 (55%) were successfully weaned (SW). Neither the aetiology (ischaemic vs. non-ischaemic) nor cardiac indexes were different in the SW as compared with the NW group (2.27±0.5 vs. 2.15±0.6 L/min/m2). The NW patients had lower LVEF (15±5% vs. 19±5%, P=0.001), higher right atrial pressure (12±6 vs. 8±6 mmHg, P=0.02), and more severe mitral regurgitation (P<0.001) than the SW patients. At discharge, 35 of 44 SW patients were receiving beta-blockers. In 29 of them, a beta-blocker could only be initiated or continued during concomitant support with i.v. enoximone for a duration of 14.1±7.2 days. Patients discharged on a beta-blocker had an LVAD/transplantation-free cumulative survival of 71% during a follow-up of 2074±201 days (confidence interval 1679­2470). CONCLUSION: It takes time to put severely ill HF patients on beta-blockers and it may require bridging with inotropes which are independent of beta-adrenergic receptors. Whether such a strategy may result in a better clinical outcome warrants further research.

Double-blind placebo-controlled comparison of enoximone and dobutamine infusions in patients with moderate to severe chronic heart failure.

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.

Apart from the other members of PDE inhibitors' family, enoximone does not enhance renal ischemic reperfusion injury: the effects of enoximone on renal ischemia reperfusion.

Many pharmacological agents were investigated for the prevention of renal ischemic reperfusion (IR) injury as well as the phosphodiesterase (PDE) inhibitors. The aim of the study was to examine the possible renoprotective effect of enoximone as a member of this family on IR injury. Thirty-six Wistar-Albino rats were allocated to six groups. Sham (S) and control groups (E1, E2) only received 0.09% NaCl, 5 mg/kg and 10 mg/kg enoximone via caudal caval vein, respectively. In ischemia (I) and treatment groups (IE1, IE2), the rats were subjected to bilateral renal artery occlusion and were given 0.09% NaCl, 5 mg/kg and 10 mg/kg enoximone in the same route, respectively. Bilateral kidneys were removed at the sixth hour of laparotomy for histopathological and biochemical analysis, such as superoxide dismutase, myeloperoxidase, malonyldialdehyde, and nitric oxide end products. Blood samples were taken in order to evaluate renal function tests. The data were analyzed by using one-way analysis of variance, and p < .05 was considered to be statistically significant. The worst results were achieved in ischemia group (p < .05). Treatments groups showed nearly similar findings with this group (p < .05). There was no significant difference between control and sham groups. In this study, we found that apart from the other members of the PDE inhibitors' family, enoximone did not contribute to the attenuation of IR injury of kidney.

Influence of continuous perioperative beta-blockade in combination with phosphodiesterase inhibition on haemodynamics and myocardial ischaemia in high-risk vascular surgery patients.

BACKGROUND: We sought to assess the intra- and postoperative haemodynamic effects of continuous perioperative beta-adrenergic blockade combined with phosphodiesterase (PDE) III inhibition and its potential benefits in limiting perioperative myocardial ischaemia in high-risk vascular surgery patients. METHODS: Seventy-five patients were randomly assigned to receive tight heart rate (HR) control by a continuous infusion of: esmolol in combination with the PDE III inhibitor enoximone (esmolol+enoximone group), esmolol infusion alone (esmolol group), or standard therapy (control group) for a period of 48 h. Myocardial ischaemia and dysfunction were detected by serial plasma Troponin T (TnT) and B-type natriuretic peptide (BNP) measurements. RESULTS: Cardiac index (CI) increased significantly only in esmolol+enoximone-treated patients [CI: from 2.4 (0.2) litre min(-1) m(-2) at baseline to 3.2 (0.2) litre min(-1) m(-2) at 24 h after surgery; P=0.001] and was significantly higher than in the esmolol [CI: from 2.5 (0.2) litre min(-1) m(-2) at baseline to 2.6 (0.2) litre min(-1) m(-2) at 24 h; P=0.18] and the control groups [CI: from 2.4 (0.2) litre min(-1) m(-2) at baseline to 2.7 (0.2) litre min(-1) m(-2) at 24 h; P=0.13]. A significant postoperative release of TnT was detected only in control patients. Plasma BNP levels increased towards the end of surgery in all patients. Peak plasma BNP concentrations were significantly higher in control patients [293 (98) pg ml(-1)] than in esmolol [118 (71) pg ml(-1)] and in esmolol+enoximone-treated patients [78 (21) pg ml(-1)]. CONCLUSIONS: Inotropic therapy with the PDE III inhibitor enoximone combined with tight HR control by a continuous infusion of esmolol improved cardiac function and reduced myocardial ischaemia in high-risk vascular surgery patients. CLINICAL TRIAL REGISTRATION INFORMATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00348101.

Long-term outcome of coronary artery bypass grafting in patients with left ventricular dysfunction.

BACKGROUND: Coronary artery bypass grafting (CABG) is a well-accepted therapeutic strategy for patients with multivessel coronary artery disease and left ventricular dysfunction. The aim of the study was to evaluate long-term results after CABG in patients with preoperative left ventricular ejection fraction (LVEF) of 0.35 or less. METHODS: Data from 302 consecutive patients (mean age, 62 +/- 8.7 years) with LVEF of 0.35 or less who had undergone CABG were analyzed. Epinephrine and enoximone with or without norepinephrine were used to increase cardiac index. Intra-aortic balloon pump or left ventricular assist devices, or both, were used in case of postoperative low output syndrome. RESULTS: Complete revascularization was achieved in 298 of 302 patients (98.7%); internal thoracic artery was used in 294 (97.4%). Operative mortality was 5.3%; independent predictors of operative mortality were emergency CABG (p = 0.005), history of ventricular arrhythmias (p = 0.007), and previous anterior myocardial infarction (p = 0.05). At follow-up, all-cause mortality was 30.8%, and 10-year survival was 63% +/- 4%; independent predictors of late all-cause mortality were history of ventricular arrhythmias (p < 0.0001), chronic renal dysfunction (p = 0.0004), and diabetes mellitus (p = 0.04). Cardiac death was 20.4%, and 10-year freedom from cardiac death was 73% +/- 3.3%; independent predictors of cardiac death were history of ventricular arrhythmias (p = 0.004), chronic renal dysfunction (p = 0.03), and more than one previous anterior myocardial infarction (p = 0.004). At 80 +/- 44 months of follow-up, echocardiography showed significant LVEF improvement (0.43 +/- 0.09 versus 0.28 +/- 0.06, p < 0.0001). Ten-year freedom from myocardial infarction was 87% +/- 3%. CONCLUSIONS: Excellent long-term results after CABG can be expected for patients with LVEF of 0.35 or less. Complete revascularization and internal thoracic artery grafting are associated with high freedom from myocardial infarction. Careful treatment of arrhythmias, diabetes, and renal dysfunction is necessary to improve long-term survival.