Primary Graft Failure After Heart Transplantation: Urgent Need for a Consensus Guideline
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We read with attention the article by Russo et al. (1) about predictive factors and outcome of patients with primary graft failure (PGF) after heart transplantation. Their results are interesting, as they provide a thorough statistical analysis including a complete list of pretransplant variables associated with the onset of PGF. However, as the authors state in their article, this analysis reveals some limitations. In our opinion, the main limitation is the definition and the inclusion criteria of the study. “Hard outcomes,” defined as death or retransplantation in the first 90 days after transplantation because of graft failure, not related to rejection or infection, does not represent the clinical reality of PGF. If death is an obligate criterion for the diagnosis of a disease, patients who have been treated successfully will not be diagnosed, and therefore, the analysis of therapeutic approaches is impossible. However, as Russo et al. stated, PGF is a complication associated with high mortality rates, and promising therapeutic strategies are urgently needed. Thus, we agree with the assumption of the authors that their analysis may underestimate the incidence of PGF. Furthermore, the rationale of excluding patients with mechanical sup-port, high-dose inotropes, and death after 90 days is unclear. In a study published by our group, the criteria for PGF were defined much stronger than in the former study by Lima et al. (2) but with a “chance to survive” for the patients who have ejection fraction less than 30%, despite the use of epinephrine (>0.1 μg/kg/min) plus milrinone (3) (>0.3 μg/kg/min). Reasonable approaches to treat patients with PGF will remain inconclusive as long as the International Society for Heart and Lung Transplantation does not provide international valid criteria (as there are for PGF after lung transplantation). These criteria should be carefully chosen to define an entity that is associated with a high early mortality but not obligatory with death. In our study, one main issue attributed to our therapeutic approach (i.e., levosimendan) was the avoidance of mechanical support, which is obviously another criterion to be included in the future definition of PGF. Andres Beiras-Fernandez Ingo Kaczmarek Florian Weis 1 Department of Cardiac Surgery University Hospital Grosshadern Ludwig-Maximilians-University Munich, Germany 2 Department of Anesthesiology University Hospital Grosshadern Ludwig-Maximilians-University Munich, GermanyKeywords:
Milrinone
Standard techniques were used to study developmental changes in the effects of amrinone and milrinone on contractile properties of isolated canine cardiac papillary and trabecular muscle. In contrast to milrinone, which induced a positive inotropic effect, amrinone had a negative inotropic effect on the neonatal canine muscles studied. For both drugs there was an age-dependent increase in contractility beyond the neonatal period. The negative inotropic effect of amrinone was not related to a change in phosphodiesterase inhibition, although developmental changes in phosphodiesterase inhibition did occur. These results highlight the differences in the mechanism of action of two similar molecules. They also suggest that use of amrinone as an inotropic agent in the early neonatal period should be viewed with caution.
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Patients who experience severe symptoms of heart failure and repeated hospitalizations for exacerbations may benefit from positive inotropic drug infusion therapy such as dobutamine or milrinone. This article provides an overview of inotropic drug delivery in the home including current controversies and best practices to ensure safe home care policies and practice.
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In the treatment of heart failure, clinical signs are low cardiac output, therapy with positive inotropic agents in an acute cardiac care is mandatory. Three classes of inotropic drugs are currently used, including beta-adrenergic agonists (especially dobutamine), phosphodiesterase inhibitors (such as milrinone) and the recently developed calcium sensitizers such as levosimendan. The classic inotropic drugs offer short-term haemodynamic enhancement in heart failure patient and their use has been connected with poor prognosis. The inotropic drugs, the Ca2+-sensitizers, may offer a choice of long-lasting result.
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Objective: To study the relationship of changing Ca2+levels, to the inotropic responses of amphibian and mammalian myocardium, to phosphodiesterase (PDE) Ill inhibitors, milrinone and trequinsin hydrochloride (HL725).
Methods: The inotropic effects of milrinone and HL725 were investigated, on the isolated perfused frog heart and the isolated electrically - paced guinea pig left atrium at different perfusate calcium levels.
Results: HL725 and milrinone produced a dose-dependent positive inotropy effect. The mammalian myocardium exhibited greater magnitude of positive inotropic response as compared to the isolated frog heart.
Conclusion: The responses to HL725 and milrinone are species specific; due to the inherent ultrastructural variations and the resultant changed intracellular Ca2+ mileu.
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The interaction of the cAMP-phosphodiesterase inhibitor milrinone and the beta-adrenoceptor agonist isoproterenol was studied on guinea-pig isolated hearts. Milrinone, (10 microns) caused a positive inotropic response which differed from that of isoproterenol (7 nM) and decreased cardiac inotropic responses to the subsequent administration of isadrin despite a significant great rise in cAMP. The interaction of the drugs is assumed to be associated with the milrinone-induced increase in cGMP which is able to restrict myocardial cAMP-activated processes.
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We describe the synthesis and positive inotropic evaluation of a series of 2-(4-substitutedbenzylpiperazin-1-yl)- N-(2-oxo-2,3-dihydrobenzooxazol-6-yl)acetamides by measuring left atrial stroke volume in preparations of isolated rabbit hearts. Several compounds were developed from and showed favorable activities compared with the standard drug milrinone. Compound 4l was the most potent with an increased stroke volume of 11.78 ± 0.18% (milrinone 6.36 ± 0.13%) at 1 10–4 M in our in-vitro study. The chronotropic effects of compounds having inotropic effects were also evaluated. Keywords: 2, 3-Dihydro-2-oxobenzo[d]oxazole, Positive inotropic activity, Stroke volume
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Summary: The question has been raised whether the in vivo positive inotropic effect of amrinone and milrinone is a primary effect or secondary to vasodilation. The effects of each drug on isolated trabeculae and resistance vessels obtained from the same dog hearts were determined separately. The positive inotropic and vasodilatory effects coincided over the same concentration range for amrinone. The active isometric force of trabeculae and resistance vessels was increased, and respectively decreased by 20% at comparable concentrations of amrinone–20% ED (effective dose) ranging between 9.5 and 18 μM. By contrast, the vasodilatory properties of milrinone (20% ED, 15–34 μM) appeared only at concentrations at which milrinone had already evoked a maximal positive inotropic response in trabecular muscle (20% ED, 0.36–0.38 μM). Based on the present experiments and their limitations, it would thus appear that, in the intact heart and at therapeutic doses, positive inotropic and vasodilatory effects may be equally present for amrinone, whereas, for milrinone, the positive inotropic effect would largely predominate the vasodilatory effect.
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Background and objective Patients in cardiac surgery and critically ill patients often demonstrate either hypothermia or fever. In addition, owing to heart failure, they frequently require inotropic support. The relative effectiveness of modern inotropic agents at various temperatures has not yet been evaluated. Therefore, we investigated the influence of levosimendan, dobutamine and milrinone on the contractile response of myocardial trabeculae at various temperatures. Methods A total of 120 guinea pig ventricular trabeculae were placed in oxygenated 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES) buffer, stimulated at a frequency of 1.3 Hz and randomly assigned to a temperature of 31°C, 34°C, 37°C or 40°C. Concentrations of all substances were increased stepwise from 10−9 to 10−5 mol l−1 (milrinone up to 10−4 mol l−1). Maximum developed force, time to peak tension, Tsystolic50% and Tdiastolic50% were continuously recorded. Results All agents showed a dose-dependent positive inotropic effect (P < 0.0001 for all). Levosimendan acted at every temperature as a positive inotrope (P = 0.0643). Dobutamine-related inotropy showed a clear trend towards temperature dependence, although statistical evaluation did not prove this (P = 0.0624). Milrinone-related inotropy was abolished at 31°C and 34°C, and temperature dependence was significant (P < 0.0001). Hypothermia induced a positive inotropic effect. Conclusion Our results suggest no modulation of levosimendan-induced inotropy under the experimental temperatures tested. This observation is possibly due to its Ca2+-sensitizing mechanism, which might not be influenced by temperature-related changes in intracellular Ca2+ levels. In contrast, the inotropic effect of cyclic AMP-coupled dobutamine and milrinone is suppressed under hypothermia-related interaction with intracellular Ca2+ homeostasis. Hence, levosimendan might prove to be the preferred inotropic drug in hypothermic patients.
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