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Cardiac effects of non-adrenergic inotropic drugs: clinical and experimental studies
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Myocardial failure and dysfunction is not uncommon during critical illness and following cardiac surgery. For optimal treatment, a better understanding of the effects of inotropic drugs is needed. In this thesis, two non-adrenergic mediated inotropes, milrinone and levosimendan were studied in different models of myocardial dysfunction. The study aims were to assess the following: the effects of milrinone on blood flow in coronary artery bypass grafts during CABG surgery; the effects of milrinone on left ventricular diastolic function during post-ischaemic myocardial dysfunction; whether milrinone or levosimendan are protective or injurious during acute myocardial ischaemia, and if levosimendan potentiates myocardial function when added to milrinone in an experimental model of post-ischaemic (stunned) myocardium.

Material and Methods: In Study I, 44 patients undergoing coronary artery bypass surgery(CABG) were included as subjects. Milrinone or saline was administrated in a single dose during cardio-pulmonary bypass (CPB) and coronary graft flow measurements were recorded after 10 and 30 min following CPB. In Study II; 24 patients undergoing CABG had estimations of peak ventricular filling rates made before and after CPB with administration of milrinone or saline as a single dose during CPB, performed by assessment of the rate of change in diastolic cross-sectional left ventricular area. In Study III, energy-metabolic effects of milrinone and levosimendan were measured in an anaesthetized porcine model during 45 minutes of regional myocardial ischemia. Microdialysis sampling of metabolites of local ischemic metabolism allowed assessment of glycolytic activity and the degree of myocardial calcium overload. In Study IV, in a porcine model of postischaemic myocardial stunning, ventricular pressure-volume relationships were analyzed when milrinone or a combination of milrinone and levosimendan were given together.

Results: In Study I, there was a clear increase in non-sequential saphenous vein graft blood flow with milrinone at 10 minutes (64.5 ± 37.4 compared to placebo 43.6 ± 25.7 ml/min (mean ± SD).). A decreasing but still measureable flow increase was seen for milrinone at 30 minutes. In Study II, an increase in early left ventricular filling rate (ventricular cross-sectional area rate of change,dA/dt) was seen in the milrinone treated group. Pre-bypass milrinone group dA/dt 22.0 ± 9.5 changed to post-bypass values dA/dt 27.8 ± 11.5 cm2/sec). Placebo group pre-bypass dA/dt was 21.0 ± 8.7 and post-bypass 17.1 ± 7.1 cm2/sec. A milrinone effect was demonstrated in an adjusted regression model (p = 0.001). In Study III, neither milrinone nor levosimendan led to a change in energy-metabolic activity during ischemia as reflected by interstitial glucose, pyruvate, lactate orglycerol. Neither drug exacerbated the relative myocardial calcium overload during ischemia. In Study IV, milrinone improved active relaxation (tau) in post-ischemic stunned myocardium, but did not markedly improve systolic function by preload recruitable stroke work. Levosimendan added to milrinone showed minimal effect on active relaxation but a positive effect on systolic function in combination with milrinone.

Conclusions: We conclude that milrinone treatment leads to an increase in blood flow in newly implanted coronary saphenous vein grafts, and improves ventricular relaxation post-cardiopulmonary bypass. Neither milrinone nor levosimendan, in this porcine model, negatively influence myocardial energy metabolism or calcium overload during acute ischaemia. Addition of levosimendan to milrinone treatment during post-ischaemic ventricular dysfunction may provide additive inotropic effects on systolic function but probably not for active relaxation.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 93 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1568
Keyword [en]
Milrinone, levosimendan, vein graft flow, myocardial ischemia, protection, inotropy, diastole
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
URN: urn:nbn:se:umu:diva-68967ISBN: 978-91-7459-610-6 (print)OAI: oai:DiVA.org:umu-68967DiVA: diva2:619215
Public defence
2013-05-30, Wilandersalen, Universitetssjukhuset, Örebro, Örebro, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-05-03 Created: 2013-05-02 Last updated: 2013-05-06Bibliographically approved
List of papers
1. Milrinone increases flow in coronary artery bypass grafts after cardiopulmonary bypass: a prospective, randomized, double-blind, placebo-controlled study
Open this publication in new window or tab >>Milrinone increases flow in coronary artery bypass grafts after cardiopulmonary bypass: a prospective, randomized, double-blind, placebo-controlled study
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2009 (English)In: Journal of Cardiothoracic and Vascular Anesthesia, ISSN 1053-0770, E-ISSN 1532-8422, Vol. 23, no 1, 48-53 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To compare the effects of a bolus of milrinone, 50 microg/kg, versus placebo on flow in coronary artery bypass grafts after cardiopulmonary bypass (CPB).

DESIGN: A prospective, randomized, double-blind study.

SETTING: A university hospital.

PARTICIPANTS: Forty-four patients with stable angina and left ventricular ejection fraction >30% scheduled for elective coronary artery bypass graft (CABG) surgery were included.

INTERVENTION: Patients were randomized to receive 50 microg/kg of milrinone (n = 22) or placebo (n = 22) after aortic declamping.

MEASUREMENTS AND MAIN RESULTS: The flow in coronary artery bypass grafts was measured with a transit time flow meter at 10 minutes and 30 minutes after termination of CPB. The hemodynamic evaluation included transesophageal echocardiography, mean arterial pressure (MAP), heart rate, and intracavitary measurement of left ventricular end-diastolic pressure (LVEDP). The flow in the saphenous vein grafts was significantly higher in the milrinone group when compared with the placebo group both at 10 and 30 minutes after termination of CPB (p < 0.001). At 10 minutes, the flow was 64.5 +/- 37.4 mL/min (mean +/- standard deviation) and 43.6 +/- 25.7 mL/min in nonsequential vein grafts for milrinone and placebo, respectively. Corresponding values at 30 minutes were 54.8 +/- 29.9 mL/min and 35.3 +/- 22.4 mL/min. The left internal thoracic artery (LITA) flow was higher in the milrinone group but did not reach statistical significance. The fractional area change was higher, and the MAP and calculated pressure gradient (MAP-LVEDP) were lower at 10 minutes in the milrinone group.

CONCLUSION: Milrinone significantly increases the flow in anastomosed saphenous vein grafts after CPB, and has beneficial effects on left ventricular function.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-68817 (URN)10.1053/j.jvca.2008.07.005 (DOI)18834820 (PubMedID)
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2017-12-06Bibliographically approved
2. Milrinone improves diastolic function in coronary artery bypass surgery as assessed by acoustic quantification and peak filling rate: a prospective randomized study
Open this publication in new window or tab >>Milrinone improves diastolic function in coronary artery bypass surgery as assessed by acoustic quantification and peak filling rate: a prospective randomized study
2010 (English)In: Journal of Cardiothoracic and Vascular Anesthesia, ISSN 1053-0770, E-ISSN 1532-8422, Vol. 24, no 2, 244-249 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To compare the effects of a bolus dose of milrinone, 50 microg/kg, to placebo on diastolic function (active relaxation) in patients undergoing on-pump coronary artery bypass grafting (CABG).

DESIGN: Prospective, randomized, double-blind, placebo-controlled study.

SETTING: University hospital.

PARTICIPANTS: Twenty-four patients with stable angina and left ventricular ejection fraction >30%, scheduled for elective CABG using cardiopulmonary bypass (CPB), were included.

INTERVENTION: Patients were randomized to receive either 50 microg/kg of milrinone (n = 12) or placebo (n = 12) after aortic declamping.

MEASUREMENTS AND MAIN RESULTS: The diastolic function of the left ventricle (LV) was measured as peak filling rate (dA/dt [maximal diastolic area change over time]) with transesophageal echocardiography (TEE) using acoustic quantification (AQ) before CPB and 10 minutes after termination of CPB. The normalized peak filling rate (dA/dt)/EDA was also calculated. Active relaxation was statistically significantly increased in the milrinone group compared with the placebo group after CPB.

CONCLUSION: Patients undergoing CABG surgery and treated with milrinone after aortic declamping had better diastolic function following cardiopulmonary bypass.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-68815 (URN)10.1053/j.jvca.2009.10.007 (DOI)20022262 (PubMedID)
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2017-12-06Bibliographically approved
3. Milrinone and levosimendan during porcine myocardial ischemia: no effects on calcium overload and metabolism
Open this publication in new window or tab >>Milrinone and levosimendan during porcine myocardial ischemia: no effects on calcium overload and metabolism
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2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 6, 719-728 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Although inotropic stimulation is considered harmful in the presence of myocardial ischaemia, both calcium sensitisers and phosphodiesterase inhibitors may offer cardioprotection. We hypothesise that these cardioprotective effects are related to an acute alteration of myocardial metabolism. We studied in vivo effects of milrinone and levosimendan on calcium overload and ischaemic markers using left ventricular microdialysis in pigs with acute myocardial ischaemia.

METHODS: Anaesthetised juvenile pigs, average weight 36 kg, were randomised to one of three intravenous treatment groups: milrinone 50 μg/kg bolus plus infusion 0.5 μg/kg/min (n = 7), levosimendan 24 μg/kg plus infusion 0.2 μg/kg/min (n = 7), or placebo (n = 6) for 60 min prior to and during a 45 min acute regional coronary occlusion. Systemic and myocardial haemodynamics were assessed, and microdialysis was performed with catheters positioned in the left ventricular wall. (45) Ca(2+) was included in the microperfusate in order to assess local calcium uptake into myocardial cells. The microdialysate was analysed for glucose, lactate, pyruvate, glycerol, and for (45) Ca(2+) recovery.

RESULTS: During ischaemia, there were no differences in microdialysate-measured parameters between control animals and milrinone- or levosimendan-treated groups. In the pre-ischaemic period, arterial blood pressure decreased in all groups while myocardial oxygen consumption remained stable.

CONCLUSIONS: These findings reject the hypothesis of an immediate energy-conserving effect of milrinone and levosimendan during acute myocardial ischaemia. On the other hand, the data show that inotropic support with milrinone and levosimendan does not worsen the metabolic parameters that were measured in the ischaemic myocardium.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-68816 (URN)10.1111/aas.12095 (DOI)000320116800007 ()23517167 (PubMedID)
Note

Epub ahead of print 20 March 2013.

Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2017-12-06Bibliographically approved
4. Systolic and diastolic effects of milrinone and levosimendan in porcine post-ischemic myocardial dysfunction
Open this publication in new window or tab >>Systolic and diastolic effects of milrinone and levosimendan in porcine post-ischemic myocardial dysfunction
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(English)Manuscript (preprint) (Other academic)
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-68823 (URN)
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2015-09-15Bibliographically approved

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