- Email: [email protected]
Levosimendan or Milrinone in the Type 2 Diabetic Patient With Low Ejection Fraction Undergoing Elective Coronary Artery Surgery
Levosimendan or Milrinone in the Type 2 Diabetic Patient With Low Ejection Fraction Undergoing Elective Coronary Artery Surgery Emad Al-Shawaf, FRCPC,* Adel Ayed, FRCSC,† Ivan Vislocky, MUDr,* Bosko Radomir, PhD,* Najat Dehrab, MD,* and Riad Tarazi, FACS† Objectives: The purpose of this study was to compare the hemodynamic profiles and the postoperative insulin requirements in 2 groups of type 2 diabetic patients with depressed myocardial function who underwent elective surgery for coronary artery disease and who received levosimendan or milrinone for postcardiopulmonary bypass low-output syndrome. Design: Randomized controlled trial. Setting: The Chest Diseases Hospital, Safat, Kuwait. Participants: Type 2 diabetic patients undergoing elective surgery for coronary artery disease. Interventions: Fourteen patients and 16 patients received levosimendan and milrinone infusions, respectively, for treatment of the low-output syndrome. Measurements and Main Results: The hemodynamic, mixed venous oxygen saturation, oxygen extraction ratios, arterial lactate concentrations, and postoperative insulin infusion rates were serially documented for the first 48 hours
T
HE INCIDENCE OF a low-output syndrome (LOS) after cardiac surgery with cardiopulmonary bypass (CPB) in patients with depressed ventricular function is approximately 30%.1 This condition causes delayed recovery, organ failure, prolonged intensive care unit (ICU) stays, and increased hospital costs.2 In addition, in patients with a depressed ventricle, the LOS adds to the risk of early postoperative mortality.3 To prevent or decrease these adverse outcomes, post-CPB LOS should be reversed whenever possible. The treatment of the syndrome requires optimization of myocardial contractility and loading conditions, which are achieved by instituting appropriate pharmacologic and fluid management plans.4 The myofilament calcium sensitizer levosimendan has been used successfully as a pharmacologic treatment for post-CPB LOS because it is an inotropic drug that enhances myocardial contractility in the stunned myocardium.5,6 Adenosine triphosphate– dependent potassium (KATP) channels are located on the sarcolemmal and inner mitochondrial membranes in the myocardial and vascular smooth muscles, and -cells of the pancreas.7,8 Levosimendan opens KATP channels and inhibits phosphodiesterase III (PDE III) without increasing the intracellular levels of cyclic adenosine monophosphate (cAMP).9-11 PDE III induces breakdown of cAMP. Diabetes, hyperglycemia, and oral hypoglycemic agents (sulfonylurea) impair the activation of KATP channels in cardiac myocytes and pancreatic -cells.12,13 Another pharmacologic agent used in the treatment of post-CPB LOS is milrinone, which is a PDE III inhibitor that increases cAMP. This inhibition enhances myocardial contractility and vasodilatation of vascular smooth muscles to increase cardiac output.14-16 The aim of this randomized controlled clinical trial was to compare the hemodynamic effects of levosimendan and milrinone in type 2 diabetic patients who developed post-CPB LOS. The study was planned for patients with preoperative depressed myocardial function who presented for elective coronary artery bypass graft (CABG) surgery with or without additional ischemic mitral valve interventions. This study also compared the postoperative diabetic control in both treatment groups.
after the diagnosis. The cardiac index and mixed venous oxygen saturation were significantly higher in the levosimendan group. The pulmonary capillary wedge pressure, systemic vascular resistance, and oxygen extraction ratios were significantly higher in the milrinone treatment group. The insulin requirements were similar for both of the treatment groups. Conclusions: Levosimendan was more efficient than milrinone for treating the hemodynamic manifestations of the postcardiopulmonary bypass low-output syndrome. However, all the values in the milrinone treatment group were normalized. In this small population, both treatment groups had similar postoperative insulin requirements. © 2006 Elsevier Inc. All rights reserved. KEY WORDS: diabetic, low ejection fraction, coronary artery bypass graft surgery, low-output syndrome, levosimendan, milrinone METHODS This prospective, randomized trial was conducted at The Chest Diseases Hospital, Safat, Kuwait, between November 2004 and September 2005. The ethics and review board at the hospital approved the study protocol, and all patients gave written informed consent. The patients were included if they satisfied the following criteria: type 2 diabetes, treated with sulfonylurea; elective CABG surgery; left ventricular ejection fraction (EF) ⱕ35% (measured by cardiac catheterization); viable myocardium (detected by nuclear perfusion scan); and manifested post-CPB LOS within the first 12 hours. LOS was defined as cardiac index (CI) ⱕ2.2 L/min/m2, pulmonary capillary wedge pressure (PCWP) ⱖ18 mmHg, mean arterial pressure (MAP) ⱖ50 mmHg, and systemic vascular resistance (SVR) ⱖ1,500 dynes/sec/ cm⫺5. Exclusion criteria were chronic obstructive lung disease, symptomatic congestive heart failure (CHF) while the patient was on bed rest, or valvular heart disease other than ischemic mitral valve regurgitation. The hemodynamic measurements included leads II and V5 on the electrocardiogram with ST-segment and arrhythmia monitoring capability, a continuous cardiac output pulmonary artery catheter (Edwards Lifesciences, Irvine, CA), and a radial artery catheter. After induction of anesthesia, a urinary bladder catheter with a temperature probe was inserted for temperature and urine-output monitoring. Intraoperative transesophageal echocardiography was used for the patients undergoing mitral valve intervention. Two hours before surgery, an equipotent dose of oral metoprolol was given for the patients who were on preoperative -blockers. Thirty minutes before the induction of anesthesia, the patients were premedicated with intramuscular scopolamine (0.4 mg) and morphine (0.1 mg/kg). Intravenous cefuroxime (1.5 g) was administered for infection
From the Departments of *Anesthesia and †Cardiothoracic Surgery, The Chest Diseases Hospital, Ministry of Health, Safat, Kuwait. Address reprint requests to Emad Al-Shawaf, FRCPC, Department of Surgery, Faculty of Medicine, PO Box 24923, Safat 13110, Kuwait. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2003-0011$32.00/0 doi:10.1053/j.jvca.2006.02.012
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prophylaxis upon arrival in the operating room. All patients were induced with midazolam (0.05 mg/kg), sufentanil (0.5 g/kg), propofol (1.0 mg/kg), and an intubating dose of rocuronium. Anesthesia was maintained with air/O2, sevoflurane, and sufentanil (infusion 0.5 g/ kg/h). At the time of aortic cannulation, the FIO2 was increased to 1.0, sevoflurane was discontinued, and a propofol infusion (5.0-7.0 mg/ kg/h) was started. The CPB flows were 2.4 L/min/m2 at a urinary bladder temperature of 34°C. Saint Thomas cardioplegic solution was delivered through the antegrade and retrograde routes (diluted with blood 1: 4) every 20 minutes. After CPB, maintenance of anesthesia was with oxygen and sevoflurane. Upon arrival in the ICU, the patient’s condition was evaluated and further sedation was administered by propofol (infusion 2-3 mg/kg/h) and intermittent boluses of morphine (2-4 mg every 30 minutes as needed). Sedation after 48 hours was conducted with a midazolam infusion (70-100 g/kg/h) and morphine infusion (20-40 g/kg/h). A hemodynamic profile (heart rate, arrhythmias, MAP, PCWP, CI, stroke volume, SVR, mixed venous oxygen saturation [SvO2], oxygen extraction ratio [O2ER]), serum creatinine, troponin I, glucose, and arterial lactate were obtained prospectively before the induction of anesthesia. Furthermore, similar hemodynamic profiles were documented before starting the bolus dose of the assigned pharmacologic treatment, 15 minutes after loading with the drug, and every 3 hours for the following 24 hours, and at the 48th hour. The other biochemical markers were serially obtained and documented every 6 hours. During and after surgery, insulin and norepinephrine infusions were administered to maintain serum glucose ⱕ8 mmol/L and MAP ⱖ70 mmHg, respectively. The norepinephrine infusion was started for hypotension with SVR ⱕ600 dynes/sec/cm⫺5. The patients who developed an LOS within 12 hours from the discontinuation of CPB were randomized by sealed envelopes to the levosimendan group or the milrinone group. The treatment goal was to achieve a MAP ⱖ70 mmHg, CI ⱖ2.4 L/min/m2, PCWP ⬍18 mmHg, and SVR ⬍1,200 dynes/sec/cm⫺5. To achieve these hemodynamic goals, the patients in the 2 treatment groups were managed as follows. A bolus of 12 g/kg of levosimendan (Simdax; Orion Corp, Espoo, Finland) was administered over 10 minutes into the central circulation and was followed by a 24-hour infusion of 0.1 to 0.2 g/kg/min. When a patient had an MAP ⱕ60 mmHg and SVR ⱕ600 dynes/sec/cm⫺5, a norepinephrine infusion was also started. An intra-aortic balloon pump (IABP) was introduced for an MAP ⱕ60 mmHg despite administering up to 0.1 g/kg/min of a norepinephrine infusion. A bolus of 50 g/kg of milrinone (Primacore; Sanofi, Paris, France) was administered over 10 minutes into the central circulation and was followed by a 24-hour infusion of 0.3 to 0.5 g/kg/min. When a patient had an MAP ⱕ60 mmHg and SVR ⱕ600 dynes/sec/cm⫺5, a norepinephrine infusion was started and an IABP was introduced for MAP ⱕ60 mmHg despite administering up to 0.1 g/kg/min of norepinephrine. Patients were withdrawn from the study when they manifested urinary bladder temperatures ⬍36.0° or ⬎37.5°C, surgical bleeding with hemoglobin of ⬍9.0 g/dL, severe arterial hypotension (MAP ⱕ60 mmHg) with SVR ⬍600 dynes/sec/cm⫺5, or persistent LOS (more than 6 hours) not responding to treatment. These patients were followed up separately just like the treatment population. The outcomes were to compare the hemodynamic and relevant biochemical profiles (SVO2, O2ER, and arterial lactate concentrations) of the 2 groups for 48 hours after starting treatment of the LOS. The study also documented the insulin requirements to maintain postoperative serum glucose ⬍8 mmol/L for both treatment groups. The continuous variables were expressed as mean ⫾ standard deviation from the mean. One-way analysis of variance was used to identify differences between the groups’ measures; a p value ⬍0.05 was considered statistically significant. The same analytic method was applied
AL-SHAWAF ET AL
Table 1. Demographic, EF, and Surgical Intervention Data on Patients in the Levosimendan and Milrinone Groups
Age (y)* Sex† Male Female EF% Grafts no.* IMR† CPB* (min) X-clamp* (min)
Levosimendan (n ⫽ 14)
Milrinone (n ⫽ 16)
60.5 ⫾ 11
58 ⫾ 10
13 1 29 ⫾ 6 3.0 ⫾ 0.8 3 115 ⫾ 42 100 ⫾ 54
15 2 31 ⫾ 6 3.1 ⫾ 0.9 3 146 ⫾ 52 120 ⫾ 34
Abbreviations: EF, left-ventricular ejection fraction %; grafts no., number of coronary artery bypass grafts; IMR, ischemic mitral ring placement; CPB, cardiopulmonary bypass time; X-clamp, aortic crossclamp time. *Values are reported as mean ⫾ SD †Values reported as number of patients.
to show the effect of each pharmacologic agent on the MAP, CI, PCWP, and SVR over time in comparison with the pretreatment values within each treatment group. When differences were found, a Tukey post hoc test was used to quantify them, and a p value ⬍0.05 was considered significant. Computerized statistical analysis was performed with SPSS 13.0 (SPSS Inc, Evanston, IL), and graphs were prepared with Sigma Plot 8 (SSPS Inc). RESULTS
From November 2004 through September 2005, 40 candidates who were treated with glibenclamide for diabetes up to the day before surgery were considered in the preoperative period. Seven patients did not manifest the LOS; 3 patients manifested postoperative hypothermia (n ⫽ 1), significant bleeding (n ⫽ 1), and persistent ST-segment elevation (n ⫽ 1) that required reinstituting CPB to implant a right coronary artery graft; these 10 patients were withdrawn from the study. The remaining 30 patients (75%) were randomized by sealed envelopes to a treatment agent when they manifested the signs of postoperative LOS and completed the study protocol with 1 fatality in each group. The demographic, preoperative EF, and surgical interventions in both of the treatment populations were comparable (Table 1). Eight patients in the levosimendan group and 10 patients in the milrinone group required loading to separate from CPB. The rest of the patients were loaded within 4 hours after CPB separation. While on the infusions and for the following 48 hours, the hemodynamic comparison (Table 2) showed that the levosimendan treatment group had higher mean CI (p ⫽ 0.01) and SVO2 (p ⬍ 0.001), with lower mean PCWP (p ⫽ 0.04) and SVR (p ⫽ 0.01) than the values in the milrinone treatment group. Norepinephrine was used in similar doses for 6 patients (42%) in the levosimendan group versus 10 patients (62%) in the milrinone group, and none of the patients needed the introduction of an IABP. The mean O2ER of the milrinone treatment group was higher than that of the levosimendan treatment group (p ⫽ 0.003). The mean arterial lactate concentrations were similar in both treatment groups. After the initiation of therapy, both treatment groups showed
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Table 2. Hemodynamic Profiles of the Levosimendan and Milrinone Groups Over the Period of Investigation
HR (beat/min) MAP (mmHg) CVP (mmHg) PCWP (mmHg) CI (L/min/m2) SV (mL/beat) SVR (dynes/sec/cm⫺5) SVO2 (%) O2 ER (%) Lactate (mmol/L) NE (g/kg) Troponin I (ng/L)
Levosimendan (n ⫽ 14)
Milrinone (n ⫽ 16)
p Value
100 ⫾ 10 76 ⫾ 9 10 ⫾ 2 13 ⫾ 3 3.5 ⫾ 0.75 65 ⫾ 17 936 ⫾ 330 73 ⫾ 6 25 ⫾ 5 1.8 ⫾ 1.2 0.009 ⫾ 0.016 3.3 ⫾ 2.7
100 ⫾ 11 76 ⫾ 9 10 ⫾ 3 14 ⫾ 3 3.3 ⫾ 0.8 62 ⫾ 19 1050 ⫾ 416 70 ⫾ 7 27 ⫾ 6 2.2 ⫾ 3 0.016 ⫾ 0.05 8.6 ⫾ 20
NS NS NS 0.04 0.01 NS 0.011 ⬍0.001 0.003 NS NS NS
NOTE. Values are reported as mean ⫾ SD Abbreviations: HR, heart rate; MAP, mean arterial pressure; CVP, central venous pressure, MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SV, stroke volume; SVR, systemic vascular resistance; SVO2, mixed venous oxygen saturation; O2 ER, oxygen extraction ratio; lactate, arterial lactate; NE, norepinephrine infusion rate; NS, not significant.
a significant increases in the mean values of MAP and CI, with decreased mean values for PCWP and SVR within the first 3 hours (Tables 3 and 4). Moreover, the hemodynamic parameters with both agents revealed a normalization over the time of the investigation (Fig 1). The comparison of mean values of the insulin infusion rates, which were needed to maintain serum glucose ⱕ8.0 mmol/L, did not show any statistical significance (3.7 ⫾ 3.2 for the levosimendan treatment group and 3.3 ⫾ 3.1 for the milrinone treatment group, p ⫽ 0.27). The number of ventilation days, myocardial injury, arrhythmias, CHF needing ventilatory support, renal dysfunction, ICU length of stay, and mortality are reported in Table 5. The ventilation days were documented when ventilatory support was discontinued after the treatment of LOS. The days started from the time of admission to the ICU; a patient was counted as having received a full-ventilation day even when he/she was ventilated for only part of that day. The ventilation time of
Table 3. Mean Hemodynamic Changes in the LevosimendanTreatment Group Over Time Compared With Pretreatment Values* t
MAP
PT 3 6 12 24 48
62 ⫾ 6 73 ⫾ 10† 75 ⫾ 9† 76 ⫾ 9† 80 ⫾ 7† 79 ⫾ 9†
CI
1.6 ⫾ 0.34 3.3 ⫾ 0.65† 3.6 ⫾ 0.8† 3.8 ⫾ 1† 3.3 ⫾ 0.65† 3.3 ⫾ 0.77†
PCWP
SVR
28 ⫾ 6 14 ⫾ 3† 14 ⫾ 4† 12 ⫾ 2† 13 ⫾ 3† 12 ⫾ 3†
1,615 ⫾ 154 948 ⫾ 265† 877 ⫾ 163† 847 ⫾ 197† 950 ⫾ 191† 1,200 ⫾ 646†
NOTE. Values are expressed as mean ⫾ SD. Abbreviations: t, time in hours after the start of the treatment; PT, pretreatment; MAP, mean arterial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SVR, systemic vascular resistance. *Number of patients ⫽ 14. †p ⬍ 0.05 compared with mean pretreatment value.
Table 4. Mean Hemodynamic Changes in the Milrinone-Treatment Group Over Time Compared With the Pretreatment Values* t
MAP
PT 3 6 12 24 48
60 ⫾ 5 76 ⫾ 9† 74 ⫾ 9† 78 ⫾ 10† 78 ⫾ 10† 80 ⫾ 10†
CI
1.61 ⫾ 0.33 2.9 ⫾ 0.74† 3.3 ⫾ 0.87† 3.6 ⫾ 0.75† 3.4 ⫾ 0.86† 3.2 ⫾ 0.84†
PCWP
SVR
33 ⫾ 4 13 ⫾ 3† 14 ⫾ 3† 13 ⫾ 2† 14 ⫾ 3† 14 ⫾ 4†
1,658 ⫾ 176 1,145 ⫾ 377† 919 ⫾ 292† 957 ⫾ 415† 990 ⫾ 416† 1,500 ⫾ 626
NOTE. Values are expressed as mean ⫾ SD. Abbreviations; t, time in hours after the start of the treatment; PT, pretreatment; MAP, mean arterial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SVR, systemic vascular resistance. *Number of patients ⫽ 16. †p ⬍ 0.05 compared with mean pretreatment value.
reintubated patients for CHF was not documented. One patient in the levosimendan treatment group and 2 patients in the milrinone treatment group required reinstitution of mechanical ventilatory support for CHF. Postoperative atrial fibrillation was the cause of arrhythmias in 6 of the 7 patients who developed postoperative arrhythmias in the levosimendan group. The seventh patient in the group developed premature ventricular contractions. In the milrinone group, atrial fibrillation was the cause of all the postoperative arrhythmias. Postoperative renal dysfunction in the study population was transient, and fluid volumes were adjusted to increase the filling pressures. However, 1 patient in the milrinone group required institution of renal replacement therapy. Five of the patients in the milrinone treatment group and 1 patient in the levosimendan group had a postoperative rise in serum troponin ⬎16 ng/L; these patients were counted as postoperative myocardial injury. DISCUSSION
In this small study, levosimendan was shown to be effective in reversing the transient ventricular dysfunction that took place after CPB. The investigation showed that levosimendan was more efficient than milrinone in reversing some of the hemodynamic manifestations of this condition. However, improvements that were sustained for 48 hours did not show clinical differences. This was shown by the arterial lactate concentrations, which were used as a biochemical marker to measure the adequacy of tissue perfusion. In comparison to the Levosimendan Infusion Versus Dobutamine Trial,17 the present investigation compared levosimendan and milrinone in type II diabetics with depressed ventricular function who were being treated for postoperative LOS. Improvements in MAP, PCWP, CI, and SVR took place within the first 3 hours with initiation of both therapies. These improvements were sustained for 48 hours despite only a 24-hour infusion period. The rise in SVR, however, noted in the milrinone treatment group could be explained by the longer half-life of levosimendan. These hemodynamic findings are in agreement with a surgical trial, which did not have a comparative arm and did not focus on the diabetic patient.5 The proposed mechanism is that KATP channel activation provides beneficial effects that work synergistically with the calcium
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Fig 1. The hemodynamic profiles of levosimendan and milrinone treatment groups over the period of the investigation (mean ⴞ standard error of the mean).
sensitization to improve myocardial performance. The peripheral vasodilatation with levosimendan reduces the afterload of the heart, which enhances cardiac output. Levosimendan’s activation of the mitoKATP channels also promotes the use of mitochondrial
Table 5. Postoperative Events
Ventilation days* Myocardial injury Arrhythmias CHF requiring ventilation Renal dysfunction ICU days* Mortality
Levosimendan (n ⫽ 14)
Milrinone (n ⫽ 16)
1.4 ⫾ 1.3 1 7 1 2 7.7 ⫾ 10.5 1
2.7 ⫾ 2.75 5 8 2 5 13 ⫾ 33 1
NOTE. Results reported as number of patients. *Results reported as mean ⫾ SD.
calcium, thus decreasing the need for extracellular calcium to increase myocardial contraction.9 These effects, along with the PDE III inhibition and fluid loading in possible combination with the norepinephrine (-agonist) infusion (42% of the levosimendan treatment group), explain the better improvements in CI, MAP, PCWP, and SVR in the levosimendan treatment group. The norepinephrine (␣-agonist) infusion also improved the MAP when used. The present results show that both treatments are efficient inodilators. There was no need to discontinue either treatment because of significant hypotension that did not respond to fluid loading and a moderate dose of norepinephrine. A study reported that a group of postacute myocardial infarction patients treated with glibenclamide manifested stressinduced myocardial dysfunction that reversed after 12 weeks of insulin treatment. The exact mechanism of this myocardial impairment was not well characterized. Therefore, replacing the sulfonylurea by insulin and tight glucose control, when the
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diabetic myocardium is at risk of undergoing prolonged ischemia, is advisable.18,19 However, because of the small study population and lack of control groups, chronic glibenclamideinduced loss of the KATP channel cardioprotective effects alone cannot explain the higher incidence of the transient postoperative myocardial dysfunction noted in this population. More importantly, the diabetic patients who have surgery in Kuwait have been noted to have a high incidence of small-caliber coronary arteries that account for longer cross-clamp and CPB times, which frequently precipitate a low-output syndrome. KATP-channel activation was also shown to decrease insulin release by the pancreatic -cells. Moreover, sulfonylurea inhibits the KATP channels in the pancreatic -cells to increase the endogenous insulin secretion.13 Therefore, in this study, it was found that the postoperative insulin requirements were the same for the drug with added KATP-channel activation (levosimendan) when used within the manufacturer’s dose recommendations. A recent review presented evidence that suggested an antiarrhythmic effect for levosimendan. The proposed mechanism was the activation of the myocardial KATP-channel, which mediated a protective role against lethal ventricular arrhythmias.20 This observation, however, was not confirmed in the present study because of the lack of statistical power; especially since atrial tachyarrhythmia was the major postoperative rhythm disturbance. The etiology of the postoperative death in
the levosimendan treatment group was sepsis-induced multiorgan failure. However, in the milrinone treatment group, the mortality was a patient who had a preoperative EF of 20%, developed severe CHF after an earlier postoperative myocardial infarction, and who progressed to multiorgan failure, needing renal replacement therapy, with death occurring on the 15th postoperative day. Therefore, the authors recommend utilization of levosimendan with post-CPB transient myocardial dysfunction, especially in high-risk patients. This study did not find a difference in the postoperative insulin requirements in either treatment group. This study has a number of limitations in addition to its small population size. These limitations include the lack of comparative control groups. Moreover, norepinephrine use as a vasopressor could have also improved the hemodynamic profiles. With the small patient population, this study was unable to show added value of KATP-channel activation in the patients with chronically inhibited myocardial KATP channels. A larger randomized controlled surgical trial is needed to overcome the shortcomings of this investigation. In addition, the short- and long-term outcomes of using either treatment in type 2 diabetic patients are needed. ACKNOWLEDGMENT The authors thank Prof Christopher H.J. Ford for his critical readings of the manuscript.
REFERENCES 1. Chernov SA: Early postoperative complications and prevention of them in ischemic heart disease patients after direct myocardial revascularization. Ter Arkh 74:45-49, 2002 2. Avery GJ , Ley SJ, Hill JD, et al: Cardiac surgery in the octogenarian: Evaluation of risk, cost and outcome. Ann Thorac Surg 71:591596, 2001 3. Nemec P, Bedanova H, Necas J, et al: Coronary artery bypass grafting in patients with left ventricular ejection fraction of 30% or less. Bratisl Lek Listy 102:15-21, 2001 4. Liu L, Gropper M: Respiratory and hemodynamic management after cardiac surgery. Curr Treat Options Cardiovasc Med 4:161-169, 2002 5. Labriola C, Siro-Brigiani M, Carrata F, et al: Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. Int J Clin Pharmacol Ther 42:204-211, 2004 6. Jamali IN, Kersten JR, Page PS: Intracoronary levosimendan enhances contractile function of the stunned myocardium. Anesth Analg 85:23-29, 1997 7. Inoue I, Nagase H, Kishi K, et al: ATP-sensitive K⫹ channel in the mitochondrial inner membrane. Nature 352:244-247, 1991 8. Yokoshiki H, Sunagawa M, Seki T, et al: ATP-sensitive K⫹ channels in pancreatic, cardiac, and vascular smooth muscle cells. Am J Physiol 274:C25-C37, 1998 9. McBride BF, White CM: Levosimendan: Implications for clinicians. J Clin Pharmacol 43:1071-1081, 2003 10. Ajiro Y, Hagiwara N, Katsube Y, et al: Levosimendan increases L-type calcium current via phosphodiesterase III inhibition in human cardiac myocytes. Eur J Pharmacol 435:27-33, 2002 11. Bowman P, Haikala H, Paul RJ: Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth
muscle through calcium desensitization. J Pharmacol Exp Ther 288:316-325, 1999 12. Kersten JR, Montgomery MW, Ghassemi T, et al: Diabetes and hyperglycemia impair activation of mitochondrial K(ATP) channels. Am J Physiol Heart Circ Physiol 280:H1744-H1750, 2001 13. Panten U, Schwanstecher M, Schwanstecher C: Pancreatic and extrapancreatic sulfonylurea receptors. Horm Metab Res 24:549-554, 1992 14. Honerjäger P: Pharmacology of bipyridine phosphodiesterase III inhibitors. Am Heart J 121:1939-1944, 1991 15. Skoyles JR, Sherry KM: Pharmacology, mechanisms of action and uses of selective phosphodiesterase inhibitors. Br J Anaesth 68: 293-302, 1992 16. Wright EM, Skoyles J, Sherry KM: Milrinone in the treatment of low-output states following cardiac surgery. Eur J Anaesthesiol Suppl 5:21-26, 1992 17. Follath F, Cleland J, Just H, et al: Efficacy and safety of intravenous levosimendan compared with dobutamine in severe lowoutput heart failure (the LIDO study): A randomised double-blind trial. Lancet 360:196-202, 2002 18. Scognamiglio R, Avogaro A, Vigili de Kreutzenberg S, et al: Effects of treatment with sulfonylurea drugs or insulin on ischemiainduced myocardial dysfunction in type 2 diabetes. Diabetes 51:808812, 2002 19. Meier JJ, Gallwitz B, Schmidt WE, et al: Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important? Heart 90:9-12, 2004 20. Polleselloa P, Mebazaab A: ATP-dependent potassium channels as a key target for the treatment of myocardial and vascular dysfunction. Curr Opin Crit Care 10:436-441, 2004
T
HE INCIDENCE OF a low-output syndrome (LOS) after cardiac surgery with cardiopulmonary bypass (CPB) in patients with depressed ventricular function is approximately 30%.1 This condition causes delayed recovery, organ failure, prolonged intensive care unit (ICU) stays, and increased hospital costs.2 In addition, in patients with a depressed ventricle, the LOS adds to the risk of early postoperative mortality.3 To prevent or decrease these adverse outcomes, post-CPB LOS should be reversed whenever possible. The treatment of the syndrome requires optimization of myocardial contractility and loading conditions, which are achieved by instituting appropriate pharmacologic and fluid management plans.4 The myofilament calcium sensitizer levosimendan has been used successfully as a pharmacologic treatment for post-CPB LOS because it is an inotropic drug that enhances myocardial contractility in the stunned myocardium.5,6 Adenosine triphosphate– dependent potassium (KATP) channels are located on the sarcolemmal and inner mitochondrial membranes in the myocardial and vascular smooth muscles, and -cells of the pancreas.7,8 Levosimendan opens KATP channels and inhibits phosphodiesterase III (PDE III) without increasing the intracellular levels of cyclic adenosine monophosphate (cAMP).9-11 PDE III induces breakdown of cAMP. Diabetes, hyperglycemia, and oral hypoglycemic agents (sulfonylurea) impair the activation of KATP channels in cardiac myocytes and pancreatic -cells.12,13 Another pharmacologic agent used in the treatment of post-CPB LOS is milrinone, which is a PDE III inhibitor that increases cAMP. This inhibition enhances myocardial contractility and vasodilatation of vascular smooth muscles to increase cardiac output.14-16 The aim of this randomized controlled clinical trial was to compare the hemodynamic effects of levosimendan and milrinone in type 2 diabetic patients who developed post-CPB LOS. The study was planned for patients with preoperative depressed myocardial function who presented for elective coronary artery bypass graft (CABG) surgery with or without additional ischemic mitral valve interventions. This study also compared the postoperative diabetic control in both treatment groups.
after the diagnosis. The cardiac index and mixed venous oxygen saturation were significantly higher in the levosimendan group. The pulmonary capillary wedge pressure, systemic vascular resistance, and oxygen extraction ratios were significantly higher in the milrinone treatment group. The insulin requirements were similar for both of the treatment groups. Conclusions: Levosimendan was more efficient than milrinone for treating the hemodynamic manifestations of the postcardiopulmonary bypass low-output syndrome. However, all the values in the milrinone treatment group were normalized. In this small population, both treatment groups had similar postoperative insulin requirements. © 2006 Elsevier Inc. All rights reserved. KEY WORDS: diabetic, low ejection fraction, coronary artery bypass graft surgery, low-output syndrome, levosimendan, milrinone METHODS This prospective, randomized trial was conducted at The Chest Diseases Hospital, Safat, Kuwait, between November 2004 and September 2005. The ethics and review board at the hospital approved the study protocol, and all patients gave written informed consent. The patients were included if they satisfied the following criteria: type 2 diabetes, treated with sulfonylurea; elective CABG surgery; left ventricular ejection fraction (EF) ⱕ35% (measured by cardiac catheterization); viable myocardium (detected by nuclear perfusion scan); and manifested post-CPB LOS within the first 12 hours. LOS was defined as cardiac index (CI) ⱕ2.2 L/min/m2, pulmonary capillary wedge pressure (PCWP) ⱖ18 mmHg, mean arterial pressure (MAP) ⱖ50 mmHg, and systemic vascular resistance (SVR) ⱖ1,500 dynes/sec/ cm⫺5. Exclusion criteria were chronic obstructive lung disease, symptomatic congestive heart failure (CHF) while the patient was on bed rest, or valvular heart disease other than ischemic mitral valve regurgitation. The hemodynamic measurements included leads II and V5 on the electrocardiogram with ST-segment and arrhythmia monitoring capability, a continuous cardiac output pulmonary artery catheter (Edwards Lifesciences, Irvine, CA), and a radial artery catheter. After induction of anesthesia, a urinary bladder catheter with a temperature probe was inserted for temperature and urine-output monitoring. Intraoperative transesophageal echocardiography was used for the patients undergoing mitral valve intervention. Two hours before surgery, an equipotent dose of oral metoprolol was given for the patients who were on preoperative -blockers. Thirty minutes before the induction of anesthesia, the patients were premedicated with intramuscular scopolamine (0.4 mg) and morphine (0.1 mg/kg). Intravenous cefuroxime (1.5 g) was administered for infection
From the Departments of *Anesthesia and †Cardiothoracic Surgery, The Chest Diseases Hospital, Ministry of Health, Safat, Kuwait. Address reprint requests to Emad Al-Shawaf, FRCPC, Department of Surgery, Faculty of Medicine, PO Box 24923, Safat 13110, Kuwait. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2003-0011$32.00/0 doi:10.1053/j.jvca.2006.02.012
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prophylaxis upon arrival in the operating room. All patients were induced with midazolam (0.05 mg/kg), sufentanil (0.5 g/kg), propofol (1.0 mg/kg), and an intubating dose of rocuronium. Anesthesia was maintained with air/O2, sevoflurane, and sufentanil (infusion 0.5 g/ kg/h). At the time of aortic cannulation, the FIO2 was increased to 1.0, sevoflurane was discontinued, and a propofol infusion (5.0-7.0 mg/ kg/h) was started. The CPB flows were 2.4 L/min/m2 at a urinary bladder temperature of 34°C. Saint Thomas cardioplegic solution was delivered through the antegrade and retrograde routes (diluted with blood 1: 4) every 20 minutes. After CPB, maintenance of anesthesia was with oxygen and sevoflurane. Upon arrival in the ICU, the patient’s condition was evaluated and further sedation was administered by propofol (infusion 2-3 mg/kg/h) and intermittent boluses of morphine (2-4 mg every 30 minutes as needed). Sedation after 48 hours was conducted with a midazolam infusion (70-100 g/kg/h) and morphine infusion (20-40 g/kg/h). A hemodynamic profile (heart rate, arrhythmias, MAP, PCWP, CI, stroke volume, SVR, mixed venous oxygen saturation [SvO2], oxygen extraction ratio [O2ER]), serum creatinine, troponin I, glucose, and arterial lactate were obtained prospectively before the induction of anesthesia. Furthermore, similar hemodynamic profiles were documented before starting the bolus dose of the assigned pharmacologic treatment, 15 minutes after loading with the drug, and every 3 hours for the following 24 hours, and at the 48th hour. The other biochemical markers were serially obtained and documented every 6 hours. During and after surgery, insulin and norepinephrine infusions were administered to maintain serum glucose ⱕ8 mmol/L and MAP ⱖ70 mmHg, respectively. The norepinephrine infusion was started for hypotension with SVR ⱕ600 dynes/sec/cm⫺5. The patients who developed an LOS within 12 hours from the discontinuation of CPB were randomized by sealed envelopes to the levosimendan group or the milrinone group. The treatment goal was to achieve a MAP ⱖ70 mmHg, CI ⱖ2.4 L/min/m2, PCWP ⬍18 mmHg, and SVR ⬍1,200 dynes/sec/cm⫺5. To achieve these hemodynamic goals, the patients in the 2 treatment groups were managed as follows. A bolus of 12 g/kg of levosimendan (Simdax; Orion Corp, Espoo, Finland) was administered over 10 minutes into the central circulation and was followed by a 24-hour infusion of 0.1 to 0.2 g/kg/min. When a patient had an MAP ⱕ60 mmHg and SVR ⱕ600 dynes/sec/cm⫺5, a norepinephrine infusion was also started. An intra-aortic balloon pump (IABP) was introduced for an MAP ⱕ60 mmHg despite administering up to 0.1 g/kg/min of a norepinephrine infusion. A bolus of 50 g/kg of milrinone (Primacore; Sanofi, Paris, France) was administered over 10 minutes into the central circulation and was followed by a 24-hour infusion of 0.3 to 0.5 g/kg/min. When a patient had an MAP ⱕ60 mmHg and SVR ⱕ600 dynes/sec/cm⫺5, a norepinephrine infusion was started and an IABP was introduced for MAP ⱕ60 mmHg despite administering up to 0.1 g/kg/min of norepinephrine. Patients were withdrawn from the study when they manifested urinary bladder temperatures ⬍36.0° or ⬎37.5°C, surgical bleeding with hemoglobin of ⬍9.0 g/dL, severe arterial hypotension (MAP ⱕ60 mmHg) with SVR ⬍600 dynes/sec/cm⫺5, or persistent LOS (more than 6 hours) not responding to treatment. These patients were followed up separately just like the treatment population. The outcomes were to compare the hemodynamic and relevant biochemical profiles (SVO2, O2ER, and arterial lactate concentrations) of the 2 groups for 48 hours after starting treatment of the LOS. The study also documented the insulin requirements to maintain postoperative serum glucose ⬍8 mmol/L for both treatment groups. The continuous variables were expressed as mean ⫾ standard deviation from the mean. One-way analysis of variance was used to identify differences between the groups’ measures; a p value ⬍0.05 was considered statistically significant. The same analytic method was applied
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Table 1. Demographic, EF, and Surgical Intervention Data on Patients in the Levosimendan and Milrinone Groups
Age (y)* Sex† Male Female EF% Grafts no.* IMR† CPB* (min) X-clamp* (min)
Levosimendan (n ⫽ 14)
Milrinone (n ⫽ 16)
60.5 ⫾ 11
58 ⫾ 10
13 1 29 ⫾ 6 3.0 ⫾ 0.8 3 115 ⫾ 42 100 ⫾ 54
15 2 31 ⫾ 6 3.1 ⫾ 0.9 3 146 ⫾ 52 120 ⫾ 34
Abbreviations: EF, left-ventricular ejection fraction %; grafts no., number of coronary artery bypass grafts; IMR, ischemic mitral ring placement; CPB, cardiopulmonary bypass time; X-clamp, aortic crossclamp time. *Values are reported as mean ⫾ SD †Values reported as number of patients.
to show the effect of each pharmacologic agent on the MAP, CI, PCWP, and SVR over time in comparison with the pretreatment values within each treatment group. When differences were found, a Tukey post hoc test was used to quantify them, and a p value ⬍0.05 was considered significant. Computerized statistical analysis was performed with SPSS 13.0 (SPSS Inc, Evanston, IL), and graphs were prepared with Sigma Plot 8 (SSPS Inc). RESULTS
From November 2004 through September 2005, 40 candidates who were treated with glibenclamide for diabetes up to the day before surgery were considered in the preoperative period. Seven patients did not manifest the LOS; 3 patients manifested postoperative hypothermia (n ⫽ 1), significant bleeding (n ⫽ 1), and persistent ST-segment elevation (n ⫽ 1) that required reinstituting CPB to implant a right coronary artery graft; these 10 patients were withdrawn from the study. The remaining 30 patients (75%) were randomized by sealed envelopes to a treatment agent when they manifested the signs of postoperative LOS and completed the study protocol with 1 fatality in each group. The demographic, preoperative EF, and surgical interventions in both of the treatment populations were comparable (Table 1). Eight patients in the levosimendan group and 10 patients in the milrinone group required loading to separate from CPB. The rest of the patients were loaded within 4 hours after CPB separation. While on the infusions and for the following 48 hours, the hemodynamic comparison (Table 2) showed that the levosimendan treatment group had higher mean CI (p ⫽ 0.01) and SVO2 (p ⬍ 0.001), with lower mean PCWP (p ⫽ 0.04) and SVR (p ⫽ 0.01) than the values in the milrinone treatment group. Norepinephrine was used in similar doses for 6 patients (42%) in the levosimendan group versus 10 patients (62%) in the milrinone group, and none of the patients needed the introduction of an IABP. The mean O2ER of the milrinone treatment group was higher than that of the levosimendan treatment group (p ⫽ 0.003). The mean arterial lactate concentrations were similar in both treatment groups. After the initiation of therapy, both treatment groups showed
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Table 2. Hemodynamic Profiles of the Levosimendan and Milrinone Groups Over the Period of Investigation
HR (beat/min) MAP (mmHg) CVP (mmHg) PCWP (mmHg) CI (L/min/m2) SV (mL/beat) SVR (dynes/sec/cm⫺5) SVO2 (%) O2 ER (%) Lactate (mmol/L) NE (g/kg) Troponin I (ng/L)
Levosimendan (n ⫽ 14)
Milrinone (n ⫽ 16)
p Value
100 ⫾ 10 76 ⫾ 9 10 ⫾ 2 13 ⫾ 3 3.5 ⫾ 0.75 65 ⫾ 17 936 ⫾ 330 73 ⫾ 6 25 ⫾ 5 1.8 ⫾ 1.2 0.009 ⫾ 0.016 3.3 ⫾ 2.7
100 ⫾ 11 76 ⫾ 9 10 ⫾ 3 14 ⫾ 3 3.3 ⫾ 0.8 62 ⫾ 19 1050 ⫾ 416 70 ⫾ 7 27 ⫾ 6 2.2 ⫾ 3 0.016 ⫾ 0.05 8.6 ⫾ 20
NS NS NS 0.04 0.01 NS 0.011 ⬍0.001 0.003 NS NS NS
NOTE. Values are reported as mean ⫾ SD Abbreviations: HR, heart rate; MAP, mean arterial pressure; CVP, central venous pressure, MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SV, stroke volume; SVR, systemic vascular resistance; SVO2, mixed venous oxygen saturation; O2 ER, oxygen extraction ratio; lactate, arterial lactate; NE, norepinephrine infusion rate; NS, not significant.
a significant increases in the mean values of MAP and CI, with decreased mean values for PCWP and SVR within the first 3 hours (Tables 3 and 4). Moreover, the hemodynamic parameters with both agents revealed a normalization over the time of the investigation (Fig 1). The comparison of mean values of the insulin infusion rates, which were needed to maintain serum glucose ⱕ8.0 mmol/L, did not show any statistical significance (3.7 ⫾ 3.2 for the levosimendan treatment group and 3.3 ⫾ 3.1 for the milrinone treatment group, p ⫽ 0.27). The number of ventilation days, myocardial injury, arrhythmias, CHF needing ventilatory support, renal dysfunction, ICU length of stay, and mortality are reported in Table 5. The ventilation days were documented when ventilatory support was discontinued after the treatment of LOS. The days started from the time of admission to the ICU; a patient was counted as having received a full-ventilation day even when he/she was ventilated for only part of that day. The ventilation time of
Table 3. Mean Hemodynamic Changes in the LevosimendanTreatment Group Over Time Compared With Pretreatment Values* t
MAP
PT 3 6 12 24 48
62 ⫾ 6 73 ⫾ 10† 75 ⫾ 9† 76 ⫾ 9† 80 ⫾ 7† 79 ⫾ 9†
CI
1.6 ⫾ 0.34 3.3 ⫾ 0.65† 3.6 ⫾ 0.8† 3.8 ⫾ 1† 3.3 ⫾ 0.65† 3.3 ⫾ 0.77†
PCWP
SVR
28 ⫾ 6 14 ⫾ 3† 14 ⫾ 4† 12 ⫾ 2† 13 ⫾ 3† 12 ⫾ 3†
1,615 ⫾ 154 948 ⫾ 265† 877 ⫾ 163† 847 ⫾ 197† 950 ⫾ 191† 1,200 ⫾ 646†
NOTE. Values are expressed as mean ⫾ SD. Abbreviations: t, time in hours after the start of the treatment; PT, pretreatment; MAP, mean arterial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SVR, systemic vascular resistance. *Number of patients ⫽ 14. †p ⬍ 0.05 compared with mean pretreatment value.
Table 4. Mean Hemodynamic Changes in the Milrinone-Treatment Group Over Time Compared With the Pretreatment Values* t
MAP
PT 3 6 12 24 48
60 ⫾ 5 76 ⫾ 9† 74 ⫾ 9† 78 ⫾ 10† 78 ⫾ 10† 80 ⫾ 10†
CI
1.61 ⫾ 0.33 2.9 ⫾ 0.74† 3.3 ⫾ 0.87† 3.6 ⫾ 0.75† 3.4 ⫾ 0.86† 3.2 ⫾ 0.84†
PCWP
SVR
33 ⫾ 4 13 ⫾ 3† 14 ⫾ 3† 13 ⫾ 2† 14 ⫾ 3† 14 ⫾ 4†
1,658 ⫾ 176 1,145 ⫾ 377† 919 ⫾ 292† 957 ⫾ 415† 990 ⫾ 416† 1,500 ⫾ 626
NOTE. Values are expressed as mean ⫾ SD. Abbreviations; t, time in hours after the start of the treatment; PT, pretreatment; MAP, mean arterial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; SVR, systemic vascular resistance. *Number of patients ⫽ 16. †p ⬍ 0.05 compared with mean pretreatment value.
reintubated patients for CHF was not documented. One patient in the levosimendan treatment group and 2 patients in the milrinone treatment group required reinstitution of mechanical ventilatory support for CHF. Postoperative atrial fibrillation was the cause of arrhythmias in 6 of the 7 patients who developed postoperative arrhythmias in the levosimendan group. The seventh patient in the group developed premature ventricular contractions. In the milrinone group, atrial fibrillation was the cause of all the postoperative arrhythmias. Postoperative renal dysfunction in the study population was transient, and fluid volumes were adjusted to increase the filling pressures. However, 1 patient in the milrinone group required institution of renal replacement therapy. Five of the patients in the milrinone treatment group and 1 patient in the levosimendan group had a postoperative rise in serum troponin ⬎16 ng/L; these patients were counted as postoperative myocardial injury. DISCUSSION
In this small study, levosimendan was shown to be effective in reversing the transient ventricular dysfunction that took place after CPB. The investigation showed that levosimendan was more efficient than milrinone in reversing some of the hemodynamic manifestations of this condition. However, improvements that were sustained for 48 hours did not show clinical differences. This was shown by the arterial lactate concentrations, which were used as a biochemical marker to measure the adequacy of tissue perfusion. In comparison to the Levosimendan Infusion Versus Dobutamine Trial,17 the present investigation compared levosimendan and milrinone in type II diabetics with depressed ventricular function who were being treated for postoperative LOS. Improvements in MAP, PCWP, CI, and SVR took place within the first 3 hours with initiation of both therapies. These improvements were sustained for 48 hours despite only a 24-hour infusion period. The rise in SVR, however, noted in the milrinone treatment group could be explained by the longer half-life of levosimendan. These hemodynamic findings are in agreement with a surgical trial, which did not have a comparative arm and did not focus on the diabetic patient.5 The proposed mechanism is that KATP channel activation provides beneficial effects that work synergistically with the calcium
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Fig 1. The hemodynamic profiles of levosimendan and milrinone treatment groups over the period of the investigation (mean ⴞ standard error of the mean).
sensitization to improve myocardial performance. The peripheral vasodilatation with levosimendan reduces the afterload of the heart, which enhances cardiac output. Levosimendan’s activation of the mitoKATP channels also promotes the use of mitochondrial
Table 5. Postoperative Events
Ventilation days* Myocardial injury Arrhythmias CHF requiring ventilation Renal dysfunction ICU days* Mortality
Levosimendan (n ⫽ 14)
Milrinone (n ⫽ 16)
1.4 ⫾ 1.3 1 7 1 2 7.7 ⫾ 10.5 1
2.7 ⫾ 2.75 5 8 2 5 13 ⫾ 33 1
NOTE. Results reported as number of patients. *Results reported as mean ⫾ SD.
calcium, thus decreasing the need for extracellular calcium to increase myocardial contraction.9 These effects, along with the PDE III inhibition and fluid loading in possible combination with the norepinephrine (-agonist) infusion (42% of the levosimendan treatment group), explain the better improvements in CI, MAP, PCWP, and SVR in the levosimendan treatment group. The norepinephrine (␣-agonist) infusion also improved the MAP when used. The present results show that both treatments are efficient inodilators. There was no need to discontinue either treatment because of significant hypotension that did not respond to fluid loading and a moderate dose of norepinephrine. A study reported that a group of postacute myocardial infarction patients treated with glibenclamide manifested stressinduced myocardial dysfunction that reversed after 12 weeks of insulin treatment. The exact mechanism of this myocardial impairment was not well characterized. Therefore, replacing the sulfonylurea by insulin and tight glucose control, when the
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diabetic myocardium is at risk of undergoing prolonged ischemia, is advisable.18,19 However, because of the small study population and lack of control groups, chronic glibenclamideinduced loss of the KATP channel cardioprotective effects alone cannot explain the higher incidence of the transient postoperative myocardial dysfunction noted in this population. More importantly, the diabetic patients who have surgery in Kuwait have been noted to have a high incidence of small-caliber coronary arteries that account for longer cross-clamp and CPB times, which frequently precipitate a low-output syndrome. KATP-channel activation was also shown to decrease insulin release by the pancreatic -cells. Moreover, sulfonylurea inhibits the KATP channels in the pancreatic -cells to increase the endogenous insulin secretion.13 Therefore, in this study, it was found that the postoperative insulin requirements were the same for the drug with added KATP-channel activation (levosimendan) when used within the manufacturer’s dose recommendations. A recent review presented evidence that suggested an antiarrhythmic effect for levosimendan. The proposed mechanism was the activation of the myocardial KATP-channel, which mediated a protective role against lethal ventricular arrhythmias.20 This observation, however, was not confirmed in the present study because of the lack of statistical power; especially since atrial tachyarrhythmia was the major postoperative rhythm disturbance. The etiology of the postoperative death in
the levosimendan treatment group was sepsis-induced multiorgan failure. However, in the milrinone treatment group, the mortality was a patient who had a preoperative EF of 20%, developed severe CHF after an earlier postoperative myocardial infarction, and who progressed to multiorgan failure, needing renal replacement therapy, with death occurring on the 15th postoperative day. Therefore, the authors recommend utilization of levosimendan with post-CPB transient myocardial dysfunction, especially in high-risk patients. This study did not find a difference in the postoperative insulin requirements in either treatment group. This study has a number of limitations in addition to its small population size. These limitations include the lack of comparative control groups. Moreover, norepinephrine use as a vasopressor could have also improved the hemodynamic profiles. With the small patient population, this study was unable to show added value of KATP-channel activation in the patients with chronically inhibited myocardial KATP channels. A larger randomized controlled surgical trial is needed to overcome the shortcomings of this investigation. In addition, the short- and long-term outcomes of using either treatment in type 2 diabetic patients are needed. ACKNOWLEDGMENT The authors thank Prof Christopher H.J. Ford for his critical readings of the manuscript.
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