REVIEW ARTICLE

William C. Oliver, Jr, MD Paul G. Barash, MD Section Editors

Levosimendan Versus an Intra-aortic Balloon Pump in Adult Cardiac Surgery Patients With Low Cardiac Output
Maqsood M. Elahi, FRCS CTh, PhD,* Jimmy Lam, MBBS, Sanjay Asopa, MRCS, PhD, and Bashir M. Matata, FRSMed, PhD NCREASINGLY, patients with high perioperative risk and decreased left ventricular (LV) function are referred for cardiac surgery. The exposure of these patients hearts to ischemia during surgery leads to the onset of postischemic dysfunction.1 Acute derangement of contractile function of ischemic myocardium (myocardial stunning) because of ischemia/reperfusion (IR) injury consists of several mechanisms. Evidence suggests that hypercontracture occurs during reperfusion and that this is induced by high cytosolic Ca2 levels or by low ATP concentrations.2 On the other hand, the intensity of free radical generation during reperfusion and hence the resultant reperfusion injury are known to be proportional to the severity of the antecedent ischemia.3 If myocardial stunning is severe, it can be reversed with several inotropic agents (eg, dobutamine, epinephrine, phosphodiesterase III inhibitors, and calcium chloride) and/or with the use of an intra-aortic balloon pump (IABP). Classic inotropes seemingly improve clinical symptoms and hemodynamics. However, they are associated with adverse reactions and increased long-term mortality. Catecholamines such as epinephrine induce Ca2 overload in cardiomyocytes. This, together with the desired positive inotropic effect, induce several deleterious effects like arrhythmias, cell death, and both systolic/diastolic dysfunction. Another deleterious effect is the impaired relation between cardiac function and oxygen consumption termed catecholamine oxygen wasting.4 These agents sensitize troponin C to calcium in a manner dependent on calcium concentration, thereby increasing the effects of calcium on cardiac myolaments during systole and improving contraction at low energy cost. Calcium sensitizers, like levosimendan, on the other hand, have an inotropic effect through a different mechanism. In contrast to epinephrine, levosimendan does not cause diastolic Ca2 overload or impairment of myocardial relaxation and increased energy expenditure. Levosimendan reduces the calcium-binding coefcient of troponin C by stabilizing the conformational shape of the protein in its active form.5 This enhances myocardial contraction similar to traditional agents but with lower intracellular calcium concentration requirements. Even though levosimendan does not enhance intracellular calcium, there is a concentration-response relationship between intracellular calcium and inotropy.5 Furthermore, levosimendan induces vasodilatation through opening potassium ATP (KATP)

channels.6 The opening of potassium ATP (KATP) channels produces myocytes mitochondrial activation5 and work synergistically with calcium sensitization to improve myocardial performance. The mechanism for these improvement effects (lusitropic effects) are attributed to phosphodiesterase III (PD III) inhibition.7 PD III inhibition leads to increased cyclic adenosine monophosphate (cAMP) levels and enhanced removal of cytosolic calcium by the sarcoplasmic-endoplasmic reticulum ATPase pump, resulting in accelerated relaxation of the myolaments.7 Levosimendan is administered in the advanced state of cardiac insufciency. During such a state, when there is evidence of catecholamine resistance, Ca2 sensitizers are likely to exert additional benecial effects. On the other hand, the IABP has a well-established place in the algorithms for managing low cardiac output (CO) after surgery. The device acts to increase diastolic blood pressure and therefore coronary perfusion, while reducing afterload, thus increasing stroke volume and CO.8 The Benchmark Registry9 describing the current practice in the use of the IABP suggests that of 16,909 uses between 1996 and 2000, 13% were in high-risk patients undergoing surgical coronary revascularization. A further retrospective analysis from the Benchmark Registry, in which outcomes from US and non-US centers were compared, advocates the early deployment of the IABP.10 There is some evidence from randomized and nonrandomized studies supporting the prophylactic use of the IABP in certain cardiac surgery patients. Based on the recent upsurge in referral of high perioperative

From the *Wessex Cardiothoracic Centre, University of Southampton, Southampton General Hospital, Southampton, United Kingdom; Department of Cardiothoracic Surgery, St Vincents Hospital, Melbourne, Victoria, Australia; Cardiothoracic Surgery, South Tees Hospital NHS Trust, Middlesbrough, United Kingdom; and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom. Address reprint requests to Maqsood M. Elahi, FRCS CTh, PhD, Wessex Cardiothoracic Centre, University of Southampton, Southampton General Hospital, Southampton, UK. E-mail: manzoor_elahi@ hotmail.com 2011 Elsevier Inc. All rights reserved. 1053-0770/xx0x-0001$36.00/0 doi:10.1053/j.jvca.2011.01.001 Key words: low cardiac output, levosimendan, intra-aortic balloon pump
1

Journal of Cardiothoracic and Vascular Anesthesia, Vol xx, No x (Month), 2011: pp xxx

ELAHI ET AL

risk patients with compromised LV function for cardiac surgery, it is important to establish which of the 2 therapies (levosimendan or IABP) is more efcient in low CO syndrome (LCOS). Levosimendan and IABP both have different mechanisms of action/pathways to help improve myocardial contractility and CO. In the authors view, the key aims were to review the literature in order to determine whether mechanisms of action for each of the 2 therapies were known, the role each plays in cardiac surgery, their side effects, and whether there is evidence to suggest 1 modality of treatment is superior to the other.
MECHANISM OF ACTION AND PHARMACOLOGIC EFFECTS OF LEVOSIMENDAN

Traditionally, patients who developed LCOS after cardiac surgery would be started on a cocktail of catecholamines (such as dobutamine, norepinephrine, epinephrine, and dopamine) for cardiovascular support.11,12 Similarly, PD III inhibitors amrinone, milrinone, and enoximone also have been used as post cardiac surgery inotropic agents.13-16 The mechanism that accounts for myocardial -adrenergic-receptor downregulation in heart failure is not entirely clear, but presumably it is related in some way to exposure to increased levels of catecholamines that increase heart rate, myocardial oxygen consumption, systemic afterload, and the risk of cardiac arrhythmias.17 It is suggested that a decrease in -receptor density leads to subsensitivity of the -adrenergic pathway and myocardial contractile protein levels in failing human hearts.18 There are also concerns that PD III inhibitors may cause an increase in mortality rate compared with placebo in patients suffering from chronic heart failure, possibly because of the detrimental effects of raised intracellular calcium levels, and elevated neurohormonal levels in the failing myocardium.19,20 It is in this setting that interest has been generated regarding newer pharmacologic agents such as levosimendan that can give cardiovascular support. Levosimendan is a pyridazinone-dinitrite calcium sensitizer. Most agents currently used for inotropic support do so by increasing myocardial concentrations of cAMP, which causes upregulation in the activity of protein kinase C, which, in turn, increases calcium inux into cardiomyocytes during cardiac contraction, causing the positive inotropic effect.21 As discussed previously, examples of such agents are catecholamines (eg, dobutamine) that stimulate 1adrenoceptors on myocardial cells and increase cAMP and phosphodiesterase inhibitors such as milrinone, which prevent the breakdown of cAMP. In contrast, levosimendan works via the following 3 main processes. 1. It decreases the calcium binding coefcient of troponin C through stabilizing the conformational shape of troponin C in its active form, thereby enhancing myocardial contraction but with lower intracellular calcium concentrations.21 2. It opens KATP channels.22-26 The opening of these channels by ATP produces vasodilation in both the peripheries and in the main coronary arteries as well as myocytes mitochondrial activation.21 3. It exhibits some phosphodiesterase activity and inhibits PD III at higher concentrations.23 The inhibition of PD

III elevates cAMP, resulting in increased phosphorylation of phospholamban. This enhances removal of cytosolic calcium by the sarcoplasmic reticulum ATPase pump and accelerates myolament relaxation.23 Although levosimendan is a potent and selective inhibitor of PD III, it is reported that at low doses, its action does not contribute to its inotropic and vasodilatory effects because of the reduction in intracellular levels of cAMP.27,28 LV diastolic function plays an important role in myocardial performance. Events that occur during diastole are crucial to effective systolic function; defects in lusitropy (the ability of the myocytes to relax) are implicated as an early sign of the development of congestive heart failure. The lusitropic state is inuenced by both biochemical and biomechanical events (active relaxation) in addition to the biophysical properties of the heart (passive stiffness). At therapeutic doses, levosimendan increases cardiac contractility without increasing myocardial oxygen demands22,23 and also does not impair lusitropy.21 It signicantly increases CO, and in the setting of heart failure, it also decreases ventricular lling pressures and pulmonary vascular resistance.29,30 In 2 different studies, the impact of levosimendan on the right ventricular performance with intractable cardiogenic shock after myocardial infarction was reported to be associated with a signicant increase in cardiac index (CI) and right ventricular cardiac power index, with a signicant drop in pulmonary vascular resistance. The observed hemodynamic improvement was sustained after the levosimendan infusion was stopped. When levosimendan was compared with catecholamines in patients with cardiogenic shock after myocardial infarction, the results suggested the addition of levosimendan produced a signicant improvement in cardiovascular hemodynamics without leading to hypotension.31,32 The most common adverse effect encountered in healthy volunteers is headache (40% of subjects taking oral levosimendan reported this and 10% of subjects on the intravascular dosing route). This effect does not correlate well with the total daily dose taken.33 Other adverse effects are associated with the vasodilatory effects such as nausea, palpitations, and dizziness.33 Higher doses of levosimendan ( 2-mg dose daily) decrease arterial pressure, systemic vascular resistance (SVR), and ventricular lling pressures,34 and this may result in the need for vasoactive drugs to support the blood pressure; this point is of particular signicance in the postcardiac surgical patient.
MECHANISM OF ACTION OF THE IABP

The IABP is usually the rst mechanical device used in perioperative cardiac failure.35 Stanley Sarnoff (Boston, MA)36 in the 1950s showed that (1) most of myocardial oxygen consumption is proportional to the pressure generated by the left ventricle in systole, (2) myocardial oxygen supply is during diastole when coronary blood ow is greatest, and (3) coronary perfusion is proportional to the difference in pressure between the aorta and coronary arteries during diastole. The benecial effects of the IABP are based on altering these dynamics in which counterpulsation augments arterial diastolic pressures, improving diastolic coronary perfusion, enhancing subendocardial perfusion, and decreasing ventricular afterload.37 The rst

LEVOSIMENDAN V IABP FOR LOW CARDIAC OUTPUT

intra-aortic device consisting of a balloon mounted on a catheter that inated during LV diastole and deated during systole was developed by Moulopoulos et al38 in 1962. Shortly after, in 1968, Kantrowitz et al39 reported the rst clinical use of this device. The IABP is comprised of the balloon catheter and the console that delivers the gas to the balloon and regulates the frequency and timing of balloon ination. The inner lumen of the catheter is used to monitor systemic arterial pressure, whereas the outer lumen delivers gas to and from the balloon. Helium usually is used because its low density facilitates rapid transmission of the gas from the console to the balloon. Most balloon catheters are inserted percutaneously using the Seldinger technique (sheathless method). The femoral artery is the usual site of access although the brachial artery also is possible.40 The balloon size is dependent on patient height, with the commonly used sizes ranging from a double-lumen 8F to a 9.5F catheter with a 25- to 50-mL balloon. Once vascular access is gained, the IABP usually is advanced under uoroscopic guidance and placed so that the tip is 2 to 3 cm distal to the left subclavian artery; the inated balloon diameter should not exceed 80% to 90% of the intra-aortic diameter. It should be noted that the use of the IABP is contraindicated in patients with aortic valvular insufciency, aortic dissection, or severe peripheral vascular disease. The timing of the IABP ination and deation is critical in order to maximize efcacy of the device. Accordingly, the console, which controls balloon ination and deation, times these events to the cardiac cycle. The balloon must inate at the end of systole (aortic valve/atrioventricular [AV] closure) to create the counterpulsation of blood and deate at the start of systole (just before aortic valve opening), and this is done via the following 2 methods. 1. Timing the balloon cycle to the patients electrocardiogram (ECG): when the console detects the peak of the R-wave (corresponds with initiation of LV contraction) it deates the balloon, and it inates the balloon in the middle of the T-wave (the onset of diastole). Although the ECG is often used as the IABP trigger, it only approximates the onset of LV systole and diastole, and adjustments may be required for balloon timing. Furthermore, ECG capture may be affected by certain rhythms (eg, atrial brillation) and electrical interference (eg, electrocautery devices), potentially diminishing the benets of an IABP. 2. Timing the IABP to the systemic arterial pressure waveform: in these circumstances, the IABP will be timed to inate at the dicrotic notch of the arterial pressure waveform (corresponding to AV closure) and deate at the point before the systolic arterial wave upstroke (just before AV opening). With either method of IABP timing, the principle is to increase diastolic blood pressure, with concomitant retrograde blood ow back toward the heart, thereby increasing coronary artery perfusion. In systole, the deation of the IABP decreases the afterload of the heart, reducing the workload on the heart and allowing the heart to use lower LV pressures. Perioperative heart failure in coronary surgery is accompanied by a high operative mortality rate. An IABP is often used to treat this

syndrome. The correct timing for IABP insertion after completion of the operation has not yet been investigated; however, postponing the use of the IABP may be deleterious in patients with drug-refractory heart failure.41 The relative prognostic impact of IABP placement before versus after cardiac surgery also is not well dened. However, a recent published report suggested that patients who require an IABP after cardiac surgery may have worse outcomes than patients who receive IABP support before surgery. In both groups, after an early peak in mortality, the midterm outcomes were characterized by a reassuring plateau in the survival rates.42 The IABP also may give varying degrees of hemodynamic support to the patient. It often is programmed initially to inate once every 2 cardiac cycles (1:2) to allow the operator to assess the efcacy of the IABP by comparing the assisted and unassisted beats. In patients with poor arterial pressures, CO, or poor pulmonary arterial occlusion pressures, the frequency of ination may increase to 1:1. Similarly, if the patient stabilizes, they may be weaned slowly from the IABP by decreasing the frequency of cycling (to 1:2, 1:3).43 Although uncommon, complications associated with the IABP can be severe. They include local infections, systemic infection, and vascular complications such as bleeding, systemic embolization, limb ischemia, and amputation or balloon rupture. In rare instances, a patient may die because of aortic dissection and/or rupture secondary to IABP insertion.40 The rate of major complications from IABP use (eg, balloon leak, major limb ischemia, severe bleeding, and death directly from IABP use) has been reported to be 2.6%.8,9 However, the authors previously have shown a signicant decrease (risk of 1% vascular complications) in the IABP-related complications even though complexity of cases referred for surgery has increased.8
SEARCH METHODOLOGY

The MEDLINE database was searched from the date of inception through the end of May 2008 using the following medical subject headings search terms: IABP, intra-aortic balloon pump, levosimendan, low cardiac index, low cardiac output, and cardiac surgery. The similar search terms were combined using the Boolean operator OR, and then all search terms combined with the operator AND to nd articles that contained all the search terms. The search was performed in stages to achieve the highest yield. This search strategy has been described in detail in the British Medical Journal.44 Additionally, bibliographies were searched to identify further articles. All English and non-English studies that met the previously described criteria that focused on adult patients were included in this review and were appraised methodologically using a critical appraisal checklist.45
RESULTS

A total of 6 articles on levosimendan and 5 articles on the IABP were identied that met the inclusion criteria after screening a total of 27 citations. These are presented in Table 1; however, no studies comparing levosimendan with the IABP were found according to the inclusion study protocol. However, Christoph et al46 recently investigated the hemodynamic effects

Table 1. Studies Reporting Levosimendan or IABP Use in the LCOS Patient

Author Year Study Type Level of Evidence* Population Characteristics and LVEF Number of Patients Intervention and Dosage/Timing Main Outcomes/Conclusions

Labriola et

al49

2004

Pilot study

LCOS adult patients after cardiac surgery LCOS dened as: LVEF 35%, CI 2.5 L/min/m2 PCWP 18 mmHg MAP 70 mmHg

11

Malliotakis et al56

2007

Case series

Alvarez et al47

2005

RCT

LCOS adult patients post cardiac surgery with CPB LCOS dened as: CI 2.2 L/min/m2 PCWP 15 mmHg Within rst 6 h after aortic cross-clamp removal LVEF per se not a factor Mean LVEF 47.5% 11.6% Adult patients post-cardiac surgery using CPB with LCOS

12

Levosimendan: Treatment commenced in ICU, initiated from 1 to 19 h after ICU admission (median 2 h) 12 g/kg loading over 10 min, then 0.1 g/kg/min continuous infusion for 12 h *patients also received combination of inotropes/ vasodilators/IABP as required intraoperatively Levosimendan: Commenced within 6 h after removal aortic cross-clamp 6- g/kg loading dose over 10 min, then 24-h infusion of 0.2 g/kg/min* patients also received combination of dobutamine -blockers noradrenaline Levosimendan: Compared against dobutamine; intervention commenced postoperatively Dobutamine 7.5 g/kg/min 24-h infusion (n 15) v Levosimendan 18 g/kg loading, then 0.2 g/kg/min for 24-h infusion (n 15) Levosimendan versus Dobutamine; intervention commenced postoperatively Dobutamine 7.5 g/kg/min 24h infusion (n 20) v Levosimendan 12 g loading, then 0.2 g/kg/min 24-h infusion (n 21)

Within 3 h of infusion, 73% (8 patients) with 30% increase in CI, and PCWP 18 mmHg; effect sustained 24 h (p 0.001) MAP, SVR lowered in all patients

Levosimendan improved CI by 50% by 6 h after infusion; improvement sustained until 24 h (p 0.001) Increase in stroke volume, mild decrease in MAP, with no change in HR

30

Levosimendan decreased MAP, SVR, PVR; increased HR, CI (p 0.05) Levosimendan comparable to dobutamine for treatment of LCOS

Alvarez et al48

2006

RCT

Adult patients after cardiac surgery using CPB with LCOS LCOS dened as: CI 2.2L/min/m2 PCWP 15mmHg LVEF per se not a factor Dobutamine mean LVEF 33.19% 5.24% Levosimendan mean LVEF 35.54% 4.20%

41

Compared with dobutamine, Levosimendan: Increased HR and CI more than with dobutamine, and this was sustained to 48 h (p 0.05) Decreased MAP, SVR, MPAP, PCWP, PVR; this was sustained to 48 h (p 0.05) ELAHI ET AL

Table 1. Studies Reporting Levosimendan or IABP Use in the LCOS Patient (Contd)
Author Year Study Type Level of Evidence* Population Characteristics and LVEF Number of Patients Intervention and Dosage/Timing Main Outcomes/Conclusions

LEVOSIMENDAN V IABP FOR LOW CARDIAC OUTPUT

Tasouli et

al50

2007

RCT

Adult patients after cardiac surgery using CPB with preoperative diagnosis of LCOS LCOS dened as: NYHA III- IV LVEF 35% CI 2.0 L/min/m2 PCWP 18mmHg

45

Levosimendan: Compared treatment with levosimendan intraoperatively v treatment on 2nd postoperative day in the ICU; patients also received regular inotropic/ IABP support as required Levosimendan infused at 0.1 g/kg/min for 24-48 h (no loading dose)

Heinze et al57

2006

Comparative case series

Adult patients after cardiac surgery using CPB with LCOS LCOS dened as: CI 2.5 L/min/m2 PCWP 20 mmHg

26

Christenson et al58

1997

RCT

Adult patients after cardiac surgery using CPB with 2 of following: LVEF 40% Main coronary artery stenosis 70% Reoperation Unstable angina despite medical treatment

52

IABP: Comparison between early (intraoperative) insertion of IABP for LCOS (n 17) v late IABP insertion in the ICU (n 9) Mean insertion time point 38.3 48.7 h after ICU admission Femoral IABP, with 1:1 ratio counterpulsation IABP: Comparison between 3 arms of trial: 1) Preoperative IABP treatment for 24 h before surgery (n 13) 2) Preoperative IABP treatment for 1 to 2 h before surgery (n 19) 3) No preoperative IABP treatment (n 20)

Levosimendan increased CI, LVEF, SV, SvO2; decreased SVR, PCWP, PVR (p 0.05) Intraoperative levosimendan treatment improved these gures greater than postoperative treatment (p 0.05) Early (ie, intraoperative) treatment decreased ICU length of stay (p 0.002) and hospital stay (p 0.001) Late (ICU) treatment associated with 4 deaths (multiorgan dysfunction from sepsis) Early IABP insertion resulted in decreased intubation time in ICU and fewer complications with ARF and ARDS (p 0.05) Both early and late IABP increase CI (p 0.05)

Ley59

1993

Review

NA

NA

IABP

Decreased CPB time with preoperative IABP (p 0.014); preoperative IABP increased CI within 5 minutes after myocardial revascularization (p 0.008) Preoperative IABP decreased postoperative LCOS (p 0.05) Preop IABP patients had shorter durations of IABP support v control patients who developed LCOS despite medical therapy and required postoperative IABP (p 0.001) Increased mortality in controls v 2 preoperative IABP groups (p 0.05). Shorter ICU stay in patients with preoperative IABP v control (p 0.004) Increased CO by 10% to 20%

6 NOTE. The 10 studies identied looked at either levosimendan or the IABP in the adult postcardiac surgery population with LCOS. Abbreviations: ARDS, acute respiratory distress syndrome; ARF, acute renal failure; CPB, cardiopulmonary bypass; HR, heart rate; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; MPAP, mean pulmonary arterial pressure; NYHA, New York Heart Association; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; SV, stroke volume; SvO2, venous blood oxygen saturation. *As described in the Centre for Evidence Based Medicine.52

ELAHI ET AL

of levosimendan in patients with cardiogenic shock complicating acute myocardial infarction in comparison to the effects of the IABP. Only 10 patients with intractable cardiogenic shock were included. The authors in this small study reported that both levosimendan and IABP initially produced signicant increases in CO and SVR with CI for levosimendan at baseline and at 24 hours to be 1.97 0.15 and 2.82 0.22 L/min/m2, respectively, as compared with baseline and 24-hour values of 1.98 0.17 and 2.66 0.08 L/min/m2 at 24 hours, respectively, for the IABP. In addition, the SVR values at baseline and at 24 hours were 1,353 106 and 846 69 dynes s cm 5, respectively, for levosimendan-compared IABP values at baseline and at 24 hours of 1,311 214 and 853 63 dynes s cm 5, respectively. However, after 3 hours of treatment, CI and SVR had improved signicantly in patients treated with levosimendan but not in the IABP group (CI of 2.72 0.28 [ 38%] for levosimendan v 2.18 0.15 [ 10%] L/min/m2 for IABP), thus concluding that the infusion of levosimendan in acute cardiogenic shock results in early and sustained hemodynamic improvement. In addition to the previously described observations, the authors would suggest that short-term hemodynamic performance compares favorably with invasive IABP use. In this analysis, of the articles included, there was 1 pilot study, 1 case series, and 3 randomized controlled trials (RCTs) identied that studied the effects of levosimendan. In addition, there was 1 comparative case series, 1 RCT, 2 review articles, and 1 metaanalysis that studied the effects of the IABP in the adult post cardiac surgery population with LCOS. Most articles dened LCOS as some combination of the following: (1) an LV ejection fraction (LVEF) 35% to 40%, (2) CI 2.0 to 2.5, and (3) a pulmonary capillary occlusion pressure 15 to 20 mmHg. With the exception of the 2 RCTs by Alvarez et al,47,48 all of the levosimendan studies required the use of some other vasoactive agent or the IABP for blood pressure support. In all levosimendan studies, the mean arterial pressure and SVR decreased, and 4 of the studies47-50 showed decreases in pulmonary capillary occlusion pressure and pulmonary vascular resistance. The study by Aksun et al51 recently investigated the best time for the administration of levosimendan in high-risk patients undergoing cardiovascular surgery. According to the authors, levosimendan was effective in high-risk cases during cardiac surgery, especially during the intraoperative and pump removal periods, although it had no signicant impact on outcomes when administered during the postoperative period. In addition, Kolseth et al52 recently investigated how prophylactic treatment with levosimendan before weaning from cardiopulmonary bypass could affect postoperative hemodynamics and outcomes in 30 patients with low preoperative LVEF. The patients in the study were matched to control patients with respect to type of surgical procedure, EuroSCORE, age, sex, and the use of an IABP. Postoperative hemodynamics in the intensive care unit at different time points (ie, arrival, approximately 7 hours after arrival, and the rst postoperative morning) were evaluated. The results showed that the prophylactic infusion of levosimendan initiated before weaning from cardiopulmonary bypass did not lead to an improved hemodynamic performance (parameters measured included CI, SVI, and SvO2) compared with controls. Levosimendan reduced the mean arterial pressure and increased the need for norepinephrine postoperatively.

Table 1. Studies Reporting Levosimendan or IABP Use in the LCOS Patient (Contd)

Number of Patients

IABP

Level of Evidence*

Study Type

2007

Westaby et al1

Author

Field et al62

2007

Year

Meta-analysis

Review

Meta-analysis of 4 RCTs All patients with LVEF 40% CI 2.0 L/min/m2

Population Characteristics and LVEF

NA

193

NA

IABP: Preoperative insertion of IABP

Intervention and Dosage/Timing

Preoperative IABP reduces mortality in high-risk cardiac surgery patients Some evidence to suggest that preoperative IABP in high-risk cardiac surgery patients decreases mortality Evidence shows cost benet for preoperative use of IABP in highrisk cardiac surgery patients

Main Outcomes/Conclusions

LEVOSIMENDAN V IABP FOR LOW CARDIAC OUTPUT

In the case of an IABP, the studies have suggested that early IABP insertion resulted in decreased intubation time in the intensive care unit and fewer complications with acute kidney injury and acute respiratory syndrome (p 0.05). Both early and late IABP insertion increase CI and CO by 10% to 20%, and preoperative IABP use has been shown to decrease postoperative LCOS. Some evidence also has suggested that preoperative IABP in high-risk cardiac surgery patients may decrease mortality. Furthermore, the effectiveness of preoperative IABP use in high-risk patients undergoing coronary bypass surgery has been reported.53 Evidence from the meta-analysis described earlier53 suggests that the use of a preoperative IABP in high-risk patients reduces hospital mortality. A more recent multicenter study investigated whether the prophylactic use of an IABP can translate into better early and long-term results in high-risk patients undergoing cardiac surgery, and the results suggested that it enhanced perioperative management and improved outcomes.54 A Cox proportional hazards model was used to compare the impact of an IABP before surgery on the short- and long-term outcomes in patients undergoing coronary artery bypass graft surgery, with the results showing the IABP was associated with a decrease in 30-day mortality.55
DISCUSSION

gesting that earlier intervention with either levosimendan or the IABP signicantly improved patient outcome more than postoperative intervention.1,49,56-58 In addition, early (as in preoperative and intraoperative) insertion of the IABP in patients with LCOS resulted in decreased time on bypass intraoperatively,58 decreased duration of intubation in the intensive care unit, and decreased incidence of acute respiratory distress syndrome or acute kidney injury in the postoperative setting.57 Intraoperative levosimendan improves CI to a greater degree than postoperative dosing. For both the IABP and levosimendan, early intervention decreased the length of stay in the intensive care unit48,58 and early mortality in LCOS.1,56,60-63 Studies have shown that levosimendan in patients with heart failure can lead to the reduction of B-natriuretic peptide; however, this did not show any survival benets.64,65 At doses of 0.1 g/kg/min, it reduces the risk of worsening heart failure and prevents death in patients with LV failure complicating myocardial infarction.66 Importantly, this not only resulted in better outcomes for patients but also demonstrable cost benet when compared with preoperative IABP insertion56,58,63 for high-risk cardiac surgery patients (all of whom had LCOS). Lack of Uniformity in Classication of LCOS

Because interventional cardiology provides less invasive alternatives for treatment of patients with coronary artery disease than surgery, surgeons are more inclined to accept patients with a higher-risk prole and with increased age.1 With this trend expected to continue, the incidence of cardiac surgical patients with LCOS both pre- and postoperatively is likely to increase. As a whole, the level of evidence supporting the use of either levosimendan or the IABP in the LCOS postcardiac surgery patient is good. Most studies identied were either RCTs or review articles/ meta-analysis. However, in general, the sample sizes involved in the RCTs were small, perhaps because of the selection of only the LCOS subgroup of cardiac surgical patients. Effect on CO Both levosimendan and the IABP signicantly increased the CO of patients in the LCOS setting in all studies. All but one of the levosimendan studies used a loading dose of between 6 and 18 g/kg, followed by an infusion at a rate of 0.1 to 0.2 g/kg/min for 12 to 24 hours.47-49,56 Tasuoli et al50 administered levosimendan with an infusion at rate of 0.1 g/kg/min for 24 to 48 hours. Within 3 to 12 hours of beginning the infusion, CI increased signicantly, with increases of up to 30% to 50%.50,56 The CI increase was reported to be statistically signicant in all studies. Among these, some studies reported sustained improvements up to 24 hours even after the cessation of levosimendan infusion. Comparatively, the IABP is reported to increase CO by 10% to 20%, and the studies reviewed supported this although at its peak the IABP could improve CI by up to 60% to 70% within the rst 12 hours.57-59 Advantage of Early Intervention Although both levosimendan and the IABP improved CI irrespective of the timing of the intervention (ie, preoperative/ intraoperative or postoperative), there was clear evidence sug-

One of the difculties of this literature review was that not all articles identied included the LVEF or CI of their patient populations. Among the studies that did set out their criteria for LCOS, there was considerable variation among authors. Levosimendan or the IABP? Levosimendan has similar effects on CO to the IABP; therefore, indications for their use in cardiac surgical patients are quite similar. Levosimendan has the obvious advantage of not requiring the insertion of a foreign body into a large artery. So far no studies were identied that compared levosimendan with the IABP with regards to efcacy, morbidity, and mortality outcomes. The lack of RCTs focusing on the use of levosimendan compared with the IABP in LCOS patients may in part be caused by the following: 1. The subpopulation in question generally is very sick, and it may be ethically difcult to randomize a patient to receive just levosimendan when there is a much larger body of evidence supporting the use of the IABP in the LCOS setting. The nature of the LCOS patient also will mean that he/she will often require multiple inotropes at varying doses and that both the IABP and levosimendan may be required to treat a patient. So, a true comparison between the 2 will inevitably be difcult. A propensity risk model to identify high-risk patients and predict the need for the IABP or levosimendan or both during or postcoronary artery surgery could predict accuracy of mortality and morbidity evaluated by the area under the receiver operating characteristic curve. This simple clinical risk model based on preoperative clinical data can be used to identify high-risk patients who may benet from decision making toward the RCTs treatment options in such a cohort of patients.67-70 2. The cost involved for either modality of treatment is quite signicant; 1 vial of 12.5 mg of levosimendan typically costs approximately $1,200 Australian dollars

ELAHI ET AL

(AUDs), and each IABP balloon catheter-introducer set similarly costs $1,200 AUDs (excluding the console, worth approximately $80,000 AUDs). 3. Most centers will not have the number of patients with LCOS pre or postcardiac surgery to enroll enough patients for high-quality trials, and, therefore, a multicenter trial may be required (which also will address the issue of cost).
CONCLUSION

There is evidence to suggest that the preoperative use of either levosimendan or the IABP improves patient outcome; early IABP insertion not only improves morbidity and mortality in the high-risk cardiac surgical patient with LCOS,

but this practice is also cost-effective. However, current data suggest that this practice still could be encouraged more widely. The indications for the use of either levosimendan or the IABP are similar, and they both improve cardiac function in cardiac surgery patients with LCOS, but there are currently no data to suggest whether levosimendan or the IABP is superior in the patient with LCOS with regards to morbidity, mortality, cardiac function, or cost benet in cardiac surgery. Is one superior to the other, or will the eld of cardiac surgery and cardiology ultimately need both? There is room for RCTs, preferably a multicentered trial, to clarify these issues.

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