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Three Part Question

In [adults with shock and where septic myocardial depression is considered to be a significant causative factor] does [levosimendan] [improve outcome]?

Clinical Scenario

A 50-year-old man attends the emergency department with a history of cough, shortness of breath and purulent sputum production. He is hypoxic and shocked. He requires intubation and ventilation, and his post-intubation chest X-ray is consistent with bronchopneumonia. Following appropriate fluid resuscitation, he remains hypotensive and norepinephrine is commenced. Despite rapidly escalating norepinephrine, additional fluids and corticosteroids (for their catecholamine sparing effect), he remains shocked. A bedside transthoracic echocardiogram demonstrates left ventricular dysfunction which you feel may be attributed to septic myocardial depression. You wonder whether he might benefit from the addition of levosimendan.

Search Strategy

Medline (1950 – January week 3, 2014), Embase (1980 to 2014, week 3) and the Cochrane library were searched via an Ovid interface: [Levosimendan] AND [(sepsis) OR (septic) OR (septic shock) OR (septicaemia). Limit search to English language.

Search Outcome

94 references were found using the above search strategy, of which eight were thought to be relevant to the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Memis et al. 2012 Turkey	30 patients with septic shock requiring more CVS support than dopamine 10μg/kg/min. Patients randomized to receive either 24 hours of dobutamine (10μg/kg/min) or levosimendan (0.1μg/kg/min).	RCT	Indocyanine green elimination test.	Significant improvement in indocyanine elimination tests suggesting improved splanchnic circulation.	Small numbers. Single centre. Randomization process unclear. Un-blinded. In 13 of the patients septic shock followed either a head injury or intracerebral bleed. Dopamine not first line choice in UK for sepsis. Unclear what rescue therapies (if any) used.
			Cardiovascular markers.	Both significantly improved SBP, DBP and MAP.
			Hospital mortality.	Non-significant trend to improved mortality (13% vs. 33%; p=0.104).
Morelli et al. 2010 France	40 patients with septic shock who, after adequate fluid resuscitation, still required noradrenaline to maintain their MAP. Randomized to receive either levosimendan (0.2μg/kg/min) or dobutamine (5μg/kg/min).	RCT	Sublingual, microvascular blood flow.	Significant improvement in all indices of microvascular blood flow.	Small numbers. Single centre. Unclear randomization process. Dose of dobutamine may not have been adequate (discussed – they did not want a direct comparison just an active comparator).
			ICU LOS.	Non-significant improvements in LOS (14 vs. 27 days; p=0.32).
			ICU mortality.	Non-significant improvement in mortality (65% vs. 75%; p=0.5).
Vaitis et al. 2009 Greece	42 patients with septic shock and confirmed cardiac dysfunction (CI≤2.2, EF≤35%). Randomized to receive either 24 hours of fixed rate levosimendan (0.1μg/kg/min) or dobutamine (5-10μg/kg/min).	RCT	Mortality at 7 and 30 days.	Mortality 30% and 60% with levosimendan and 36% and 68% with dobutamine (p=0.05 and 0.03 respectively).	Abstract. Small numbers. Unclear randomization. No information about patient groups. Single centre. Un-blinded. Lower dose of levosimendan with no titration.
			Cardiac index and ejection fraction.	CI and EF significantly improved with levosimendan.
Alhashemi et al. 2009 Saudi Arabia	42 patients with severe sepsis or septic shock randomized to receive either levosimendan (0.05μg/kg/min increasing to max. 0.2μg/kg/min for 24 hours) or dobutamine (5μg/kg/min increasing to max 20μg/kg/min for 7 days).	RCT	ICU mortality	Non-significant improvement in mortality (48% vs. 62%; p=0.35).	Small numbers. Unclear randomization. No information about patient groups. Single centre. Un-blinded. Severe sepsis group included.
			ScvO2	No change in ScvO2.
			Lactate	Significant improvement in lactate on first day (2.1 +/- 0.2 vs. 3.5 +/-0.3 mmol; p=0.01).
Adanir et al. 2007 Turkey	15 patients with septic shock not responding to standard therapy including dopamine or adrenaline and activated protein C. Received levosimendan 0.2μg/kg/min for 24 hours.	Retrospective observational study	Mortality	70% mortality	Study type. No information about patient groups. Single centre. Use of dopamine and activated protein C. No comparator group.
			Dopamine doses	Significant reduction in dopamine doses after starting levosimendan.
			MAP	No change in MAP with levosimendan
Powell and De Keulenaar 2007 UK	6 patients with septic shock not responding to conventional resuscitation methods. Received levosimendan (0.1-0.2μg/kg/min) for 24 hours.	Case series	28-day mortality.	17% mortality (despite approx. predicted mortality 60% according to APACHE II).	Study type (with very small numbers). Single centre. No patient characteristics. No comparator group.
			Cardiovascular markers.	Improved MAP, CI, SVRI.
			Biochemical markers.	Improved pH, base excess and lactate.
Morelli et al. 2006 Italy	35 patients with ARDS from septic shock (25 extra-pulmonary cause, ten pulmonary). 18 were randomized to receive an infusion of levosimendan (0.2 mcg/kg/min) for 24 hours, 17 randomized to placebo. Noradrenaline was used to maintain MAP 70-80 mmHg.	RCT	Cardiac index	Increased from 3.8 +/-1.1 to 4.2 +/-1.0 L/min/m2, p=0.004	This was a pilot study. Physiological endpoints were assessed rather than clinical outcomes.
			MPAP	Decreased from 29 +/-3 to 25 +/-3 mmHg, p=0.004.
			PVRI	Decreased from 290 +/-77 to 214 +/-50 dynes/sec/cm5/m2, p=0.001.
			RVEF	Increased from 45 +/-10 to 59 +/-10 %, p=0.002.
			SvO2	Increased from 63 +/-8% to 70 +/-8%, p<0.01.
			Right ventricular systolic overload	Reduced as shown by decreased MPAP, PVRI, and increased CI, SVI, and RVEF
			SVI	Increased from 41 +/-11 to 45 +/-10 ml/m2, p=0.006.
Morelli et al. 2005 Italy	30 patients with septic shock, initially with a normal EF, who after 48 hours of treatment with fluids, noradrenaline and dobutamine developed myocardial depression (EF<45%). Randomized to receive either 24 hours of levosimendan (0.2μg/kg/min) or dobutamine (5μg/kg/min).	RCT	Mortality.	Non-significant improvement in ICU, hospital and 28-day mortality.	Single centre. Small numbers. Unclear randomization. Not intention to treat. Dose of dobutamine may not have been adequate.
			Cardiovascular markers.	Levosimendan significantly improved CI (4.1 +/-0.2 vs. 4.5+/-0.2; p<0.05) and EF (37.1+/-3.0 vs. 45.4+/-8.4%) whereas dobutamine had no effect.
			Gastric mucosal perfusion.	Significant improvement in perfusion.
			Biochemical markers.	Significant improvements in lactate and creatinine clearance.

Comment(s)

The hypotension associated with septic shock is predominantly due to a vasodilatory state secondary to toxins. In this circumstance, a vasopressor such as norepinephrine is the most appropriate agent to improve blood pressure and systemic perfusion. In addition, end organ perfusion may be compromised by new left ventricular dysfunction. This occurs in up to half of patients with septic shock and is associated with a higher mortality (Rudiger and Singer, 2007). There are several factors thought to play a role in sepsis induced myocardial depression, and one of these is thought to be an alteration in calcium homeostasis within the cardiac myocyte secondary to circulating cytokines (Morelli, 2005). Levosimendan is an inodilator which works predominantly by enhancing myocyte sensitivity to calcium, thereby increasing the force of contraction and improving cardiac output. This would theoretically reduce some of the deleterious effects of altered calcium homeostasis displayed in sepsis induced myocardial depression. Other beneficial effects of levosimendan include relaxation of vascular smooth muscle which could lead to improvements in blood flow to areas that usually become hypoperfused such as the gut (Memis, 2012; Morelli, 2005) and ameliorating the inflammatory response. Levosimendan is a more logical choice of inotrope in septic myocardial depression compared with dobutamine, which is generally regarded as the agent of choice (usually in conjunction with vasopressors). Despite these theoretical advantages of levosimendan, this does not appear to translate into consistent evidence of an improved outcome. There does seem to be a trend in improved cardiac parameters and possibly mortality but the current data are limited by small numbers, a lack of randomised controlled trials, varying definitions of septic shock and inconsistency with dosing regimens of both levosimendan and the comparator agent. A current randomised controlled trial will hopefully help determine the role of levosimendan in septic shock. An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) has recently started recruiting patients in the UK (http://www.controlled-trials.com/ISRCTN12776039/ accessed 21 February 2014). The primary outcome being evaluated is mean Sequential Organ Failure Assessment score, and secondary outcomes include cardiac output.

Editor Comment

ARDS, adult respiratory distress syndrome; APACHE II: Acute Physiology and Chronic Health Evaluation II; CI, cardiac index; CVS, cardiovascular; DBP, diastolic blood pressure; EF, ejection fraction; ICU, intensive care unit; LOS, length of stay; MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; PVRI, pulmonary vascular resistance index; RCT, randomised controlled trial; RVEF, right ventricular ejection fraction; SBP: systolic blood pressure; ScvO2 central venous oxygen saturation; SVI, stroke volume index; SvO2 mixed venous oxygen saturation; SVRI, systemic vascular resistance index.

Clinical Bottom Line

There are theoretical advantages to the use of levosimendan in sepsis induced myocardial depression, and evidence supports the fact that it can improve cardiovascular parameters. However, the current evidence does not demonstrate improved survival. Dobutamine in conjunction with a vasopressor is therefore likely to remain the agent of choice in the treatment of sepsis induced myocardial depression. The LeoPARDS study will help define the efficacy of levosimendan in septic shock.

References

1. Memis D, Inal MT, Sut N. The effects of levosimendan vs dobutamine added to dopamine on liver functions assessed with noninvasive liver function monitoring in patients with septic shock. Journal of Critical Care 2012;27:318.e1-318.e6.
2. Morelli A, Donati A, Ertmer C, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Critical Care 2010;14:R232.
3. Vaitis J, Michalopoulou H, Thomopoulos C, et al. Use of levosimendan in myocardial dysfunction due to sepsis. Critical Care. 2009;3 (Suppl 1):P165.
4. Alhashemi JA, Alotaibi QA, Abdullah GM, et al. Levosimendan vs dobutamine in septic shock. Journal of Critical Care 2009;24:e14-15.
5. Adanir T, Karahan N, Yetkin U, et al. The role of calcium desensitization in the pathophysiology of septic myocardial depression and effects of levosimendan: results of fifteen septic shock patients. Internet Journal of Thoracic & Cardiovascular Surgery 2007;10 (2).
6. Powell BP, De Keulenaer BL. Levosimendan in septic shock: a case series. British Journal of Anaesthesia British Journal of Anaesthesia 2007;99:447-448.
7. Morelli A, Teboul J-L, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 2006;34:2287-2293.
8. Morelli A, De Castro S, Teboul J-L, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Medicine 2005;31:638-644.