Despite advances in perioperative care, patients with heart failure undergoing major surgery suffer substantial morbidity and mortality . The risk for adverse outcome is further increased in emergency or urgent cases. The urgency of surgery limits the time necessary to stabilize for concurrent medical problems, to optimize cardiac performance and volume status or to correct electrolyte imbalances, which increases the risk of serious cardiac complications.
Hip fracture is one of the most common traumatic injuries in the elderly and urgent surgical repair seems to be crucial. In up to 25% of these patients cardiovascular comorbidities are present at admission predisposing them to develop cardiac complications perioperatively. It was demonstrated that the most important complication in patients following hip fracture repair was the occurrence of heart failure, causing a 30-day mortality rate of 65% . With the intention to reduce mortality, attention has to focus on stabilizing and optimizing cardiac function in the perioperative period. For that purpose, positive inotropic drugs are often inevitable . However, there are several limitations of currently available positive inotropic substances including β-adrenergic agonists and phosphodiesterase inhibitors. The reason for their detrimental effects are related to the mechanism of action, provoking substantial elevation in intracellular calcium with subsequent aggravation on myocardial oxygen demand and arrhythmogenesis [4,5]. The new inodilator levosimendan does not use the physiologic pathway of increasing intracellular calcium, but promotes inotropy on inducing calcium sensitization of myofilaments by binding to cardiac troponin C . This action stabilizes the calcium-induced conformational changes of troponin C, thereby modifying actin–myosin cross bridge kinetics without increasing the cycling rate of the cross bridges or myocardial adenosine triphosphate (ATP) consumption . This approach shows the advantage of enhancing contractile performance with unaffected myocardial oxygen demand  and with decreased potential for arrhythmia. In addition, β-blockers, generally accepted as a basic treatment in heart failure, do not conversely interact with levosimendan like it does with β-adrenergic substances, i.e. dobutamine . Levosimendan activates ATP-sensitive potassium (K+ATP) channels [10,11], resulting in vasodilation and may exert cardioprotective effects through this mechanism.
Previous clinical trials have established the favourable haemodynamic effects of intravenously administered levosimendan in patients with severe heart failure , in cardiac surgical patients , or in the postoperative period . There is currently no data on the preoperative use of levosimendan in patients undergoing non-cardiac procedures. However, it has been speculated that levosimendan might have promising effects when optimizing patients with heart failure undergoing major surgery preoperatively . In this study we report on our experience in elderly patients with heart failure and low cardiac output syndrome undergoing urgent hip fracture surgery.
The investigation was performed according to the principles of the Helsinki declaration and with reference to the guidelines of the local Ethics Committee. Due to the observational nature of our study and the fact that levosimendan was used in accordance with the Guidelines of the European Society of Cardiology (ESC)  concerning treatment of left ventricular heart failure, the local Ethics Committee waived the necessity for informed consent. The study was performed at a regional university-affiliated trauma centre. A consecutive sample of 10 patients presenting clinical signs of impaired left ventricular function and left ventricular ejection fraction (LVEF) <35% suffering from fracture of the proximal femoral bone were studied. These patients were admitted to the hospital with traumatic injury of the proximal femoral bone (i.e. fracture of the femoral head, per- and sub-trochanteric fracture, re-fracture or periprothetic fracture), and needed to undergo urgent major orthopaedic surgery of the femur or hip (i.e. total hip prosthesis, hip hemiarthroplasty or stabilizing operations on the proximal femoral bone). Preoperative transthoracal two-dimensional echocardiography (TTE) was performed in all patients to quantify LVEF. All patients included into the present study showed symptoms of cardiac decompensation, such as dyspnoea, jugular venous distension or pleural effusions in the chest X-ray.
To evaluate patients before being included into the study, we used two cardiac scoring systems that try to define the risk of severe cardiac complications in patients undergoing operative non-cardiac procedures. One was the Cardiac Risk Index by Goldman ; the other one was the Revised Cardiac Risk Index, published by Lee in 1999 . Exclusion criteria were age under 18 yr, acute myocardial infarction on admission, heart failure due to hypertrophic cardiomyopathy (CMP), severe aortic valve stenosis, sustained ventricular tachycardia or ventricular fibrillation, a heart rate (HR) more than 120 beats min−1, and a systolic blood pressure (BP) beyond 80 mmHg.
On admission, actual medication and pre-existing comorbidities were recorded, the patients were clinically examined, and the stage of heart failure (NYHA I–IV) was documented. LVEF was quantified by TTE using biplane Simpson's Rule Method on the same apparatus (Vivid I; GE Medical system, Chicago, IL, USA) on admission and 48 h thereafter to identify possible changes of LVEF and segmental wall motion abnormalities. TTE was performed by our internist, who had achieved additional specific training in Cardiology. In all patients, blood samples were taken on admission and after 48 h for the determination of plasma B-type natriuretic peptide (BNP) concentrations and serum cardiac troponin T concentrations. BNP was measured on an AxSYM analyzer (Abbott Laboratories, Abbott Park, IL, USA), and cardiac troponin T was quantified by an electrochemiluminescence immunoassay on a E 170 platform (Roche Diagnostics, Mannheim, Germany).
Prior to surgery, all patients were admitted to the ICU, where a central venous catheter was inserted into a subclavian vein, and an arterial PiCCO-Catheter® (Pulsion Medical Systems, Munich, Germany) was inserted into the femoral artery on the opposite side of the fractured limb. Transpulmonary thermodilution cardiac output measurements were obtained using an inert indicator 20 mL of NaCl 0.9% at a temperature of 8–14°C. Haemodynamic parameters (cardiac index (CI), stroke volume index (SVI), indexed systemic vascular resistance (SVRI), mean arterial pressure (MAP), HR and central venous pressure (CVP)) were obtained at baseline and at 4, 8, 12, 16, 20, 24, 28, 36 and 48 h after the start of levosimendan infusion. Prior to the infusion of levosimendan and the measurements, patients were fluid-loaded with hydroxyethyl starch (500 mL; Voluven® HES 130/0.4) 6% infusion solution (Fresenius Kabi Austria GmbH, Graz, Austria) to optimize volume status to reach a value of ITBVI in a narrow range of 900–1000 mL m−2.
In all patients, levosimendan was administered with an infusion rate of 0.1 μg kg−1 min−1 for a minimum duration of 24 h. No other inotropes were used during levosimendan treatment. The dose administered was 12.5 mg in total for each patient. No loading dose was given. Norepinephrine was administered, when necessary to keep MAP > 60 mmHg. After start of levosimendan infusion, patients were transferred to the operating room, when they showed stabilization and enhancement of cardiac performance in cardiac index by 10% from baseline measured by transpulmonary thermodilution method.
Anaesthesia was induced with etomidate (0.2–0.3 mg kg−1), fentanyl (2 μg kg−1) and cisatracurium (0.15 mg kg−1). After intubation, anaesthesia was maintained with sevoflurane 1.2–1.5 vol% end-tidally, lungs were mechanically ventilated with oxygen in air mixture (FiO2 of 0.4) and the ventilator set to maintain normocapnia between 36 and 40 mmHg. Additional doses of fentanyl were given, when needed. During anaesthesia, norepinephrine was added to maintain a BP of MAP > 60 mmHg, but no other inotropes were administered. At the end of surgery, all patients were extubated in the operating room and transferred to the ICU.
All data are presented as mean ± SD. Changes in haemodynamic variables from baseline to 48 h were assessed using repeated measures analysis of variance. Differences between baseline and the 4, 8, 12, 16, 20, 24, 28, 36 and 48 h data were determined by Student–Newman–Keuls test. BNP plasma concentrations on admission and after 48 h were compared with the paired t-test. A P value <0.05 was considered significant.
Ten Patients (5 female and 5 male), were investigated. The mean ± SD age was 86 ± 7 yr (range 77–94), and the mean ejection fraction (EF) was 29 ± 5% (range 20–35). Patient characteristics are given in Table 1.
The course of patients haemodynamics is presented in Table 2. Administration of levosimendan caused a significant increase in CI by 33% within 24 h. At baseline, CI was 2.4 ± 0.3 L min−1 m−2 and increased to 3.2 ± 0.6 L min−1 m−2 at 24 h (P < 0.05). The increase in CI was paralleled by an increase in SVI (Fig. 1), as HR did not change. SVI increased from 27 ± 5 mL m−2 at baseline to 37 ± 10 mL m−2 after 24 h (P < 0.05). Levosimendan had a profound effect on SVRI, which significantly decreased from 2718 ± 841 dyn s cm−5 m−2 at baseline to 1964 ± 385 dyn s cm−5 m−2 (P < 0.05) after 24 h. Despite the decrease in SVRI, MAP remained stable throughout the observation period (Fig. 2), according to administration of low doses of norepinephrine. Administration of norepinephrine was necessary in a dose of 0.06–0.15 μg kg−1 min−1 to prevent hypotension in six patients. In two patients dobutamine in a dose of 2–10 μg kg−1 min−1 had to be administered after stopping levosimendan infusion for inotropic supply for 12 h until the maximum plasma level of the active metabolite OR-1896 was reached. CVP remained within a narrow range of 9–11 mmHg throughout the study.
BNP plasma concentrations decreased significantly from 1143 ± 792 ng L−1 at baseline to 935 ± 724 ng L−1 48 h after initiation of levosimendan (P = 0.006). In two patients cardiac troponin T increased after surgical treatment (maximum, 0.165; and 0.056 ng mL−1, respectively).
TTE was performed in all patients after levosimendan, but no additional segmental wall motion abnormality was detected by echocardiography that had not been described in the entry examination. Though perioperative myocardial infarction cannot be ruled out, the clinical significance seems to be marginal, especially because patents did not show decline of cardiac performance.
No clinically significant adverse events of levosimendan were observed during the study. Two patients presented with a facial flush under levosimendan infusion, but there was no concomitant tachycardia or change in BP. One patient showed intermittent atrial fibrillation, but converted to sinus rhythm spontaneously. No perioperative death was observed within the first 30 days. One patient died 12 days after discharge from hospital and 36 days after the operation. Another patient died 43 days after operation in hospital because of bilateral pneumonia and respiratory insufficiency. Eight patients survived the first 3 months, six patients survived 6 months and one a year after the operation.
This is the first report on the use of levosimendan in cardiac high-risk patients undergoing major non-cardiac surgery. In these patients with impaired left ventricular function undergoing emergent hip fracture repair levosimendan exerted positive haemodynamic effects. Preoperative start of levosimendan infusion increased CI by increases in SVI and resulted in stable intraoperative and postoperative haemodynamics. The mean age of these trauma patients was 86 ± 7 yr. To our knowledge, this is the oldest population in which levosimendan has been studied so far. Our results indicate that levosimendan can be used safely in elderly patients like octagenarians.
Patients with heart failure suffering from acute trauma have to face substantial perioperative haemodynamic disturbances caused by preoperative hypovolaemia due to diuretics use and traumatic haemorrhage. Patients on admission suffer from pain and change of habitual daily life procedures, so these patients are under high stress in this situation. Sympathomimetic stimulation and adrenergic response, though being reduced in elderly, might explain our findings in haemodynamic values in cardiac index being as high as it was on admission. Anaesthetic drugs and intraoperative fluid changes further compromise cardiac function necessitating inotropic support.
Both scoring systems to assess risk of major cardiac complications during non-cardiac procedures showed our patients in the highest or second highest risk group for perioperative cardiac events. This suggests to develop new innovative preoperative settings and special environment to optimize cardiac performance in the forefront of operative treatment of this endangered population. However, the conventional inotropes such as β-mimetics and phosphodiesterase inhibitors increase myocardial oxygen demand and the risk for arrhythmias. Therefore in this high-risk population the use of a calcium sensitizer without this disadvantage might be useful. In contrast to β-mimetics, levosimendan has a delayed onset of action when administered as a continuous infusion without a bolus dose. So we decided to start levosimendan preoperatively, as the need for inotropes is very likely in such patients. In addition levosimendan has known cardioprotective effects, which are thought to be mediated by activation of the ATP-sensitive potassium (K+ATP) channels. While there are some experimental studies supporting this idea [17,18], there is only little data in humans so far. Tritapepe and colleagues  have reported on the preconditioning effects of levosimendan in patients undergoing coronary revascularization. Levosimendan or placebo was infused just before going on cardiopulmonary bypass. Compared with control patients, levosimendan-treated patients had significant lower troponin I levels, indicating its potential preconditioning effect.
BNP levels are sensitive markers to predict postoperative cardiac morbidity and mortality . Therefore in cardiac high-risk patients, the attention should focus on optimizing cardiovascular function preoperatively to reduce BNP levels and cardiac risk. In attempting a rapid reduction of elevated BNP levels, it is important to note that levosimendan is considered favourable as compared to dobutamine . In this case series, preoperative BNP levels were extremely high, suggesting that early use of levosimendan might be useful in improving outcome .
Our study must be interpreted with the restrains of several limitations. First, due to the uncontrolled nature of the study, we cannot comment on time-dependent physiological changes that may have contributed to the observed alterations in haemodynamic parameters. However, we see that the substantial increase in SVI is a result of the inotropic effect of levosimendan rather than a result of fluid substitution, as CVP remained constant during the study period. Second, it might be argued that delivering spinal anaesthesia would be more feasible. In spinal anaesthesia, the loss of adrenergic response may cause a significant decrease in MAP, which might be aggravated by the vasodilating properties of levosimendan. Third, it might be argued that the concomitant use of other vasoactive drugs might have influenced the results. While it is unlikely that the use of the vasopressor norepinephrine in some patients might have caused increases in CI, the use of dobutamine should be associated with increases in CI. The temporary need of dobutamine in two patients shows the consequence of delayed formation of the active metabolite OR-1896 reaching a maximum 36–48 h after initiation of levosimendan therapy .
Nevertheless, the concomitant use of other vasoactive drugs may also have influenced the observed results and cannot be strictly excluded from the analysis.
In conclusion, this study involving elderly patients with heart failure undergoing urgent hip fracture repair demonstrates that preoperative levosimendan infusion appears to improve cardiac index and SVI. The combined inotropic and cardioprotective properties of levosimendan may improve the perioperative outcomes of patients with preoperative, moderate to severe heart failure. Though the results are encouraging and it is suspected that levosimendan is responsible for the good outcomes, we have to face the caveat that the lack of control allows no firm conclusion to be reached about the merit of any one particular intervention but mandates further investigation. Due to the preliminary nature of this study, further research is necessary to evaluate the role of preoperative levosimendan administration in patients with failing myocardium undergoing major non-cardiac surgery.
The study was supported by a grant of ‘Interdisziplinäres Zentrum für gesundheitsökonomische Studien – Health Economics Research' to WP.
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