Abstract
Objective
To explore the therapeutic effect of levosimendan in patients with prolonged ventilator weaning and cardiac dysfunction.
Method
Patients with prolonged ventilator weaning and cardiac dysfunction were randomly allocated to receive conventional treatment (control group) or intravenous infusion of levosimendan for 24 h based on conventional treatment (levosimendan group). Weaning success rates were then compared between the two groups. The study was retrospectively registered with Research Registry (ID No. researchregistry10304).
Results
A total of 40 patients were included (20 per group). Within 3 days after initiation of treatment, significantly more cases were successfully weaned in the levosimendan group versus control group (eight versus four cases, respectively). Among the eight patients who underwent pulse indicator continuous cardiac output monitoring in the levosimendan group, the global ejection fraction increased 24 h after treatment, and the cardiac function index and cardiac index increased 72 h after treatment.
Conclusion
For patients requiring prolonged mechanical ventilation who have concomitant cardiac dysfunction, levosimendan may be considered to increase the probability of weaning success.
Keywords
Introduction
A considerable number of mechanically ventilated patients in the intensive care units (ICUs) are difficult to wean from the ventilator. ICU patients with explicit or implicit cardiopulmonary dysfunction exhibit a higher risk of weaning failure, with left ventricular systolic and/or diastolic dysfunction considered to be a common cause. 1 Levosimendan, a novel calcium sensitizer that additionally opens adenosine triphosphate-dependent potassium channels, is used in the treatment of acute decompensated heart failure or in patients who require positive inotropic therapy. 2 Levosimendan not only enhances myocardial contractility without increasing myocardial oxygen consumption, but also improves myocardial diastolic function. These pharmacologic properties allow levosimendan to be applied in a wide variety of critical-illnesses in hospital ICUs. In 2020, an Italian expert group proposed that levosimendan should be used in patients on mechanical ventilation with difficult weaning and cardiac dysfunction, to facilitate early weaning from the ventilator by improving cardiac function and oxygenation. 3 Levosimendan has potential roles and advantages in providing cardiopulmonary support for patients during weaning, but clinical evidence remains limited. In view of this, the aim of the present study was to conduct a prospective, randomized, single-blind, controlled study to evaluate the effects of continuous intravenous infusion of levosimendan on successful-weaning rate in patients with prolonged weaning and cardiac dysfunction.
Patients and methods
Study population and definition of cardiac dysfunction
The present prospective, single-blind, randomized, controlled study included mechanically ventilated patients with acute respiratory failure resulting from various causes who had been admitted to the Department of Critical Care Medicine of Chongqing University Three Gorges Hospital between December 2021 and January 2024. The study was approved by the Ethics Committee of Chongqing University Three Gorges Hospital (2021ky158), and was conducted in accordance with the Helsinki Declaration of 1975 as revised in 2013. Written informed consent was obtained from each patient or their legal proxy and the reporting of the study conforms to CONSORT guidelines. 4 Eligible patients met all three of the following inclusion criteria: (1) were aged ≥18 years; (2) experienced prolonged weaning, 5 comprising duration of mechanical ventilation ≥7 days, or ≥ three spontaneous breathing trials (SBTs); and (3) the patient’s legal proxy provided informed consent. Patients who met the following criteria were excluded: (1) age < 18 years; (2) weaning was not possible due to muscle or neurological disorders; (3) presence of severe liver or kidney failure; (4) unsuitability for transthoracic echocardiography, including heart rate (HR) > 110 beats/min, a non-sinus rhythm, atrioventricular conduction abnormalities, pacing rhythm, or severe valvular disease that may interfere with Doppler measurement; (5) administration of levosimendan within 2 weeks prior to study inclusion; (6) absence of indwelling subclavian or internal jugular venous catheters; and (7) no signs of cardiac dysfunction. Patients with one of the following findings confirmed by bedside ultrasonography were defined as showing cardiac dysfunction: 3 (1) left ventricular systolic dysfunction, with an ejection fraction <40%; (2) left ventricular diastolic dysfunction that included increased left ventricular end diastolic pressure, ratio of peak E to peak A < 1, and a deceleration time of peak E < 140 ms; and (3) a cardiac index (CI) < 2.5 L/min.
Research process
All enrolled patients experienced their first SBT after inclusion; and each SBT was performed with a T-piece for 120 min. The SBT was terminated and defined as a weaning failure if the patient experienced the following conditions during the process: respiratory rate (RR) > 35 breaths/min; pulse oxygen saturation < 90%; HR > 120 beats/min or increased by more than 20% compared with the rate before the SBT; systolic blood pressure (SBP) > 180 mmHg (1 mmHg =0.133 kPa) or < 90 mmHg; arrhythmias; sweating; increased respiratory work; and the appearance of obvious discomfort. In patients with successful SBT, the endotracheal tubes were removed.
Patients who had failed their first SBT after study inclusion and whose bedside ultrasonography indicated cardiac dysfunction (either before or after the SBT) were allocated to either a control group or a levosimendan group using a random-number table method. According to the judgment of the attending physicians, the patients in the control group received an infusion of dopamine (5–10 µg/kg/min), or were administered diuretics, recombinant human brain natriuretic peptide (rhBNP), ultrafiltration, or other drugs and methods. Patients in the levosimendan group were infused with levosimendan (0.1–0.2 µg kg−1 min−1) for 24 h, but dobutamine or rhBNP was not provided. SBT was reattempted every 24 h. The endotracheal tubes were removed in patients with a successful SBT, while patients with weaning failure continued mechanical ventilation before undergoing the next SBT. In error, the trial was not prospectively registered, but was retrospectively registered at the Research Registry (https://www.researchregistry.com/: registration number 10304).
Data collection
Demographic, clinical, and laboratory data were obtained, in addition to information on weaning. Laboratory data included measurements of oxygenation index (PaO2/FiO2 [P/F] ratio), albumin, total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, and N-terminal pro-brain natriuretic peptide (NT-proBNP), assessed before and 24 h after initiation of treatment for each patient in the two groups. Patient age, sex, RR, SBP, diastolic blood pressure, mean arterial pressure, and central venous pressure were also recorded. For patients who underwent pulse indicator continuous cardiac output (PiCCO) monitoring in the levosimendan group, the cardiac function index (CFI), CI, stroke volume index, extravascular lung water index, global end diastolic volume index, pulmonary vascular permeability index, global ejection fraction (GEF), systemic vascular resistance index, and left ventricular contractility index (measured as dPmx) were assessed every 8 h within 72 h after treatment initiation. The primary outcome was the success rate of weaning. Weaning success was defined as extubation within 72 h after initiation of treatment. Reintubation within 48 h after extubation was considered as weaning failure. Sample size was not considered in the present study as several previously published studies focusing on patients with prolonged weaning and cardiac dysfunction involved relatively small sample sizes.
Statistical analyses
Data were analysed using IBM SPSS Statistics software, version 23.0 (IBM Corp., Armonk, NY, USA). Normally distributed quantitative continuous data are presented as mean ± SD, with independent samples t-test used for intergroup comparisons and paired t-tests used for intragroup before and after comparisons. Non-normally distributed continuous data are presented as median (interquartile range: M [P25, P75]), with Mann–Whitney U-test used for intergroup comparisons and Wilcoxon signed–rank test used for intragroup before and after comparisons. Categorical data are presented as cases and percentages with χ2-test applied for between-group comparisons. A P value < 0.05 was considered to be statistically significant.
Results
Patient characteristics and weaning success rate between the two groups
A total of 40 patients who experienced their first failed SBT after inclusion and were diagnosed with combined cardiac dysfunction were finally included in the study, with 20 cases each assigned to the control group and levosimendan group, respectively. No statistically significant between-group differences in sex, age, medical history, aetiology of intubation, or ventilation duration before inclusion were noted (all P > 0.05). Eight patients were successfully weaned from mechanical ventilation in the levosimendan group within 3 days after initiation of treatment, which was statistically higher than the four patients who were successfully weaned in the control group (P = 0.027). There were no serious adverse events and no deaths in either group within 3 days of treatment initiation (Table 1).
Comparison of characteristics and weaning success rates of patients with prolonged ventilator weaning and cardiac dysfunction.
Data presented as mean ± SD, median (interquartile range) or n (%).
COPD, chronic obstructive pulmonary disease.
NS, no statistically significant between-group difference (P > 0.05; independent samples t-test, Mann–Whitney U-test, or χ2-test).
Respiratory and hemodynamic parameters in each patient group
Respiratory and hemodynamic parameters in each group of patients at different time-points are shown in Table 2. There were no statistically significant differences in the various parameters between the two groups before treatment and 24 h after initiation of treatment (all P > 0.05). There were also no statistically significant within-group differences in the various parameters before treatment compared with 24 h after initiation of treatment (all P > 0.05).
Oxygenation and hemodynamic parameters at different time-points in patients with prolonged ventilator weaning and cardiac dysfunction treated with levosimendan or conventional therapy (controls).
Data presented as mean ± SD or median (interquartile range).
1 mmHg = 0.133 kPa.
RR, respiratory rate; P/F, oxygenation index; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; CVP, central venous pressure.
Laboratory parameters in each patient group
Laboratory parameters in each group of patients at different time-points are shown in Table 3. There were no statistically significant differences in the various parameters between the two groups before treatment and 24 h after initiation of treatment (all P > 0.05). Compared with before treatment, both groups showed a statistically significant decrease in total bilirubin and direct bilirubin after starting treatment, while NT-proBNP increased (all P < 0.05).
Laboratory parameters at different time-points in patients with prolonged ventilator weaning and cardiac dysfunction treated with levosimendan or conventional therapy (controls).
Data presented as mean ± SD or median (interquartile range).
P < 0.05 versus before treatment (Wilcoxon signed–rank test).
ALB, albumin; TBil, total bilirubin; DBil: direct bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; SCr, serum creatinine; NT-proBNP, N-terminal pro brain natriuretic peptide.
PiCCO parameters in the levosimendan group
Eight patients in the levosimendan group completed PiCCO monitoring for 72 h after inclusion, with PiCCO parameters at different time-points shown in Table 4. Compared with before treatment, GEF increased 24 h after starting treatment, while CFI and CI increased 72 h after starting treatment (all P < 0.05).
PiCCO parameters at different time-points in eight patients with prolonged ventilator weaning and cardiac dysfunction who received levosimendan treatment.
Data presented as mean ± SD or median (interquartile range).
P < 0.05, versus 0 h (paired t-test).
1 mmHg = 0.133 kPa.
PiCCO, pulse indicator continuous cardiac output; CFI, cardiac function index; CI, cardiac index; SVI, stroke volume index; EVLWI, extravascular lung water index; GEDVI, global end diastolic volume index; PVPI, pulmonary vascular permeability index; GEF, global ejection fraction; SVRI, systemic vascular resistance index; dPmx, left ventricular contractility index.
Discussion
In the current study, levosimendan was used on the basis of conventional treatments to improve the weaning success rate in patients with difficult ventilator weaning complicated by cardiac dysfunction, as confirmed by bedside ultrasonography or other examinations, with the observation of no serious adverse events.
Prolonged mechanical ventilation increases the risk of pneumonia, barotrauma, airway damage, and skeletal muscle dysfunction. Approximately 26–42% of ICU-intubated patients exhibit difficulty in weaning from the ventilator, and delayed weaning is associated with increased length of ICU stay and total hospital stay, in addition to elevated mortality rates. 6 Therefore, appropriate weaning is of crucial importance for critically ill patients requiring respiratory support. 3 Ventilator weaning may be classified as simple, difficult, or prolonged. 7 In difficult weaning, a patient requires up to three SBTs, or as long as 7 days, to be liberated from mechanical ventilation; in prolonged weaning, a patient fails more than three SBTs or requires more than 7 days to wean. 7
The pathophysiology of weaning failure is complex, but weaning-induced pulmonary oedema (WIPO) is one of its major established causes. 8 Preexisting cardiopathy, chronic respiratory failure, and obesity have been demonstrated to be independent risk factors for developing WIPO. 9 During the transition from positive-pressure ventilation to spontaneous breathing, rapid changes in cardiopulmonary interaction, sudden changes in cardiac load conditions, and increased oxygen demand may cause excessive burdens on the respiratory and cardiovascular systems that result in a rapid increase in left ventricular filling pressure and ultimately lead to the occurrence of WIPO and difficult weaning. 10 Weaning failure caused by cardiac dysfunction is principally due to diastolic left ventricular dysfunction. 9 Diuretics, which reduce circulating blood volume and may also reduce airway oedema and resistance, constitute the mainstay of WIPO management. 10 The use of inotropes, such as dobutamine, does not appear to be an ideal treatment option, as it is accompanied by an increase in cardiac oxygen consumption along with an increase in HR. In addition, sympathetic nerve excitation induces catecholamine release during SBT failure, leading to peripheral vascular constriction and increased cardiac load, and does not support the use of exogenous catecholamines. Therefore, the use of non-adrenergic drugs prior to SBT to optimize cardiac function constitutes an attractive treatment strategy. 11
Levosimendan is a unique cardiovasodilator that combines three characteristics: calcium sensitization, phosphodiesterase inhibition, and vasodilation. 2 As a calcium sensitizer, levosimendan binds to troponin C on myocardial filaments, stabilizing the conformation of troponin C binding to Ca2+ and thereby prolonging the interaction between actin and myosin. 12 Levosimendan can enhance myocardial contractility without increasing the transient amplitude of intracellular Ca2+. 13 Unlike traditional inotropes, such as adrenaline, dobutamine, or dopamine, levosimendan not only enhances myocardial contractility but also improves myocardial diastolic function without increasing myocardial oxygen consumption. The following pharmacologic advantages of levosimendan can be widely applied in the ICU: hemodynamic support for cardiogenic or septic shock; detachment from mechanical ventilation or extracorporeal membrane oxygenation; treatment of pulmonary hypertension and right ventricular dysfunction; and abatement of cardiorenal syndrome.14,15
Levosimendan, which establishes a favourable effect in promoting the withdrawal of cardiopulmonary support in critically ill patients, has been used in recent years to augment cardiac output without increasing myocardial oxygen consumption. We certainly acknowledge that mechanical ventilation can cause rapid loss of diaphragm strength and recognize that respiratory muscle troponin is similar to cardiac troponin, with levosimendan thus potentially enhancing respiratory muscle contractility by enhancing cardiac contractility. 14 In a prospective observational study of ICU patients (with a left ventricular ejection fraction [LVEF] < 40%) with difficult ventilator weaning, levosimendan increased the LVEF, improved oxygen levels, and increased the success rate of weaning compared with dobutamine. 16 In a study comparing the short-term hemodynamic effects of levosimendan versus dobutamine in 10 patients with chronic obstructive pulmonary disease who had difficult ventilator weaning, both drugs were revealed to significantly reduce the increase in pulmonary artery occlusion pressure during spontaneous respiration, while the decrease with levosimendan was even greater. 17 In another study, 39 mechanically ventilated ICU patients were treated with levosimendan (0.2 µg kg−1 min−1) or placebo for 5 h, and the results showed that the tidal volume and ventilation volume increased by 11% and 21%, respectively; however, there was no indication of increased neuromechanical efficiency or contractility of the diaphragm. 18 Patients who benefited from levosimendan during weaning were still only those with concurrently low LVEF.
In a meta-analysis conducted by Luo et al., 6 levosimendan significantly increased the successful-weaning rate in patients requiring cardiopulmonary support (including those with difficult weaning and extracorporeal membrane oxygenation), particularly in patients with concomitant cardiac dysfunction. Subgroup analysis revealed that levosimendan was significantly associated with a reduced mortality rate in patients receiving extracorporeal membrane oxygenation, but not in patients receiving mechanical ventilation. 6 The use of levosimendan should be considered when cardiac dysfunction arising from causes such as increased left ventricular preload and afterload, or a diminution in left ventricular compliance arising from the transition to negative intra-thoracic pressures, is a major factor in weaning failure. 11
In the present study, both the control group and levosimendan group showed no significant improvement in P/F ratio before or after treatment, suggesting that the P/F ratio in each patient group had reached a relatively acceptable level before treatment. Bilirubin levels dropped in each patient group after treatment, and this may have been related to an improvement in heart function. Intriguingly, NT-proBNP increased in both groups after treatment for reasons that are difficult to explain.
The results of the present study may be limited by several factors. First, cardiac function was not evaluated by echocardiography on all patients in the two groups, so that changes in cardiac function before and after treatment were not compared in either group. Fortunately, PiCCO monitoring was conducted in eight patients in the levosimendan group. In these patients, compared with before treatment, GEF increased 24 h after starting treatment, and CFI and CI increased 72 h after starting treatment. Secondly, the sample size of this study was relatively small, and it was not possible to evaluate the factors needed to predict difficult weaning.
In conclusion, the present study has shown that levosimendan may improve the weaning success rate in patients with prolonged ventilator weaning and cardiac dysfunction. Since there were no serious adverse events, we recommend that levosimendan should be used for patients with difficult weaning, once cardiac dysfunction is confirmed by bedside ultrasonography or other examinations. Further clinical studies should be conducted with larger sample sizes so as to provide more evidence-based medicine for the application of levosimendan in patients with prolonged ventilator weaning.
Footnotes
Acknowledgements
Author contributions
FX and ZH collected and analysed the data and wrote the manuscript; CL, KZ, QZ, JC, HL, XY and JZ collected the data and approved the final manuscript; PP analysed the data, wrote the manuscript, and approved the final manuscript. All authors read and approved the manuscript.
Data availability
The raw data are publicly available upon request to the corresponding author, Dr Pengfei Pan.
Declaration of conflicting interest
The authors declare that there are no conflicts of interest.
Funding
This research was funded by Chongqing Science and Technology Commission (CSTC2020JCYJ-MSXMX1069) and also by the Joint Medical Scientific Research Project of the Health Commission and Science and Technology Bureau of Wanzhou, Chongqing (wzstc-kw2021001).