Background
Circulatory shock affects about one-third of patients admitted to the intensive care unit (ICU) [
1]. Shock is defined as insufficient oxygen and energy supply to organs and is associated with increased mortality [
1,
2]. Traditionally, four types of circulatory shock have been distinguished by pathophysiological mechanisms, namely hypovolemic, cardiogenic, distributive and obstructive shock [
3]. Critically ill patients present with one or a combination of these four types of circulatory failure [
4].
Treatment of circulatory shock relies on timely initiation of adequate fluid resuscitation combined with the use of vasoactive medication to restore tissue perfusion [
5,
6]. Despite these therapeutic measures, cardiac output (CO) is often inadequate to deliver enough oxygen to tissues in patients with circulatory shock [
7]. Inotropes might improve CO and organ perfusion in patients with circulatory shock [
8,
9]. Several guidelines for different types of circulatory shock give different recommendations for the use of inotropes [
10‐
13]. Despite these different recommendations and the apparent lack of evidence, inotropes are used in daily practice [
13,
14]. Data on how inotropes are used in clinical practice are sparse [
15]. Individual registries, observational studies, and trials with patients in shock provide insight into the current standard of care. For example, in patients with cardiogenic shock, vasopressors and inotropes were administered in 94%, where dobutamine (49%) and levosimendan (24%) were the most commonly used inotropes [
16]. For levosimendan, two systematic reviews with meta-analyses and three large randomized trials have shown neutral effects on various outcomes [
17‐
21], while one trial reported a possibility of harm (lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia)[
22]. A recent Cochrane review underlines the low quality of evidence on the use of inotropes in cardiogenic shock with levosimendan showing a short-term survival benefit over dobutamine, while this benefit vanished on long-term follow-up [
23]. In other types of shock, use of inotropes is less common. Some patients with septic shock may have improved tissue perfusion with inotropic therapy aimed at increasing oxygen delivery and in this situation, dobutamine is the first-line inotrope [
8,
24]. However, a recent network meta-analysis suggests that levosimendan has the highest probability of being the best treatment in septic shock [
25]. Yet, no large randomized trials have provided evidence for a mortality benefit of levosimendan over dobutamine in septic shock [
26].
Hence, further studies are needed on optimal treatment with inotropes in circulatory shock states. To aid the design and interpretation of future studies on inotropes, it is imperative to evaluate current practice and therapeutic goals of inotropic treatment of shock states to establish what is considered standard of care. The aim of the present study was to establish an overall picture of the standard of care, which was identified from a survey among members of the European Society of Intensive Care Medicine (ESICM). Furthermore, we developed recommendations on the use of inotropes based on a subsequent questionnaire and consensus finding by international experts in the field.
Discussion
According to the results of this international survey, preferences around the use of inotropes differ among physicians. Most physicians (84%) chose dobutamine as their first-line inotrope, and dopamine, levosimendan, and milrinone (or another PDE-inhibitor) were considered first-line in up to 5% of respondents for patients with circulatory shock. Furthermore, the reasons for using an inotropic agent were diverse. Also, the variation in the primary therapeutic target was diverse, where CO, ScvO2, lactate level and urine output were all well-represented answers among the respondents. Furthermore, the reasons for adding a vasopressor/inotrope if the patient did not respond to the inotropic agent administered to the patient were virtually uniformly distributed among the respondents, underscoring that balancing maximal doses, side effects, possible synergistic drug effects, etc., is challenging for clinicians in late/critical stages of circulatory shock.
The heterogeneous choices of physicians when it comes to inotropes may have various reasons. First, no solid evidence is available to support choosing one agent over another [
12]. Recently, meta-analyses showed that for many inotropes evidence to support benefit is absent or weak [
17,
18,
30]. Moreover, even a statistically significant effect should still be interpreted with caution since the effects might be small and the clinical relevance uncertain. Second, the evidence is sparse and not robust, not only because of between-trial heterogeneity, but also because of high within-trial patient heterogeneity, combined with little or no individualization in the treatment protocols. In turn, an effect of an inotrope might be present for certain (groups of) patients equalized by harm of the same inotrope in other (groups of) patients in the same trial [
31]. As part of patient heterogeneity, the underlying pathophysiology and its impact on hemodynamics may be incompletely understood and therefore, choosing the right agent might be difficult. Third, the optimal therapeutic targets for individual patients or groups of patients are unknown. More data have recently become available supporting different targets in different patients, an example being blood pressure [
32]. Furthermore, specific targets for a variable such as CO or cardiac index might be suboptimal. For one patient, a CO of 3.0 L min
−1 might be sufficient to maintain organ perfusion, for another patient, this level of CO might be associated with organ hypoperfusion and organ dysfunction. Clearly, bedside titration of inotropes, based on individual patient responses, seems the most rational approach, but defining what those resuscitation targets should be, remains difficult. Finally, despite being available for many years (except for levosimendan in some countries), the optimal use of inotropes is incompletely understood, particularly beyond the choice of the first-line agent. Optimal treatment concepts for timing, dosing, interaction, and preferred combination of agents remain ill-defined.
Standard of care or daily practice is obviously not uniform among the respondents. Solid meta-analyses of all inotropes, performed according to contemporary standards and taking into account bias from funding sources, should become available and updated if new evidence arises [
17,
30]. Outcome measures should be uniformly defined and incorporate patient-centred outcomes and not limited to surrogate outcomes such as CO. Therefore, triggers and goals/targets for treatment should be optimized by interpreting evidence of studies on hemodynamic monitoring.
Although primarily being a vasopressor, norepinephrine (in combination with dobutamine) was considered a preferred catecholamine for the treatment of circulatory shock. Even among experts there was disagreement on whether norepinephrine should be considered a pure vasoconstrictor or an agent with combined vasopressor and inotropic effects. Actually, through beta-1 adrenergic receptor stimulation, norepinephrine has been shown to increase systemic and microcirculatory blood flow along with blood pressure and preload in patients with septic shock [
33‐
36]. Some clinicians might think of norepinephrine and also epinephrine as pure vasopressors because of their most dominant physiological effect, whereas others see it as a vasopressor with clinically relevant inotropic effects that may be enough to support contractility as a single agent. The difficult to target inotropic effect (these agents are titrated primarily based on their vasopressor effect) and their potential arrhythmogenic effects at high doses should be taken into account when these agents are used in this context. Epinephrine was hardly cited, possibly due to studies indicating safety concerns [
37,
38].
Another interesting result is that most experts recommended using more than one inotropic agent in the same patient. Reasons for this might be synergistic effects by adding an independent mechanism of action, e.g., in case of adrenoceptor downregulation, or the wish to limit the dose and side effects of each agent [
6].
The majority of the respondents of the survey as well as the experts chose dobutamine as preferred inotrope in patients with hypoperfusion to increase CO, which is in accordance with current guidelines [
8,
9,
24]. More evidence might come from the ongoing ADAPT multicenter trial (ClinicalTrials.gov ID: NCT04166331), which tests the hypothesis that dobutamine will reduce tissue hypoperfusion and associated organ dysfunctions in patients with septic shock and associated septic cardiomyopathy.
Since clinicians prefer having recommendations accompanying evidence summaries in the context of low certainty of evidence [
39], we asked international experts in the field to draft and agree on recommendations regarding inotropic treatment. In general, experts agreed that a recommended trigger for starting inotropic treatment should also be a therapeutic target, except for LVEF. Less than half of the experts using LVEF as a trigger for the use of an inotrope, also considered LVEF as the target for this use. This might be due to LVEF not being a continuously available variable, and its value is considered less reliable since it is mostly based on rough estimation of echocardiographic images (eyeballing) rather than exact measurements in clinical practice.
In view of the lack of evidence on the use of inotropes in circulatory shock, we suggest the following research agenda for the coming years:
1.
Determine univocal and personalized triggers and targets to start inotrope therapy in circulatory shock states.
Current evidence and expert opinion differ on the initial triggers to start and then guide inotrope therapy as targets in patients with circulatory shock. Consensus needs to be established on which triggers and target endpoints to use, ideally based on data rather than on expert opinion alone. These could be macro-hemodynamic values (e.g., cardiac output), surrogates of regional (organ) blood flow, or microcirculatory values (tissue perfusion, peripheral circulation) [
40].
As an example, interventional trials have used various triggers to initiate inotropic therapy such as “shock”, “low ejection fraction”, “low cardiac index” or “low SvO2 not responding to fluids”. Also, some trials use a fixed dose while others attempt to reach a given value of cardiac index or SvO2 or an improvement in a given variable (lactate, capillary refill time, microcirculation variables, etc.). It should be determined whether these triggers and targets should be identical for all patients or individualized based on cardiac function, organ perfusion, and underlying patient condition establishing an individualized benefit/risk profile.
2.
Determine pharmacokinetics and pharmacodynamics of inotropes in shock.
Little is known about the pharmacokinetics and pharmacodynamics (e.g., clearance) of available inotropes in the presence of shock. Information on clearance and uptake of inotropes in shock may have implications for specific aspects related to the timing of interventions, the weaning of these drugs, limiting the risk of delayed hemodynamic failure or rebound effects. This might also include research on the concomitant use of other medication (e.g., beta-blockers) and the effects of the various inotropes on the host (inflammatory or immune) response [
41]. Finally, the individual variation in responses to inotropic drugs related to genetic related alterations in receptors and/or signaling pathways should be evaluated.
3.
Compare and combine available inotropic agents and identify new, safer inotropes.
Further multicenter randomized controlled trials (with adaptive designs) are needed to compare different inotropic agents (a vs. b) and their combinations (a + b vs. a or b alone) on different outcomes such as organ function, adverse effects and survival. For instance, combining two inotropic agents acting through different mechanisms or receptors (e.g., dobutamine + levosimendan) could permit minimizing the doses of each drug, thus reducing the incidence of adverse effects and increasing safety. The choice of combination should be based on the pharmacologic properties of the different agents (see point 2). New, non-catecholamine inotropic agents that are not associated with side effects such as arrhythmia or hypotension should be identified and tested.
4.
Combine inotrope therapy with personalized care bundle.
While inotrope use needs to be personalized in future research, the other mainstays of circulatory shock treatment must be employed in a similar personalized manner to improve comparability. For instance, optimal MAP targets in circulatory shock and the role of fluid therapy should ideally be established as these will influence inotrope therapy. However, this in itself will be challenging as there is no current consensus on types of fluid, monitoring and other interventions being delivered, nor on how to adopt an optimal personalized approach. For example, a one-size-fits-all approach for MAP targets cannot be optimal.
5.
Develop and implement core outcome sets for patients with circulatory shock.
Core outcome sets (i.e., standardized collection of outcomes measured and reported in all trials for a specific clinical area) should be developed for circulatory shock research due to established inconsistencies in trial outcome selection. Any new trial assessing the benefit/risk of inotropes should include the selection of an adequately targeted study population to improve the “noise/signal ratio” inherent to heterogeneous cohorts (in terms of hemodynamic profile).
6.
Evaluate the impact of prolonged (> 72 h) inotropic therapy on myocardial energetics.
Experimental and clinical data on inotrope use demonstrate direct effects of inotropes on myocardial injury, energetics and modulation of the immune/inflammatory response. The relevance of this to further organ injury and patient outcomes needs to be established. Data from experimental and clinical studies in chronic heart failure suggest that long-term inotropic therapy leads to interstitial calcinosis, myocardial fibrosis and contraction band necrosis [
42]. Does this also apply to the context of shock where the duration of inotropic stimulation is expected to be shorter (less than one month)? What is the maximal duration of intravenous inotropic therapy before receptor down regulation, diastolic dysfunction, myocardial injury, and persistent arrhythmias develop in this setting?
7.
Establish specific use of inotropes in patients under mechanical circulatory support.
The use of inotropic agents should be adapted in patients under mechanical circulatory support for cardiogenic shock secondary to acute myocardial infarction. When are these agents indicated in this specific setting, and which hemodynamic targets should be used? The purpose of inotropic stimulation and the choice and doses of the inotropic agent may not be identical at the initiation of mechanical circulatory support, during the maintenance phase, or during the weaning process.
8.
Evaluate the best hemodynamic strategy in predominant right ventricular failure.
In patients with circulatory shock, which is predominantly associated with right ventricular failure, the question should be answered by comparative effectiveness trials if inotropic agents or vasopressors (e.g., norepinephrine to increase coronary perfusion pressure) should be preferred.
9.
Better define the interaction between IV fluids and vasoactive agents.
The physiologic interplay between vasoactive agents and intravenous fluids is evident, but the scientific evidence in terms of comparative effectiveness trials (fluids vs. early vasopressor use, addition of inotropes, etc.) is scarce. For instance, inotropic agents can only increase myocardial contractility, lusitropy, and heart rate. They do not primarily increase cardiac output. For cardiac output to increase there also needs to be sufficient blood volume and vascular tone, as known from the poor impact of inotropic agents in hemorrhagic shock and profound vasoplegia. Therefore, the optimal vasopressor/fluid/inotrope ratio remains to be determined at the individual level.
Ongoing and upcoming studies such as ADAPT (NCT04166331: Effects of dobutamine on tissue hypoperfusion and associated organ dysfunctions in patients with septic shock and associated septic cardiomyopathy) and LevoHeartShock (NCT04020263: Early use of levosimendan versus placebo on top of conventional inotropes in patients with cardiogenic shock) will probably provide important answers to some of these questions.
Limitations
The number of responses is considered high (corresponding to 27% of ESICM members who opened the e-mail invite), but the methods used to invite individuals to respond did not allow us to report a conclusive response rate. Therefore, response bias might be present, in which case, external validity could be somewhat hampered.
The results presented in this manuscript come from an online survey. Online surveys have limitations like potential multiple responses by a single person. We did not use cookies or log-file/IP address analyses to prevent multiple responses. On the other hand, individual persons are unlikely to spend time answering a survey more than once. Another limitation is the multiple-choice character of our survey, limiting answers to those offered. In addition, studies published after the survey was performed [
38,
43‐
46] might have altered the answers of the respondents. Nevertheless, after careful analysis of the results of those studies we believe that the experts’ recommendation would not have changed significantly. Furthermore, the recommendations of experts can only reach excellent agreement if the available evidence is solid and clear. The evidence for inotropes in circulatory shock lack this evidence for many questions raised. Furthermore, both patients and studies show high heterogeneity. Therefore, recommendations should be interpreted with caution.
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