Which inotropes to use

Furthermore, specific targets for a variable such as CO or cardiac index might be suboptimal. For one patient, a CO of 3. 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. 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 , 34 , 35 , 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. 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 ].

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. 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:. 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. Also, some trials use a fixed dose while others attempt to reach a given value of cardiac index or SvO 2 or an improvement in a given variable lactate, capillary refill time, microcirculation variables, etc.

Little is known about the pharmacokinetics and pharmacodynamics e. 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. Further multicenter randomized controlled trials with adaptive designs are needed to compare different inotropic agents a vs.

For instance, combining two inotropic agents acting through different mechanisms or receptors e. 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. 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. Core outcome sets i. 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?

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.

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. The physiologic interplay between vasoactive agents and intravenous fluids is evident, but the scientific evidence in terms of comparative effectiveness trials fluids vs.

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. Ongoing and upcoming studies such as ADAPT NCT Effects of dobutamine on tissue hypoperfusion and associated organ dysfunctions in patients with septic shock and associated septic cardiomyopathy and LevoHeartShock NCT 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.

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. 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 , 44 , 45 , 46 ] might have altered the answers of the respondents.

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. In conclusion, the use of inotropes in critically ill patients is quite heterogeneous as reported by individual caregivers.

While experts recommend using dobutamine as the first-line agent, they recommend against the use of dopamine. Future studies reporting patient-centred outcomes should focus on specific subpopulations based on prespecified and measurable triggers, targets, and with clear stopping criteria in order to ensure comparability across trials.

This would allow a better summary of the evidence and its implementation in future guidelines. Does dopamine administration in shock influence outcome? Crit Care Med. Consensus on circulatory shock and hemodynamic monitoring. Consult with your doctor about your dosage and the consumption of grapefruit. You should also avoid alcohol and beverages that contain caffeine, such as coffee, tea, and soft drinks. You should not take positive inotropes if you are already taking negative inotropes, such as beta-blockers, calcium channel blockers, or antiarrhythmics, unless your doctor has prescribed both.

These medicines can be taken together, but only your doctor can prescribe the right balance of each. Talk to your doctor about your medical history before you start taking inotropes. The risks of taking the medicine need to be weighed against its benefits. Here are some things to consider if you and your doctor are deciding whether you should begin taking inotropes. Sometimes a medicine causes unwanted effects.

These are called side effects. Not all of the side effects for inotropes are listed here. If you feel these or any other effects, you should check with your doctor.

Many of these side effects are rare. Tell your doctor right away if you have any of these side effects. Do not stop taking your medicine unless your doctor tells you to.

If you stop taking your medicine without checking with your doctor, it can make your condition worse. The information in this Medicines for Cardiovascular Disease section has been taken from a number of sources.

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The mechanism of action is independent of adrenergic receptors and therefore PDE3inhibitors are particularly useful if these receptors have become down-regulated eg, in patients with chronic heart failure. Milrinone is the most commonly used PDE3 inhibitor. It has a relatively long half-life two hours and can accumulate inpatients with renal failure. Levosimendan is a novel inotrope that sensitises troponin-C to calcium, thereby increasing the force of contraction.

It also acts on potassium channels in smooth muscle to cause vasodilation. Levosimendan increases CO without increasing myocardial oxygen consumption. Levosimendan is administered as a continuous infusion with or without an initial bolus dose over 24 hours.

It has a half-life of about one hour, but active metabolites mean that the inotropic effect can continue for up to five days after the infusion has finished.

It is essential that pharmacists in critical care understand the pharmacology of inotropes and the haemodynamic monitoring required to ensure safe practice. Pharmacists can help to identify medicines that might need to be stopped when these therapies are started eg, beta-blockers. Effect of oral milrinone on mortality in severe chronic heart failure. New England Journal of Medicine ;— Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial FIRST.

American HeartJournal ;— ESC guidelines for the diagnosis and treatment of acute and chronic heart failure