Perspectives on adjunctive use of ketamine for analgosedation during extracorporeal membrane oxygenation

ABSTRACT

Analgosedation on ECMO is more than the choice of any drug, it has to be context specific. Ketamine may be considered as an adjunctive therapy in patients requiring high-dose opioids and sedatives during ECMO support with difficulty to achieve a target RASS. Considering ketamine provides analgesia while maintaining airway reflexes, it could be useful for early ECMO weaning and use of ECMO in awake, non-intubated, spontaneously breathing patients with respiratory failure (‘awake’ ECMO), especially for patients having considerable waiting periods while being bridged to transplant. The hemodynamic effects of ketamine may provide the benefit of decreasing vasopressor requirements, thereby potentially improving microcirculation. In this context, the effects on end-organ function and the need for renal replacement therapy should be investigated. Pharmacokinetic and pharmacodynamic studies on ketamine ex- and in vivo are of utmost importance to delineate its pharmacological profile and effectiveness during ECMO therapy and to create admissible future study hypothesis.

KEYWORDS:

• Analgesics
• awake ECMO
• ECLS
• ECMO
• ketamine
• pharmacodynamics
• pharmacokinetics
• sedatives
• transplant

1. Introduction

Extra-corporeal membrane oxygenation (ECMO) is a miniaturized evolution from cardiopulmonary bypass (CPB) and is among the most frequently used forms of Extracorporeal life support (ECLS). It can be viewed as a spectrum of modalities that provide cardiac (veno-arterial, VA) [1], respiratory (veno-venous, VV) [2] or combined cardiorespiratory support for extended periods of up to several months [3]. Since Bartlett et al. [4] successfully supported the first newborn with ECMO in 1975, ECMO has been used with great and growing enthusiasm in both the pediatric and adult population and is nowadays even used for extended resuscitation in patients with cardiac arrest (E-CPR) [5]. The complexity of management and the relevant complications limit its use to specialized centers. However, over the last decade, the development of new materials and the simplification of procedures and devices and adapted coagulation management has led to a significant increase in the centers providing ECLS and in the number of ECMO runs worldwide, for both cardiocirculatory and respiratory indications [6]. It is important to note that ECMO is a supportive treatment that can be used as bridge to either recovery, as bridge to other forms of mechanical circulatory support such as ventricular assist devices (VAD) and as bridge to cardiac/pulmonary transplantation or organ donation. As for bridge to recovery, the underlying pathology needs to be addressed and treated to liberate the patient from mechanical support. Despite the expansion of research and knowledge on ECMO, generally accepted guidelines are missing and the clinical management of ECMO remains primarily based on local protocols and experience [3].

2. Pharmacotherapy during ECMO support

One of the most challenging aspects in ECMO research and in achieving optimal patient outcome is the development of effective pharmacotherapy. The understanding of pharmacokinetics (PK) and pharmacodynamics (PD) is crucial since the ECMO circuitry profoundly increases the volume of distribution (Vd) by sequestration and hemodilution. Decreased organ perfusion and microcirculatory failure may also contribute to end-organ damage/failure, often involving kidneys and liver, thereby alterating drug clearance. Degradation of drugs may further worsen PK derangements. ECMO has also been shown to exacerbate the PK alterations of some drugs and may lead to either therapeutic failure or toxicity [7].

Most recently, Cheng et al. [8] published an excellent review article, summarizing the present literature on antimicrobials, sedatives, and analgesics during ECMO. They clearly delineated the PK/PD of several drugs based on their group’s extensive contribution to pharmacological research in ex vivo models with ECMO circuits and in vivo using large animal models of ECMO [9]. Following their substantial work in this field, we would like to give a clinical perspective on analgosedation during ECMO support.

2.1. Analgosedation during ECMO support

Patients undergoing ECMO are often paralyzed and deeply analgosedated to achieve optimal circuit flow and ventilation. In addition, psychological protection from pain and anxiety is often required. These drugs can be titrated at the bedside to achieve the set goals and to overcome problems such as sequestration and tachyphylaxis, they also carry a high risk of dependency as elevated analgosedative requirements can continue throughout the course of ECMO support. When focusing on the pharmacological effects of analgesics and sedatives for ECMO, opioids such as fentanyl and morphine are frequently used by many providers. Fentanyl is highly lipophilic and showed a mean drug loss of 97% in ex vivo studies, while the hydrophilic morphine demonstrated 99% drug recovery in the same study, indicating the significant superiority of morphine in this specific setting [8]. Similar to the results of fentanyl, benzodiazepines like midazolam show significant sequestration in ex vivo with 50% sequestration of the drug into the circuit within the first hour. Other sedatives such as dexmedetomidine and propofol are moderately to highly lipophilic with a high degree of sequestration and require, similar to midazolam, higher initial loading and higher daily doses [8]. When critically reviewing the scarce data and evidence available, the pharmacological profile of morphine presently may represent the drug of choice for analgosedation during ECMO support.

Other opioids like alfentanil and remifentanil are also lipophilic and their potential effects may be very similar to fentanyl. In a PubMed search for this manuscript, we have not found any study on alfentanil and only one study on remifentanil in critically ill adult patients receiving VA-ECMO. Remifentanil concentrations were affected by sex and ECMO pump speed, volume and clearance were increased in these patients compared with previously reported patients not on ECMO, and remifentanil dosing needed to be increased to achieve the desired level of sedation [10].

2.2. Ketamine during ECMO support

A drug that has not yet been included in PK and PD studies is ketamine. This may be a promising adjunct to opioids and sedatives in the setting of ECMO. It is a noncompetitive antagonist at the N-methyl-d- aspartate (NMDA) receptor that blocks glutamate, causing dissociation of the thalamus from the limbic cortex, providing analgesia with relative hemodynamic stability, while maintaining airway reflexes. Ketamine also exhibits hypnotic and amnestic properties that may be beneficial. The ability to increase blood pressure and cardiac output add to the favorable profile of this agent, especially in non-cardiac patients for VV ECMO who are not at risk for coronary ischemia as compared to patients who require VA ECMO for cardiocirculatory support. However, ketamine may also have undesirable side effects, such as dose-related hallucinations, delirium, lacrimation, tachycardia, and the potential for increased intracranial pressure as well as coronary ischemia as mentioned above. Ketamine shows different affinities and activity on opioid receptors, and may be synergistically used with morphine, which has been shown to improve pain perception and an opioid-sparing effect. Recent data suggest that combination of opioids with low doses of ketamine may not be associated with adverse events and may improve outcomes in the critically ill population [11].

To date, ketamine has only been reported in a small number of case reports and low patient number studies and an optimal dosing strategy is not clear. Floroff et al. [12] described the case of a patient with hypoxic respiratory failure requiring ECMO. No adverse effects were reported and while receiving low-dose ketamine, infusion rates of opioids and/or sedatives were maintained or decreased. The report illustrated that use of low-dose ketamine infusion may be a useful adjunctive agent to high-dose opioid and sedative medications during ECMO support. In a retrospective cohort study of 26 ECMO patients receiving ketamine infusion, ketamine initiation was associated with a decrease in vasopressor requirement in 11/26 patients within 2 h, and 0/26 required an increase (p < 0.001). All patients were receiving sedative and/or opioid infusions at the time of ketamine initiation; 9/26 had a decrease in these infusions within 2 h of ketamine initiation, and 1/26 had an increase. The median RASS score did not change before and after ketamine was started [13].

In contrast, Dzierba et al. [14] reported that in a small study of 20 patients (N = 10 standard sedation practice = control group; N = 10 standard sedation practice plus low dose ketamine infusion = protocol group), the addition of ketamine to standard sedation did not reduce the use of sedatives or opioids. Despite these findings, patients’ receiving low-dose ketamine infusion had similar improvements in their RASS scores over the 72 h after decision to achieve wakefulness (DTAW). The authors observed increased requirements in the protocol group may be in part due to titration to other parameters such as respiratory rate despite a RASS score of −5, or the lack of a standardized sedation protocol. Additionally, while ketamine may have provided synergistic sedative effects, the non-protocolized use of the other sedatives may have prevented their down titration due to a lack of experience in the combined use with ketamine.

In another case report under different circumstances, ketamine was also satisfactorily used for palliative sedation and symptom management in a patient on very high doses of opioids and sedatives prior to discontinuation of life-sustaining ECMO treatment [15].

3. Expert opinion

Analgosedation on ECMO is more than the choice of any drug, it has to be context specific. Ketamine, even though lipophilic and therefore in theory in a suboptimal category of drugs to be used for ECMO, may be considered as an adjunctive therapy in patients requiring high-dose opioids and sedatives during ECMO support with difficulty to achieve a target RASS. The growing research and publications on all aspects of ECLS are not only much-needed, but imperative to further develop the management of these patients. Future studies should focus on protocolized withdrawal of standard sedatives and analgesics in these patients to clearly delineate the effects of adjunctive ketamine. Considering ketamine provides analgesia while maintaining airway reflexes, it could be the ideal drug for early ECMO weaning and use of ECMO in awake, non-intubated, spontaneously breathing patients with respiratory failure (‘awake’ ECMO). There is a strong rationale for this type of respiratory support as it avoids several side effects related to sedation, intubation, and mechanical ventilation and may especially be useful for patients having considerable waiting periods while being bridged to VAD or transplant. However, data is presently scarce and prospective trials are needed. In addition, the hemodynamic effects of ketamine may provide the benefit of decreasing vasopressor requirements, thereby potentially improving microcirculation. In this context, the effects on end-organ function and the need for renal replacement therapy should be investigated. PK and PD studies on ketamine ex- and in vivo are of utmost importance to delineate its pharmacological profile and effectiveness during ECMO therapy and to create admissible future study hypothesis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.