Elsevier

Resuscitation

Volume 144, November 2019, Pages 54-59
Resuscitation

Clinical paper
Elimination of glutamate using CRRT for 72 h in patients with post-cardiac arrest syndrome: A randomized clinical pilot trial

https://doi.org/10.1016/j.resuscitation.2019.09.020Get rights and content

Abstract

Aim

Glutamine and glutamate are major mediators of secondary brain cell death during post-cardiac arrest syndrome. As there is an equilibrium between brain tissue and plasma concentrations of glutamine and glutamate, their elimination from systemic circulation by extracorporeal blood purification may ultimately lead to reduced secondary cell death in the brain. We hypothesized that systemic glutamine and glutamate can be significantly reduced by continuous venovenous hemodiafiltration (CVVHDF).

Methods

This was a prospective, randomized clinical trial in post cardiac-arrest survivors evaluating standard of care or additional CVVHDF over 72 h immediately after admission. Glutamine and glutamate plasma concentrations were analyzed at eight time points in both groups. Primary endpoint was reduction of glutamine and glutamate plasma concentrations. The trial has been registered at clinical trial.gov (NCT02963298).

Results

In total, 41 patients were randomized over a period of 12 months (control n = 21, CVVHDF n = 20). The primary aim reduction of glutamine and glutamate plasma concentrations by CVVHDF, was not achieved; both groups-maintained concentrations within a normal range over the study period (glutamate: 4.7–11.1 mg/dL; glutamine: 0.2–3.7 mg/dL). However, post-filter concentrations of glutamine and glutamate in CRRT patients were significantly decreased as compared to pre-filter concentrations (glutamate: pre-filter median 8.85 mg/dL IQR 7.1–9.6; post-filter 0.95 mg/dL IQR 0.5–2; p < 0.001; glutamine: pre-filter 0.7 mg/dL IQR 0.6–1; post-filter 0.2 mg/dL IQR 0–0.2; p < 0.001).

Conclusion

In this trial, CVVHDF was not able to statistically significantly lower systemic plasma glutamine and glutamate levels. Post-cardiac arrest patients had plasma glutamine and glutamate levels within the normal range.

Introduction

The severity of post-resuscitation syndrome is a major factor determining neurological outcome. Current guidelines recommend a combination of several treatments to ameliorate post-resuscitation syndrome, and therefore improve overall and neurological outcomes.1 It is well known that secondary cell death following return of spontaneous circulation can aggravate hypoxic brain damage2. Glutamate, an excitatory neurotransmitter, is an important excitotoxic mediator by inducing cellular calcium overload leading to apoptosis.3, 4 Glutamine can be generated in two enzymatic steps from glutamate, with equilibrium of both molecules in the body; therefore, reduction in plasma glutamine leads to decreased plasma glutamate. Additionally, as glutamate follows a gradient at the blood-brain barrier, its brain concentration can be decreased by lowering its plasma concentration.5, 6, 7 A reduction of glutamate by using different scavengers in rat models resulted in decreased neuronal injury.8, 9, 10, 11 To date, there are no clinical data in post-cardiac arrest patients to indicate whether a systemic reduction of plasma glutamate and glutamine concentrations by CVVHDF is feasible and safe, nor whether decreased concentrations ultimately result in improved neurological outcomes. This clinical feasibility study therefore aimed to evaluate the plasma concentrations of glutamate and glutamine over the first 72 h following hospital admission in patients randomized to either standard therapy or standard therapy plus CVVHDF.

Section snippets

Methods

This study was approved by the local ethics committee of the Charité-Universitätsmedizin Berlin (EA4/048/16) and registered at clinical trial.gov (NCT02963298). Written informed consent for trial participation was obtained by a legal custodian as all patients were undergoing sedation at time of inclusion. The design was a prospective, randomized open-label trial. Randomization was performed by use of a sealed envelope system following application of inclusion (out-of-hospital cardiac arrest,

Results

In total, 165 patients were admitted to our ICU following cardiac arrest between August 2016 and August 2017;41 were included in the trial (Fig. 1). There were no significant differences in baseline characteristics between groups in the study population (Table 1).

Discussion

The main results of this monocentric, randomized pilot trial were (1) patients after cardiac arrest had plasma glutamate and glutamine levels that were within normal limits, (2) there was no significant decrease in plasma glutamate concentration following CRRT, (3) there was no significant difference between randomized groups in terms of neurological prognostic parameters and neurological outcome, and (4) CRRT was used safely in patients after cardiac arrest and resuscitation for 72 h. Notably,

Limitations

First, this randomized pilot trial is small and has therefore limitations in interpretation. Second, the brain tissue concentration of glutamate and glutamine was not known in the investigated group and our findings of glutamate and glutamine within the normal range could be a limitation as well. Third, randomization was performed by a sealed envelope system instead of more advanced techniques such as central phone or computer methods. Fourth, post cardiac arrest patients are known to be

Conclusion

This randomized clinical pilot trial showed that post-cardiac arrest patients have normal plasma concentrations of glutamate and glutamine, both initially on presentation and over the first 72 h following ROSC. In this study, there was no significant effect of CRRT on plasma levels. Neurological outcome was equally distributed among the two experimental groups; however, the sample size was small and not adequately powered for outcome analysis.

Follow-up studies are needed to determine if

Source of funding

The study was supported by a grant of 198.000€ by Fresenius Medical Care Deutschland GmbH.

Conflict of interest

CS has received honoraria as a speaker and consultant from BD BARD GmbH and Sedana Medical and as speaker from Zoll GmbH and Philips. CM and SS are full-time employees of Fresenius Medical Care Deutschland GmbH. AK has no conflict of interest related to this publication but independent from this publication and the presented topic, however, AK has a financial relationship to Pfizer Deutschland GmbH (Linkstraße 10, 10785 Berlin, Germany). CL has received remuneration for presentations and travel

References (17)

There are more references available in the full text version of this article.

Cited by (3)

View full text