Elsevier

Resuscitation

Volume 149, April 2020, Pages 10-16
Resuscitation

Clinical paper
Safe prognostication following cardiac arrest: The role of the pharmacokinetics of fentanyl in patients treated with targeted temperature management

https://doi.org/10.1016/j.resuscitation.2020.01.028Get rights and content

Abstract

Background

Neurological prognostication following cardiac arrest (CA) is complex and sedative agents may significantly impair responses to clinical examination. This study investigates the elimination of fentanyl in patients treated with targeted temperature management (TTM).

Methods

We measured the blood concentration of fentanyl in 23 post-cardiac arrest patients treated with TTM following discontinuation of continuous infusion. Fentanyl was discontinued when the patients were rewarmed to a temperature of 36–36.5 °C and a blood sample taken 12 h later. Measured concentrations were compared with predicted concentrations using population pharmacokinetic parameters. Variables likely to prolong half-life were analysed using a multivariate regression model.

Results

We found a statistically significant difference between median measured and predicted concentrations (measured 0.93 μg/L [range 0.11–8.29 μg/L] vs. predicted 0.30 μg/L [range 0.16-0.59 μg/L]; p < 0.05). Univariate analysis identified a significant relationship between estimated fentanyl half-life and serum lactate concentrations (r = 0.45, p < 0.05). Multivariate linear regression identified two variables (SAPS score and genotype), which together were able to explain approximately 30 % of the variation in the population (adjusted R2 = 0.3177, p = 0.0194). No significant relationships were found between fentanyl half-life and patients’ clinical or biochemical variables or co-administration of drugs metabolized by cytochrome p450.

Conclusions

There is marked variation in the clearance of fentanyl following continuous infusion during TTM after CA which correlates with illness severity, lactate concentration and genetic polymorphisms of the cytochrome p450 liver enzymes. Sustained presence of fentanyl may influence response to neurological examination at 12 h post discontinuation in patients receiving the drug as an infusion as part of TTM.

Introduction

Neurological prognostication following cardiac arrest (CA) is complex and sedative agents may significantly impair responses elicited during clinical examination as part of multifactor assessment of patients.1 The European Resuscitation Council recommends waiting 12 h from stopping sedative infusions before prognostication, accepting the limited evidence for this recommendation.1 In patients who have received sedatives less than 12 h before neurological assessment the reliability of clinical examination may be reduced, but a 12 h delay in prognostication may be insufficient in patients treated with targeted temperature management (TTM).2, 3 Whilst the recommendation is to wait for longer than 12 h before prognostication following TTM, the pharmacokinetics and potential accumulation of drugs infused during this period is unknown and as the infusions may be continued into the normothermic period, of clinical significance.

There is a recognised subset of patients with delayed awakening and good outcome following CA who may have unfavourable neurological signs at 48 h following discontinuation of TTM and sedation.3, 4, 5 Both animal and human research demonstrates that hypothermia delays the clearance of opioid drugs.6, 7, 8, 9, 10 The clearance of fentanyl is significantly lower in hypothermic patients, being reduced by as much as 45 % in some cases.7, 11 There is evidence that concomitant administration of CYP3A substrates/inhibitor drugs commonly used on the ICU also reduces metabolism of fentanyl.12 Polymorphisms in the gene coding for CYP3A5 liver enzymes can also potentially influence fentanyl plasma levels.13 It is not known how these multiple factors may influence the elimination of fentanyl in patients treated with TTM after CA.

We hypothesised that in patients receiving TTM following CA, concentrations of fentanyl will be significantly higher than would be expected based upon their dose rate, and population estimates of volume of distribution (V) and half-life (t1/2) under normal conditions (i.e. the absence of TTM). A secondary consideration is that there may be certain clinical factors, including organ perfusion, genotype, and patient characteristics that can be used to predict patients with residual plasma fentanyl at 12 h post-infusion.

Section snippets

Materials and methods

The Health Research Authority approved our protocol in June 2016 IRAS 178665.

Recruitment and patient demographics

Seventy-two patients were initially considered for recruitment. 23 of these were excluded, as they did not receive TTM. 25 patients were withdrawn from the study as their clinical condition prevented discontinuation of fentanyl on rewarming. One patient had a blood sample taken for fentanyl analysis at an incorrect time. Twenty-three patients completed the study, two of which were re-warmed prior to fentanyl being stopped (Fig. 1). All patients were sedated with propofol, which was stopped with

Pharmacokinetics of fentanyl

The American College of Critical Care Medicine practice guidelines consider fentanyl by infusion in ICU patients to have a context-sensitive half-life of 300 min after 12 h.21 During prolonged infusion there is an increased volume of distribution presumably due to equilibration between plasma and deep tissues,22 which may also effect the alpha-distribution phase. Patients may have a terminal half-life of fentanyl of greater than 12 h even with normal organ function if they received a continuous

Conclusion

There is marked variation in the clearance of fentanyl by continuous infusion following TTM after CA. This correlates with illness severity, lactate concentration and genetic polymorphisms of the cytochrome p450 liver enzymes but not age, BMI, renal dysfunction or drug administration. Great care should be taken when assessing neurological function in patients sedated with fentanyl and receiving TTM as the half-life of fentanyl might be increased to a clinically relevant degree. Further work

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee Health Research Authority IRAS 178665 and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

The study was funded by NHS Blood and Transplant from a grant provided by the Brighton and Sussex University Hospitals NHS Trust Organ Donation Committee.

Conflicts of interest

None

Acknowledgements

We are grateful for the contributions of Carl Egan and Laura Ortiz-Ruiz De Gordoa for assisting with data collection for this study.

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