Clinical paperSafe prognostication following cardiac arrest: The role of the pharmacokinetics of fentanyl in patients treated with targeted temperature management
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.
References (36)
- et al.
Pharmacokinetic drug interactions of synthetic opiate analgesics
Psychosomatics
(2009) - et al.
Estimating a drug’s elimination rate-constant or half-life from a single blood sample: a practical approach with particular benefits for critically ill/vulnerable patients
Biosystems
(2019) Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO)
Kidney Int
(2005)Pain management principles in the critically ill
Chest
(2009)Time to awakening after cardiac arrest and the association with target temperature management
Resuscitation
(2018)The current temperature: a survey of post-resuscitation management across Australian and New Zealand intensive care units
Austr Crit Care
(2018)- et al.
Decreased use of active temperature management following publication of the TTM trial
Resuscitation
(2017) Comparison of two sedation regimens during targeted temperature management after cardiac arrest
Resuscitation
(2018)Prognostication in comatose survivors of cardiac arrest: an advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine
Intensive Care Med
(2014)Sedation confounds outcome prediction in cardiac arrest survivors treated with hypothermia
Neurocrit Care
(2011)
Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest
Pharmacotherapy
Delayed awakening after cardiac arrest: prevalence and risk factors in the Parisian registry
Intensive Care Med
Targeted temperature management at 33 °C versus 36 °C after cardiac arrest
N Engl J Med
The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs
Anesth Analg
Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients
Drug Metab Dispos
Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest
Crit Care Med
Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats
Crit Care Med
The influence of hypothermia on the disposition of fentanyl—Human and animal studies
Eur J Clin Pharmacol
Cited by (3)
Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole – A probe drug of CYP2C19 metabolism
2022, Biomedicine and PharmacotherapyCitation Excerpt :Additionally, Baldwin et al. showed that the half-life of fentanyl, which is metabolized by CYP3A4, is significantly longer in patients after cardiac arrest undergoing TTM compared to healthy controls, but not compared to an ICU population. This study examined plasma levels 12 h after cessation of continuous administration and compared them to expected levels in historical control groups [42]. Interestingly, although fentanyl is metabolized via CYP3A4, they observed a 46% reduced clearance, which is comparable to our data (−40% in P1).
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