This study is part of a project intended to develop guidelines to optimise the dosing of fentanyl in intensive care patients.

This study will focus on determining:

• Whether the pharmacokinetics of fentanyl change during the ICU stay.
• To what extent / the degree of change in fentanyl pharmacokinetics in ICU patients.
• Which factors (e.g. physiological variables) that cause such a change.
• Based on simulations, determine context-sensitive half-times of fentanyl in ICU patients.

Background:

Patients admitted to the Intensive Care Unit (ICU) for treatment involving mechanical ventilation will be in need of sedation and analgesia in order to relieve pain and discomfort from necessary therapeutic procedures (1-7). The opioid fentanyl is frequently used as part of these sedation regimens(1-7).

The pharmacokinetics (PK) and pharmacodynamics (PD) of fentanyl after long-term administration in ICU patients has not been studied extensively. In a study in children (fentanyl infusion time 7-144 hrs.), increased volume of distribution was found when compared to data obtained after short-term use (9). The volume of distribution of alfentanil was increased when compared with data obtained after short-term use in a study of adult ICU patients sedated with propofol and alfentanil (a rapid-onset opioid) for 24 hrs. post-operatively (10). A similar increase in distribution volume of another opioid, sufentanil, was found in adult ICU patients (average sufentanil infusion time 12 days)(11).

Experience obtained during clinical anaesthesia suggests that the duration of action in fentanyl is significantly prolonged after long-term intravenous infusions (12-13). This property of fentanyl seems to be caused by a combination of factors. Since fentanyl has a large volume of distribution there will be a continuous return of the drug from peripheral tissues, and the concentration of fentanyl in plasma will be maintained in a clinically active range for some time after a fentanyl infusion has been terminated (9). Fentanyl also potentiates the sedative effects of e.g. propofol and midazolam which contributes to a further protraction of the wake-up time (14-15).

In ICU patients these undesirable effects of fentanyl will probably be amplified as a result of major changes in volume of distribution and administration of fentanyl infusions for extensive periods of time (weeks). The investigators believe that knowledge of the PK of fentanyl in this population will be valuable to help designing optimised infusion regimens of fentanyl in the clinical setting of the ICU.

Study Objective:

The main study objective is to determine wether the pharmacokinetics of fentanyl change during the ICU stay, and the extent of this change. The investigators will try to unveil which factors (e.g physiological variables) that cause such change, and based on simulations, determine context-sensitive half-times of fentanyl in ICU patients. As a result of this study the investigators aim to develop an infusion pump program to predict fentanyl plasma concentrations, and the recovery time of fentanyl effect (time to plasma concentration 1 ng/ml). Furthermore the investigators intend to test if the fentanyl infusion pump program predicts fentanyl plasma concentrations in a separate group of ICU patients.

Study Procedures:

In this study there will not be administration of an investigational product per study protocol. The dosage and administration of fentanyl will be according to the ICUs established procedures and the treating physician's judgment of what is appropriate for the patient. In the ICUs of Oslo University Hospital fentanyl is administered intravenously as a continuous infusion on an infusion pump System or if needed as single bolus doses given by a handheld syringe. By routine ICUs in Oslo University Hospital usually dose the fentanyl infusion as 0,5 - 6 μg/kg/hrs, where kg is a calculation of the patients Ideal Body Weight. The fentanyl used is from marketed stock in the ICUs and is delivered by the hospital pharmacy. All medication is labelled with information and stored according to local regulations. Participants will be recruited from surgical, neurosurgical and medical ICUs.

On study days the investigator will screen the patients admitted to the ICU during the last 24 hrs. If patients are eligible for the study due to the selection criteria, they will be included in a chronological order.

Each subject must give his/hers informed consent. The gravity of the clinical situation for ICU patients may preclude informed consent before inclusion in the study. In that case, the patient's relatives (or legal representative) will receive information about the study, and will be provided the opportunity to express their opinion. If the patient´s relatives (or legal representative) are against participation, the patient will not be included.

Daily sedation cessation and spontaneous awakening trials are implemented as standard treatment regimens in the ICU's of Oslo University Hospital. In this study the investigators intend to collect blood samples over a sedation cessation period, when no fentanyl is to be administered to the patient. If the participants needs opioid analgesia during this period, alternative opioid painkillers will be given.

The first blood sample will be collected right before administration of fentanyl is to be temporarily stopped. During the following hours repeated samples will be collected. The samples will be collected randomly within a time block containing consecutive time points. Each participant will accordingly contribute samples from the entire collection time period. Fentanyl will again be given as prescribed by the treating physician when the sedation cessation period has ended.

Samples will be spinned and stored on ice in a biobank for later analysis at The Dept. of Clinical Pharmacology, St.Olavs Hospital, Trondheim, Norway.

If participants in the study undergo treatment with continuous veno venous haemodialysis (CVVHD), investigators want to assess whether haemodialysis influences the degree of change in fentanyl PK. Haemodialysis is thought to have minimal effect upon the clearance of fentanyl, since fentanyl is mostly cleared by non-renal mechanisms. In addition fentanyl has high molecular weight, high protein binding capacity, low water solubility and an abundant volume of distribution that make it less likely dialyzable (16-17). There will be collected blood samples from the prefilter and postfilter line of the hemodialysis machine to asses if the dialysis filter might absorb fentanyl and remove drug from the circulation. The sampling times will follow the predefined block-sampling regimen of the arterial blood tests. Investigators also plan to calculate dialysis clearance of fentanyl in a subset of 10 patients.

Fentanyl is primarily metabolized in the liver by the Cytochrome P450 3A (CYP3A) enzymatic route (18-19). A study of genetic markers and polymorphism in the genes coding for these enzymes could possibly explain some of the variation in fentanyl PK in the ICU population (20-21). There will be collected a blood sample for later DNA processing to search for relevant genetic markers and polymorphisms in Cytochrome P450 enzymes.

The main metabolite of fentanyl is norfentanyl (18-19). Concentration of norfentanyl in the daily arterial blood samples will be quantified to make it possible to calculate the metabolic ratio of fentanyl/norfentanyl. The metabolic ratio will indicate to which extent each participant metabolizes fentanyl without having to take the plasma concentrations into account.

Norfentanyl is eliminated by the kidneys(18-19). There will be taken daily samples of urine to determine the urine concentrations of this metabolite.

To further asses possible covariates of fentanyl PK, patient demographics, medical history, co-morbidity, data descriptive of the population, concomitant medication and daily registrations of organ function parameters will be recorded for each patient during the study period.

Assessments and blood sampling will continue as long as the patient needs artificial ventilation and are treated with significant amounts of fentanyl.

Inclusion Criteria:

• Consecutive patients admitted to the ICU at Oslo University Hospital - Ullevål, in whom mechanical ventilation for > 72 hrs. is expected
• Aged 18 - 80 years, both inclusive
• Serum beta-HCG negative if female of childbearing potential, aged 18 - 45 years (both inclusive)

Exclusion Criteria:

• Tracheally intubated > 12 hrs. before admittance to the ICU
• Known hypersensitivity to fentanyl or other opioids
• Post partum < 6 weeks and/or lactating
• Informed consent not received
• Any reason why, in the opinion of the investigator and/or the treating physicians, the patient should not participate in the study