Hyperalgesia, Persistent Pain, and Fentanyl Dosing in On-Pump Coronary Artery Bypass Grafting

Randomized, double-blinded, three arm study in adult patients undergoing first time coronary artery bypass grafting (CABG) surgery with median sternotomy. The investigators will examine the effects of three fentanyl dosing schemes (high-dose bolus, low-dose bolus, continuous dose) on the area of hyperalgesia and allodynia at 24 and 48h as well as on persisting pain at 3, 6, and 12 months. Additionally, the investigators will measure fentanyl concentrations throughout anesthesia.

A prospective, randomized, double-blinded (patient, anesthesiologist, assessor) clinical study. This study will examine three different clinically used application schemes of fentanyl, an opioid used as the standard of care in routine practice. Patients will be randomized to receive one of the following three treatment arms for anesthesia maintenance (pre-sternotomy): High-dose fentanyl bolus (20 µg/kg of body weight [BW]; e.g. 70kg 1400 µg or 1.4mg) Low-dose fentanyl bolus (3 µg/kg BW; e.g. 70kg 210 µg or 0.2mg) Continuous fentanyl application by Shibutani scheme This study will include data from 69 adult patients (23 per arm) undergoing first time, elective, on-pump CABG surgery with median sternotomy and central cannulation. Following randomization by the sealed envelope technique, fentanyl kits will be drawn up by an anesthesiologist not involved in patient care or outcome assessment. Patients with preexisting chronic pain, opioids in the last 30 days, a BMI>36kg/m2, sleep apnoea, renal failure (clearance <30ml/min), with neuraxial anesthesia, pregnant, with planned wound infiltration, known allergies/intolerance to opioids, and unable to understand pin-prick testing will be excluded. At induction, all patients will receive a standard 3 µg/kg bolus of fentanyl (not study medication, but rather standard of care). 5 minutes prior to sternotomy, the patient will receive analgesia maintenance (one of the three fentanyl study arms). Clinicians will at all times be able to administer a bolus of fentanyl on a perceived "as needed" basis (not study medication, but rather standard of care). The primary objective of this trial is to assess whether or not different intraoperative dosing schemes of fentanyl during on-pump CABG surgery influence the area of hyperalgesia as measured by sternal pin-prick testing on the first postoperative day. As the mechanisms causing opioid-induced analgesia are poorly understood but appear to be dosis-related, the investigators will examine 3 clinically used fentanyl application schemes in cardiac surgery: 1) a high-dose bolus group, 2) a low-dose bolus group, and 3) a low-dose continuous infusion group. [i.e. does fentanyl dosing influence the area of hyperalgesia?] The secondary objectives of this trial are 1) to explore the intraoperative concentrations of fentanyl in these various dosing schemes during and after extracorporeal circulation (ECC). [i.e. determine the time course of fentanyl with ECC and its association with hyperalgesia; explorative] 2) to explore a possible association between fentanyl dosing, hyperalgesia, and persisting pain 3, 6, and 12 months after surgery. [i.e. clinical implication on persistent/chronic pain; explorative]

5 minutes prior to sternotomy, patients will receive a fentanyl bolus of 20 mcg/kg BW (verum) and a perfusion pump with sodium chloride (NaCl 0.9%; placebo) will be begun according to the Shibutani dosing scheme. As in the other arms, patients will be induced with 3mcg/kg BW fentanyl and the treating physician may administer boli on an "as needed" basis.

5 minutes prior to sternotomy, patients will receive a fentanyl bolus of 3 mcg/kg BW (verum) and a perfusion pump with sodium chloride (NaCl 0.9%; placebo) will be begun according to the Shibutani dosing scheme. As in the other arms, patients will be induced with 3mcg/kg BW fentanyl and the treating physician may administer boli on an "as needed" basis.

5 minutes prior to sternotomy, patients will receive a NaCl 0.9% bolus (placebo) and a perfusion pump with fentanyl (verum) will be begun according to the Shibutani dosing scheme. As in the other arms, patients will be induced with 3mcg/kg BW fentanyl and the treating physician may administer boli on an "as needed" basis.

We routinely use fentanyl as the opioid of choice in CABG surgery. However, how much and whether or not to apply it in boli or continuously remain uncertain. We will apply 3 routinely used fentanyl dosing schemes in our hospital. To blind care-givers and patients, in each of the arms a bolus and a continous injection will occur, as delineated in the treatment arms.

Fentanyl will be measured from samples taken prior to, during, and after a pump run as specified by the time frame of this outcome and the following outcomes.

Inclusion Criteria: Consenting patients aged ≥18 years Undergoing first-time, elective, on-pump CABG surgery with median sternotomy and central cannulation. Exclusion Criteria: Documentation of preexisting chronic pain as per electronic record Use of opioids in the last 30 days or history/documentation of opioid abuse as per electronic record BMI > 35kg/m2 or history of obstructive sleep apnea syndrome Patients with renal failure (clearance < 30 ml/min) Neuraxial anesthesia Pregnancy Planned wound infiltration with local anesthetics Known drug allergies or intolerance to fentanyl or other opioids Expected to be unable to understand pinprick/allodynia testing / follow-up questions