Perioperative hemodynamic optimization using the photoplethysmography in colorectal surgery (the PANEX3 trial): study protocol for a randomized controlled trial

The perioperative hemodynamic optimization using photoplethysmography in colorectal surgery (PANEX3) study is a randomized, controlled, two-arm trial. The institutional review board (IRB) of the University Hospital of Caen (Comité de Protection des Personnes Nord-Ouest III, Avenue la Côte de Nacre, Niveau 03, Porte 03–508, 14 033 Caen Cedex 9, France) approved the study (Registration number ID RDB: 2014-A00870-47 on 3 December 2014). The PANEX3 study is being conducted in accordance with the Declaration of Helsinki and was registered on 13 June 2014 on the ClinicalTrials.gov website with the trial identification number NCT02343601. The PANEX3 trial follows the CONSORT statement [13], and the CONSORT diagram is given in Fig. 1. All patients are asked for written informed consent, as required by the IRB, in accordance with the Declaration of Helsinki; informed consent will be obtained from all participants.

All patients for planned colorectal surgeries are eligible for the study.

Patients fulfilling one or more of the following criteria will not be included: lack of informed consent prior to randomization, use of another hemodynamic monitor for cardiac output measurement, chronic kidney disease with creatinine clearance < 30 ml/min, black skin (limit of photoplethysmography technology), pregnant patients, age < 18 years, or under legal protection. This provides good technical conditions for the photoplethysmography and a relatively homogenous study population for the interpretation of the results.

The included patients are at moderate surgical risk, based on the surgical procedure and/or the medical history for each patient. Patients with high surgical risk according to the medical history will have a cardiac output monitor [4, 5], and they will be not included in the study.

Randomization is performed by the anesthesiologist the day before surgery using a scratch card available 24/7 in the hospital. The randomization sequence is generated using permutated blocks.

On arrival in the operating room, each patient receives the usual monitoring, including a lead ECG, noninvasive blood pressure, pulse oximetry, and a photoplethysmography monitor using a digital sensor (ClearSight, Edwards Lifesciences) connected to a dedicated monitor (EV 1000, Edwards Lifesciences). Included patients are assigned to the control group (blinded monitor) or the photoplethysmography group (monitor available to guide anesthesia), according to the randomization. After the heart reference system is zeroed at the mid-axillary line, the monitoring is continuously recorded from the start of general anesthesia induction until discharge from the recovery room. All photoplethysmography data is then recovered by an independent investigator not involved in the patient care.

In the control group (Fig. 2), the hemodynamic goal is a mean arterial pressure (MAP) > 65 mmHg; if the MAP is under this value, the clinician can prescribe an intravenous fluid challenge using 3 ml/kg of gelatin over 10 minutes, renewable once, and then a vasopressor thereafter (ephedrine until 30 mg, and norepinephrine thereafter).

In the photoplethysmography group (Fig. 3), the hemodynamic target includes the stroke volume and the MAP: the fluid challenge prescription depends on the changes in stroke volume, according to recent guidelines [4], whereas the vasopressor use depends on a MAP < 65 mmHg after the maximization of the stroke volume.

The allocated therapy is delivered until discharge from the recovery room.

The anesthesia medications follow the local protocol for the induction (propofol, sufentanil, and atracurium) and the maintenance of anesthesia (sevoflurane, sufentanil, and atracurium). The postoperative pain management follows another local protocol using intravenous (IV) lidocaine (1.5 mg/kg intravenous drip (IVD) at the start of anesthesia, then 2 mg/kg/h in a syringe driver during surgery, and 1.5 mg/kg/h during recovery room), paracetamol (1 g x 4 per day), nefopam (80 to 100 mg in syringe driver per day), and oxycodone (5 mg up to 4 per day if pain evaluation > 3/10). For all patients, surgeons perform scar infiltration with 20 ml of ropivacaine 0.75 %. The concomitant use of regional anesthesia (transverse abdominal plane block with 20 ml of ropivacaine 0.75 %, and/or spinal anesthesia using morphine 150 to 400 μg) is left to the discretion to the attending anesthesiologist.

The antibiotic prophylaxis and enhanced recovery after the elective colorectal surgery program follow the recent guidelines [14].

The ventilator settings include a tidal volume using 6 to 8 ml/ideal body weight, a positive end-expiratory pressure between 5 and 8 cm H₂O, lung recruitment maneuvers (30 cm H₂O during 30 seconds every 30–45 minutes), a respiratory rate and an FiO₂ according to a range of end-tidal carbon dioxide tension between 35 and 45 mm Hg, and a pulse oximetry > 96 %.

The primary outcome is the incidence of at least one postoperative complication during the 30 days following surgery. Two independent experts confirm the presence of the complication using an a priori classification (Table 1) in accordance with recent guidelines [15]. These experts are not involved in the study and work in a different university hospital.

The secondary outcomes are the total number of postoperative complications, the real length of hospital stays, and the postoperative mortality.

A coding list has been generated using the SAS software package V.9.4. During surgery and postoperative care, both surgeons and patients are blinded to the allocated group. The material used in the photoplethysmography group and in the control group is similar, in keeping with the blinded design. Therefore, patients in each group remain indistinguishable. Only the anesthesiology staff and the research staff can view the monitor (blinded in the control group) and know the group allocation. The surgeons are the postoperative care providers, who will decide the length of hospital stay while staying totally blinded to the group allocation. The two independent experts are also blinded to the group allocation.

Patients with a serious undesirable event during the surgery, which justifies invasive hemodynamic monitoring (arterial catheter or cardiac output monitoring), or without photoplethysmography signal will not be treated using the study group algorithm allocation. They will then receive different monitoring or treatment at the discretion of the attending anesthesiologist but will be analyzed according to their initial assigned group following the intention-to-treat principle.

Based on previous published studies [16, 17], two groups of 80 patients are needed to detect a decrease in the incidence from 40 % to 20 % of patients suffering at least one postoperative complication, using a two-sided α-risk at 0.05 and a β-risk at 0.20. Because the incidence of complications is uncertain, checking the number of patients having at least one postoperative complication in the control group will be conducted after 80 patients have been included to verify the power of the study. However, no interim analysis is planned. We anticipate no missing data for the primary outcome (incidence of at least one postoperative complication). For the per-protocol analysis (sensitivity analysis), the handling of missing data (surgery cancelled, failure of photoplethysmography monitoring, or serious undesirable event during the surgery) will be anticipated, with five supplemental patients being included for each group. Nevertheless, all randomized patients will be analyzed in the allocated group for the main intention-to-treat analysis. In addition, to comply with the intent-to-treat analysis, missing data for the primary outcome will handled by multiple imputations (PROC MI in SAS) and analyzed in sensitivity analyses using PROC MIANALYZE in SAS V9.4 (SAS institute, Cary, NC, USA).

Data will be collected and registered using electronic case report forms (eCRFs) by a dedicated local research technician. A research coordinator will centralize and verify the data.

Baseline characteristics and pre-randomization data will be collected: sex, age, height, weight, ideal body weight, Lee score [18], smoking status, history and type of diabetes mellitus, dyslipidemia, history of cardiovascular disease (systemic hypertension, ischemic heart disease, valvular heart disease, peripheral vascular disease, or cardiac medications), history of respiratory disease (asthma with chronic treatment, chronic obstructive pulmonary disease requiring corticosteroid daily or oxygen at home or history of hospitalization for decompensation or noninvasive ventilation), history of hepatic disease (Child Pugh classification of cirrhosis [19]), renal insufficiency (classified according to the glomerular filtration rate [20]), history of neoplasia, and baseline bloods (creatinine, bilirubin, albumin, and rate of prothrombin).

During the anesthesia and surgical procedures, the following will be recorded: the type of procedure (first or reoperation), surgical site (right, left, or total colectomy, protectomy, or coloprotectomy), duration of anesthesia and surgery, blood loss and transfusion requirements, all drugs used during anesthesia (anesthetics, opiates, and neuromuscular blocking agents), all administered fluids (number of titrated fluid loadings, and total fluid loading), and all vasoactive drugs.

Data from the EV 1000 monitor will be extracted (mean MAP, mean stroke volume, mean stroke volume variation, mean heart rate, mean MAP/Heart rate ratio, and proportion (%) of time during MAP < 65 mm Hg and < 55 mm Hg). The clinical tolerance of the sensor will be evaluated with a numerical pain scale, and a skin examination (paresthesia, erythema, and necrosis).

During postoperative days 1, 3, and 5, blood samples will be sent for the following analyses: creatinine, troponin Ic, leukocyte, and hemoglobin. If the core temperature > 38 °C, a blood culture, urine culture, and drain fluid culture (if available) will be performed.

From postoperative day 0 until 30 days following surgery, the postoperative complications will be recorded (Table 1).

The real hospital length of stay and the survival status at day 30 following the inclusion will be recorded.

Consent forms and eCRFs will be retained for 15 years at the University Hospital of Caen in accordance with the French law.

The study promotion is performed by the University Hospital of Caen, France. Industry does not provide financial support; nor is it involved in the study protocol.

Patients from the French University Hospitals of Caen can be included during a 2-year period beginning in December 2014.

Protocol, approval from the ethical committee, financial support, the eCRF, and the interactive web response system (IWRS) were developed in 2014. Inclusions of patients were planned to take place during 2015 and 2016. The database should be closed during 2016 and will be followed by data analysis, manuscript writing, and submission for publication.

The trial is ongoing and actively enrolling.