Clinical trial NCT04104334: Impact of an Optimised Monitored Anesthesia on the Patients' Recovery After Cytoreduction Surgery Plus HIPEC
Official title: Evaluation of the Impact of Combined Intraoperative Monitoring of Depth of Analgesia, Depth of Anesthesia and Continuous Hemodynamic Data on the Patients Recovery After Cytoreduction Surgery and Hyperthermic Intraperitoneal Chemotherapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Hyperthermia
Colorectal Neoplasms
Oxaliplatin
Keywords: Cytoreduction
HIPEC
Oxaliplatin
Colorectal
Peritoneal
Carcinomatosis
Monitoring
Anesthesia
Lead sponsor: Ciusss de L'Est de l'Île de Montréal
Sponsor class: OTHER
First posted: 2019-09-26
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2 groups of patients. Randomization into Monitored group "M" (BIS + NOL + Flotrac EV1000) vs control group "C" (standard of care anesthesia) according to randomization list for a total number of 80 patients.
Primary purpose: PREVENTION

Brief summary: The objective of our PILOT study is to evaluate the impact of a controlled (monitored) randomized anesthesia during cytoreductive surgery with HIPEC to oxaliplatin in order to treat adenocarcinomas of colorectal origin. The combination of NOL monitoring, BIS monitoring and continuous hemodynamic monitoring (FloTrac EV1000 system) can improve patient safety by reducing the length of hospital stay by decreasing total hypnotic doses and intraoperative opioids and side effects following anesthesia.

Detailed description: Title: Evaluation of the combined intraoperative monitoring of depth of analgesia (NOL), depth of anesthesia (BIS) and continuous hemodynamic data (Flotrac EV1000 system) on the patients' recovery after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). A pilot study.

Hypothesis: Investigators hypothesize that the intraoperative combination of new monitors, NOL index for depth of analgesia, BIS index for depth of anesthesia and Flotrac EV1000 system as continuous hemodynamic monitoring, to guide the delivery of opioids, hypnotics, fluids and inotropes, respectively, will improve the quality of recovery as well as the safety after anesthesia in patients undergoing HIPEC (Hyperthermic Intraperitoneal Chemotherapy) surgery.

Background: so far, only vital signs (mostly, blood pressure and heart rate) helped the anesthesiologist to administer hypnotics agents, analgesics, fluids and inotrope. Many devices have offered pain monitoring for anesthetized patients. The NOL index, a nociception monitor using a multiparametric approach, has shown an excellent sensitivity and specificity in detecting noxious stimuli under general anesthesia. More recently, it has been shown a strong inverse correlation between NOL index response to nociceptive stimulus and the increasing doses of opioid analgesia during surgery. Studies on post-operative outcomes when using intraoperative NOL monitoring to adapt nociception/anti-nociception balance during general anesthesia (GA) also reported in our center an improvement of the time to extubation and of the postoperative recovery criteria in PACU after colorectal surgery in the monitored group, leading to a quicker discharge from PACU (presented as an abstract at ASA 2018; manuscript in preparation). Recent studies also showed that avoiding too deep anesthesia by using the BIS index would improve patients' outcome in terms of morbi-mortality. It is also accepted that intra-venous fluid and inotropic/vasopressor drugs have an important effect on intra and postoperative patients' outcomes, in particular following major gastrointestinal surgery. The use of hemodynamic therapy management algorithms has been recommended in a report commissioned by the Centers for Medicare and Medicaid Services in the USA, and by the National Institute for Health and Care Excellence (NICE) in the UK as well as many groups working in ERAS protocols in Canada (and especially Montreal, McGill University) and worldwide.

Based on our recent systematic review (in preparation) and out of the 69 selected published articles, there is no study so far evaluating precisely the impact of anesthesia on postoperative outcomes, and no study combining the NOL, the BIS indexes and the Flotrac EV1000 system to evaluate the impact of a more precise anesthesia management on the postoperative outcomes after cytoreduction and HIPEC for peritoneal carcinomatosis of colorectal origin. Thus, the idea to propose the present study.

Specific Objectives: primary objective: to compare the time to reach the readiness for discharge from hospital and the total postoperative in-hospital length of stay between the Monitored group "M" (optimized, personalized and controlled anesthesia) versus the control group "C" (standard of care anesthesia). Secondary objectives: to evaluate the quality of recovery from anesthesia in the PACU and on the wards and all the adverse events every day and until patient's discharge from hospital. The emergence and extubation time of patients after anesthesia, time spent in PACU (Aldrete score), intra- and postoperative opioid requirements, pain scores (NRS) for several postoperative days, patients' postoperative recovery and satisfaction (the Quality of Recovery: QOR-15, 6min walking test, MOCA, etc.) will be also compared between the 2 groups. Finally, biological outcomes such as blood gas analysis, serum electrolytes, creatinine, DFG, hemoglobin, white blood cell and platelet counts, CRP, serum albumin, INR, PTT will be evaluated on a standard basis in both the groups.

Methods: 80 patients scheduled for HIPEC surgery with oxaliplatin for bowel adenocarcinoma surgery (without digestive resection) will be included. Randomisation will occur after the participant has provided informed consent and shortly before the surgical procedure is due to start. Patients in the Control group "C" will be managed by clinical staff according to usual practice, desflurane will be administered to keep MAC at 1, and remifentanil infusion rate will be adapted to the mean arterial blood pressure to keep it between 65 and 100. In the Monitored group "M", the NOL index will guide the administration of remifentanil to keep the index between 5-25, and the desflurane will be titrated to keep a BIS index between 45 and 55. Cardiac output and stroke volume variation will be measured by the Flotrac EV1000 system. Patients will receive 250ml fluid challenges with a recommended solution as required, in order to achieve a maximal value of stroke volume. Intraoperative epidural analgesia will be the same for all. Postoperative analgesia will be based on PCEA and hydromorphone for all. All anesthesia related side effects and quality of analgesia and rehabilitation will be evaluated daily and until patient's discharge from hospital.

Data Analysis: all data collected will be analyzed using an intent-to-treat approach. Summary statistics for each group, treatment effects, 95% confidence intervals, and p-values will be presented for primary and secondary outcomes, and process measures. Intraoperative data in the "M" and "C" groups will be compared using parametric (e.g. Student t-test) or non-parametric tests (e.g. Mann-Withney U test, Chi-squared test) depending on type of variables and distribution. General linear models will be used to carry out group comparisons on data on length of hospital stay. Potential pitfalls: analyses for secondary objectives may not be sufficiently powered but will nevertheless provide useful information for designing and conducting a future multicentric study. Bonferroni corrections will be used to protect against type I error.

Significance/Importance: Adding the NOL, the BIS and continuous hemodynamic monitoring will very likely reduce the total length of stay, and improve the postoperative speed and quality of recovery as well as will likely reduce the incidence of complications after cytoreduction + HIPEC procedures.

Study Design: Prospective, randomized controlled study.

Subject Population: Adult patients scheduled to undergo laparotomy for cytoreduction surgery + HIPEC for peritoneal carcinomatosis of colorectal origin and under general anesthesia with an active intraoperative epidural analgesia.

Sample Size: 80 patients will be evaluated in this study.

Study Duration: 2 year(s)

Study Center: Maisonneuve-Rosemont Hospital, Departments of Anesthesiology and Pain Medicine and Department of General Oncologic Surgery, CIUSSS de l'Est-de-l'Île-de-Montreal, Montreal, Quebec, Canada

Adverse Events: None expected.

Subvention/support: Department of Anesthesiology and Pain Medicine of HMR/CEMTL.

Eligibility criteria: Inclusion Criteria:

* ASA status I, II or III
* Patients older than 18 years
* HIPEC for bowel surgery with oxaliplatin + dextrose 5% for a duration of 30 min
* Duration and type of surgery requiring an epidural analgesia via an epidural catheter placed and tunnelled prior the general anesthesia induction and an arterial line placed after induction of general anesthesia.

Exclusion Criteria:

* Any allergy to one drug used in our anesthesia or HIPEC protocol
* Any contra-indication or patient's refusal for epidural placement
* Chronic arrhythmic cardiac conditions
* Chronic pain with use of opioids more than 3 times per week for 4 weeks
* Bowel occlusion
* Physical/mental incapacities
* Unexpected difficult airway requesting excessive, possibly painful airway manipulations.
* Epidural failure

Primary outcomes:
measure: The hospital length of stay in days
timeFrame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days
measure: Tolerance of oral intake
timeFrame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days
measure: Recovery of lower gastrointestinal function
timeFrame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days
measure: Adequate pain control with oral analgesia
timeFrame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days
measure: Ability to mobilize and self-care
timeFrame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days
measure: Clinical examination and laboratory tests show no evidence of complications or untreated medical problems
timeFrame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days
Secondary outcomes:
measure: Intraoperative anesthetic gas' consumption in ml/kg/h
timeFrame: Intraoperative
measure: Intraoperative remifentanil consumption in mcg/kg/min
timeFrame: Intraoperative
measure: Intraoperative fluid's consumption in ml/h
timeFrame: Intraoperative
measure: Intraoperative number of hypotensive events
timeFrame: Intraoperative
measure: Intraoperative phenylephrine consumption in mcg/kg/min
timeFrame: Intraoperative
measure: Intraoperative epidural consumption in 3 ml/h
timeFrame: Intraoperative
measure: Time for awakening in seconds
timeFrame: Intraoperative
measure: Time for extubation in seconds
timeFrame: Intraoperative
measure: Time for transfert to the PACU in seconds
timeFrame: Intraoperative
measure: First NRS pain score (0-10 scale) at times of awakening
timeFrame: Intraoperative
measure: First NRS pain score (0-10 scale) at arrival in PACU
timeFrame: Postoperative, evaluated at arrival in PACU
measure: NRS pain score (0-10 scale) at rest, in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: NRS pain score (0-10 scale) with cough, in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: NRS pain score (0-10 scale) on the Shoulder, in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: Hydromorphone consumption (mg) in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: PONV score (0-3 scale) in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: POSS score (1-4 scale) in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: Respiratory depression number in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: Blood pressure (mmHg) in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: Time for PACU discharge based on Aldrete scores (0-10 scale), in PACU
timeFrame: Postoperative, evaluated every 15 minutes until time for PACU discharge
measure: NRS pain score (0-10 scale) at rest, evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: NRS pain score (0-10 scale) with cough, evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: NRS pain score (0-10 scale) on the Shoulder, evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Hydromorphone consumption (mg), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Epidural consumption (mg), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: PONV score (0-3 scale), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: POSS score (1-4 scale), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Respiratory depression number, evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Blood pressure (mmHg), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Heart rate (bpm), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Oxygen saturation (%), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Respiratory rate (bpm), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Temperature (°C), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Overall patient's satisfaction (0-100%), evaluated everyday from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Quality of recovery (QoR-15), evaluated every day from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: 6-minutes walking score, evaluated every day from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: MOCA scores, evaluated every day from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Time for first walking/mobilization, evaluated every day from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Time for first flatus, evaluated every day from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Time for return to food oral intake, evaluated every day from 24 hours postoperative to hospital
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Biological analysis, evaluated every day from 24 hours postoperative to hospital discharge
timeFrame: Evaluated 24 hours postoperative, then everyday until hospital discharge, an average of 21 days
measure: Rate of hospital readmission and mortality postoperative
timeFrame: Postoperative evaluation, up to 30 days following surgery
Other outcomes:
Locations:
city: Montréal-Est
country: Canada
facility: Hopital Maisonneuve Rosemont, CIUSSS de l'Est de l'Ile de Montréal
state: Quebec
Study officials:
affiliation: CIUSSS Est de l'île de Montréal
name: Philippe PR Richebé, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: