Impact of an Optimised Monitored Anesthesia on the Patients' Recovery After Cytoreduction Surgery Plus HIPEC

Ciusss de L'Est de l'Île de Montréal9 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

Interventions

Remifentanil infusion, desflurane titration and fluid infusion will be guided by NOL index, BIS index and Flotrac EV1000 system respectivelyDRUG

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

Remifentanil infusion and desflurane titration will be guided by anesthesia usual practicesDRUG

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, according to anesthesia usual practices

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (1)

Hopital Maisonneuve Rosemont, CIUSSS de l'Est de l'Ile de Montréal

Montreal East, Quebec, Canada

Outcomes

Primary Outcomes

The hospital length of stay in days

The length of hospital stay in group "M" versus group "C" will be evaluated with the readiness for discharge from hospital criteria. These criteria for hospital discharge will be precisely and daily evaluated based on the previous published literature from experts who reached a consensus (J.F. Fiore et al. Disease of the Colon and Rectum, volume 55: 4, 2012). After these criteria are achieved, discharge may take place.

Time frame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days

Tolerance of oral intake

The length of hospital stay in group "M" versus group "C" will be evaluated with the readiness for discharge from hospital criteria. These criteria for hospital discharge will be precisely and daily evaluated based on the previous published literature from experts who reached a consensus (J.F. Fiore et al. Disease of the Colon and Rectum, volume 55: 4, 2012) and this will include: \- Tolerance of oral intake. After these criteria are achieved, discharge may take place.

Time frame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days

Recovery of lower gastrointestinal function

The length of hospital stay in group "M" versus group "C" will be evaluated with the readiness for discharge from hospital criteria. These criteria for hospital discharge will be precisely and daily evaluated based on the previous published literature from experts who reached a consensus (J.F. Fiore et al. Disease of the Colon and Rectum, volume 55: 4, 2012) and this will include: \- Recovery of lower gastrointestinal function. After these criteria are achieved, discharge may take place.

Time frame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days

Adequate pain control with oral analgesia

The length of hospital stay in group "M" versus group "C" will be evaluated with the readiness for discharge from hospital criteria. These criteria for hospital discharge will be precisely and daily evaluated based on the previous published literature from experts who reached a consensus (J.F. Fiore et al. Disease of the Colon and Rectum, volume 55: 4, 2012) and this will include: \- Adequate pain control with oral analgesia. After these criteria are achieved, discharge may take place.

Time frame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days

Ability to mobilize and self-care

The length of hospital stay in group "M" versus group "C" will be evaluated with the readiness for discharge from hospital criteria. These criteria for hospital discharge will be precisely and daily evaluated based on the previous published literature from experts who reached a consensus (J.F. Fiore et al. Disease of the Colon and Rectum, volume 55: 4, 2012) and this will include: \- Ability to mobilize and self-care. After these criteria are achieved, discharge may take place.

Time frame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days

Clinical examination and laboratory tests show no evidence of complications or untreated medical problems

The length of hospital stay in group "M" versus group "C" will be evaluated with the readiness for discharge from hospital criteria. These criteria for hospital discharge will be precisely and daily evaluated based on the previous published literature from experts who reached a consensus (J.F. Fiore et al. Disease of the Colon and Rectum, volume 55: 4, 2012) and this will include: \- Clinical examination and laboratory tests show no evidence of complications or untreated medical problems. After these criteria are achieved, discharge may take place.

Time frame: Evaluated 24 hours postoperative and everyday until hospital discharge, up to 21 days

Secondary Outcomes

Intraoperative anesthetic gas' consumption in ml/kg/h

Total consumption and absorption of desflurane in ml/kg/h during surgery and for each hour of surgery

Time frame: Intraoperative

Intraoperative remifentanil consumption in mcg/kg/min

Total consumption of i.v. remifentanil during surgery and for each hour of surgery

Time frame: Intraoperative

Intraoperative fluid's consumption in ml/h

Total of fluid perfused during surgery and for each hour of surgery

Time frame: Intraoperative

Intraoperative number of hypotensive events

Total number of hypotensive events during surgery (defined as mean blood pressure below 60)

Time frame: Intraoperative

Intraoperative phenylephrine consumption in mcg/kg/min

Total doses of intraoperative infused i.v. phenylephrine and doses per hour

Time frame: Intraoperative

Intraoperative epidural consumption in 3 ml/h

Total doses of intraoperative Epidural infusion (lidocaine 2%+epinephrine) and doses per hour

Time frame: Intraoperative

Time for awakening in seconds

Time for awakening (eyes opening) at the end of the surgery. Elapsed time in seconds between stopping the gas and opening the eyes of the patient

Time frame: Intraoperative

Time for extubation in seconds

Time for extubation in seconds. Elapsed time in seconds between stopping the gas and patient's extubation

Time frame: Intraoperative

Data from ClinicalTrials.gov

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Time for transfert to the PACU in seconds

Time for transfert to the PACU (Post Anesthesia Care Unit) in seconds, after extubatiuon

Time frame: Intraoperative

First NRS pain score (0-10 scale) at times of awakening

NRS (Numeric Rating Scale) Pain Score evaluated at times of awakening, evaluation from 0 (no pain) to 10 (worst imaginable pain) scale

Time frame: Intraoperative

First NRS pain score (0-10 scale) at arrival in PACU

First NRS Pain Score evaluated at arrival in PACU, evaluation from 0 (no pain) to 10 (worst imaginable pain)

Time frame: Postoperative, evaluated at arrival in PACU

NRS pain score (0-10 scale) at rest, in PACU

NRS Pain Score at rest, evaluated every 15 minutes until time for readiness for PACU discharge, evaluation from 0 (no pain) to 10 (worst imaginable pain)

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

NRS pain score (0-10 scale) with cough, in PACU

NRS Pain Score with cough, evaluated every 15 minutes until time for readiness for PACU discharge, evaluation from 0 (no pain) to 10 (worst imaginable pain)

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

NRS pain score (0-10 scale) on the Shoulder, in PACU

NRS Pain Score on the Shoulder, evaluated every 15 minutes until time for readiness for PACU discharge, evaluation from 0 (no pain) to 10 (worst imaginable pain)

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

Hydromorphone consumption (mg) in PACU

Total cumulative dose of titration of intravenous hydromorphone (mg), evaluated every 15 minutes until time for readiness for PACU discharge

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

PONV score (0-3 scale) in PACU

PONV (PostOperative Nausea and Vomiting) score, evaluated every 15 minutes until time for readiness for PACU discharge, evaluation from 0 (no nausea) to 3 (nausea and vomiting)

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

POSS score (1-4 scale) in PACU

POSS (Pasero Opioid-induced Sedation Scale) score evaluated every 15 minutes until time for readiness for PACU discharge, evaluation from 1 (awake and alert) to 5 (asleep deeply)

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

Respiratory depression number in PACU

Respiratory depression number evaluated every 15 minutes until time for readiness for PACU discharge

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

Blood pressure (mmHg) in PACU

Blood pressure (TAS/TAD/TAM) in mmHg evaluated every 15 minutes until time for readiness for PACU discharge

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

Time for PACU discharge based on Aldrete scores (0-10 scale), in PACU

Time for readiness for PACU discharge based on Aldrete scores (0-10), Aldrete score must be ≥ 9 for PACU discharge

Time frame: Postoperative, evaluated every 15 minutes until time for PACU discharge

NRS pain score (0-10 scale) at rest, evaluated everyday from 24 hours postoperative to hospital discharge

NRS Pain Score at rest, evaluated every day, from 24 hours postoperative until time for readiness for hospital discharge, evaluation from 0 (no pain) to 10 (worst imaginable pain)