Clinical trial NCT03715517: Spinal Anesthesia For Enhanced Recovery After Liver Surgery
Official title: Spinal Anesthesia for Enhanced Recovery After Liver Surgery
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Hepatectomy
Pain, Postoperative
Liver Neoplasms
Keywords: Injections, Spinal
Analgesia, Epidural
Anesthesia, Spinal
Patient Reported Outcome Measures
Postoperative Period
Lead sponsor: University of Manitoba
Sponsor class: OTHER
First posted: 2018-10-23
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This project proposes to compare epidural versus spinal anesthesia in patients having liver resection surgery. The investigators hypothesize that spinal anesthesia will result in improved blood pressure control postoperatively and reduce the amount of intravenous fluids required after surgery. Spinal anesthesia is expected to provide the same pain control benefits as epidurals, with faster recovery of function. Spinal anesthesia may be a simple and effective way to improve and enhance the recovery in the increasing number of patients requiring liver resection.

Detailed description: Hepatic resection surgery (hepatectomy) for primary or metastatic malignancy is a major operation involving large, painful upper abdominal incisions, as well as considerable postoperative physiological derangements.

Uncontrolled postoperative incisional pain results in significant respiratory impairment, delayed mobilization, and augmentation of the surgically-induced stress response, placing patients at increased risk of postoperative complications and chronic post-surgical pain. Acute pain management with high-dose parenteral opioids further compounds this risk. Multimodal opioid-sparing therapy, and regional anesthesia in particular, is therefore an essential component of enhanced recovery after surgery (ERAS) pathways and patient-centred care.

Regional anesthesia using neuraxial block (intraoperative spinal anesthesia or thoracic epidural anesthesia) followed by postoperative continuous thoracic epidural analgesia (CTEA; postoperative administration of epidural local anesthetic and/or opioid) is the best method for treating pain following large abdominal surgeries, including liver resection, and has been shown to improve postoperative respiratory function and decrease respiratory complications in other surgeries.

However, the effects of intraoperative neuraxial block and postoperative CTEA on fluid balance, systemic hemodynamics, and functional recovery after hepatic resection surgery remain controversial. CTEA is frequently associated with postoperative hypotension, resulting in increased perioperative intravenous (IV) fluid administration, red blood cell transfusion, and vasopressor use in liver resection patients. For major hepatectomies, CTEA may also be an independent risk factor for postoperative acute kidney injury (AKI), presumably due to impairment of renal autoregulation. Excessive IV fluid administration in the postoperative period is associated with significant weight gain, often necessitating diuretic therapy; delayed return of gastrointestinal function; increased need for packed red blood cell (pRBC) transfusion due to hemodilution; increased infective complications due to this increased pRBC transfusion rate; and increased length of hospital stay.

In addition, concerns remain about the use of CTEA following liver resection surgery due to the potentially increased risk of epidural hematoma formation in the setting of postoperative coagulopathy. This concern has resulted in unplanned delays in epidural catheter removal postoperatively, due to persistent coagulation abnormalities, prolonging hospitalization by 1-3 d in up to 15% of patients.

These concerns about the consequences of excess fluid administration and the safety of CTEA for liver resection surgery have prompted the use of alternative and/or ancillary analgesic techniques, particularly for major resections and in patients with preoperative liver dysfunction, for whom a prolonged period of postoperative coagulopathy is anticipated.

Intraoperative spinal anesthesia (SA) using local anesthetic (LA) and/or opioid (most commonly intrathecal morphine \[ITM\]) for neuraxial block without CTEA is frequently used as postoperative analgesia for various surgeries. Spinal anesthesia using ITM without LA has been reported in four randomized and three non-randomized studies of patients undergoing liver resections. ITM has provided superior analgesia to IV patient-controlled analgesia (IV-PCA) with opioids, and equivalent analgesia to epidural infusions. Compared with CTEA and/or IV-PCA, ITM was associated with reduced IV fluid administration; earlier mobilization, and resumption of normal dietary intake; decreased incidence of respiratory complications; and decreased hospital length of stay.

Spinal anesthesia using both LA and ITM may provide an additional benefit by providing a degree of preemptive analgesia, as well as by decreasing the stress and inflammatory response, thereby possibly decreasing the incidence of surgical stress-related complications such as postoperative delirium. High-spinal anesthesia (HSA) uses larger doses of LA to achieve a "high" block for this purpose. HSA combined with ITM has been used in cardiac surgery, and decreases the stress and inflammatory response to surgery; facilitates early extubation; improves postoperative analgesia; decreases the incidence of postoperative delirium; and decreases intensive care unit (ICU) readmissions. Neither the use of HSA (with or without ITM) for analgesia following non-cardiac surgical procedures, nor the effectiveness of SA with ITM versus CTEA following hepatic resection surgery has been investigated to date.

Eligibility criteria: Inclusion Criteria:

* Male or female, Adults aged ≥ 18 years (there will be no upper age restriction);
* American Society of Anesthesiologists Physical Status classification (ASA-PS) of I to III;
* Undergoing subcostal or midline laparotomy for elective liver resection surgery under general anesthesia; if the planned procedure is a combined operation (i.e., concomitant extrahepatic surgery) , the associated procedure should not add more than one hour to the surgical time of the primary hepatic resection procedure alone;
* Stated willingness to comply with all study procedures and availability for the duration of the study
* Provision of signed and dated informed consent form
* Body mass index (BMI) between 17 and 40 kg·m-², inclusive;
* Negative result on serum pregnancy test at Screening and negative urine pregnancy test at Baseline (for women of childbearing potential, defined as those who have not undergone a hysterectomy or been postmenopausal for at least 12 consecutive months); and not currently breastfeeding, or planning to do so within 7 d following surgery;
* Stated willingness and ability to comply with all study and/or follow-up evaluations and communicate clearly with the Investigator and staff; and
* Voluntary participation and ability to provide written informed consent prior to any study procedures.

Exclusion Criteria:

* Emergency surgery;
* Age \< 18 years;
* Planned laparoscopic hepatic resection;
* Planned laparotomy incision other than (right) subcostal, midline, or extended midline;
* Patients with obvious non-resectable disease prior to signing informed consent;
* Liver transplant recipient or previous hepatic resection or living-donor hepatectomy surgery;
* Major surgery (open abdominal and/or thoracic) under general anesthesia ≤ 30 d preoperatively;
* Contraindications to neuraxial (spinal or epidural) anesthesia: (a) anticipated difficult intubation; (b) coagulation or hemostatic abnormalities within 30 d of surgery (defined as thrombocytopenia \[platelet count \< 100 × 10⁹ L-¹\]; INR \> 1.4; or activated partial thromboplastin time \[aPTT\] \> 40 s); (c) bleeding diathesis; (d) ongoing use (≤ 7 d before surgery) or planned perioperative use of antiplatelet agents (apart from acetylsalicylic acid 81 mg) or anticoagulants (excluding deep-vein thrombosis prophylaxis); (e) recent (≤ 30 d preoperatively) systemic infection or current (≤ 48 h) fever (≥ 38.4 °C), or evidence of infection (including superficial cutaneous infection in the thoracic and/or lumbar regions); (f) history of neurologic disorder affecting the spinal cord or the hemithorax or below; or impaired bladder/bowel function; (g) acute or subacute (≤ 90 d preoperatively) intracranial hemorrhage; or (h) technical contraindications to epidural placement: (i) local skin or soft tissue infection at proposed site for thoracic epidural insertion; (ii) previous cervicothoracic, thoracic, or thoracolumbar spinal surgery; (iii) history of spinal tumor, fracture or infection; or (iv) recent (≤ 14 d preoperatively) epidural corticosteroid injection;
* Significant cardiac arrhythmias (including pacemaker-dependence) or clinically significant cardiovascular disease (New York Heart Association \[NYHA\] functional classification III-IV);
* Volume overload (hyperhydration), particularly in cases of pulmonary edema or acute decompensated congestive heart failure (CHF);
* Acute kidney injury (AKI) and/or chronic kidney disease (CKD) based on the 2012 Kidney Disease Improving Global Outcomes (KDIGO) AKI (excluding the oliguria criterion) and CKD guideline definitions: AKI: increase in serum creatinine (SCr) (≥ 26.5 μmol·L-¹ within 48 h or ≥ 1.5× baseline within 7 d); CKD: abnormalities of kidney structure or function, present for \> 3 mo, defined as either of the following present for \> 3 mo: (1) ≥ 1 marker(s) of kidney damage: (a) albuminuria (24-h albumin-creatinine ratio \[ACR\] ≥ 30 mg·g-¹ \[≥ 3 mg·mmol-¹\]), (b) urine sediment abnormalities, (c) electrolyte and other abnormalities due to tubular disorders, (d) abnormalities detected by histology, (e) structural abnormalities detected by imaging, (f) history of kidney transplantation; and/or decreased glomerular filtration rate (GFR \< 60 mL-¹·min-¹·1.73 m-², estimated using the 2009 CKD-EPI creatinine equation \[eGFR_creat\]);
* Severe hypernatremia (\[Na⁺\] ≥ 155 mmol·L-¹) and/or hyperchloremia (\[Cl-\] ≥ 125 mmol·L-¹);
* Chronic pain; current (≤ 30 d preoperatively) and/or prior chronic (for a period of ≥ 90 d) opioid use; or history of alcohol, opiate, and/or other drug abuse or dependence;
* Use of supraphysiologic glucocorticoid (GC) doses (≥ 7.5 mg·day-¹ of prednisone or equivalent): recent (≤ 30 d), prolonged (\> 2 consecutive weeks), or multiple courses totalling \> 3 weeks in the preceding 6 months;
* Known allergy or sensitivity (e.g., glucose-6-phosphate dehydrogenase \[G6PD\] deficiency) to amide local anesthetics, opioids, or acetaminophen, or hypersensitivity to other materials to be used in the study (e.g., latex \[epidural catheter adapter\], epidural dressing or tape); or
* Altered mental status or educational, psychiatric, or communication (language, literacy) barriers that would impede accurate assessment of postoperative pain and/or ability to complete questionnaire instruments.

Primary outcomes:
measure: Cumulative 72-hour volume of intravenous fluids and blood products administered
timeFrame: Intraoperatively and during the first 72 hours postoperatively or until hospital discharge, whichever occurs earlier
measure: Area under the curve over 72 hours of the summed pain intensity difference scores at rest (AUC-SPID-PAR_0-72h)
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Cumulative 72-hour opioid consumption (OC_0-72h)
timeFrame: Intraoperatively and during the first 72 hours postoperatively or until hospital discharge, whichever occurs earlier
Secondary outcomes:
measure: Vasopressor-free days to day 30
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
measure: Cumulative intraoperative vasopressor and/or inotrope consumption
timeFrame: Intraoperatively (from anesthesia start time to anesthesia end time)
measure: Cumulative perioperative vasopressor and/or inotrope consumption
timeFrame: Intraoperatively and during the first 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Cumulative 72-hour volume of intravenous fluids administered
timeFrame: Intraoperatively and during the first 72 hours postoperatively
measure: Area under the curve over 72 hours of the summed pain intensity difference scores of movement-evoked pain (MEP) (AUC-SPID-MEP_0-72h)
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Cumulative incidence (proportion) of rescue analgesia (parenteral opioid) use (%)
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Cumulative fluid balance (CFB) at 72 hours
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Percentage fluid overload (% FO) at 72 hours
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Volume-related weight gain (VRWG) at 72 hours
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Quality of recovery, as measured by the change from baseline 15-item Quality of Recovery (QoR-15) scale score over the first 72 hours postoperatively
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Time to mobilization (h)
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Time to gastrointestinal (GI) recovery (h)
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Time to removal of urinary catheter (h)
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Time to adequate pain control with PO medications (h)
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Sleep disturbance, as measured by the change from baseline Patient-Reported Outcomes Measurement Information System (PROMIS®) Short Form v1.0 - Sleep Disturbance 8a scale T-score over the first 7 days postoperatively
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Overall Benefit of Analgesia Score (OBAS) at 72 hours
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Index hospitalization length of stay
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
measure: Analgesic-related adverse events: incidence rate ratio of severe respiratory depression
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
measure: Analgesic-related adverse events: incidence rate ratio of sedation
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
measure: Analgesic-related adverse events: cumulative incidence (proportion) of postoperative delirium
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
measure: Number (count) of surgical complications with Clavien-Dindo grade ≥ III
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
measure: Number (count) of non-surgical complications based on the Postoperative Morbidity Survey (POMS)
timeFrame: Postoperative non-surgical complications are assessed using the Postoperative Morbidity Survey (POMS) based on retrospective review of medical charts and patient telephone follow-up at 30 days.
measure: Comprehensive Complication Index (CCI) score Comprehensive Complication Index (CCI) score Comprehensive Complication Index (CCI) score
timeFrame: During index hospital admission (censored at the earliest of hospital discharge, in-hospital death, or 30 days postoperatively)
Other outcomes:
measure: Cumulative 24-hour volume of intravenous fluids and blood products administered
timeFrame: Intraoperatively and during the first 24 hours postoperatively
measure: Area under the curve (AUC) over 24 hours of the summed pain intensity difference (SPID) scores at rest (AUC-SPID-PAR_0-24h)
timeFrame: 24 hours after surgery
measure: Cumulative 24-hour (IV) opioid consumption (OC_0-24h)
timeFrame: Intraoperatively and during the first 24 hours postoperatively or until hospital discharge, whichever occurs earlier
measure: Time to first parenteral opioid dose administration (min)
timeFrame: 72 hours after surgery or until hospital discharge, whichever occurs earlier
measure: Cumulative incidence (proportion) of patient-controlled analgesia (PCA) utilization postoperatively (%)
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
measure: Cumulative incidence (proportion) of postoperative vasopressor and/or inotrope dependency (%)
timeFrame: 7 days after surgery or until hospital discharge, whichever occurs earlier
Locations:
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
Study officials:
affiliation: University of Manitoba
name: Alex Grunfeld, MD
role: PRINCIPAL_INVESTIGATOR
References: