Spinal Anesthesia For Enhanced Recovery After Liver Surgery

NCT ID: NCT03715517

Last Updated: 2023-12-07

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 128 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-04
• Study Completion Date: 2026-01-31

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.

Conditions

Hepatectomy; Pain, Postoperative; Liver Neoplasms

Keywords

Injections, Spinal; Analgesia, Epidural; Anesthesia, Spinal; Patient Reported Outcome Measures; Postoperative Period

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intrathecal morphine

Spinal anesthesia with intrathecal morphine

Bolus (pre-induction): High-spinal anesthesia with 0.25 mg⋅kg-¹ hyperbaric bupivacaine 0.75% plus 3 mcg⋅kg-¹ intrathecal morphine (preservative-free)

Postoperative analgesia: IV-PCA hydromorphone (bolus: 0.2 mg [range: 0.1-0.4 mg]; 5 min lockout; no infusion)

Group Type: EXPERIMENTAL

Spinal anesthesia with intrathecal morphine

Intervention Type: PROCEDURE

Needle/catheter: 25 Ga. × 90 mm high-flow Whitacre spinal needle (Becton-Dickinson, Franklin Lakes, NJ, USA)

Level of insertion and patient positioning: L2-L3, lateral decubitus position during injection; immediately post-injection, patient is placed supine in <5% degree of Trendelenburg

Confirmation of correct placement: Aspiration of cerebrospinal fluid

Bupivacaine 0.75% in Dextrose Inj 8.25%

Intervention Type: DRUG

0.25 mg⋅kg-¹ hyperbaric bupivacaine 0.75%

Morphine

Intervention Type: DRUG

3 mcg⋅kg-¹ intrathecal morphine (preservative-free)

Thoracic epidural analgesia

Continuous thoracic epidural analgesia

Bolus (pre-induction): 0.25 mg⋅kg-¹ bupivacaine 0.25% plus 1 mcg⋅kg-¹ hydromorphone (0.1 mL⋅kg-¹)

Infusion (initial): 0.25 mg⋅kg-¹⋅h-¹ bupivacaine 0.25% plus 1 mcg⋅kg-¹⋅h-¹ hydromorphone (0.1 mL⋅kg-¹⋅h-¹)

Infusion (range): 0.19-0. 3 mg⋅kg-¹⋅h-¹ bupivacaine 0.25% plus 0.75-1.25 mcg⋅kg-¹⋅h-¹ hydromorphone (0.075-0.125 mL⋅kg-¹⋅h-¹) (3-10 mL⋅h-¹)

Postoperative analgesia: (1) Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range as above (0.075-0.125 mL⋅kg-¹⋅h-¹) (3-10 mL⋅h-¹), continued for a maximum of 72 h postoperatively; (2) IV-PCA hydromorphone (bolus: 0.2 mg [range: 0.1-0.4 mg]; 5 min lockout; no infusion).

Group Type: ACTIVE_COMPARATOR

Continuous thoracic epidural analgesia

Intervention Type: PROCEDURE

Needle/catheter: 17 Ga. × 80 mm Tuohy epidural needle (Perican®, B. Braun Medical Inc., Bethlehem, PA, USA); Arrow FlexTip Plus® 19 Ga. epidural catheter (Arrow International Inc., Reading, PA, USA)

Level of insertion and patient positioning: T6-T8, upright sitting position for insertion of needle and catheter (to 5 cm beyond loss-of-resistance point) and for injection of test dose (3 mL 2% lidocaine with epinephrine 1:200,000); supine for injection of bolus dose

Confirmation of correct placement: Loss of resistance to air or saline; negative aspiration of the epidural catheter; negative test dose; and ease of injection of an initial bolus dose

Bupivacaine 0.25% Preservative-Free Injectable Solution

Intervention Type: DRUG

0.25 mg⋅kg-¹ bupivacaine 0.25%

Bupicavaine 0.125% epidural solution

Intervention Type: DRUG

Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range 0.075-0.125 mL⋅kg-¹⋅h-¹

Hydromorphone 10 mcg/mL epidural solution

Intervention Type: DRUG

Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range 0.075-0.125 mL⋅kg-¹⋅h-¹

Interventions

Continuous thoracic epidural analgesia

Needle/catheter: 17 Ga. × 80 mm Tuohy epidural needle (Perican®, B. Braun Medical Inc., Bethlehem, PA, USA); Arrow FlexTip Plus® 19 Ga. epidural catheter (Arrow International Inc., Reading, PA, USA)

Level of insertion and patient positioning: T6-T8, upright sitting position for insertion of needle and catheter (to 5 cm beyond loss-of-resistance point) and for injection of test dose (3 mL 2% lidocaine with epinephrine 1:200,000); supine for injection of bolus dose

Confirmation of correct placement: Loss of resistance to air or saline; negative aspiration of the epidural catheter; negative test dose; and ease of injection of an initial bolus dose

Intervention Type: PROCEDURE

Spinal anesthesia with intrathecal morphine

Needle/catheter: 25 Ga. × 90 mm high-flow Whitacre spinal needle (Becton-Dickinson, Franklin Lakes, NJ, USA)

Level of insertion and patient positioning: L2-L3, lateral decubitus position during injection; immediately post-injection, patient is placed supine in <5% degree of Trendelenburg

Confirmation of correct placement: Aspiration of cerebrospinal fluid

Intervention Type: PROCEDURE

Bupivacaine 0.75% in Dextrose Inj 8.25%

0.25 mg⋅kg-¹ hyperbaric bupivacaine 0.75%

Intervention Type: DRUG

Morphine

3 mcg⋅kg-¹ intrathecal morphine (preservative-free)

Intervention Type: DRUG

Bupivacaine 0.25% Preservative-Free Injectable Solution

0.25 mg⋅kg-¹ bupivacaine 0.25%

Intervention Type: DRUG

Bupicavaine 0.125% epidural solution

Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range 0.075-0.125 mL⋅kg-¹⋅h-¹

Intervention Type: DRUG

Hydromorphone 10 mcg/mL epidural solution

Epidural solution, bupivacaine 0.125% with hydromorphone 10 mcg·mL-¹, infusion range 0.075-0.125 mL⋅kg-¹⋅h-¹

Intervention Type: DRUG

Other Intervention Names

Spinal heavy bupivacaine; Intrathecal morphine; Bupivacaine 0.25% epidural solution; Bupivacaine 0.125% preservative-free injectable solution

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Manitoba

OTHER

Sponsor Role: lead

Responsible Party

Alex Grunfeld

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Alex Grunfeld, MD

Role: PRINCIPAL_INVESTIGATOR

University of Manitoba

Locations

University of Manitoba

Winnipeg, Manitoba, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Alex Grunfeld, MD

Role: CONTACT

Phone: 204-787-1125

Email: alexander.grunfeld@umanitoba.ca

Facility Contacts

Alex Grunfeld, MD

Role: primary

Other Identifiers

B2018:048

Identifier Type: -

Identifier Source: org_study_id