Preoperative High Dose Steroids for Liver Resection- Effect on Complications in the Immediate Postoperative Period (STEREO)

High Dose Steroids for Liver Resection - Effect on Complications and Endothelial Function in the Immediate Postoperative Phase - a Randomized, Doubleblind, Controlled Trial

Background:

Several randomized clinical trials have shown beneficial effects of pre-operative glucocorticoids on post-operative complications.

Studies on the effects of glucocorticoids on the postoperative recovery after liver-resection show significantly lower markers of infection and liver damage, and some studies have shown a shorter hospital stay.

Studies on the effects in the immediate postoperative phase are lacking.

Methods: Randomized, double-blind, controlled trial evaluating incidence of postoperative complications in the immediate postoperative phase (and during admission) after open liver surgery. Participants are randomized to either active treatment (methylprednisolone 10 mg/kg) or control (8 mg dexamethasone), administered just prior to surgery.

All patients undergoing open liver resection at our institution are eligible. Included patients are stratified according to extent of surgery into minor (<3 segments) or major (≥3 segments) group.

Patients in major group participate in Substudy I (markers of endothelial damage).

Patients operated between January and July 2018 participate in Substudy II (delirium).

Study Overview

• Status: Completed
• Conditions: Complication, Postoperative
• Intervention / Treatment: Drug: Methylprednisolone; Drug: Dexamethasone

Detailed Description

Post-surgery, patients are traditionally observed and treated in post-anesthesia care units (PACU) until they are discharged to the ward (or directly home) assessed by standardized international discharge criteria.

The research project "Why in PACU?" (Rigshospitalet, Denmark), has since the beginning of 2016 systematically collected and analyzed procedure-related complications in the recovery phase. The complications include pain, nausea/vomiting, circulatory and respiratory problems, orthostatic intolerance and cognitive disorders. Common to all the above-mentioned post-operative problems are the possible links to the inflammatory response caused by the surgical trauma.

Glucocorticoids (GC) can in this context be central for the reduction of acute postoperative organ dysfunctions, caused by the anti-inflammatory effect. In a number of different surgical procedures, single dose, pre-operative glucocorticoids have been shown to reduce post-operative nausea and vomiting (PONV), acute pain and need of opioids as well as accelerate the convalescence. Meta-analyses also showed that single-dose administration of glucocorticoids (methylprednisolone and dexamethasone) for surgical patients is safe as opposed to long-term treatment.

Studies on pre-operative glucocorticoids before liver surgery have shown beneficial effects in regards to markers of liver damage and infection, but studies on clinical outcomes in the immediate post-operative phase are lacking.

The primary aim of this study is to investigate whether high dose pre-operative glucocorticoids reduce complications in the immediate post-operative course.

The investigators will also perform two hypothesis-generating sub studies:

• Sub study I - markers of endothelial dysfunction

The endothelial lining of blood vessels contributes to maintaining haemostasis, and damage can increase risks of cardiovascular and thromboembolic complications. In a recent randomized trial, pre-operative high dose glucocorticoids diminished circulating markers of endothelial damage (after knee arthroplasty). In this study we will investigate whether this also applies liver surgery, and if so, if there is any connection to cardiovascular and thromboembolic complications.

• Sub study II - delirium Studies on delirium after liver surgery show an incidence around 20%. It has not been investigated whether pre-operative glucocorticoids have an effect on this incidence.

The investigators will investigate the incidence of emergence delirium and delirium during the first postoperative day s after liver surgery.

Sample size:

The "Why in PACU?" database shows that complications requiring treatment in PACU occur in up to 40 % of patients after liver surgery. These complications are primarily respiratory and circulatory.

A 50 % reduction in the number of patients with complications requiring treatment is regarded clinically relevant. This will require a sample size of 174 patients, including 10 % dropout (80 % power, 5% level of significans, superiority design). Patients will be stratified according to extent of surgery, into minor or major resection.

The sub studies are hypothesis-generating, and are not subject to power calculations. Sub study I will include all major resections, sub study II will include patients during the first 5 months.

Analysis: Primary end point (complications in the two groups) is compared with chi square test and described with odds ratio (95%CI). Level of significance is p=0,05 Standard statistical analysis will include normally or near-normally distributed variables reported as means and non-normally distributed variables as medians. Means will be compared using the student's t test and medians using the Mann-Whitney U test. Differences in proportions among categorical data will be assessed using Fischer's exact test. A p value < 0.05 will represent statistical significance for all comparisons.

Hypothesis: Preoperative GC administration will decrease the incidence of postoperative complications and overall hospital length of stay following liver surgery. Preoperative GC administration will decrease markers of endothelial dysfunction following major liver surgery. Preoperative GC administration will decrease incidence of delirium following liver surgery.

Data collection:

Data elements to be collected will include, but not be limited to:

• Demographics (age, gender, height, weight, tobacco and alcohol consumption, comorbidities, American Society of Anaesthesiology (ASA) score)
• Preoperative chemotherapy, preoperative use of analgesics and/or other central stimulants
• Preoperative biochemistry
• Diagnosis, procedure, surgery duration
• Blood loss, transfusions, use of drain, hepatic inflow occlusion (length of)
• Postoperative pain, nausea, sedation and vitals, every 30 minutes until transfer to ward
• Postoperative pain, nausea, mood and quality of sleep, self reported, every day until discharge or postoperative day 5 (what comes first)
• Postoperative use of analgesics and anti emetics until discharge or postoperative day 5 (what comes first)
• Complications (hepatic failure, ascites, intraabdominal collection, postoperative bleeding, bile leak, bowel obstruction, wound dehiscence, reoperations, pleural effusion, pulmonary embolus, deep venous thrombosis, infections, cardiac events, cerebral events, other causes of prolonged hospital stay)
• 3-minute Diagnostic Confusion Assessment Method (3D-CAM), postoperative day 0 (all) 1-3 (major resections)
• Endothelial markers (Syndecan-1, soluble thrombomodulin, SE-selectin, vascular endothelial growth factor (VEGF) postoperative day0-3 (major resections)
• Hospital stay, length of stay in PACU
• Mortality (30 days)

The study is not placebo-controlled since the positive effects of dexamethasone 8 mg on PONV have been shown in numerous trials, and is already being administered to all patients at the clinic. It would therefore not be ethically correct to withdraw from this practise.

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age minimum 18
• Planned open liver resection (with or without combined ablation and/or
• cholecystectomy)
• Able to participate (self report pain/nausea)
• Understands danish/english, or has an interpreter during admission
• Signed consent form

Exclusion Criteria:

• ALPPS (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) procedure
• Combined ventral herniotomy with implantation of mesh
• Combined with operation on tumor in other organs
• Insulin dependent diabetes
• Current (<10 days) treatment with systemic glucocorticoids and/or immunosuppressive treatment (not including inhalations)
• Epidural anesthesia not feasible
• Pregnancy/breastfeeding
• Allergy toward study medication
• Inoperability

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylprednisolone; 10 mg/kg, single preoperative infusion	Drug: Methylprednisolone; 10 mg/kg methylprednisolone mixed in 100 ml NaCl (sodium chloride), infusion over 30 minutes, prior to surgery; Other Names: solu-medrol
Active Comparator: Dexamethasone; 8 mg dexamethasone, single preoperative infusion	Drug: Dexamethasone; Dexamethasone mixed in 100 ml NaCl, infusion over 30 minutes, prior to surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complications, Post-anesthesia Care Unit (PACU)	Number of patients with any complication at any time, during stay in the PACU. Complications according to DASAIMS discharge criteria (modified Aldrete criteria)	up to 24 hours
Substudy I: Markers of Endothelial Dysfunction	Amount of endothelial markers (Syndecan-1, soluble thrombomodulin, SE-Selectin, vascular endothelial growth factor (VEGF) )	post-operative days 0 to 3
Substudy II: Delirium	Number of patients with post-operative cognitive impairment, according to 3-minute diagnostic confusion assessment method (3D-CAM)	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	any cause mortality	30 days
Total Complication Rate	any complications, 30 day morbidity	30 days
Hospital Stay	from operation to discharge	3 months
PACU Stay	from operation to discharge from PACU	up to 24 hours
Pain at Movement	every 60 minutes, during stay in PACU. Numeric Rating Scale (NRS 0-10)	up to 24 hours
Pain, Abdominal (Postoperative)	During admission, self reported. Numeric Rating Scale (NRS 0-10)	up to five days
Nausea	During admission, self reported. (Light, none, moderate, heavy nausea)	up to five days
Analgesic Requirements	All analgesics other than standard medication, during admission. From Medical record.	up to five days
Antiemetic Requirements	All antiemetics other than standard medication, during admission. From Medical record.	up to five days
ALAT	impact on ALAT (alanin-aminotransferase) post surgery	up to five days
Bilirubin	impact on bilirubin post surgery	up to five days
INR	impact on INR (International Normalized Ratio) post surgery	up to five days

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Steinthorsdottir KJ, Awada HN, Schultz NA, Larsen PN, Hillingso JG, Jans O, Kehlet H, Aasvang EK. Preoperative high-dose glucocorticoids for early recovery after liver resection: randomized double-blinded trial. BJS Open. 2021 Jul 6;5(5):zrab063. doi: 10.1093/bjsopen/zrab063.

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2017
• Primary Completion (Actual): August 28, 2020
• Study Completion (Actual): September 28, 2020

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: January 11, 2018
• First Posted (Actual): January 18, 2018

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 8, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: steroids; glucocorticoids; hepatectomy; liver surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Dexamethasone; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: DEXLEV01; 2017-002652-81 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No