High Dose Steroids for Liver Resection - Effect on Complications and Endothelial Function in the Immediate Postoperative Phase - a Randomized, Doubleblind, Controlled Trial
Phase: PHASE4
Conditions: Complication, Postoperative
Sponsor: Rigshospitalet, Denmark

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PROTOCOL 
Early recovery after preoperative high dose glucocorticoids for 
liver resection- a randomized double-blinded trial 
EudraCT number: 2017-002652-81 
 
Approved date: 06.09.2017 
 
Sponsor: 
Name: 
 
Eske Kvanner Aasvang 
Title: 
 
DMSc, consultant 
 
Principal Investigator:  
Name: 
 
Kristin Julia Steinthorsdottir 
Title: 
 
MD, Clinical assistant 
 
 

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Aim .................................................................................................................................. 3 
Outcomes ........................................................................................................................ 3 
Primary outcome ........................................................................................................ 3 
Secondary outcomes ................................................................................................. 4 
Methods .............................................................................................................................. 4 
Study design ................................................................................................................... 4 
Randomization and blinding ...................................................................................... 4 
Intervention ................................................................................................................. 5 
Time schedule ................................................................................................................ 5 
Location .......................................................................................................................... 5 
Participants ..................................................................................................................... 5 
Inclusion criteria ......................................................................................................... 5 
Procedures ..................................................................................................................... 5 
Inclusion and randomization ..................................................................................... 5 
Standard care procedures ......................................................................................... 5 
Data management .......................................................................................................... 6 
Case Report Form ....................................................................................................... 7 
Clinical evaluations and outcome registration ........................................................ 7 
Sample size ..................................................................................................................... 7 
 

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Introduction 
Liver resection is mainly performed for primary or secondary tumors (hepatocellular carcinoma, 
cholangiocellular carcinoma and colorectal cancer metastases). Advances in surgical techniques 
and perioperative optimization in fast track protocols have reduced morbidity and mortality with a 
subsequent reduced length of stay1. However, the existing pre-operative morbidity of most 
patients undergoing liver resection and the extent of the surgical procedure means that recovery 
still represents a challenge with postoperative complication rates in up to 40% depending on 
definitions and time frame2–6. Furthermore, postoperative complications are also related to the 
extent of surgery, type of anesthesia, any intraoperative complications, and in the immediate 
postoperative phase potentially also to the extent of the surgical stress response7,8. The surgical 
stress response can theoretically be reduced by the use of pre-operative glucocorticoids (GCs) by 
the  downregulation of pro-inflammatory proteins and upregulation of anti-inflammatory proteins, 
resulting in an overall negative feedback on immunostimulation9,10. Several studies have reported 
the effect of preoperative GCs compared with control groups in reducing inflammatory cytokines 
and biomarkers of liver damage after liver resection surgery6,11–13. The GC effect on these 
surrogate outcomes has been shown to be statistically significant mostly on postoperative day 
one, but also evident immediately after surgery when measured within the first postoperative 
hours12,13. However, there is no evidence as to whether inflammatory control is related to a 
reduction in clinically relevant complications, as these have not been investigated as the primary 
outcomes in previous liver resection studies of preoperative GC administration.  However, a lower 
overall morbidity rate6 and reduced length of stay6,11 in the GC intervention groups suggest that 
there might be an effect on these clinical outcomes in liver resection surgery as well as in other 
surgical procedures14–19. To investigate the preventive effects of GCs on adverse clinical outcomes, 
we chose to focus on the immediate postoperative phase (during post-anesthesia care unit (PACU) 
stay) where all patients are closely monitored, treated and discharged according to well-defined 
protocols. 
 
Aim 
The aim of this study therefore was to investigate whether a high dose of GCs (10 mg/kg 
methylprednisolone (MP)) given as a single pre-operative injection could reduce complications in 
the immediate post-operative phase compared to a standard low dose postoperative nausea and 
vomiting (PONV) prophylaxis of glucocorticoids (8 mg of dexamethasone) after liver resection. The 
primary outcome was number of patients with complications requiring treatment during 
observation in the PACU according to predefined criteria. We additionally hypothesized that high 
dose glucocorticoids would reduce length of stay in the PACU, lower pain scores and opioid 
consumption in the first 3-4 days after surgery without increasing 30-day morbidity. 
 
Outcomes 
Primary outcome 
The primary endpoint was number of patients with a complication requiring treatment in the 
PACU, defined according to a standardized post-anesthesia discharge score (a modified version of 
the Aldrete discharge score22 – supplemental digital content (SDC) 1). The score consists of six 
modalities (sedation, oxygen saturation, blood pressure (BP), heart rate (HR), pain (at rest) and 
nausea).  

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A PACU complication was defined as any score > 1 (except > 2 for saturation), on two consecutive 
measurements 30 minutes apart OR a score >1 at one timepoint accompanied by a relevant 
treatment (e.g. pain on a numeric rating scale (NRS)> 3, accompanied by a rescue opioid 
administration, brady- or tachycardia accompanied by frequency regulation/conversion for 
arrythmia, PONV accompanied by antiemetic treatment) OR relevant treatment for > 30 minutes 
regardless of score  (continuous inotropic infusion for hypotension, >2L oxygen supply or other 
respiratory treatment). 
 
Secondary outcomes 
1. Mortality, all cause 30-day mortality.  
2. Morbidity, 30 days (liver failure, ascites, intraabdominal fluid collection, bleeding, 
cholascos, bowel obstruction, perforated visceral organ, fascial disruption, other causes for 
reoperation, pleural effusion, pulmonary embolus, deep venous thrombosis, acute 
myocardial infarction, transitory cerebral ischemia, stroke, infections (pneumonia, UTI, 
sepsis, wound infection), other causes for prolonged hospitalization).  
3. Number of patients with a complication requiring treatment during the first 24 
postoperative hours. Any complication requiring treatment (procedural, medication, 
alterations in standard care).  
4. Pain during movement (mobilization to sitting position or coughing). Pain scores (Numeric 
Rating Scale (NRS) 0-10), measured every hour during PACU stay (average).  
5. Pain during admission. Reported once daily on a NRS scale (0-10), on postoperative day 0 
to 4 (or day 3 if discharged).  
6. Analgesic medication, rescue opioids during admission (postoperative day 0 to 4 (or day 3 if 
discharged). Converted to oral morphine equivalents (OMEQ) according to a standardized 
opioid conversion chart23.  
7. Nausea during admission. Reported once daily on a 4-NRS scale (no, light, moderate or 
severe nausea), postoperative day 0 to 4 (or day 3 if discharged).  
8. Length of stay, PACU and hospital (measured from time of operation until time of 
discharge).  
9. Changes in liver enzymes and function tests (alanine transferase (ALT), prothrombin time, 
total bilirubin) at baseline (preoperative evaluation) and on postoperative days 1 (all 
patients), 2 and 3 (major resections).  
 
Methods 
Study design 
Randomized, double-blind, controlled intervention study. Superiority design. 
Randomization and blinding 
Patients were informed by trial personnel (KJS or HNA) in relation to the pre-operative 
appointment, usually 1-2 weeks prior to the operation and included in the trial on the day of 
surgery after written consent. Participants were stratified according to planned extent of surgery 
(major resections (≥ 3 liver segments) and minor resections (< 3 liver segments) and randomized 
1:1 in parallel groups by block randomization. Block sizes varied (4,6,8) and were unknown to 
study personnel. The allocation sequence was generated by an independent physician using 

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Sealed Envelope Ltd 201720. The allocation sequence with intervention details was concealed in 
consecutively numbered opaque envelopes by two other investigators not otherwise involved in 
the trial. Before sealing, 20% of the envelopes were randomly controlled, and the allocation 
sequence was stored by a physician not otherwise involved in the trial. After trial completion, the 
principal investigator received the allocation sequence without intervention revealed. The 
intervention allocation was revealed after performing statistical analysis and drafting the paper, 
including results, conclusion and comments from all authors. Throughout the trial, all participants, 
trial personnel, health care providers including surgeons, anesthetists and nurses, outcome 
assessors and data monitor were blinded. There were no code breaks during the trial.  
Intervention 
The high dose (HD) group received 10 mg/kg of MP (Solu-medrol®, Pfizer, Denmark) and the 
standard dose (SD) group received 8 mg of dexamethasone (Dexavit, Vital Pharma Nordic, 
Denmark). On the day of surgery, trial personnel (only assigned to prepare the intervention) 
received and opened the sealed envelope and prepared the trial drug. Both the HD and the SD 
were injected in a sterile (drip) bag containing 100 ml NaCl, covered in foil concealing content and 
amount. The bag was labelled with patient identification and handed to trial personnel together 
with the resealed and signed envelopes. Trial personnel administered the medication in 10 
minutes immediately after anesthesia induction, around 30 minutes prior to surgery. The drip was 
flushed with NaCl at the end of administration of the trial drug.  
Time schedule 
Study expected to start: December 2017 
Study expected to finish: August 2020 
Location 
Copenhagen University Hospital, Rigshospitalet, Denmark. Department of Orthopedic Surgery, and 
Department of Anesthesiology, Centre of Head and Orthopedics. 
Participants 
Number of participants: 174, 87 in each group. 
Inclusion criteria 
All patients scheduled for open liver surgery without biliary reconstruction were consecutively 
screened for inclusion. Patients considered were 18 years of age or older and able to provide 
informed oral and written consent. Exclusion criteria were planned simultaneous operation on 
other organs, simultaneous operation for herniation with insertion of mesh, planned two-stage or 
ALPPS procedure (Associating Liver Partition and Portal vein Ligation for staged hepatectomy), 
active Hepatitis C virus infection, daily/current use of glucocorticoids or immunosuppressant 
medication (within 10 days before the procedure), insulin-dependent diabetes, pregnancy or 
lactation. 
Procedures 
Inclusion and randomization 
Eligible patients are informed about the trial in relation to the pre-operative appointment.  
Enrolled participants are randomized and assigned to consecutive numbers at the morning of 
surgery. 
Standard care procedures 
All patients were treated according to a well-implemented enhanced recovery after surgery (ERAS) 
protocol described previously 1,21. Before surgery, all patients had an epidural analgesia catheter 

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inserted at Thoracic level 8-10, which was maintained with a continuous infusion of 
bupivacaine/morphine (2.5 mg + 50.0 µg ml-1). After induction a 30 mg bolus of 0.5% bupivacaine 
was administered, and 15 mg 0.5% bupivacaine was repeated every hour during surgery. 
Anesthesia was induced with propofol (1.5-2.5 mg kg-1), remifentanil (0.3-0.8 µg kg-1) and 
cisatracurium (0.1 mg kg-1) or suxamethonium (1 mg kg-1). Anesthesia was maintained with 
propofol 0.05-0.15 mg kg-1 min-1, remifentanil (0.3-0.8 μg kg-1 min-1) and cisatracurium aiming at a 
train of four (TOF) response of 0%. In cases with impaired liver function in combination with major 
resection, sevoflurane could replace propofol. Norepinephrine infusion was administered to 
maintain a mean arterial pressure (MAP) > 60 mmHg. During resection, central venous pressure 
(CVP) was maintained around 4-5 mmHg. Ondansetron (4 mg) was administered 30-45 minutes 
before the end of surgery. Before extubation, a TOF ratio >90% was confirmed. 
Monitoring included invasive arterial blood pressure, central venous pressure, ECG, pulse 
oximetry, nasopharyngeal temperature, nerve stimulator, urinary catheter and a nasogastric tube.  
The surgical procedure was preferably performed through a curved subcostal incision extended in 
the midline to the xiphoid process (Th 7-10). In case of resections in the left lateral segment an 
upper midline incision was used. The resection was categorized as major if the resection equalized 
3 or more segments, otherwise as minor. If hepatic clamping was performed, intermittent Pringle 
maneuver was applied for a maximum of 15 minutes at a time with 5 minutes intervals in between 
if repeated. Perioperative antibiotic was a single dose 2 grams of ceftriaxone. In case of bleeding 
exceeding 1000 ml it was continued as 1500 mg of cefuroxime 3 times daily and metronidazole 
1500 mg once daily for three days. Drains were placed according to intraoperative bleeding and 
the surgeon´s evaluation of risk for bile leakage (typically major resections). It was planned 
removed on POD 1 in case there was no bleeding or bile leakage. Low molecular weight heparin 
was initiated on the morning of surgery and continued until full mobilization.  
Nasogastric tubes were removed immediately after the procedure in the operating room. The 
radial artery cannula was removed on POD 0 before discharge from the PACU, the central venous 
catheter was removed on POD 1 in minor resections, and POD 3 in major resections. Urinary 
catheter was removed on POD 1. 
Postoperative pain management consisted of epidural infusion of bupivacaine/morphine (2.5 mg + 
50.0 µg-1 ml-1) infusion starting intraoperatively at 5 ml h-1 but titrated depending on 
effect/adverse effects and continued for a maximum of 3 postoperative days. Modified release 
acetaminophen 1330 mg every 8 h was started immediately after surgery (individual prescription 
in the major resection group). On the evening of POD 2 additional 200 mg celecoxib and 
gabapentin 600 mg was started (reduced dose if weight< 50 kg or age >65 years or in case of 
impaired renal function), and continued every 12 h (celecoxib 200 mg, gabapentin 300 mg in the 
morning and 600 mg in the evening) for one week.  
In uneventful postoperative courses, discharge was expected and planned on POD 3 or 4. 
Data management 
Before patient enrolment, the trial is approved by the local ethics committee, the Danish data 
protection agency and the Danish Medicines Agency. The trial will be registered at 

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ClinicalTrials.gov and EudraCT and will be monitored by the Good Clinical Practice unit at a 
Copenhagen University Hospital. 
Data belongs to sponsor. 
Case Report Form 
Every patient enrolled will have a case report form signed by investigator. REDCap (Research 
Electronic Data Capture) electronic data capture tools hosted at Rigshospitalet will be used as case 
report form. Signed informed consent forms will be kept in a separate folder. 
 
Clinical evaluations and outcome registration 
Data are collected from the EPIC based electronic medical record and managed using REDCap 
electronic database hosted at Rigshospitalet24 . Variables collected are:  
Demographics (age, gender, weight, height, indication for surgery (disease), comorbidities, 
smoking and alcohol habits, medication, prior abdominal operative history, recent chemotherapy 
history) and intraoperative data (time of start and end of surgery, time of extubation, duration of 
hepatic clamping, insertion of drains, amount of anesthetics and fluids administered, bleeding, 
blood component therapy, level of epidural insertion, type of incision, procedures performed, 
including additional (unplanned) procedures). Postoperatively PACU data were collected (time of 
admission and discharge, vital values (BP, HR, oxygen saturation, respiratory rate) and pain, 
nausea and sedation every 30th minute, pain at mobilization every 60 minutes, and treatments 
administered (oxygen supply, analgesics, antiemetics, blood component therapy, fluid 
administered, vasopressors) ) and the ward (vital values, pain, nausea and sedation at admission 
and any complications requiring treatment within 24 hours, analgesic and antiemetic treatment 
until POD 4 or discharge (whichever came first), discharge from hospital). All-cause mortality, 
readmissions (unplanned and related to surgery) and morbidity as described in secondary 
outcomes were assessed 30 days after surgery.     
Biomarkers (hemoglobin (Hb), platelets, creatinine, potassium, sodium, prothrombin time 
(International Normalized Ratio (INR)), alanine aminotransferase (ALT), bilirubin) were collected 
for all patients at baseline and POD1, and for major resections also on POD 2-3. 
Patients were requested to fill out a questionnaire every day on POD 0 to 4 (or discharge, 
whichever came first) containing following elements pertaining to the last 24 hours (except on 
POD 0, only time from after surgery until bedtime): Pain (NRS 0-10) in average and at worst, 
nausea (none, light, moderate, severe) in average and at worst, vomiting (yes/no), feelings of 
sadness (yes/no), restlessness (yes/no) or fatigue (yes/no), quality of sleep (good, trouble falling 
asleep, frequent awakenings, no sleep). 
 
Sample size 
The sample size calculation was based on internal audit and previous reports of a 40% 
complication rate in the PACU. An expected 50% reduction in the intervention group required 174 
patients (87 in each group), with a 5% significance level and a power of 80%. 
As patients were included and randomized at the time of operation, no dropout rate was 
expected. 

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