Clinical trial NCT03403517
Conditions: Complication, Postoperative
Keywords: steroids glucocorticoids liver surgery hepatectomy
Sponsor: Rigshospitalet, Denmark
Start date: 2017-12-11; Completion date: 2020-09-28
Enrollment: 174 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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).

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.

Arms: arm 1: 10 mg/kg, single preoperative infusion arm 2: 8 mg dexamethasone, single preoperative infusion
Interventions: intervention 1: Methylprednisolone intervention 2: Dexamethasone
Intervention descriptions: intervention 1: 10 mg/kg methylprednisolone mixed in 100 ml NaCl (sodium chloride), infusion over 30 minutes, prior to surgery intervention 2: Dexamethasone mixed in 100 ml NaCl, infusion over 30 minutes, prior to surgery

Protocol documents:
Prot_001.pdf: 
1 
 
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 
 
 


2 
 
 
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 
 


3 
 
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).  


4 
 
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 


5 
 
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 


6 
 
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 


7 
 
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. 


8 
 
 
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surgery: randomised controlled trial (DREAMS Trial). BMJ 2017; 357:1455 
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Oliveira GS De, Castro-Alves LJS, Ahmad S, Kendall MC, McCarthy RJ: Dexamethasone to 
Prevent Postoperative Nausea and Vomiting. Anesth Analg 2013; 116:58–74 
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Oliveira GS De, Almeida MD, Benzon HT, McCarthy RJ: Perioperative single dose systemic 
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Li X, Sun Z, Han C, He L, Wang B: A systematic review and meta-analysis of intravenous 
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Svendsen K, Borchgrevink P, Fredheim O, Hamunen K, Mellbye A, Dale O: Choosing the unit 
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SAP_000.pdf: 
Statistical analysis plan, STEREO 
SAP v. 3_300920 
Content 
Administrative information ............................................................................................................................... 2 
Introduction ....................................................................................................................................................... 2 
Background and rationale ............................................................................................................................. 2 
Objectives- main study .................................................................................................................................. 3 
Objectives- sub study I (endothelial markers) ............................................................................................... 3 
Study methods ................................................................................................................................................... 3 
Trial design..................................................................................................................................................... 3 
Randomisation ............................................................................................................................................... 3 
Sample size .................................................................................................................................................... 3 
Framework ..................................................................................................................................................... 4 
Statistical interim analyses and stopping guidance ...................................................................................... 4 
Timing of final analysis .................................................................................................................................. 4 
Timing of outcome assessments ................................................................................................................... 4 
Statistical principles ........................................................................................................................................... 4 
Confidence intervals and P values ................................................................................................................. 4 
Adherence and protocol deviations, analysis populations ........................................................................... 4 
Trial population ................................................................................................................................................. 4 
Eligibility ........................................................................................................................................................ 4 
Recruitment ................................................................................................................................................... 5 
Baseline patient characteristics ..................................................................................................................... 5 
Operative characteristics ............................................................................................................................... 6 
Outcome definitions and analysis methods ...................................................................................................... 7 
Primary outcome ........................................................................................................................................... 7 
Secondary outcomes ..................................................................................................................................... 7 
Endothelial markers (sub study I) .................................................................................................................. 8 
Missing data....................................................................................................................................................... 9 
Harms ................................................................................................................................................................ 9 
Statistical software ............................................................................................................................................ 9 
 
 
 
 


Statistical analysis plan, STEREO 
SAP v. 3_300920 
Administrative information 
 
Introduction 
Background and rationale  
Preoperative use of glucocorticoids has been shown to reduce markers of systemic inflammation (IL-6, IL-
10, TNF-α, CRP) after several procedures. In studies of preoperative glucocorticoid use in liver resections, 
markers of liver function (alanine amine transferase (ALT), prothrombin time/international normalized ratio 
(PT/INR) and total bilirubin) have also been positively affected, as a surrogate of decreased inflammatory 
response and liver dysfunction1–4. Few studies have also shown a clinical benefit, with reduced hospital 
length of stay3,4 and the Enhanced Recovery After Surgery (ERAS) Society recommendations include 
preoperative glucocorticoids with moderate level of evidence to decrease liver injury and intraoperative 
stress5. However, meta-analyses of available RCTs have not shown an effect on morbidity or hospital length 
of stay6,7. Thus, the clinical impact during hospitalization is not clear, and whether high dose steroids 
influence clinically relevant complications altogether, and especially in the immediate postoperative phase 
has not been investigated.  
Title and trial registration 
Preoperative high dose steroids for liver resection- effect on 
complications in the immediate postoperative period- a randomised, 
double blind, controlled trial (STEREO) 
NCT03403517, EudraCT 2017-002652-81 
SAP version 
1, 30.09.2020 
Protocol version 
9, 21.11.2019 
Roles and responsibility 
Kristin J Steinthorsdottir (primary investigator, SAP creator) 
Eske K Aasvang (Chief investigator/sponsor, final approval) 
Theis Lange, biostatistician, consultation 
Date of approval 
30-09-2020 
Signatures 
 
 
 
 


Statistical analysis plan, STEREO 
SAP v. 3_300920 
The most common postoperative complications in the immediate phase (in the post-anaesthesia care unit 
(PACU)) are pain, postoperative nausea and vomiting (PONV) and depending on extent of surgery and the 
surgical population; circulatory and respiratory complications and cognitive disturbances (emergence 
delirium and postoperative delirium)8 After open liver resection surgery, the most common complications 
in the PACU are pain (including right shoulder pain [reference theis studie]), low oxygen saturation and 
hypotension, with around 40% of patients requiring treatment during PACU stay. All complications are 
caused by numerous factors, but in general controlling the inflammatory response and reducing the 
surgical stress response should theoretically reduce complication rates.  
Objectives- main study 
The objective is to determine whether a high dose of glucocorticoids can reduce complications in the 
immediate postoperative phase after open liver resection, compared to a standard, low dose of 
glucocorticoid 
Objectives- sub study I (endothelial markers) 
The objective of the endothelial sub study is to determine whether a single preoperative high dose of 
glucocorticoids reduce shedding of endothelial glycocalyx markers in the first 72 hours after liver resection, 
compared to a standard, low dose of glucocorticoids.  
Study methods 
Trial design 
Double-blind, parallel group, 1:1 randomisation to either dexamethasone 8 mg or methylprednisolone 10 
mg/kg  
Randomisation 
Randomisation at the day of operation. Patients are stratified according to planned extent of operation 
(minor/major resection (<3/ ≥3 liver segments resected)). This stratification is only used for sub study I 
(endothelial markers). Only patients that are stratified to major resection, that are also operated 
accordingly, participate in sub study I. 
Sample size 
174 patients, approximately 87 in each group. An estimated 20% are part of sub study I. The sample size 
assumes reducing the proportion of patients with complications requiring treatment in the PACU from 40% 
to 20%, with an estimated 10% drop-out rate, a statistical power (superiority trial) of 80% with an α level of 
5%.  


Statistical analysis plan, STEREO 
SAP v. 3_300920 
Framework 
Superiority. 
Statistical interim analyses and stopping guidance 
No planned. 
Timing of final analysis 
Thirty days after the last patient is operated and after the final GCP monitoring visit, all analyses of the 
main and sub study I are performed, with allocation still blinded. The main findings are drafted in an 
abstract, and all authors approve of the analyses and the interpretation. Only thereafter the allocation is 
revealed. The main study and sub study I can be analysed at different times, but allocation can only be 
revealed when all authors have accepted drafts with allocation unknown.     
Timing of outcome assessments 
Outcomes are assessed ongoing, up to 30 days after the operation. 
 
Statistical principles 
Confidence intervals and P values 
Level of statistical significance: P<0.05. Confidence intervals to be reported: 95%CI. 
Adherence and protocol deviations, analysis populations 
All randomized patients are analyzed as intention to treat. Patients that receive the intervention and 
undergo liver resection will be analyzed as per protocol.   
Protocol deviations are recorded and presented if occurring in >5% of participants (deviations from the 
standard surgical, anesthetic and postoperative protocol, e.g. length of epidural anesthesia, deviations 
from postoperative analgesic regime). 
Trial population 
Eligibility  
Patients aged ≥ 18 years scheduled for open liver resection surgery, including combined resection and 
ablation procedures, during the study period are eligible. Patients can be included if they speak Danish or 


Statistical analysis plan, STEREO 
SAP v. 3_300920 
English (or if they have a translator during admission), if they can participate in answering questions about 
pain/nausea etc., and if they sign an informed consent form. 
Exclusion criteria are insulin dependent diabetes mellitus, ongoing (within 10 days) treatment with systemic 
glucocorticoids or other immunosuppressive medication, pregnancy/breastfeeding, active hepatitis C virus,  
planned two-stage liver resection, planned combined liver resection and operation on other abdominal 
organs or herniotomy with implantation of a mesh. 
Recruitment 
Information to be included in the CONSORT flow diagram: Screening data; includes all patients eligible to 
participate (e.g. adults planned for open liver resection in the study period). Reasons for non-inclusion 
listed. Included patients, all patients signing inclusion forms. Randomized patients; all patients included, 
that received the intervention. Reasons for non-randomization. Participants in each group. Intention to 
treat and per-protocol numbers.  
Baseline patient characteristics 
List of baseline characteristics to be summarized. Categorical data will be described as numbers 
(percentage) and continuous data as mean (SD) or median (IQR) depending on distribution. 
 
A (n=86) 
B (n=88) 
Total 
Age 
64 ± 12 
65 ± 11 
65± 12 
Sex (male) 
56 (65%) 
61 (69%) 
117 (67) 
BMI 
28 ± 6 
27 ± 5 
28 ± 5 
Smoking status 
Current (number of package years) 
Past (number of package years) 
Never 
 
16 (19%), xx (x,x) 
46 (53%), xx (x,x) 
24 (28%) 
 
18 (20%), xx (x,x) 
43 (49%), xx (x,x) 
27 (31%) 
 
Alcohol intake 
> 7(women)/14(men) units/week, no of units 
< 7(women)/14(men) units/week 
No 
 
Xx (x%), xx (x,x) 
Xx (x%) 
Xx (x%) 
 
Xx (x%), xx (x,x) 
Xx (x%) 
Xx (x%) 
 
Disease/indication for surgery 
- 
Colorectal liver metastasis 
- 
Non-colorectal metastasis 
- 
Hepatocellular carcinoma 
- 
Cholangiocellular carcinoma 
- 
Benign diseases 
 
Xx (x%) 
 
Xx (x%), x (x%) 
Xx (x%) 
 
Xx (x%) 
 
Xx (x%), x (x%) 
Xx (x%) 
 
Comorbidities 
- 
Hypertension 
- 
Chronic cardiac disease 
- 
Atrial fibrillation 
 
Xx (x%) 
Xx (x%) 
Xx (x%) 
 
Xx (x%) 
Xx (x%) 
Xx (x%) 
 


Statistical analysis plan, STEREO 
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- 
Chronic pulmonary disease 
- 
Non-insulin dependent diabetes mellitus 
- 
Cirrhosis 
- 
Hypercholesterolemia 
- 
Depression 
- 
Other 
 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
ASA score 
I 
II 
III 
 
1 (1) 
42 (49) 
43 (50) 
 
2 (2) 
41(47) 
45(51) 
 
3 (2) 
83 (48) 
88 (50) 
Prior abdominal operation 
- 
Open, liver 
- 
Laparoscopic, liver 
- 
Open, other 
- 
Laparoscopic, other  
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
 
Preoperative blood test results 
- 
Haemoglobin (mmol/l) 
- 
Platelets (E9/l) 
- 
eGFR (ml/min) 
- 
Protrombin time (INR) 
- 
Alanine transaminase (IU/l) 
- 
Total bilirubin (mg/dl) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
 
 
Preoperative stratification 
- 
Minor 
- 
Major 
 
Xx (x%) 
Xx (x%) 
 
Xx (x%) 
Xx (x%) 
 
 
 
Operative characteristics  
 
 
A (n=86) 
B (n=88) 
- 
 
 
 
Liver-first (colorectal liver metastasis) 
 
 
Operation (primary) 
- 
Left hepatectomy 
- 
Right hepatectomy 
- 
Resection of two liver segments 
- 
Resection of one liver segment 
- 
Atypical resection 
- 
Radio frequency ablation  
 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Other operation 
- 
Cholecystectomy 
 
Xx (x%) 
 
Xx (x%) 


Statistical analysis plan, STEREO 
SAP v. 3_300920 
- 
Radio frequency ablation 
- 
Resection of one liver segment 
- 
Colonic resection 
- 
Hernia repair 
- 
Resection, other  
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Xx (x%) 
Operative time, min 
Xx (xx) 
Xx(xx) 
Abdominal drain 
Xx (x%) 
Xx (x%) 
Pringle manoeuvre 
- 
Ischemia time (min) 
Xx (x%) 
Xx (x,x) 
Xx (x%) 
Xx (x,x) 
Intraoperative bleeding (ml) 
Xx (x,x) 
Xx (x,x) 
Intervention group, methylprednisolone dose 
 
XX (x,x) 
 
Outcome definitions and analysis methods 
Primary outcome 
Number of patients with a complication in the postoperative care unit (PACU). Complications are evaluated 
with the DASAIM discharge score (see appendix 1 in the protocol). Any score > 1 (except > 2 for saturation), 
on two consecutive measures 30 minutes apart OR relevant treatment (inotropic for hypotension, >2L 
oxygen supply or other respiratory treatment, frequency regulation/conversion for arrythmia, opioids for 
pain, antiemetics for nausea). 
Primary comparison will be a Fisher’s exact test. Effects will be presented as number (percentage), with risk 
ratios and risk differences along with 95% CI based on Generalized Linear Model (GLM) with the appropriate 
link-functions. 
Presence of individual complications of the composite primary outcome (described according to the DASAIM 
score, e.g. pain, PONV, respiratory complication, circulatory complication, sedation) will be analysed in the 
same way, and presented together with the primary outcome. 
Secondary outcomes  
 
1. Length of stay, PACU and Hospital (measured from time of operation until time of discharge). 
Compared between groups using t-test and Mann-Whitney U test with the primary p-value being 
the one form the Mann-Whitney test. 
2. Mortality, all cause 30-day mortality. Analysed as the primary outcome. 
 


Statistical analysis plan, STEREO 
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3. Pain during  movement. Pain scores (Numeric Rating Scale (NRS) 0-10), measured every 60th minute 
during PACU stay. Depending on length of stay in the PACU, there will be 1 to 8 measures per 
patient, that will be calculated into an average pain score. Average pain scores for each patient will 
be compared between groups using t-test and Mann-Whitney U test with the primary p-value being 
the one form the Mann-Whitney test. 
4. Number of patients with a complication requiring treatment during the first 24 postoperative 
hours. Any complication requiring treatment (procedural, medication, alterations in standard care). 
Defined according to protocol.  Analysed as the primary outcome. 
5. Pain during admission. Reported once daily on a NRS scale (0-10), on postoperative day 0 to 4 (or 
day 3 if discharged). Pain scores for each patient (worst and average pain) will be compared 
between groups using t-test and Mann-Whitney U test with the primary p-value being the one form 
the Mann-Whitney test. 
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 chart. Cumulated OMEQs will be compared and analysed as the primary outcome. 
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). Compared between groups using t-test 
and Mann-Whitney U test with the primary p-value being the one form the Mann-Whitney test. 
8. Blood level of liver enzymes and function tests (ALT, INR, total bilirubin) at baseline (preoperative 
evaluation) and on postoperative days 1 (all patients), 2 and 3 (major resections). Postoperative 
changes from baseline will be compared between groups using t-test and Mann-Whitney U test 
with the primary p-value being the one form the Mann-Whitney test. 
9. Morbidity, 30 days (liver failure, ascites, intraabdominal fluid collection, bleeding, cholascos, 
mechanical ileus, perforated visceral organ, fascial disruption, other causes for reoperation, pleural 
effusion, lung embolus, deep venous embolus, acute myocardial infarction, transitory cerebral 
ischemia, apoplexy, infections (pneumonia, UTI, sepsis, wound infection), other causes for 
prolonged hospitalisation). Total morbidity and Individual complication rates will be analysed as the 
primary outcome. 
 
Endothelial markers (sub study I) 
Endothelial markers: syndecan-1, soluble thrombomodulin, SE-selectin, vascular endothelial growth factor 
and pecam. 


Statistical analysis plan, STEREO 
SAP v. 3_300920 
Blood samples are drawn preoperatively (baseline, T0), at the end of the operation (T1), 2 hours after the 
end of operation (T2), and once daily day 1-3 (T3,4,5). Analysis will be performed on T0, T2, T3 and T5. 
 Data will be evaluated for normal distribution, log transformed if required, before analysis. Postoperative 
changes from baseline will be compared with paired samples t-test. The overall development in endothelial 
markers will be assessed using a two-way mixed MANOVA with group as between-subjects factor and time 
as within-subjects factor. 
Missing data 
For each analysis available data will be presented. No imputation of missing data will occur. 
Harms 
Adverse events (AE) is any event occurring within 40 hours from administration of the trial drug, except 
events not requiring any treatment/actions (e.g. deviant laboratory results), moderate hypotension (MAP> 
60 mmHg) and/or tachycardia (heartrate < 120 bpm) in the first 24 postoperative hours, pain from the 
operative area, urinary retention, intraoperative bleeding, affected motor function during epidural 
treatment.  All AEs are evaluated by the primary investigator as to whether they are related, likely related, 
unlikely related or unrelated to the trial drug and graded from 1 to 4 (1 = mild, 2 = moderate, 3 = severe, 4 
= life-threatening, disabling or deadly). All serious AEs (grade3/4) are reported and analysed for each group.  
Statistical software 
R Studio for Windows, newest version available will be used for the statistical analysis. GraphPad Prism for 
Windows version 8.0.2 will be used for graphical presentation. 
 
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