Effect of High vs Low Dose Intravenous Dexamethasone on Complications in the Immediate Postoperative Phase After Mastectomy- a Randomized, Double-blind, Controlled Trial
Phase: PHASE4
Conditions: Dexamethasone, Glucocorticoids, Mastectomy, Breast Cancer, Pain, Postoperative, Nausea and Vomiting, Postoperative, Steroid, Systemic Inflammatory Response Syndrome, Postoperative Complications
Sponsor: Rigshospitalet, Denmark

 
 
 
Title: High vs. Low Dose Dexamethasone on Complications in the 
Immediate Postoperative Phase after Mastectomy (DEX-MAS).  
 
NCT number: NCT03125941 
 
Document date: 16-05-2018  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Statistical Analysis Plan  
Categorical data are presented as numbers with percentages, and tests for significant 
differences between the groups are assessed with χ2test. Continuous data are presented as 
mean (95% CI) or as median with inter-quartile range or range and assessed for normal 
distribution with the Kolmogorov-Smirnov/Shapiro-Wilk test. Tests for significant differences 
between groups are performed with an independent-samples t-test or Mann-Whitney U test 
when appropriate. The primary outcome is evaluated using χ2test, and the different 
modalities in the discharge criterion system and length of stay (secondary outcome) are 
evaluated using the independent-samples Mann-Whitney U test. Need for seroma drainage, 
readmissions and wound infections are evaluated using χ2test.  
All available data are used, missing data is not imputed. Data from the questionnaire on 
PONV and sleep is dichotomized into categories, PONV/no PONV and sleep problems/no 
sleep problems. A two-sided 5% significance level is chosen for the primary and secondary 
outcomes. To adjust for multiple comparisons in the tertiary outcome (questionnaire, 40 tests), 
we chose a Bonferroni corrected significance level of 0.125%. 
Data analyses were conducted using SPSS for Windows, version 22 (IBM Corp., New York, USA). 

 
Data processing is done by the investigator, who will continue to be blinded until all results are 
analyzed, and the abstract is written and accepted by co-authors.  
 

PROTOCOL 
Effect of high vs low dose intravenous dexamethasone on complications in the 
immediate postoperative phase after mastectomy- a randomized, double-blind, 
controlled trial 
 
EudraCT number: 2017-000227-27 
 
Sponsor: 
Name: 
 
Eske Kvanner Aasvang 
Title: 
 
DMSc, consultant 
 
Principal Investigator:  
Name: 
 
Kristin Julia Steinthorsdottir 
Title: 
 
MD, Clinical assistant 
 
 

 
Introduction ...................................................................................................................................................... 3 
Aim ................................................................................................................................................................ 4 
Outcomes ..................................................................................................................................................... 4 
Primary outcome ..................................................................................................................................... 4 
Secondary outcomes .............................................................................................................................. 4 
Methods ............................................................................................................................................................ 5 
Studydesign ................................................................................................................................................. 5 
Randomization ........................................................................................................................................ 5 
Intervention .............................................................................................................................................. 5 
Control ..................................................................................................................................................... 5 
Concealment ............................................................................................................................................ 5 
Blinding .................................................................................................................................................... 5 
Time schedule ............................................................................................................................................. 6 
Location ........................................................................................................................................................ 6 
Participants .................................................................................................................................................. 6 
Inclusion criteria ..................................................................................................................................... 6 
Exclusion criteria .................................................................................................................................... 6 
Procedures ................................................................................................................................................... 6 
Inclusion and preoperative treatment ................................................................................................... 6 
Anesthesia and surgery ......................................................................................................................... 7 
Post-operative treatment ........................................................................................................................ 7 
Data management ....................................................................................................................................... 7 
Case Report Form ................................................................................................................................... 7 
Clinical evaluations and outcome registration .................................................................................... 8 
Other collected data ............................................................................................................................... 9 
Sample size .................................................................................................................................................. 9 
 
Appendix 1. Danish Society of Anesthesiology and Intensive Care Medicine 
(DASAIM)- score, modified. 
 

Introduction 
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 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. 
Based on positive results in other procedure-specific studies, all mastectomy patients at 
Rigshospitalet, have received pre-operative high-dose steroids, in the form of 24 mg 
dexamethasone injection since mid-2015. This has resulted in a decrease in the proportion of 
patients who need observation in PACU from 30 % to 10 %. The reduction is primarily due to less 
pain, less sedation, and lower opioid administration.  
Whether this is also partly due to a "systemic effect" (Hawthorn effect) as a result of increased 
focus on the area cannot be excluded. 
Prior to creating clinical recommendations and standards, it is required that the results be tested 
in a randomized, controlled, clinical trial. 
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 practice. 
 

Aim 
The aim of this study is to investigate the effect of a single preoperative high-dose steroid injection 
on complications in the immediate postoperative phase after breast cancer surgery, with removal 
of the breast (mastectomy). Primary outcome is the proportion patients who require transfer to 
the post anesthesia care unit (PACU) and the proportion that can be transferred directly to the 
ward. Secondary outcomes are organ specific complications in the post anesthesia phase, pain and 
nausea the first 5 days, seroma and wound infection the first 14 days and readmissions the first 30 
days after surgery.  
The investigators hypothesize that the frequency of transfer to the PACU and organ specific 
complications will be lower among patients receiving high dose dexamethasone. The investigators 
hypothesize, that there will be no difference in wound infections, seroma or readmissions. 
 
Outcomes 
Primary outcome 
The number of patients meeting criteria for postoperative transfer to the post-anesthesia care 
unit (PACU) according to the DASAIM-score (Appendix  
 
Secondary outcomes 
• Discharge score in the operating room (according to discharge criteria, Appendix 1). 
• Discharge score at arrival to the ward or PACU (according to discharge criteria, Appendix 
1). 
• Complications/adverse events in the ward the first 24 h or until discharge. 
• Lenght of stay (PACU/Hospital) 
• Pain, self-reported in patient questionnaire. Days 0-4. 
• Nausea/vomiting, self-reported in patient questionnaire. Days 0-4. 
• Analgetics and antiemetics,use of, self-reported in patient questionnaire. Days 0-4. 
• Quality of sleep, self-reported in patient questionnaire. Days 0-4. 
• Feelings of anxiety, restlessness, fatigue, self-reported in patient questionnaire. Days 0-4. 
• Seroma, requiring drainage, the first 14 postoperative days  
 

Methods 
Studydesign 
Randomized, double-blind, controlled intervention study. Superiority design. 
Randomization 
Computer generated, double-blind block randomization. Allocation ratio 1:1, block sizes (2,4,6,8) 
randomly vary and unknown to study personnel. 
The allocation sequence with intervention details (24 mg or 8 mg dexamethasone) will be 
concealed in consecutively numbered (1-130), opaque envelopes by two other investigators not 
otherwise involved in the trial. Before sealing, 20 % of the envelopes are randomly controlled. 
Intervention 
A single dose of 24 mg dexamethasone iv (Dexamethasone sodium phosphate, Krka, Novo mesto, 
Slovenia), (6 ml), administered immediately after anesthesia induction, between 30 and 15 
minutes prior to surgery. 
Control 
A single dose of 8 mg dexamethasone iv (2 ml) with isotonic saline (4 ml), administered 
immediately after anesthesia induction, between 30 and 15 minutes prior to surgery. 
Concealment 
The trial drug is contained in a syringe with 6 ml solution, transparent and identical in appearance 
regardless of dose, labeled with patient identification and handed to trial personnel together with 
the re-sealed and signed envelopes. 
Blinding 
Participants, all healthcare providers, trial personnel, data monitoring committee, principal 
investigator and outcome adjudicators will be blinded throughout the study. After trial 
completion, the principal investigator receives the allocation sequence without intervention 
revealed. The intervention allocation will be revealed after performing statistical analysis and 
drafting the paper, including comments from all authors. 

Time schedule 
Study expected to start: March 2017 
Study expected to finish: August 2018 
Location 
Copenhagen University Hospital, Rigshospitalet, Denmark. Department of Breast Surgery and 
Department of Anesthesiology, Centre of Head and Orthopaedics. 
Participants 
Number of participants: 130, 65 in each group. 
Inclusion criteria 
• Planned unilateral mastectomy with or without axillary dessection 
• Age 18 years or older  
• Able to understand Danish or English and to provide informed oral and written consent.  
Exclusion criteria 
• Simultaneous contralateral procedure  
• Breast conserving surgery  
• Daily/current use of glucocorticoids or immunosuppressant medication  
• Insulin-dependent diabetes  
• Pregnancy or lactation 
• Allergies to any of the trial drugs.   
Procedures 
Inclusion and preoperative treatment 
Eligible patients are informed about the trial in relation to the pre-operative appointment.  
Enrolled participants are randomized and assigned to consecutive numbers (1-130) at the time of 
enrollment.  
On the morning of surgery, patients received acetaminophen 1 g 1-2 hours before surgery. 

Anesthesia and surgery  
Participants in the trial follow standard procedures. Anesthesia is induced with propofol 2 mg/kg iv 
and a total dose of fentanyl 0.25 mg and maintained as total intravenous anesthesia (TIVA) with 
propofol (5 mg/kg/h) and remifentanil (25µg/kg/h). The airway is handled with a laryngeal mask, 
or in case of obesity or reflux an endotracheal tube. Intraoperative fluid therapy is standardized 
with Ringers lactate, 25-30 ml/kg. Ondansetron 4 mg iv is administered 20-30 minutes prior to end 
of surgery. Local infiltration analgesia at the surgical site (wound infiltration) is performed 
intraoperatively with 20 ml bupivacaine 2.5 mg/ml by the surgeon. No routine use of drains. 
Post-operative treatment 
Analgesics: By request, acetaminophen 1 g up to 4 times daily, ibuprofen 400 mg up to three times 
daily, from the evening of surgery up to and including the fifth postoperative day.. Opioids are only 
given in hospital, on request based on moderate or severe pain. 
Antiemetics: By request, or if vomiting occurs. 
 
Data management 
Before patient enrolment, the trial has to be approved by the local ethics committee, the Danish 
data protection agency and the Danish Medicines Agency. The trial will be registered at 
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 
Pain (at rest) is evaluated on a numeric rating scale (NRS) by the patient, assigning pain a number 
between 0-10. Study personnel assigne a score according to the criteria listed in appendix 1, were 
NRS 0 = 0 (no pain), 0<NRS≤3 = 1 (light pain), 3<NRS<7 = 2 (moderate pain), NRS≥7 = 3 (severe 
pain). If patients are not able to assign a number (e.g. due to sedation/doubt), it is accepted with a 
verbal rating scale (no/light/moderate/severe pain). 
Nausea is evaluated by patients and assigned a score from 0 (no nausea) to 3 (severe nausea or 
vomiting).  
Length of stay (hospital) is measured as time (hours and minutes) from start of the procedure until 
discharge from the ward.  
Length of stay (PACU) is measured as time from arrival to PACU until the patient is deemed ready 
to transfer to the ward (as the actual transfer time depends on transport etc.).  
The occurrence of seroma requiring drainage is recorded the first 14 postoperative days from 
patient records.  
Readmissions for any reason, except planned procedures or oncological admissions, are collected 
from patient records for 30 days. 
Side-effects and/or complications (any) are registered during hospital stay and up to 60 hours 
postoperatively. Adverse events/serious adverse events are defined according to ICH-GCP. 
Patients receive a questionnaire to fill out on days 0-4. The elements of the questionnaire are: 
• pain on average and at worst on the 11-point numeric rating scale (0 no pain, and 10 worst 
pain imaginable)  
• nausea on average and at worst on the four-point numeric scale (0, none; 1, slight; 2, 
moderate; 3, severe) and vomiting (if any) 

• use of analgesics  
• feelings of sadness, restlessness or fatigue (yes/no) 
• quality of sleep (good, difficulty falling asleep, frequent awakenings, no sleep) 
Other collected data 
Demographical data (sex, age, height, weight, smoking status, use of alcohol, comorbidities), 
operative data (date and time of operation, diagnosis, duration of surgery, extent of axillary 
dissection, intraoperative bleeding). Type and dose of medication given by request. 
All data are collected from patient record. 
 
Sample size 
After modification of our ERAS protocol introducing high-dose glucocorticoids (125 mg 
methylprednisolone (equivalent to 24 mg dexamethasone) we observed a 30 % to 10 % decrease 
in PACU referral after mastectomy. To test the isolated effect of the increased glucocorticoid 
dosage in a well-implemented ERAS protocol, we chose to compare 24 vs 8 mg dexamethasone. 
Considering the observed 20 % absolute (66% relative) reduction in need for PACU transfer 
clinically relevant, a sample size of 130 patients (65 in each group) was calculated 
(www.sealedenvelope.com) with a two-sided 5 % significance level, a power of 80 % and an 
anticipated 10 % exclusion rate.  
 
 

Appendix 1. Danish Society of Anesthesiology and Intensive Care Medicine (DASAIM)-score, 
modified. 
Modifications: Pain score is numeric rating scale 0-10 instead of Visual analogue scale 0-100 mm. Oxygen saturation 
was measured with 2L supplementary oxygen in the operating room. Respiratory rate as category is omitted.  
Patients are considered dischargeable to the ward when the score sum of all criteria is four or less and no single score 
is above one. 
Modality 
Score 
Criteria 
Sedation  
(nurse evaluation) 
3 
2 
1 
0 
Sleeping, cannot be aroused 
Sleeping, aroused by physical stimuli 
Sleeping, aroused by verbal stimuli 
Fully awake 
Oxygen saturation; % 
3 
2 
1 
0 
< 85 
85-89 
90-93 
 ≥ 94 
Blood pressure, systolic (mmHg) 
(automatic NIBP) 
3 
2 
1 
0 
 < 80 
80-89 or > 220 
90-99 
100-220 
Heart rate; pr. min. (automatically 
derived from ECG) 
 
3 
2 
1 
0 
< 40 or > 130 
40-49 or 121-130 
101-120 
50-100 
Pain (at rest) 
Numeric Rating Scale (NRS) 0-10 
(patient evaluation) 
3 
2 
1 
0 
Severe (NRS ≥ 7) 
Moderate (3 ≤ NRS < 7) 
Light (0 < NRS < 3) 
None (NRS = 0) 
Nausea (patient evaluation and nurse 
observation) 
3 
2 
1 
0 
Severe 
Moderate 
Light 
None 
Total 
Sum