Clinical trial NCT03161938
Conditions: Hip Dysplasia Postoperative Complications
Sponsor: Rigshospitalet, Denmark
Start date: 2017-04-24; Completion date: 2019-08-20
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 periacetabular osteotomy. Primary outcome is the proportion of patients who have moderate to severe postoperative pain in the post anaesthesia care unit. Secondary outcomes are organspecific complications in the post anaesthesia phase, pain and nausea the first 5 days, wound infection and readmissions the first 30 days after surgery.

The investigators hypothesize that the frequency of moderate to severe pain and organspecific complications in the post anaesthesia care unit will be lower among patients receiving high dose dexamethasone. The investigators hypothesize, that there will be no difference in wound infections or readmissions.

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 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.

The "Why in PACU?" database shows that 70 % of patients experience moderate to severe pain in the immediate postoperative phase. This is despite a multimodal analgesic regime with preoperative analgesics and local analgesic catheter in the surgical site.

Opioids are frequently administered to relieve pain, resulting in sedation, risk of hypoxia and delaying mobilization.

Patients having Ganz osteotomy are primarily young women with hipdysplasia, that are otherwise healthy. Lenght of stay is typically 5 days, due to pain and lack of mobilisation.

In this study patients are randomized to either high dose (48 mg) or standard/low dose (8 mg) dexamethasone, administered preoperatively. The hypothese is that patients receiving high dose dexamethasone will experience less pain in the immediate postoperative course and receive less opioids.

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: Dexamethasone 48 mg pre-operative, single shot injection arm 2: Dexamethasone 8 mg pre-operative, single shot injection
Interventions: intervention 1: Dexamethasone
Intervention descriptions: intervention 1: intravenous

Protocol documents:
Prot_001.pdf: 
1 
 
PROTOCOL 
Effect of high vs low dose intravenous dexamethasone on complications in the 
immediate postoperative phase after periacetabular osteotomy- a randomized, 
double-blind, controlled trial (DEX-GANZ) 
 
EudraCT number: 2017-000544-17 
 
Approved date: 06.03.2017 
 
Sponsor: 
Name: 
 
Eske Kvanner Aasvang 
Title: 
 
DMSc, consultant 
 
Principal Investigator:  
Name: 
 
Kristin Julia Steinthorsdottir 
Title: 
 
MD, Clinical assistant 
 
 


2 
 
 
Introduction ........................................................................................................................ 3 
Aim .................................................................................................................................. 3 
Outcomes ........................................................................................................................ 4 
Primary outcome ........................................................................................................ 4 
Secondary outcomes ................................................................................................. 4 
Methods .............................................................................................................................. 5 
Study design ................................................................................................................... 5 
Randomization ............................................................................................................ 5 
Intervention ................................................................................................................. 5 
Control ......................................................................................................................... 5 
Concealment ............................................................................................................... 6 
Blinding ....................................................................................................................... 6 
Time schedule ................................................................................................................ 6 
Location .......................................................................................................................... 6 
Participants ..................................................................................................................... 6 
Inclusion criteria ......................................................................................................... 6 
Exclusion criteria ........................................................................................................ 6 
Procedures ..................................................................................................................... 7 
Inclusion and randomization ..................................................................................... 7 
Standard care procedures ......................................................................................... 8 
Data management .......................................................................................................... 9 
Case Report Form ....................................................................................................... 9 
Clinical evaluations and outcome registration ........................................................ 9 
Other collected data ................................................................................................. 11 
Sample size ................................................................................................................... 11 
 


3 
 
Introduction 
Periacetabular osteotomy (PAO) is the joint-preserving treatment of choice in young adults with 
symptomatic hip dysplasia.1 There are currently no studies describing pain in the immediate 
postoperative period after this procedure, but unpublished data from our institution (the research 
project “Why in PACU?”) shows that around 70% of patients have moderate to severe pain in the 
post anaesthesia care unit (PACU). The procedure, involving three osteotomies in otherwise 
healthy individuals, is likely to produce a substantial surgical stress response, that potentially could 
be alleviated by multimodal analgesia including high dose glucocorticoids, similar to results from 
other orthopaedic procedures.2,3   
Preoperative low dose glucocorticoids (4-8 mg dexamethasone) are routinely used as a 
prophylaxis against postoperative nausea and vomiting (PONV).4,5  Higher doses (>0.11 mg/kg 
dexamethasone) have been shown to reduce postoperative pain scores (early and late) and opioid 
consumption across procedures6, and in a meta-analysis of intravenous glucocorticoid versus 
placebo in total hip arthroplasty (THA), glucocorticoids (8-40 mg of dexamethasone equivalents) 
were reported to significantly reduce acute pain and total morphine consumption, without 
increasing complications.7  
 
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 PAO (primarily pain).Thus, in order 
to investigate if a high dose of dexamethasone was superior to the low/intermediate dose used 
routinely for PONV prophylaxis in decreasing immediate pain and other complications after PAO, 
we conduct a randomised, double-blind trial of 48 mg versus 8 mg of dexamethasone. The primary 


4 
 
hypothesis is that patients who are given 48 mg of dexamethasone (equivalent to approximately 
250 mg of methylprednisolone) will be less likely to have moderate or severe pain in the 
immediate postoperative period (at the operating room and PACU) compared to patients given 8 
mg of dexamethasone.  
Secondary outcomes include other complications requiring treatment in the immediate 
postoperative phase (circulatory and respiratory complications, sedation and PONV), length of 
stay (in PACU and in hospital), readmissions, wound infections, self-reported pain and sleep 
problems, the first four days after the operation. The investigators hypothesize that patients 
receiving 48 mg of dexamethasone will have fewer complications and report lower pain scores. 
The investigators hypothesize that there will be no differences between groups in frequency of 
wound infections, readmissions or length of stay.  
 
Outcomes 
Primary outcome 
The proportion of patients reporting moderate to severe pain at rest (>3 out of 10 on a Numeric 
Rating Scale from 0-10 (NRS)) in the immediate postoperative phase (after extubation in the 
operating room, and in the PACU until transfer to the ward).  
 
Secondary outcomes 
• Differences between groups in average and maximal level of pain in the immediate 
postoperative phase  
• Occurrence of any complications requiring treatment in the PACU (nausea, circulatory or 
respiratory events)  
• Complications/adverse events in the ward the first 24 h 
• Length of stay (PACU/Hospital) 


5 
 
• Pain, self-reported. Days 0-4. 
• Nausea/vomiting, self-reported. Days 0-4. 
• use of opioid and/or antiemetic treatment other than standard, during hospital stay and up 
to postoperative day 4 
• Quality of sleep. Days 0-4. 
• Feelings of anxiety, restlessness, fatigue. Days 0-4. 
• Any complications (including wound infections) up to 30 days postoperatively days  
 
Methods 
Study design 
Randomized, double-blind, controlled intervention study. Superiority design. 
Randomization 
Computer generated, double-blind block randomization. Allocation ratio 1:1, block sizes =8, 
unknown to study personnel. 
The allocation sequence with intervention details (48 mg or 8 mg dexamethasone) will be 
concealed in consecutively numbered (1-64), 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 48 mg dexamethasone iv (Dexamethasone sodium phosphate, Krka, Novo mesto, 
Slovenia), (12 ml), administered immediately after anesthesia induction, around 30 minutes prior 
to surgery. 
Control 
A single dose of 8 mg dexamethasone iv (2 ml) with isotonic saline (10 ml), administered 
immediately after anesthesia induction, around 30 minutes prior to surgery. 
 


6 
 
Concealment 
The trial drug is contained in a syringe with 12 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 2019 
Location 
Copenhagen University Hospital, Rigshospitalet, Denmark. Department of Orthopedic Surgery, and 
Department of Anesthesiology, Centre of Head and Orthopedics. 
Participants 
Number of participants: 64, 32 in each group. 
Inclusion criteria 
• Planned PAO 
• Age 18 years or older  
• Able to understand Danish or English and to provide informed oral and written consent.  
Exclusion criteria 
• Previous enrolment in the trial 
• Planned simultaneous cheilectomy procedure  


7 
 
• Daily/current use of glucocorticoids or immunosuppressant medication  
• Insulin-dependent diabetes  
• Pregnancy or lactation 
• Allergies to any of the trial drugs.   
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 (1-64) at the morning 
of surgery. 


8 
 
Standard care procedures 
 
 
*However, the dosage could vary depending on indication and decision by the responsible 
anaesthetist. Data on accurate dosage is collected. 
 
Pre-operative 
medication 
Thromboprophylaxis (low molecular weight heparin) (on the morning of surgery, 
continued to discharge) 
 
Acetaminophen 1g  (oral, 1-2 hours before surgery) 
 
Gabapentin 600 mg (oral, 1-2 hours before surgery) 
Anaesthesia  
 
- 
Induction 
Propofol ~ 2 mg kg-1 i.v. 
- 
Maintenance  
Total intravenous anaesthesia with propofol (5 mg kg-1 h-1) and remifentanil (25 
µg kg-1 h-1)*. 
- 
Relaxant  
Cicatracurium 0.1 mg kg-1 (before skin incision) 
- 
airway 
Endotracheal tube. Extubation only after train of four ratio >0.9 
Intraoperative fluid 
therapy/medication 
Ringers lactate, 25-30 ml kg-1 
 
Dicloxacillin 2 gram (continued for 24 hours, every 8th hour)  
 
Morphine 0.25 mg kg-1 (i.v., 45-30 minutes prior to the end of surgery). 
 
Ondansetron 4 mg (i.v., 30-20 min prior to end of surgery) 
Local wound 
injection 
A thin catheter is placed in the wound cavity for injection of local anaesthetics of 
0.2% ropivacaine and 0.25 mg epinephrine (100 ml) prior to closure. Every 8th 
hour for the first 24 hours after surgery, 20 ml 0.75% ropivacaine and 0.25 mg 
epinephrine are injected through the catheter.   
Post-operative 
medication 
Acetaminophen 1g  (oral, 4 times daily, for up to 14 days) 
 
Ibuprofen 400 mg (oral, 3 times daily, for up to 14 days) 
 
Oxycodone 10 mg (oral, 2 times daily, for up to 7 days) 
 
Antiemetics (ondansetron 4 mg) on request 
Discharge criteria 
Acceptable radiologic control of the hip and clinical control of the wound.  
Patients should be able to mobilise in and out of bed, walk safely and climb one 
flight of stairs supported by crutches without other complications hindering 
discharge. 


9 
 
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 
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 (NRS) at rest is evaluated every 15th minute in the PACU. The patient is asked to assign pain a 
number between 0 (no pain) and 10 (worst pain imaginable). Numbers are transformed into a 4 
level-score (NRS 0 = 0 (no pain), NRS 1-3 = 1 (light pain), NRS 4-6 = 2 (moderate pain), NRS 7-10 = 3 
(severe pain)). If patients are unable to assign a number (sedation), a verbal rating scale 
(no/light/moderate/severe pain) is used. Maximal level of pain is defined as the single highest pain 
score from the time of extubation until PACU discharge to the ward. The average level of pain is 
calculated for each patient by dividing the cumulated pain scores with the number of 
measurements from the time of extubation and during PACU stay.  
Nausea is evaluated by patients on a four-point NRS (0, none; 1, slight; 2, moderate; 3, severe 
nausea). Opioid and antiemetic treatment is evaluated through electronic patient records. To 
allow comparison, opioids are converted into oral morphine equivalents (OMEQs) in mg, using the 
equianalgesic ratios8. Pain, nausea and sedation are assessed from the time of extubation and 


10 
 
every 15 minutes in the operating room, at transfer from the operating room and the PACU and 
upon arrival at the ward. Side-effects are registered up to 60 hours postoperatively. Adverse 
events/serious adverse events were defined according to ICH-GCP. Complications requiring 
treatment during the first 24 hours (including PACU and ward) are defined as; pain requiring 
opioids, nausea requiring antiemetics, bleeding resulting in transfusion or reoperation, 
hypotension requiring the use of vasopressors, >2 l min-1 oxygen supplement or additional lung 
physiotherapy (CPAP etc.). Complications (any) are registered during hospital stay and up to 30 
days postoperatively. Data on potential wound infections were collected from patient records and 
defined as superficial (involving skin and/or subcutaneous tissue) or deep (involving tissues down 
to and including the fascia, muscle and bone), based on clinical and microbiological evidence.  
Hospital length of stay (LOS) is defined as the time (hours and minutes) from start of operation 
until discharge to home, PACU LOS is defined as the time (hours and minutes) from transfer from 
the operating room until discharge to the ward. Readmission within the first 30 days are defined 
as any readmission to hospital. 
To explore duration of possible effects and evaluate effect on wellbeing/sleep we include a 
questionnaire with variables as tertiary outcomes. Self-reported pain and nausea, quality of sleep, 
presence of fatigue, restlessness, and sadness are investigated by a questionnaire once a day from 
the day of surgery until the fourth postoperative day. The elements of the questionnaire are; 
average and worst pain (NRS), average and worst nausea 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). 


11 
 
Other collected data 
Demographical data (sex, age, height, weight, smoking status, use of alcohol, comorbidities), 
operative data (date and time of operation, duration of surgery, intraoperative bleeding). Type 
and dose of medication given by request. 
All data are collected from patient record. 
 
Sample size 
The estimated sample size for the primary outcome was based on unpublished data from our 
institution where 70% of patients had moderate and/or severe pain at some point during the 
PACU stay. We considered a 50% reduction in the proportion of patients with moderate/severe 
pain from 70% to 35% in the 48 mg vs. 8 mg dexamethasone group clinically relevant. A two-sided 
significance level of 5% and power of 80% was chosen, with equal allocation to two treatment 
arms, resulting in the requirement of 32 patients in each arm. As patients were included and 
randomized at the time of operation, no dropout rate was expected. 
 
1. 
Troelsen A, Elmengaard B, Søballe K: Medium-Term Outcome of Periacetabular Osteotomy 
and Predictors of Conversion to Total Hip Replacement. J Bone Jt Surgery-American Vol 
2009; 91:2169–79 
2. 
Wu H, Wang H, Liu Y, Wu Z: Can Preoperative Intravenous Corticosteroids Administration 
Reduce Postoperative Pain Scores Following Spinal Fusion?: A Meta-Analysis. J Investig Surg 
2019; 1:1–10 
3. 
Kehlet H, Lindberg-Larsen V: High-dose glucocorticoid before hip and knee arthroplasty: To 
use or not to use—that’s the question. Acta Orthop 2018; 89:477–9 
4. 
DREAMS Trial Collaborators and West Midlands Research Collaborative: Dexamethasone 
versus standard treatment for postoperative nausea and vomiting in gastrointestinal 
surgery: randomised controlled trial (DREAMS Trial). BMJ 2017; 357:1455 
5. 
Oliveira GS De, Castro-Alves LJS, Ahmad S, Kendall MC, McCarthy RJ: Dexamethasone to 


12 
 
Prevent Postoperative Nausea and Vomiting. Anesth Analg 2013; 116:58–74 
6. 
Oliveira GS De, Almeida MD, Benzon HT, McCarthy RJ: Perioperative single dose systemic 
dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. 
Anesthesiology 2011; 115:575–88 
7. 
Li X, Sun Z, Han C, He L, Wang B: A systematic review and meta-analysis of intravenous 
glucocorticoids for acute pain following total hip arthroplasty. Medicine (Baltimore) 2017; 
96:e6872 
8. 
Svendsen K, Borchgrevink P, Fredheim O, Hamunen K, Mellbye A, Dale O: Choosing the unit 
of measurement counts: the use of oral morphine equivalents in studies of opioid 
consumption is a useful addition to defined daily doses. Palliat Med 2011; 25:725–32 
 

SAP_000.pdf: 
 
 
 
Title: Effect of high vs. low dose intravenous dexamethasone on 
complications in the immediate postoperative phase after 
periacetabular osteotomy (DEX-GANZ).  
 
NCT number: NCT03161938 
 
Document date: 16-05-2018  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 Statistical Analysis Plan  
Dichotomous variables are presented as numbers with percentages, and between-group 
comparisons are assessed with the Fisher exact test. Ordinal variables are presented as median 
with interquartile range. Continuous variables are assessed for normal distribution with the 
Shapiro-Wilk test and/or visual examination of histograms and normal QQ-plots. Normally 
distributed data are presented as mean ± SD and otherwise as median with interquartile range. 
Test for significant differences between groups is performed with an independent-samples t-test 
(normal distribution) or Mann-Whitney U test (non-normal distribution). Data from the 
questionnaire on PONV and sleep is dichotomized into categories, PONV/no PONV and sleep 
problems/no sleep problems and assessed as described for dichotomous variables. 
Comparison of group differences of pain from the questionnaires is analysed in a two-way ANOVA 
model (factors being day and group), taking into account the repeated measurements on the same 
individual (a mixed model with compound symmetric covariance structure).  
All available data are used. Missing data mainly occurred in the questionnaires and is assumed to 
be missing at random. Cases missing all data were ignored (listwise deletion).   
Data analyses are conducted using SPSS for Windows, version 25 (IBM Corp., New York, USA) and 
R for Windows, package version 1.0.153 (R foundation for Statistical Computing, Vienna, Austria) 
(or newer versions, depending on availability). Author (KS) conducts all analyses, that will be 
evaluated by HNA. Statistical consultancy will be used for the mixed effects model.All available 
data are used, missing data is not imputed.  
 


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.