Short summary

Patients undergoing periacetabular osteotomy for hip dysplasia, are suffering from difficulties with sufficiently pain managment as well as opioid related side effects, especially nausea and vomiting. With the expectation of improvement on the issue, we want to investigate the effect of perioperatively high dose dexamethasone administered once or twice on morphine and antiemetic consumption among others.

Rationale

CHOICE OF COMPARATORS

Effective early postoperative multimodal pain management promoting early mobilisation, fluid and food intake, and recovery of normal activities is essential for wellbeing and rehabilitation of surgical patients.

Recently, an unpublished local observational pilot study on 10 patients indicated that periacetabular osteotomy (PAO) for hip dysplasia is associated with considerable pain treatment and nausea. A supplemental unpublished local pilot study on patient reported endpoint measures indicated that postoperative nausea and vomiting (PONV) was highly rated by the included patients. Pain was rated just below PONV. Therefore, there is a great need for optimisation on pain and PONV treatment.

To manage pain different regimes can be considered; repeated local infiltration in combination with oral opioids showed no superiority to solitary opioids within 48 hrs. To our knowledge, other regimens using continuous lumbar epidural analgesia or paravertebral psoas blockade are to our knowledge not yet investigated in this population in prospective randomized trials. Opioids are associated with complicating side effects such as nausea, vomiting, drowsiness and respiratory depression. Poor postoperative pain management and opioid side effect related malaise lead to prolonged time to resumption of fluids and food intake. Moreover, risk of prolonged immobilisation is known to increase the risk of deep vein thrombosis, though the crude incidence for development of venous thromboembolism has been reported to be low (0.94%).

There is a need for effective postoperative pain management with a minimum of side effects. Several strategies to manage pain and PONV have been suggested of which glucocorticoids are gaining ground. To our knowledge there is yet no evidence supporting the use of short-term high dose intravenous glucocorticoid for postoperative analgesia after PAO.

PATHOPHYSIOLOGY AND GLUCOCORTICOIDS:

There is strong evidence supporting the use of glucocorticoids in multimodal analgesia protocols to optimize postoperative recovery and reduce opioid consumption and related side effects, in particular surgery with substantially trauma, pain and oedema. Gradually, the use of glucocorticoids for postoperative pain relief gain acceptance, though concerns regarding side effects as adrenal suppression, osteonecrosis, impaired wound-healing and efficacy influence the application. Adrenal suppression is well described in literature during short-term use of glucocorticoids, however, this suppression is a clinically benign and reversible condition. Well known anti-inflammatory properties of glucocorticoids have repeatedly shown significant reduction in the postsurgical inflammatory response after orthopaedic surgery.

Short-term perioperative administration of glucocorticoids is considered safe and low risk, including wound infection, hyperglycaemia or severe adverse events. Though, it is well established that glucocorticoids can elevate the blood glucose levels in patients (both with and without diabetes). One or two consecutive doses peri- and postoperatively, did lead to significant, but clinically irrelevant elevations of blood glucose (approximately 1-2 mmol/l), and no adverse effects was linked to this risk.

POPULATION

Hip dysplasia typically manifests itself in adolescence or young adulthood, after decades of subclinical developmen. The prevalence of radiographically hip dysplasia has been found to be 5% in both females and males of which not all are symptomatic. A resent epidemiologic study reported that 83% of patients undergoing PAO were of female gender with mean age of 25.5 years. Generally, this populations has a low grade of severe comorbidities.

Symptomatic hip dysplasia is shown to reduce physical activity as walking, and increase self-reported pain scores 21,22. Hip dysplasia significantly increase the risk of developing secondary hip osteoarthrosis, why this population is offered PAO18,19, as PAO outcome studies have demonstrated major clinically important improvements in pain, function, quality of life and activity level23.

6D EVIDENCE-BASED RESEARCH

In total knee and hip arthroplasty perioperative administration of a single dose glucocorticoid has been reported to reduce pain and PONV15. A recent meta-analysis on total joint arthroplasty reports significant reduction in PONV and pain at 12, 24 and 48hrs postoperatively after a single dose of glucocorticoid, most significantly at 12 and 24 hrs13. Other reported benefits include reduced pain during activity and improved mobility after surgery10. Furthermore, a single study on total joint arthroplasty shows extended effect on pain and opioid consumption after a repeated dose of dexamethasone (DXMT) 24hrs postoperatively compared to a single dose 10. Recently, the need for further research into repeated administration of glucocorticoids to improve postoperative pain after knee arthroplasty was suggested24. The knee and hip arthroplasty populations are markedly older with more comorbidities than hip dysplasia patients25,26. Several reports conclude that more and larger RCTs concerning efficacy and safety are warranted before making final recommendations on perioperative use of glucocorticoids 6,13,15,24.

6E MOTIVATION:

In spite of careful attention to perioperative pain management after PAO pain and nausea remain a major challenge to the patients. The sizable need for opioids increase the risk of opioid-related side effects in a low-comorbidity population already in increased risk of PONV27. Therefore, it is relevant to investigate regimens to reduce opioid consumption and PONV.

To our knowledge, no experience with glucocorticoids as analgesic in PAO patients exists. As the PAO-procedure leads to major surgical trauma and pain, we consider it likely that these patients will benefit from glucocorticoid administration, based on the assumption that perioperative glucocorticoid treatment in other orthopaedic procedures with major trauma has shown significant reduction in pain and PONV.

A regime including a repeated postoperative glucocorticoid administration is expected to result in a clinically relevant reduction in opioid consumption and opioid-related side effects. Generally, analgesic regimes including administration of repeated glucocorticoid doses are not sufficiently investigated.

DOSE AND DRUG SELECTION, INCLUDING POTENTIAL RISK/BENEFITS

A recent systematic review evaluates glucocorticoids for pain management in total joint arthroplasty. The included RCTs use different types of glucocorticoids; prednisolone, methylprednisolone, hydrocortisone and DXMT15. After converting the trial doses for comparison, we decided to use a high-dose DXMT of 24mg, as we wanted to evaluate the efficacy on pain, requiring larger doses compared to PONV management.

Furthermore, we selected DXMT based on the known postoperative pattern of pain, with highest intensity on postoperative day (POD)4. DXMT is categorised as a long-acting glucocorticoid with a biologic half-life of 36-54hrs, with superior anti-inflammatory potency compared to other glucocorticoids. A repeated dose on POD1, is intended to cover in the most pain-intense period. Based on present evidence this trial should not involve risk of adverse effects exceeding those considered normal for this surgical procedure. Generally, DXMT is well tolerated and is standard use in high-risk PONV patients, though in lower doses. For long term use DXMT has multiple adverse effects.

In this trial the treatment period is short-term (0-24 hrs postoperatively), and the risk of serious adverse events are considered low. We believe that participation in this trial is associated with very low risks short as long term.

We hope that patients receiving the intervention will benefit from the analgesic and anti-inflammatory effects of DXMT, including better mobilization and rehabilitation.

EXPLANATION FOR CHOICE OF COMPARATORS

Previously, glucocorticoids have not been investigated in a population comparable to our study population. This justifies a placebo group as comparator. We assume that DXMT reduces postoperative opioid consumption. Not knowing the most effective regime justifies comparing one dose versus repeated doses of glucocorticoids.

In this trial, DXMT will be administrated in doses of 24mg being within the range of normally recommended doses for pain management, but beyond the recommended 4-10mg doses for PONV. The trial medication (DXMT or placebo) will be administered intravenously starting just after induction of anaesthesia, and the following dose after 24 hrs.

Purpose of the study:

The primary objective is to compare the effect of intravenous DXMT relative to placebo on cumulated postoperative morphine consumption from baseline to 48 hours in hip dysplasia patients undergoing PAO.

The secondary objectives are to compare the effect of repeated doses of intravenous DXMT relative to a single dose on cumulated postoperative morphine consumption from baseline to 48 hours in hip dysplasia patients undergoing PAO, and to determine if DXMT is superior to placebo for:

- Perception of pain intensity postoperatively and need for supplemental analgesics

- Prevalence and degree of PONV, including antiemetic consumption

- Patient-reported outcome measures (PROMs)

- Perception of sleep quality

- Mobilization postoperatively

- Prevalence and degree of serious adverse events (SAE), e.g. complicating wound infection, which need antibiotic treatment or revision surgery.

The explorative objective is to determine if DXMT relative to placebo:

- Affect the glucose-homeostasis postoperatively

- Affect the immune-response postoperatively

- Affect patient reported health and life quality, activity and pain

Description of the cohort

83% of patients undergoing periacetabular osteotomy were of female gender with mean age of 25.5 years. Generally, this populations has a low grade of severe comorbidities. Including diagnose: Hip dysplasia.

Data and biological material

Data:

Height, weight, ASA-classification, blood pressure, sex, date of birth, smoking status, fluid administration, amount of bleeding, dispended anaesthetics and analgesics. Duration of operation. Comorbidities.

Medication administered from operation until discharge or 72 hrs. post operation

Daily medicine consumption before operation

PCA-pump morphine consumption.

Pain and nausea score. Timed up and go score, sleep score, patient reported outcome measures

Questionaries:

UCLA, Oxford HIP, EQ-5D.

Bloodsamlpes:

CRP, Leucocytes, blood glucose, and standard analyses prior to PAO-procedure. Cytokines.

Collaborating researchers and departments

Department of Orthopaedic Surgery, Odense University Hospital

• Consultant Ole Ovesen
• Consultant Morten Bøgehøj
• Project Nurse Annie Gam Pedersen

Department of Anaesthesiology and Intensive Medicine, Odense University Hospital

• MD Viktoria Lindberg-Larsen, PhD
• MD Stine Hebsgaard
• Consultant Stine Zwisler, PhD
• Consultant Peter Lindholm

Research Unit of Rheumatolohy, Department of Clinical Research, University of Southern Denmark, Odense University Hospital

• Professor Robin Christensen, BSc, MSc, PhD

GCP-Unit, Odense University Hospital

• Henriette Koy Bendixen, Cand.pharm.

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

• Mette Andreasen, Project Biomedical Laboratory Scientist

Odense Patient data Explorative Network (OPEN)