Dexamethasone and Robotic-assisted Hysterectomy

• ClinicalTrials.gov Identifier: NCT04762381
• Recruitment Status: Not yet recruiting
• First Posted: February 21, 2021
• Last Update Posted: February 21, 2021
• Sponsor: Herning Hospital
• Collaborator: Hospital of Southern Jutland
• Information provided by (Responsible Party): Finn Lauszus, Hospital of Southern Jutland

Study Description

Brief Summary:

Robotic-assisted hysterectomy is an alternative to laparoscopic surgery as part of a minimal invasive regimen. Several treatment strategies are followed to improve the overall outcome and minimize surgical stress. Glucocorticoids provide significant analgesic and antiemetic effects but its role in a fast-track, multi-modal setting is not settled when discharge is planned within 24-36 hours.

This study will evaluate in a randomized trial the effect of a single dose of 24 mg dexamethasone on women undergoing robotic-assisted hysterectomy with regard to surgical stress measured by c-reactive protein as primary outcome and, further, other stress markers like white blood cells, Il-6, cortisol, and creatinine kinase. The postoperative recovery will be registered in validated charts and questionnaires for pain and analgesic use, quality of recovery, incontinence, sexual and work life. Furthermore, in a sub-analysis, transcriptional profiling will be applied to explore, which parts of the innate and cellular immune system is activated to explore the mechanisms of surgical stress response.

The hypothesis is that women undergoing robotic hysterectomy would benefit from peroperative glucocorticoid treatment on important life qualities like pain, fatigue, freedom of medications and resuming work and sexual activities. Further, future adjuvant peroperative regimens may be able to target the stress response in a more appropriate way

Condition or disease	Intervention/treatment	Phase
Inflammatory Response; Pain, Postoperative; Nausea, Postoperative; Incontinence; Sexual Behavior	Drug: Dexamethasone phosphate; Other: Placebo	Not Applicable

Detailed Description:

Background Robotic operations in gynecology is one of the fastest growing fields in applied robotic technology.

In Denmark 4000 hysterectomies are performed each year on benign indications and minimal invasive techniques has risen from 35 to 80%. These operations consist of vaginal, laparoscopic assisted und the latest robotic assisted hysterectomy. The robotic surgical system DaVinci was introduced in 2000 and, by 2016, 3803 robot units were established all over the world and 644 of these were in Europe. Hysterectomy and prostate operations are the most common robotic assisted operations as an alternative to conventional laparoscopy.

Robotic surgery on benign indications in gynecology is still a discussion on the cost vs. benefit due to increased cost and lack of evidence on superiority in surgical outcome compared to conventional laparoscopy. For minimal invasive surgery is but a part of a complex series of treatment in a strategy, the so-called multi-modal regimen (1-7,16). By this, the day of discharge has dramatically decreased without compromising safety during surgery and postoperative recovery. However, not all single elements are proven for efficacy, let alone the specific targets for effect (16).

To further improve the overall outcome of surgery the surgical stress response are investigated, which includes inflammatory components and are of importance of postoperative pain and recovery (8,9,16). Here amongst others, glucocorticoids have proven to relieve pain in a number of procedures, applied in general surgery on colon, gallbladder, and breast, in orthopedic surgery on knee and breast surgery, and in gynecology, too, in laparoscopic hysterectomy (1-10,15,16). The dose of steroid to provide significant analgesic effect is, at least, dexamethasone of 0.1-0.2 mg/kg or 15 mg, which is substantiated in some reduction in inflammatory response (7,15,16). Glucocorticoids are known for analgesic, opioid-sparing and antiemetic effects but procedure-specific outcome are lacking. Similarly, the specific anti-inflammatory and sites of surgical stress-related responses are not well elucidated.

Aim The PhD study evaluate the effects of a single dose of steroid on acute postoperative stress response and pain after hysterectomy. The evaluation is on clinical relevant outcome that directly benefit the patients. We will measure surgical stress by c-reactive protein and other inflammatory markers based on transcriptional profiling, register pain and medication needed during hospital stay and after discharge, and when work and sexual function could be resumed.

Outcome The primary endpoint is reduction of postoperative c-reactive protein (crp) after robotic hysterectomy as an objective measurement of the stress amelioration by the given steroid. The rise postoperatively will be ascertained by two baseline measurements and every 4-6 hours after operation as long as the women is not discharged. The crp is not expected to be dependent on each operation team eagerness to perform well or the postoperative care to reach certain standards.

As secondary outcome we register pain scores from baseline to 24 h and later on, the postoperative analgesics medication from baseline to discharge and later on, quality of recovery (QoR-15D) in the latest 24 hours (12). Further, after discharge incontinence (ICIQ-UI), start of sexual life (PISQ-12/31), inflammatory markers, and resumption to recreational and work life will be ascertained in a diary. The baseline and early acute postoperative pain scores (visual analog scale, VAS) at rest and at movement (0-4 h postoperatively), late acute postoperative pain scores (VAS) at rest and at movement (24 h postoperatively); and cumulative opioid consumption (up to 24 h) will be registered. Blood samples will be analyzed for white blood cells, Il-6, cortisol, and creatinine kinase and a part will be stored for analysis of the cellular inflammatory systems by NanoString to explore the innate system and cellular activation (19,20). NanoString has the capacity to demonstrate activation of immune-related genes in the bloodstream during inflammatory induction and highlight an exciting role of immune competent cell in linking peripheral inflammation with immune activation and possibly anti-nociception. NanoString methodology investigates gene expression and currently quantifies the expression of 770 genes by determining the amount of messenger RNA (mRNA). mRNA is the end-product of gene transcription and, therefore, allows the study of gene up-regulation.

Monitoring cycles and levels of rest and activity will be done by an actigraph in a non-invasive method (13,14).

Hypothesis Women undergoing robotic hysterectomy would benefit from peroperative glucocorticoid treatment on important life qualities like pain, fatigue, freedom of medications and resuming work and sexual activities. Biological substrates such as inflammatory markers will be explored as underlying mechanism behind surgical stress response in order to direct perioperative medical interventions (19).

Perspectives and impact The randomized design will evaluate the effects of the single dose dexamethasone on the highest level of evidence. The anti-emetic effects of steroid are already incorporated in several guidelines on perioperative care; however, this study could further enhance our knowledge on minimal invasive surgery and optimize the treatment for surgical stress. The stress response in humans have evolved over millennia and is embedded in our genes but has no natural association with modern days surgery and may be ill placed and timely inadequate for recovery. The exploratory study may help identify pathways and specific mechanism in surgical stress that can be targeted in future to enhance women's recovery after surgery. The perspective is in further studies to target these specific sites in the immune activation.

Methods:

The PhD study in robotic hysterectomy will include a randomized trial with a single dose intravenously of 24 mg dexamethasone (Dexavit®) corresponding to 128 mg methyl prednisolone (Solumedrol®). The robotic hysterectomy is performed with the Intuitive surgical Da Vinci Xi system.

The randomization will be performed in Redcap and data stored the same place under each patient cpr.-no. but in a separate section. A person not involved in the project in any other form will perform the randomization. The patient will then receive the dose of either steroid or placebo saline intravenously, blinded to the patient and operation team (gynecology, operation ward and anesthesiology). The applicant PhD student will later enter the data in Redcap unknowing to the randomization results.

All women in the department operated by with a robotic assisted hysterectomy will be monitored and fill out a diary with validated questionnaires (names of quest.) to streamline the information gathering in a high flow work place and not to discriminate those outside of the project. These data will be presented as the drop-out analysis to evaluate the external validity of the trial. The flow of data collection is displayed below.

Sample size was calculated to be 49 women included in each arm on the primary outcome of c-reactive protein rising to the level of 40 mg/l with an expected reduction of 10 % a with a standard deviation of 7 calculated by https://clincalc.com/stats/samplesize.aspx (1,17,18). This may seem a parsimonious reduction but in practical terms, it translates to more than halving the need of opioids early and late postoperatively (2). On the assumption of incomplete data in less than 10 % of cases, 50 women in each group with complete data will be included. Robotic hysterectomy is a standard procedure in our department with about 80-90 hysterectomies each year, so we expect the study inclusion to last 1½-2 years.

Statistics Analysis are performed on the intention-to-treat principle with women on current use of analgesics as a subgroup analysis. The statistics will be unpaired and paired analysis (2-ways ANOVA) including relevant co-variates. Regression analysis will be performed with the primary outcome as dependent variable and the secondary outcomes and anthropometrics as dependent variable.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, double blinded trial
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Blinded, results enteree into RedCap, logged and masked for participants
• Primary Purpose: Treatment
• Official Title: Effect of 24 mg Dexamethasone Preoperatively on Surgical Stress, Pain and Recovery in Robotic-assisted Laparoscopic Hysterectomy
• Estimated Study Start Date: June 1, 2021
• Estimated Primary Completion Date: June 1, 2024
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Dexamethasone; 24 mg dexamethasone as single dose intravenously peroperatively	Drug: Dexamethasone phosphate; 24 mg dexamethasone infused peroperatively; Other Name: glucocorticoid
Placebo Comparator: Placebo; saline infusion intravenously in a single dose	Other: Placebo; Saline

Outcome Measures

Primary Outcome Measures :

1. level of c-reactive protein (CRP) [ Time Frame: 0-36 hours ]
   c-reactive protein measured in mg/l

Secondary Outcome Measures :

1. level of IL-6 [ Time Frame: 0-36 hours ]
   Interleukin 6
2. Leucucytes [ Time Frame: 0-36 hours ]
   White blood cell count
3. mRNA [ Time Frame: 0-36 hours ]
   Transcription of mRNA after surgery
4. Incontinence [ Time Frame: 0- 14 days ]
   ICIQ-UI postoperatively
5. Sexual function [ Time Frame: 0 - 14 days ]
   PISQ-12 postoperatively
6. work life checklist [ Time Frame: 0-14 days ]
   Diary postoperatively
7. Number of steps count measured by pedometer [ Time Frame: 0- 14 days ]
   daily activity

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Meno-metrorrhagia,
• dysmenorrhea,
• fibroma,
• dysplasia,
• dysmenorrhea,
• ability in Danish writing

Exclusion Criteria:

• current treatment with glucocorticoids, opioids and NSAID analgesics,
• diabetes,
• current treatment of malignant disease,
• renal or hepatic disease,
• unable to communicate in Danish language.

Contacts and Locations

Contacts

Contact: Finn Lauszus; 0045 79972192; finn.lauszus@rsyd.dk

Locations

Denmark

Gyn. Dept.;Aabenraa Hospital, Sygehus Sønderjylland

Aabenraa, Denmark, 6400

Contact: Finn F Lauszus, PhD 0045 79972192 finn.lauszus@rsyd.dk

Contact: Karsten Kaiser 0045 799 72193 karsten.kaiser@rsyd.dk

Sponsors and Collaborators

Herning Hospital

Hospital of Southern Jutland

Investigators

• Study Chair: Britta Frederiksen, PhD; Gyn. Dept. Aabenraa Hospital, Sygehus Sønderjylland

More Information

Publications:

Lunn TH, Kristensen BB, Andersen LØ, Husted H, Otte KS, Gaarn-Larsen L, Kehlet H. Effect of high-dose preoperative methylprednisolone on pain and recovery after total knee arthroplasty: a randomized, placebo-controlled trial. Br J Anaesth. 2011 Feb;106(2):230-8. doi: 10.1093/bja/aeq333. Epub 2010 Dec 3.

De Oliveira GS Jr, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2011 Sep;115(3):575-88. doi: 10.1097/ALN.0b013e31822a24c2. Review.

Jokela RM, Ahonen JV, Tallgren MK, Marjakangas PC, Korttila KT. The effective analgesic dose of dexamethasone after laparoscopic hysterectomy. Anesth Analg. 2009 Aug;109(2):607-15. doi: 10.1213/ane.0b013e3181ac0f5c.

Steinthorsdottir KJ, Kehlet H, Aasvang EK. Surgical stress response and the potential role of preoperative glucocorticoids on post-anesthesia care unit recovery. Minerva Anestesiol. 2017 Dec;83(12):1324-1331. doi: 10.23736/S0375-9393.17.11878-X. Epub 2017 Jun 12. Review.

Lirk P, Thiry J, Bonnet MP, Joshi GP, Bonnet F; PROSPECT Working Group. Pain management after laparoscopic hysterectomy: systematic review of literature and PROSPECT recommendations. Reg Anesth Pain Med. 2019 Apr;44(4):425-436. doi: 10.1136/rapm-2018-100024. Epub 2019 Feb 3.

Wijk L, Nilsson K, Ljungqvist O. Metabolic and inflammatory responses and subsequent recovery in robotic versus abdominal hysterectomy: A randomised controlled study. Clin Nutr. 2018 Feb;37(1):99-106. doi: 10.1016/j.clnu.2016.12.015. Epub 2016 Dec 23.

• Responsible Party: Finn Lauszus, Associate Professor, Hospital of Southern Jutland
• ClinicalTrials.gov Identifier: NCT04762381
• Other Study ID Numbers: Robotic surgery and steroid
• First Posted: February 21, 2021
• Last Update Posted: February 21, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: after PhD submission and evaluation and publiaction of results the data can be shared anonymously
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: 2025
• Access Criteria: personal contact

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Finn Lauszus, Hospital of Southern Jutland:

inflammatory response; surgical stress; leucocytes; IL-6; mRNA transcription; incontinence; sexual function; work life

Additional relevant MeSH terms:

Pain, Postoperative; Postoperative Nausea and Vomiting; Nausea; Signs and Symptoms, Digestive; Postoperative Complications; Pathologic Processes; Pain; Neurologic Manifestations; Vomiting; Dexamethasone; Glucocorticoids; Dexamethasone 21-phosphate; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents