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Peeling the Research Onion Intraoperative dexamethasone and the risk of post-operative infection. Tomás Corcoran School of Medicine and Pharmacology University of Western Australia Department of Anaesthesia and Pain Medicine Royal Perth Hospital Western Australia. Layers Rationale

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peeling the research onion intraoperative dexamethasone and the risk of post operative infection

Peeling the Research OnionIntraoperativedexamethasone and the risk of post-operative infection

Tomás Corcoran

School of Medicine and Pharmacology

University of Western Australia

Department of Anaesthesia and Pain Medicine

Royal Perth Hospital

Western Australia

research onion
Layers

Rationale

Research Studies

Results

Proposals

Research Onion
dexamethasone
Dexamethasone commonly used as a component of multimodal therapy for PONV

Doses of 2-12mg used

Recommendation of 0.15mg/kg

Gan et al

Dexamethasone
dexamethasone1
Biological half life of ~ 3 hours

DOA probably up to 24 hours

x 20-50 more potent than hydrocortisone

Dexamethasone
dexamethasone2
Glucocorticoids influence B / T-cell development

Single dose of dexamethasone in vivo inhibits cell proliferation and reduces.1

Dexamethasone reduces collagenisation, epithelialisation and fibroblast content in wounds.2

When given as PONV prophylaxis in tonsillectomies, 0.5mg/kg increased the risk of bleeding (RR=6.9, p=0.003).3

Dexamethasone
dexamethasone3
Increased cortisol with 8 mg 4

Genomic and non-genomic influences

hence single doses may produce rapid effects

1 Kunicka. Cellular immunology, 1993. Mice.

2 Durmus. AnesthAnalg 2003. Rats.

3 Czarnetzki et al. JAMA 2008

4.Anaesth Intensive Care 2010; 38: 667-670

Dexamethasone
evidence
No RCT with infection as a primary outcome

One PRCT

80 ASA I-III patients undergoing anorectal day surgery under sedation

Dex 4mg versus placebo

Primary outcome was home readiness

Follow up for wound infections at 24 hours and 10 days

No differences in infection rates [ 8% vs 12% ]

Evidence
evidence1
BUT

27 / 80 patients had HIV, 15 / 80 had systemic cancer

Follow-up limited to 10 days

Short procedures with little systemic inflammatory activation

Underpowered to detect differences in infection

Other infective complications were not identified

Coloma M, et al. Dexamethasone facilitates discharge after outpatient anorectal surgery.

AnesthAnalg. Jan 2001;92(1):85-88.

Evidence
our work to date
One retrospective observational cohort study

439 patients undergoing single procedure, non-emergency surgery in a university trauma centre

Follow up for infections up to 90 days

98 episodes of infection ( 22% )

No differences between those who did and did not receive dex

Our work to date
our work to date1
One matched Case-Control study

63 cases who developed postoperative infection

Operational definitions

127 Age, Gender and procedure matched controls

4:1 optimal power in CCS

Hypothesis generating study

Build upon the cohort study

Our work to date
current mechanistic studies
One pilot study

32 volunteers receive saline / dex 2mg, 4mg or 8mg

Serum sampled at baseline / 4 / 24 hours and 7 days

Lymphocyte subsets [ T, B, NK, Memory B and naieve B cells ]

Serum MIF and cytokines measured

Current mechanistic studies
current mechanistic studies1
Two PRCT

1. Laparoscopic gynae surgery [ ~ Half-way ]

2. Mastectomy patients [ Recruitment complete ]

Dex versus granisetron

Serum sampled and lymphocyte subsets at baseline, 24 hours, 7 and 42 days

Infective complications a secondary endpoint until 90 days

Current mechanistic studies
discussion
What is the mechanism ?

Short term alteration in cell numbers

(margination, sequestration in lymphoid tissue)

Change in differentiation of myeloid and lymphocyte progenitor cells

?? Altered clonal expansion

What are the expected responses in patients undergoing a potent surgical inflammatory response ?

Discussion
discussion1
Preliminary work asking further questions

What is the pattern in patients with surgical stress response ?

What affect does dexamethasone have on this response and the incidence of infection ?

MRCT in the design phase

Discussion
conclusion
Common, cheap and highly effective

Cannot assert it’s safety in the absence of evidence (MRCT)

Potentially significant long-term implications

Pilot data suggests an influence on key immune cells

Surgical data will clarify the relevance of this

Conclusion
acknowledgements
Research Nursing staff

Consultant Colleagues in Royal Perth Hospital

ANZCA Research Grant 2010 / 2011

ANZCA CTG

ASM organising committee

Acknowledgements