Download - Peeling the Research Onion Intraoperative dexamethasone and the risk of post-operative infection
Peeling the Research OnionIntraoperative dexamethasone and the risk of
post-operative infection
Tomás CorcoranSchool of Medicine and Pharmacology
University of Western Australia
Department of Anaesthesia and Pain MedicineRoyal Perth Hospital
Western Australia
Layers
− Rationale
− Research Studies
− Results
− Proposals
Research Onion
Dexamethasone for antiemesis
Saint or Sinner ?
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• Biological half life of ~ 3 hours
• DOA probably up to 24 hours
• x 20-50 more potent than hydrocortisone
Dexamethasone• 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
• 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. Anesth Analg 2003. Rats.3 Czarnetzki et al. JAMA 20084. Anaesth Intensive Care 2010; 38: 667-670
MOA of Glucocorticoids
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– 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. Anesth Analg. Jan 2001;92(1):85-88.
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
Cohort Study
Cohort Study
Our work to date• 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
Case Control 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• 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
0
500
1000
1500
2000
2500
T0 T1 T2 T3
x 10
*6 /
L
Time Point
Absolute T-helper cell numbers
ControlDex 2Dex 4Dex 8
p=0.032p=0.0001
0
500
1000
1500
2000
T0 T1 T2 T3
x 10
*6 /
L
Time Point
Absolute Suppressor T-cell Numbers
ControlDex 2Dex 4Dex 8 p=0.0007 p=0.049
0
200
400
600
800
T0 T1 T2 T3
x 10
*6 / L
Time Point
Naïve B cell numbersControlDex 2Dex 4Dex 8
p=0.0001
p=0.01
0
40
80
120
160
T0 T1 T2 T3
x 10
*6 /
L
Time Point
Memory B cell numbers
ControlDex 2Dex 4Dex 8
p=0.035
0
20
40
60
80
100
120
T0 T1 T2 T3
x 10
*6 /
L
Time Point
Switched Memory B cell numbersControlDex 2Dex 4Dex 8
p=0.01
T0 T1 T2 T30
300
600
NK cell numbers
ControlDex 2Dex 4Dex 8
Time Point
x 10
*6 /
L
T0 T1 T2 T30
50
100
150
200
250
300
350
400
450
500
MIF Concentrations
ControlDex 2Dex 4Dex 8
Time Point
pg/m
l
DiscussionWhat 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
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
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
Acknowledgements
• Research Nursing staff• Consultant Colleagues in Royal Perth Hospital• ANZCA Research Grant 2010 / 2011• ANZCA CTG • ASM organising committee