Transcript Single dose dexamethasone for post

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
Research Onion
 Layers
− Rationale
− Research Studies
− Results
− Proposals
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 2008
4. 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, nonemergency 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
Absolute Suppressor T-cell Numbers
Absolute T-helper cell numbers
2500
Control
Dex 2
Dex 4
2000
p=0.0001
Control
2000
p=0.032
Dex 2
Dex 4
Dex 8
Dex 8
p=0.0007
p=0.049
1500
x 10*6 / L
x 10*6 / L
1500
1000
1000
500
500
0
0
T0
T1
T2
Time Point
T3
T0
T1
T2
Time Point
T3
800
Naïve B cell numbers
Control
Dex 2
Dex 4
600
p=0.01
x 10*6 / L
Dex 8
p=0.0001
400
200
0
T0
T1
T2
T3
Time Point
Switched Memory B cell numbers
Memory B cell numbers
Control
160
p=0.01
Control
Dex 2
Dex 4
Dex 8
p=0.035
Dex 2
120
Dex 4
Dex 8
100
120
x 10*6 / L
x 10*6 / L
80
80
60
40
40
20
0
0
T0
T1
T2
Time Point
T3
T0
T1
Time Point
T2
T3
NK cell numbers
600
Control
Dex 2
Dex 4
x 10*6 / L
Dex 8
300
0
T0
T1
T2
Time Point
T3
MIF Concentrations
500
Control
450
Dex 2
Dex 4
400
Dex 8
350
pg/ml
300
250
200
150
100
50
0
T0
T1
T2
Time Point
T3
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
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