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