Delaney shares insights into the mysterious world of statistics and trials. This 12 minute podcast is particularly useful for Registrars preparing for their exams and was recorded at BCC4. For similar podcasts and audio; head to www.intensivecarenetwork.com and to rego for BCC5 in Cairns, check out www.bedsidecriticalcare.com

1. STATS AND TRIALS STUFF
Anthony Delaney MBBS MSc FACEM FCICM
Staff Specialist Malcolm Fisher Department of Intensive Care Medicine

2. Disclaimer
 I ain’t a statistician
 More of an enthusiastic amateur

3. So…..
 Difference between mortality and survival?
 How to interpret a “negative” trial result?

4. Mortality or survival?
 Mortality:
 Number of deaths/number at risk at the end of a
period of time
 28 day mortality
 Rate
 Survival:
 Time to event analysis
 How long it takes for the event to happen
 If you have survived for x time, what are your chances
of dying in x+1 time
 Hazard

5.  Population:
 >18 yo
 Source of infection
 Temperature >38.3oC or <35.6oC
 Heart rate > 90bpm
 SBP <90 mmHg for 1 hour if adequate fluids and some pressors
 Urine output <0.5 ml/kg/hr for > 1 hr or PaO2/FiO2 <280
 Lactate >2 mmol/L
 Ventilated
 Excluded:
 pregnant, contra/indication to steroids, advanced cancer, AMI, PE,
AIDS,

6.  Intervention:
 Hydrocortisone mg q6h ivi
 Fludrocortisone 50mg po daily
 For 7 days
 Comparison:
 Placebo
 For 7 days

7.  Outcome:
 The primary endpoint was the 28-day survival
distribution from randomisation in non-
responders to the short corticotropin test

8.  Point one
 Post-randomisation sub groups are dubious

9.  Is the subgroup variable a characteristic
measured at baseline or after
randomisation?
 “The credibility of subgroup hypotheses based on
post-randomisation characteristics is severely
compromised, and can be rejected simply on this
criterion”

10.  Subdivision of patients in ISIS-2 with
respect to birth signs
 Gemini and Libra shows an adverse effect on
mortality

12.  Results:
 300 participants
 In non-responders
 Placebo 73/115 (63%)
 Steroids 60/114 (53%)
 Hazard ratio 0.67 95% CI 0.47-0.95; P=0.02
 Conclusion:
 Treatment with hydrocortisone and fludrocortisone
significantly reduced the risk of death in patients
with septic shock and adrenal insufficiency

13. Date of download: 9/11/2013
Copyright © 2012 American Medical
Association. All rights reserved.
From: Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With
Septic Shock
JAMA. 2002;288(7):862-871. doi:10.1001/jama.288.7.862
Results are according to the response to the short corticotropintest. In nonresponders, the median time to death was 12 days in the
placeboand 24 days in the corticosteroid groups; in responders, 14 days in the placeboand 16.5 days in the corticosteroid groups;
and in all patients, 13 days inthe placebo and 19.5 in the corticosteroid groups.
Figure Legend:

14.  In nonresponders, the median time to
death was 12 days in the placebo and
24 days in the corticosteroid groups;
 in responders, 14 days in the placebo
and 16.5 days in the corticosteroid
groups;
 and in all patients, 13 days in the
placebo and 19.5 in the corticosteroid
groups.

15. Mortality or Survival
Time (days)
28
Survival
1.0
0.5

17.  i

19.  How big a difference in mortality do you
think putting a tracheostomy in at Day 4
compared to Day 10 would make on 30 day
mortality?
 50% RRR (15% ARR)
 25% RRR (7.5% ARR)
 10% RRR (3% ARR)
 5% RRR (1.5% ARR)

20. “Negative trials”
 n

21.  Population:
 Mechanically ventilated adults
 Had been ventilated for 4 days and thought to
require at least 7 more days of ventilation
 Excluded:
 Those requiring a tracheostomy, contraindication to
tracheostomy, respiratory failure due to chronic
neurological disease

22.  Intervention:
 Trachesotomy by Day 4
 Comparison:
 Tracheostomy after Day 10 if still required
 Outcome:
 All cause mortality 30 days from randomisation

23.  Sample Size Calculation:
 Baseline mortality of 30%
 Absolute risk reduction 6.3% (21% RRR)
 Power 80%
 Alpha 5%
 4% loss to follow up
 N=1692

24.  Due to study fatigue and exhaustion of
funding
 N=899

26.  “Tracheostomy within 4 days of critical
care admission was not associated with
an improvement in 30 day mortality”

27.  We are 95% certain that early
tracheostomy might be between
 5.4% worse to 6.7% better in absolute risk
 About 20% better or worse in terms of relative
risk

28.  6.3% of patients had a complication of
tracheostomy
 53% of patients who were randomised to
delayed trache didn’t need one
 2 year mortality was 52.3%
 Only 5 lost to follow up

29.  Conclusions:
 Unable to rule out a clinically important difference
between early and late trache
 It probably doesn’t make a big difference to
mortality
 Unknown about patient perspective
 Useful information about the patient cohort
 Not really a “negative trial”

30. QUESTIONS??