Critical appraisal of: Glickman SW et al. Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis. Acad Emerg Med. 2010 17:383-90 Interactive quiz on early goal-directed therapy, surviving sepsis guidelines and EBM topic of prognosis studies.

1. JOURNAL CLUB
Disease Progression in Hemodynamically Stable Patients Presenting
to the Emergency Department With Sepsis
Glickman SW, Cairns CB, Otero RM, Woods CW, Tsalik EL, Langley RJ, van Velkinburgh JC, Park LP,
Glickman LT, Fowler VG Jr, Kingsmore SF, Rivers EP.
Acad Emerg Med. 2010 17:383-90
Farooq Khan MDCM
PGY2 FRCP-EM
McGill University
Joseph Choi MD
PGY1 FRCP-EM
McGill University
April 6th 2011

2. Objectives
• Refresh knowledge on sepsis and EGDT
• Understand the author’s rationale for doing the study
• Understanding the elements of appraising a prognosis study
• Appraise the article using what was covered in the questions

3. Quiz
Early Goal Directed Therapy (EGDT)
Surviving Sepsis Campaign
EBM topic: Prognostic studies

4. Which of the following were eligibility
criteria in Rivers’ original EGDT study?
A. Lactate > 4mmol/L
B. sBP < 90mmHg despite fluids
C. O2 saturation < 92%
D. Heart rate > 100bpm
E. Respiratory rate > 20
F. PaCO2 < 32
1. A, B, C, D only
2. A, B, D, E only
3. A, B, D, E, F only
4. A and B only
5. All of the above

5. Which of the following were eligibility
criteria in Rivers’ original EGDT study?
A. Lactate > 4mmol/L
B. sBP < 90mmHg despite fluids
C. O2 saturation < 92%
D. Heart rate > 100bpm
E. Respiratory rate > 20
F. PaCO2 < 32
1. A, B, C, D only
2. A, B, D, E only
3. A, B, D, E, F only
4. A and B only
5. All of the above

6. EGDT

7. Barriers to identifying septic patients in
the ED do not include:
A. Patients with sepsis have complex and varied presentations with clinical
signs and symptoms that often overlap with non-infectious disease
states
B. There is significant variation in the microbial etiology of sepsis
C. Lab tests are neither sensitive nor specific
D. SIRS criteria are specific but not sensitive
E. SIRS criteria are sensitive but not specific
1. A, B, and D
2. A, B, and C
3. C, D and E
4. D only
5. All of the above
6. None of the above

8. Barriers to identifying septic patients in
the ED do not include:
A. Patients with sepsis have complex and varied presentations with clinical
signs and symptoms that often overlap with non-infectious disease
states
B. There is significant variation in the microbial etiology of sepsis
C. Lab tests are neither sensitive nor specific
D. SIRS criteria are specific but not sensitive
E. SIRS criteria are sensitive but not specific
1. A, B, and D
2. A, B, and C
3. C, D and E
4. D only
5. All of the above
6. None of the above

9. SIRS and Sepsis
• Sepsis occurs in only 48% of those with SIRS

10. Whichof the followingare barriersto cost-
effectivetreatmentof sepsisin the ED
A. EGDT is invasive, labour intensive and associated with significant
potential complications
B. EGDT studies were limited to the sickest patients and are not necessarily
generalizable to all septic patients presenting to the ED
C. Mortality benefit from EGDT is time sensitive
D. Mortality benefit from EGDT is statistically significant but not clinically
significant
E. It is difficult to identify which patients will deteriorate quickly and
benefit the most from aggressive protocolized treatment
1. A, B, C, and D
2. B, C, D, and E
3. A, B, C and E
4. D only
5. All of the above
6. None of the above

11. Whichof the followingare barriersto cost-
effectivetreatmentof sepsisin the ED
A. EGDT is invasive, labour intensive and associated with significant
potential complications
B. EGDT studies were limited to the sickest patients and are not necessarily
generalizable to all septic patients presenting to the ED
C. Mortality benefit from EGDT is time sensitive
D. Mortality benefit from EGDT is statistically significant but not clinically
significant
E. It is difficult to identify which patients will deteriorate quickly and
benefit the most from aggressive protocolized treatment
1. A, B, C, and D
2. B, C, D, and E
3. A, B, C and E
4. D only
5. All of the above
6. None of the above

12. EGDT
• Patients with septic shock experience a 15% ARR
with EGDT vs conventional therapy (Rivers 2001)
• EGDT costs $26,600/QALY

13. EGDT requires…
• Intensive nursing/physician care
• Central lines
• ScvO2 measurement
• Arterial lines
• Vasoactive agents/inotropes

14. Central Lines
• 15% complication rate
• Mechanical 5-19%
• Infection 5-26%
• Thrombosis 2-26%
McGee, DC, Gould, MK. Preventing Complications of Central Venous Catheterization. N Engl J Med 2003; 348:1123-1133.

16. Progression of Sepsis
• Sepsis often worsens
quickly
• Median 1 day
• Mortality increases
proportionately
• SIRS 7%
• Sepsis 16%
• Severe sepsis 20%
• Septic shock 46%
Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP.
The natural history of the systemic inflammatory response syndrome
(SIRS). A prospective study. JAMA. 1995;273(2):117.

17. Time Sensitivity
• Retrospective, multi-centered,
2154 patients
• Antibiotic therapy in severe
sepsis/septic shock patients most
powerful predictor of survival
• 44.4% patients from ED to ICU
• 79.9% patients survive if
antibiotics given in 1st hour
• 7.2% decrease in survival per
hour delay of antibiotics in first 6
hours from onset of hypotension
Kumar, A, Roberts, D, Wood, KE, et. al. Critical Care Medicine. 34(6):1589-1596, June 2006.

18. Youaredesigningastudyontheprognosisofa
particulargroupofpatients,whichofthefollowing
couldsystematicallybiasyour results?
A. All patients are selected from tertiary referral centers
B. The study’s inclusion and exclusion criteria are clearly defined
C. Your sample includes a mixture of newly diagnosed patients and end-
stage patients
D. Your sample is divided into subgroups based on factors known to affect
outcome
E. Your definition of disease and outcome is very objective
1. A, B, and C
2. A and C
3. B and D
4. C only
5. All of the above
6. None of the above

19. Youaredesigningastudyontheprognosisofa
particulargroupofpatients,whichofthefollowing
couldsystematicallybiasyour results?
A. All patients are selected from tertiary referral centers
B. The study’s inclusion and exclusion criteria are clearly defined
C. Your sample includes a mixture of newly diagnosed patients and end-
stage patients
D. Your sample is divided into subgroups based on factors known to affect
outcome
E. Your definition of disease and outcome is very objective
1. A, B, and C
2. A and C
3. B and D
4. C only
5. All of the above
6. None of the above

20. Was the sample
representative?
• Were clear inclusion/exclusion criteria used?
• Was there selection bias?
• Was the sampling method clear and
appropriate?
• Were disease definitions objective?

21. Were patients sufficiently
homogeneous with respect to risk?
• Were they at a similar well-described point in
their disease process?
• Were subgroups identified that may have a
higher or lower risk than the overall group?

22. Nowthatyou haveawellselectedsampleofpatients
foryourstudy,whichofthefollowingcould
potentiallybiasyourinterpretationofthedata?
1. A, B and C
2. B, C, and D
3. C, D and E
4. D and E only
5. All of the above
6. None of the above
A. Factors known to affect outcome were analyzed in relation to one another
using sophisticated statistical techniques
B. Your follow-up time is longer than the expected natural history of the
outcome studied
C. Patients lost to follow-up were more likely to be associated with the
adverse outcome
D. Your observed event rate of the outcome was low (e.g. 1%) with an
average loss to follow up (e.g. 10%)
E. The risk of adverse outcomes is variable over time

23. Nowthatyou haveawellselectedsampleofpatients
foryourstudy,whichofthefollowingcould
potentiallybiasyourinterpretationofthedata?
1. A, B and C
2. B, C, and D
3. C, D and E
4. D and E only
5. All of the above
6. None of the above
A. Factors known to affect outcome were analyzed in relation to one another
using sophisticated statistical techniques
B. Your follow-up time is longer than the expected natural history of the
outcome studied
C. Patients lost to follow-up were more likely to be associated with the
adverse outcome
D. Your observed event rate of the outcome was low (e.g. 1%) with an
average loss to follow up (e.g. 10%)
E. The risk of adverse outcomes is variable over time

24. Was statistical analysis
appropriate?
• Were prognostic factors analyzed in relation to
one another?
• Is there confounding?

25. Follow up
• Was follow up sufficiently long?
• Was there significant loss to follow up?
• Is there a relationship between losses to follow-
up and adverse outcome of interest?
• Is the event rate low enough for small losses to
follow up to have significant impact?

26. Outcomes
• Were objective and unbiased outcome criteria
used?
• How likely are the outcomes over time?
• How precise are the estimates of likelihood?

27. Change of risk over time

28. Confidence Intervals

29. The following could have an impact on
outcome in a prognosis study..
A. The selection of patients eligible for treatment varied across participating
centers
B. Patients were offered different treatment agents at different participating
centers
C. Patients were treated at different times in their disease process
D. New treatment guidelines were implemented over the course of the study
period
E. New technology was introduced in the diagnosis and treatment of the
disease within study period
1. A, B, and C
2. B and D
3. C, D, and E
4. A only
5. All of the above
6. None of the above

30. The following could have an impact on
outcome in a prognosis study..
A. The selection of patients eligible for treatment varied across participating
centers
B. Patients were offered different treatment agents at different participating
centers
C. Patients were treated at different times in their disease process
D. New treatment guidelines were implemented over the course of the study
period
E. New technology was introduced in the diagnosis and treatment of the
disease within study period
1. A, B, and C
2. B and D
3. C, D, and E
4. A only
5. All of the above
6. None of the above

31. Applicability
• Bias of treatment effect on prognosis
• Difference in practice patterns over region/time
• Evolving technology and data
• Affects your ability to apply the data to your patients

32. DISCUSSION
Group interactive

33. Was the sample
representative?
• What was the study population?
• Were clear inclusion/exclusion criteria used?
• Was the sampling method clear and appropriate?
• Were disease definitions objective?
• Was there selection bias?

34. Study population
• Enrolled from 3 urban EDs in the US
• Part of a larger CAPSOD study

35. Inclusion/exclusion criteria
– Inclusion
• Known or suspected infection
• 2 or more SIRS criteria
• Over 18
– Exclusions
• Imminently terminal comorbid condition
• Advanced AIDS (CD4 <50)
• On antibiotics
• Enrolled in another trial
– Not analyzed
• Patients in septic shock at presentation
• Patients later determined not to have had an infection
• Appropriate or inappropriate?

36. Sampling method
• Convenience sampling
• Authors say this was necessary given the need
for prompt study specimen handling for
metabolic studies
• Issues with this?

37. Disease definitions
• Sepsis defined as SIRS plus suspected infection
• Independent adjudicators of infection status (up to 3 with high
interrater agreement κ > 0.8)
• Severe sepsis/septic shock included multiple objective
criteria
• evidence of end organ dysfunction:
• Lactate > 1.5 times upper limit of normal
• Arterial pH < 7.3
• Platelets < 80 × 103
• Intubation or PaO2/FiO2 < 250
• Urine output < 0.5mg/kg/hr despite adequate fluid resuscitation
• sBP < 90 mm Hg or MAP < 65 mm Hg despite adequate fluid resuscitation
• Evidence of shock
• sBP < 90 mm Hg or MAP < 65 mm Hg despite initial fluid challenge
• Lactate > 4 mmol/L
• Issues with these definitions?

38. Selection bias
• Tertiary care centers
• Included more ethnic diversity
• Sampled more community patients with uncomplicated
disease
• Problems inherent with the definitions of sepsis
• Not necessarily representative of night-time disease. Is
this significant?

39. Were patients sufficientlyhomogeneous
with respect to prognostic risk?
• Were they at a similar well-described point in their disease
process?
• Were subgroups identified that may have a higher or lower
risk than the overall group?
• Can you think of factors that the investigators have neglected
that are likely to define subgroups with very different
prognoses?
• Were prognostic factors analyzed in relation to one another?

40. Similar point in disease
process?
• At presentation to ED

41. Subgroups at higher or lower
risk than the overall group?

42. Subgroups at higher or lower
risk than the overall group?

43. Factors investigators neglected that are
likely to define subgroups with very
different prognoses?
• Demographics
• Physiological markers
• Comorbidities
• Infection site
• Causative organisms
• Treatment!
• Any others?

44. Were prognostic factors analyzed in
relation to one another?
• Multiple variable logistic regression model

45. Follow-up, Outcome and
Applicability
• Was follow up sufficiently complete?
• Were objective and unbiased outcome criteria used?
• How likely are the outcomes over time?
• How precise are the estimates of likelihood?
• What does this study add? Can I apply it to my practice?

46. Was follow up sufficiently
complete?
• 100% at 72h
• ? Losses to follow-up at 30 days

47. Were objective and unbiased
outcome criteria used?
• Progression to septic shock at 72 hours
• Progression to severe sepsis and/or septic shock
at 72 hours?
• Death at 30 days

48. How likely are the outcomes
over time?

49. How likely are the outcomes
over time?

50. How precise are the estimates
of likelihood?
• Mortality with early progression
OR = 4.72, 95% CI = [2.01 to 11.1]

51. Prognostic risk factors
• Hyperthermia (per °C) OR 1.34 [1.06–1.68]
• Female Sex OR 2.57 [1.50–4.40]
• Vascular access site OR 5.06 [1.81–14.1]
• Age (per decade) OR 1.22 [1.05–1.42]
• Hematocrit (per %) OR 0.96 [0.92–1.00]
• Lung disease OR 2.30 [1.29–4.10]
• Issues?

52. What does this study add? Can
I apply it to my practice?
•The floor is open!

53. References
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to identify infected patients in the emergency room. Intensive Care Medicine, 2003. 29(8):
p. 1368-1371.
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for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference
Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest,
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sepsis and septic shock: taking advantage of a window of opportunity. CMAJ, 2005. 173(9):
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54. References
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Host Response to Endotoxin. The Journal of Infectious Diseases, 1996. 174(5): p.
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