journal club - disease progression in hemodynamically stable patients presenting to the emergency...

JOURNAL CLUB

Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With SepsisGlickman 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 MDCMPGY2 FRCP-EM

McGill University

Joseph Choi MDPGY1 FRCP-EM

McGill University

April 6th 2011

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

QuizEarly Goal Directed Therapy (EGDT)Surviving Sepsis CampaignEBM topic: Prognostic studies

Which of the following were eligibility criteria in Rivers’ original EGDT study?

A. Lactate > 4mmol/LB. sBP < 90mmHg despite fluidsC. O2 saturation < 92%D. Heart rate > 100bpmE. Respiratory rate > 20F. PaCO2 < 32

1. A, B, C, D only2. A, B, D, E only3. A, B, D, E, F only4. A and B only5. All of the above

Which of the following were eligibility criteria in Rivers’ original EGDT study?

A. Lactate > 4mmol/LB. sBP < 90mmHg despite fluidsC. O2 saturation < 92%D. Heart rate > 100bpmE. Respiratory rate > 20F. PaCO2 < 32

1. A, B, C, D only2. A, B, D, E only3. A, B, D, E, F only4. A and B only5. All of the above

EGDT

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 sepsisC. Lab tests are neither sensitive nor specificD. SIRS criteria are specific but not sensitiveE. SIRS criteria are sensitive but not specific

1. A, B, and D2. A, B, and C3. C, D and E4. D only5. All of the above6. None of the above

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 sepsisC. Lab tests are neither sensitive nor specificD. SIRS criteria are specific but not sensitiveE. SIRS criteria are sensitive but not specific

1. A, B, and D2. A, B, and C3. C, D and E4. D only5. All of the above6. None of the above

SIRS and Sepsis

• Sepsis occurs in only 48% of those with SIRS

Which of the following are barriers to cost-effective treatment of sepsis in 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 sensitiveD. Mortality benefit from EGDT is statistically significant but not clinically

significantE. It is difficult to identify which patients will deteriorate quickly and benefit the

most from aggressive protocolized treatment 1. A, B, C, and D2. B, C, D, and E3. A, B, C and E4. D only5. All of the above6. None of the above

Which of the following are barriers to cost-effective treatment of sepsis in 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 sensitiveD. Mortality benefit from EGDT is statistically significant but not clinically

significantE. It is difficult to identify which patients will deteriorate quickly and benefit the

most from aggressive protocolized treatment 1. A, B, C, and D2. B, C, D, and E3. A, B, C and E4. D only5. All of the above6. None of the above

EGDT

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

EGDT requires…

• Intensive nursing/physician care• Central lines• ScvO2 measurement• Arterial lines• Vasoactive agents/inotropes

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.

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.

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.

You are designing a study on the prognosis of a particular group of patients, which of the following could systematically bias your results?A. All patients are selected from tertiary referral centersB. The study’s inclusion and exclusion criteria are clearly definedC. Your sample includes a mixture of newly diagnosed patients and end-stage

patientsD. Your sample is divided into subgroups based on factors known to affect outcomeE. Your definition of disease and outcome is very objective

1. A, B, and C2. A and C3. B and D4. C only5. All of the above6. None of the above

You are designing a study on the prognosis of a particular group of patients, which of the following could systematically bias your results?A. All patients are selected from tertiary referral centersB. The study’s inclusion and exclusion criteria are clearly definedC. Your sample includes a mixture of newly diagnosed patients and end-stage

patientsD. Your sample is divided into subgroups based on factors known to affect outcomeE. Your definition of disease and outcome is very objective

1. A, B, and C2. A and C3. B and D4. C only5. All of the above6. None of the above

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?

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?

Now that you have a well selected sample of patients for your study, which of the following could potentially bias your interpretation of the data?

1. A, B and C2. B, C, and D3. C, D and E4. D and E only5. All of the above6. 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

Now that you have a well selected sample of patients for your study, which of the following could potentially bias your interpretation of the data?

1. A, B and C2. B, C, and D3. C, D and E4. D and E only5. All of the above6. 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

Was statistical analysis appropriate?• Were prognostic factors analyzed in relation to

one another?• Is there confounding?

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?

Outcomes

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

Change of risk over time

Confidence Intervals

The following could have an impact on outcome in a prognosis study..A. The selection of patients eligible for treatment varied across participating centersB. Patients were offered different treatment agents at different participating

centersC. Patients were treated at different times in their disease processD. New treatment guidelines were implemented over the course of the study

periodE. New technology was introduced in the diagnosis and treatment of the disease

within study period

1. A, B, and C2. B and D3. C, D, and E4. A only5. All of the above6. None of the above

The following could have an impact on outcome in a prognosis study..A. The selection of patients eligible for treatment varied across participating centersB. Patients were offered different treatment agents at different participating centersC. Patients were treated at different times in their disease processD. New treatment guidelines were implemented over the course of the study periodE. New technology was introduced in the diagnosis and treatment of the disease

within study period

1. A, B, and C2. B and D3. C, D, and E4. A only5. All of the above6. None of the above

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

DISCUSSIONGroup interactive

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?

Study population

• Enrolled from 3 urban EDs in the US• Part of a larger CAPSOD study

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?

Sampling method

• Convenience sampling • Authors say this was necessary given the need

for prompt study specimen handling for metabolic studies• Issues with this?

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?

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?

Were patients sufficiently homogeneous 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?

Similar point in disease process?• At presentation to ED

Subgroups at higher or lower risk than the overall group?

Subgroups at higher or lower risk than the overall group?

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

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

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?

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

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

How likely are the outcomes over time?

How likely are the outcomes over time?

How precise are the estimates of likelihood?

•Mortality with early progression OR = 4.72, 95% CI = [2.01 to 11.1]

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?

What does this study add? Can I apply it to my practice?

•The floor is open!

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identify infected patients in the emergency room. Intensive Care Medicine, 2003. 29(8): p. 1368-1371.

• Bone, R.C., R.A. Balk, F.B. Cerra, et al., Definitions for sepsis and organ failure and guidelines 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, 1992. 101(6): p. 1644-1655.

• Dellinger, R.P., M.M. Levy, J.M. Carlet, et al., Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Critical Care Medicine, 2008. 36(1): p. 296-327 10.1097/01.CCM.0000298158.12101.41.

• Rangel-Frausto, M.S., D. Pittet, M. Costigan, et al., The Natural History of the Systemic Inflammatory Response Syndrome (SIRS) A Prospective Study. JAMA, 1995. 273(2): p. 117-123.

• Rivers, E., B. Nguyen, S. Havstad, et al., Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine, 2001. 345(19): p. 1368-1377.

• Jones, A.E., M.D. Brown, S. Trzeciak, et al., The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis *. Critical Care Medicine, 2008. 36(10): p. 2734-2739 10.1097/CCM.0b013e318186f839.

• Rivers, E.P., L. McIntyre, D.C. Morro, et al., Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity. CMAJ, 2005. 173(9): p. 1054-1065.

References• Pollmächer, T., J. Mullington, C. Korth, et al., Diurnal Variations in the Human Host

Response to Endotoxin. The Journal of Infectious Diseases, 1996. 174(5): p. 1040-1045.

• Scheff, J.D., S.E. Calvano, S.F. Lowry, et al., Modeling the influence of circadian rhythms on the acute inflammatory response. Journal of Theoretical Biology, 2010. 264(3): p. 1068-1076.

• Fromm, R.E., Jr., L.R. Gibbs, W.G. McCallum, et al., Critical care in the emergency department: a time-based study. Crit Care Med, 1993. 21(7): p. 970-6.

• Magid, D.J., Y. Wang, J. Herrin, et al., Relationship Between Time of Day, Day of Week, Timeliness of Reperfusion, and In-Hospital Mortality for Patients With Acute ST-Segment Elevation Myocardial Infarction. JAMA, 2005. 294(7): p. 803-812.

• Alberti, C., C. Brun-Buisson, S. Chevret, et al., Systemic Inflammatory Response and Progression to Severe Sepsis in Critically Ill Infected Patients. Am. J. Respir. Crit. Care Med., 2005. 171(5): p. 461-468.

• Martin, GS, Mannino, DM, Eaton, S, Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl Med 2003; 348:1546.

• User’s Guide to the Medical Literature, JAMA, online pubs.ama-ssn.org/misc/usersguides.dtl