Journal Club Handout Template - Goldilocksthedoc



2/11/16 Journal Club Handout

By Izzy Pines

|Background and Overview |

|Article Title/Citation |Torres A., Sibila O., Ferrer M., et al. (2015). Effects of corticosteroids on treatment failure among hospitalized|

| |patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. |

| |JAMA, 313(7), 677-686. |

|Study objectives/purpose |Assess the effect of corticosteroids in patients with severe CAP and high inflammatory response |

|(and research hypothesis if applicable) | |

|Brief Background |Mortality after treatment failure is significantly higher (25% vs 2%) |

|(why issue is important, summary of previous |Corticosteroids inhibit expression of cytokines that are released in response to pneumonia |

|literature) |It is controversial as to whether corticosteroids should be used in severe CAP |

| |A subgroup analysis in 2 meta-analyses found that corticosteroids improved mortality among those with severe CAP |

|Funding Source(s) |Sociedad Espanola de Neumolgia |

| |Societat Catalana de Pneumologia |

| |Fundacio Catalana de Pneumologia |

| |Grup de Recerca de Qualitat de la Generalitat de Catalunya |

| |Fondo de Ivestgacion Sanitaria |

| |Institut dInvestigacions Biomediques August Pi I Sunyer |

| |Centro de Investigacion Biomedica En Red-Enfermedades Respiratorias |

|Methods |

|Study design and |Type: Randomized, double-blind, placebo-controlled trial |

|Methodology (type of trial, randomization, |Setting: 3 Spanish teaching hospitals |

|blinding, Controls, study groups, Length of |Study Groups: steroids vs. placebo |

|study, etc.) |Length of Study: June 2004 through February 2012 |

| |Randomization: 1:1 allocation of pre-numbered boxes containing steroid and placebo (simple randomization) |

|Interventions |IV methylprednisolone bolus of 0.5mg/kg per 12 hours |

|(if applicable) |Placebo |

| | |

| |For 5 days |

| |Started within 36 hours of admission |

|Patient selection and |Sample Size: 120 |

|Enrollment (inclusion/exclusion criteria, sample |Inclusion criteria: |

|size etc.) |( 18 yo |

| |Clinical symptoms of CAP (cough, fever, pleuritic chest pain, dyspnea) |

| |New infiltrate on CXR |

| |Met severe CAP criteria per modified America Thoracic Society criteria or risk class V for the Pneumonia Severity |

| |Index |

| |CRP ( 150mg/L (per Neumofail Group) |

| |Exclusion criteria: |

| |Prior tx with systemic corticosteroids |

| |Nosocomial pneumonia |

| |Reported severe immunosuppression |

| |Life expectancy < 3 months |

| |Uncontrolled diabetes mellitus |

| |Major GI bleed within 3 months |

| |Condition requiring acute tx with greater than 1mg/kg/d of methylprednisolone |

| |H1N1 influenza A pneumonia |

|Outcome measures/Endpoints |Primary outcome: rate of treatment failure (early, late, both) |

| | |

| |Early treatment failure = clinical deterioration within 72 hours |

| |Development of shock |

| |Need for invasive mechanical ventilation not present at baseline |

| |Death |

| |Late treatment failure = clinical deterioration 72-120 hours |

| |Radiologic progression ((50% of pulmonary infiltrates compared to baseline |

| |Persistence of severe respiratory failure (PaO2/FiO2 < 200mmHg with RR ( 30 in non-intubated patients |

| |Development of shock |

| |Need for invasive mechanical ventilation not present at baseline |

| |Death between 72 and 120 hours after treatment initiation |

| | |

| |Secondary outcomes: |

| |Time to clinical stability |

| |Temp ( 37.2 |

| |HR ( 100 |

| |SBP ( 90 |

| |PaO2 ( 60 mmHg |

| |Length of ICU stay |

| |Length of hospital stay |

| |In-hospital mortality |

|Statistical analysis |Analyzed both intention-to-treat (ITT) and per-protocol (PP) |

| |Logistic regression to analyze primary outcome |

| |Kaplan-Meier was used to analyze difference in time to treatment failure |

| |Cox proportional hazard regression used to analyze secondary outcomes |

|Results |

|Enrollment & Baseline |See table 1 (Significant differences in IL-10 [4.7 vs 8.1], procalcitonin [1.3 vs 3.1], and septic shock [17 vs |

|Characteristics |31%]) |

|Summary of primary & secondary outcomes |Less treatment failure in prednisolone group vs placebo (13 vs 31% p = 0.02) |

|(including subgroup analysis, etc. include both |Unadjusted OR = 0.34 (p=0.02) |

|efficacy and safety parameters) |Adjusted OR = 0.33 (p=0.03) |

| |Less late treatment failure in prednisolone group |

| |Mainly due to radiographic progression (2% vs 15%) |

| |Unadjusted OR = 0.10 (p=0.003) |

| |Adjusted OR = 0.09 (p=0.004) |

| |Secondary outcomes had no significant difference btwn groups |

| |Time to treatment failures was significantly different (@ day 5, 12 vs 30%, p=0.03) |

| |Post hoc analysis excluding radiographic progression still favored the prednisolone group |

|Discussion and Conclusions |

|Brief summary of authors’ main discussion |Administration of corticosteroids in severe CAP is associated with less late treatment failure and lower |

|points/conclusions |inflammatory response |

| |Radiographic progression has previously been found to be an independent surrogate marker of mortality |

|Study strengths |Inclusion of severe CAP and high systemic inflammatory response |

|Study limits, weakness, |Study was not powered to detect mortality |

|Potentials for bias, etc. |Not generalizable to all patients with CAP |

| |Did not assess adrenal function before or after to see if patients had a level of adrenal insufficiency prior to |

| |treatment |

| |Other studies have shown more benefit with longer administration of corticosteroids |

| |Slow patient accrual |

| |Long study duration (8 years) |

|Applicability & impact |Other studies have shown benefit for treating inpatient CAP, mild/moderate, with corticosteroids leading to |

|On healthcare providers |decrease treatment failure, shorter time to clinical stability, and decreased in-hospital mortality. However, |

| |little was concluded for the severely ill |

| |This study shows that individuals who present with severe CAP and high inflammatory response may also find benefit|

| |from immediate adjunctive corticosteroid administration |

JAMA Editorial by Wunderink, JAMA (2015) 313(7), 673-4

Criticisms:

• Measured effect was almost exclusively due to less radiologic progression

• Cortisol levels were not taken at baseline

• Imbalances in the randomization (septic shock and mechanical ventilation rates)

• Accrual rate

Poses the question, what are the steroids preventing?

• Uncontrolled pneumonia

• Development of acute respiratory distress – lots of evidence to support this

• Blocking Jarisch-Herxheimer-like reaction in patients with high bacterial load

o High concentrations of cytokines right after antibiotic initiation

Conclusions

• Corticosteroids are not for every patient with severe CAP because their patient population had both severe CAP AND a high inflammatory response

• A larger study needs to be done to confirm that less radiographic progression means less mortality

• Treatment approach to severe CAP should be individualized, otherwise significant changes in mortality will not be appreciated

Letter to the Editor by Pepper JAMA (2015) 313(21), 2184-5

Dr. Pepper brought up that fluid status and fluid resuscitation during the first 5 days would have been a helpful metric because previous studies have shown a negative fluid balance to be a predictor of survival in patients with septic shock. It also may explain some of the difference in the radiologic progression. She also provides a reference for conservative fluid management in patients with acute lung injury that showed improved lung function, duration of mechanical ventilation, and ICU stay.

Dr. Torres’ response:

The study did not collect fluid balance data. The authors don’t believe that the changes in fluid balance would account for the difference in radiologic progression. However, authors agree that fluid balance should be included in future research.

Check these out:





ATS Severe CAP Criteria (( 3 = ICU admit)

Minor criteria

o RR ( 30 breaths/min

o PaO2/FiO2 ratio ( 250

o Multilobar infiltrates

o Confusion/disorientation

o Uremia (BUN ( 20 mg/dL)

o Leukopenia (WBC < 4000)

o Thrombocytopenia (platelet < 100,000)

o Hypothermia (core temperature < 36C)

o Hypotension requiring aggressive fluid resuscitation

Major criteria

o Invasive mechanical ventilation

o Septic shock with the need for vasopressors

Pneumonia Severity Index (PSI)

| |

|Demographic factors |

| |

|Risk |

|Risk Class |

|Score |

|Mortality |

|Management |

| |

|Age (in years) |

| |

| |

| |

| |

| |

| |

| |

| |

|Men |

| |

| |

|Low |

|II |

|(70 |

|0.6% |

|Outpatient |

| |

|Women |

|-10 |

| |

|Low |

|III |

|71-90 |

|0.9% |

| |

| |

|Nursing home resident |

|+10 |

| |

|Mod |

|IV |

|91-130 |

|9.3% |

| |

| |

|Coexisting illnesses |

| |

|High |

|V |

|>130 |

|27% |

|Inpatient |

| |

|Neoplastic disease |

|+30 |

| |

| |

| |

| |

| |

| |

| |

|Liver disease |

|+20 |

| |

| |

| |

| |

| |

| |

| |

|Congestive heart failure |

|+10 |

| |

| |

| |

| |

| |

| |

| |

|Cerebrovascular disease |

|+10 |

| |

| |

| |

| |

| |

| |

| |

|Renal disease |

|+10 |

| |

| |

| |

| |

| |

| |

| |

|Findings on physical examination |

| |

| |

| |

| |

| |

| |

| |

|Altered mental status |

|+20 |

| |

| |

| |

| |

| |

| |

| |

|RR ( 30/min |

|+20 |

| |

| |

| |

| |

| |

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|SBP ................
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