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Hydrocortisone in Community Acquired Pneumonia
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Summary of Key Findings Oxygenation and Respiratory Outcomes: Hydrocortisone significantly improved oxygenation (PaO₂/FiO₂ ratio) and increased the number of mechanical ventilation-free days. This suggests that hydrocortisone could be beneficial in enhancing respiratory outcomes. Reduction in Major Complications: There was a notable reduction in the incidence of major complications, including delayed septic shock and MODS, among patients treated with hydrocortisone. Mortality: ICU, hospital, and 60-day mortality were significantly lower in the hydrocortisone group, indicating a potential survival benefit. Length of Stay and Ventilation Duration: Patients in the hydrocortisone group had shorter ICU stays, hospital stays, and duration on mechanical ventilation, supporting its efficacy in reducing the burden of intensive care needs. Safety Profile: Although complications like ARDS, ventilator-associated pneumonia, and acute renal failure were monitored, there were no significant increases in these adverse events with hydrocortisone. This supports its safety profile in the ICU setting.

pneumonia Cape Cod Hydrocortisone

1. Introduction

Table
Variable Confalonieri 2012 Nafae 2013 Cape Cod 2023
Mortality Outcomes      
ICU Mortality 7/23 (30%) Placebo, 0/23 (0%) Hydrocortisone Not reported Not reported
28-day Mortality Not reported Not reported 47/395 (11.9%) Placebo, 25/400 (6.2%) Hydrocortisone
60-day Mortality 8/23 (35%) Placebo, 0/23 (0%) Hydrocortisone Not reported Not reported
Hospital Mortality 7/23 (30%) Placebo, 0/23 (0%) Hydrocortisone 6/20 (30%) Placebo, 4/60 (6.7%) Hydrocortisone Not reported
Mechanical Ventilation      
Need for Mechanical Ventilation 15/23 (65%) Placebo, 6/23 (26%) Hydrocortisone 5/20 (25%) Placebo, 8/60 (13.3%) Hydrocortisone 65/220 (29.5%) Placebo, 40/222 (18%) Hydrocortisone
Mechanical Ventilation-Free Days 0 (0-6) Placebo, 4 (0-7) Hydrocortisone Not reported Not reported
Duration of Mechanical Ventilation 10 (2-44) days Placebo, 4 (1-27) days Hydrocortisone 12-22 days Placebo, 5-24 days Hydrocortisone Not reported
PaO₂/FiO₂ Ratio      
Baseline PaO₂/FiO₂ Ratio 237 ± 92 Placebo, 332 ± 80 Hydrocortisone 319.4 ± 54.3 Placebo, 343.9 ± 51.6 Hydrocortisone Not reported
PaO₂/FiO₂ Improvement ≥ 100 8/23 (35%) Placebo, 20/23 (87%) Hydrocortisone Not reported Not reported
Inflammatory Markers      
CRP (mg/L) - Baseline 34 (0–225) Placebo, 18 (0–44) Hydrocortisone 95.4 ± 45.64 Placebo, 91.3 ± 39.96 Hydrocortisone Not reported
CRP (mg/L) - Reduction Not reported 43.7 ± 46.2 Placebo, 16.3 ± 18.9 Hydrocortisone Not reported
ESR (mm/hr) Not reported 81.7 ± 6 Placebo, 79.9 ± 9.7 Hydrocortisone Not reported
Length of Stay      
ICU Stay (days) 18 (3–45) Placebo, 10 (4–33) Hydrocortisone 6.3 ± 8.2 Placebo, 3.1 ± 4.9 Hydrocortisone Not reported
Total Hospital Stay (days) 21 (3–72) Placebo, 13 (10–53) Hydrocortisone 16.5 ± 2.24 Placebo, 9.27 ± 2.4 Hydrocortisone Not reported
Safety and Complications      
Delayed Septic Shock 10/23 (52%) Placebo, 0/23 (0%) Hydrocortisone Not reported Not reported
ARDS 4/23 (17%) Placebo, 0/23 (0%) Hydrocortisone 6/20 (30%) Placebo, 4/60 (6.7%) Hydrocortisone Not reported
Nosocomial Infection 4/23 (18%) Placebo, 0/23 (0%) Hydrocortisone Not reported 44/395 (11.1%) Placebo, 39/400 (9.8%) Hydrocortisone
Gastrointestinal Bleeding 1/23 (4%) Placebo, 1/23 (4%) Hydrocortisone 1/20 (5%) Placebo, 1/60 (1.6%) Hydrocortisone 13/395 (3.3%) Placebo, 9/400 (2.2%) Hydrocortisone
Hypokalemia Not reported 5/20 (25%) Placebo, 35/60 (58.3%) Hydrocortisone Not reported
Uncontrolled Diabetes (glucose > 250 mg/dL) Not reported 8/20 (40%) Placebo, 19/60 (31.7%) Hydrocortisone Not reported
Blood Chemistry and Hematology      
WBC (·10³/cm) Not reported 17 ± 4.5 Placebo, 17.8 ± 4.5 Hydrocortisone Not reported
Hematocrit (%) Not reported 28.9 ± 2.7 Placebo, 30 ± 4.2 Hydrocortisone Not reported
BUN (mg/dL) Not reported 41.8 ± 19.5 Placebo, 31.6 ± 14.2 Hydrocortisone Not reported
Creatinine (mg/dL) Not reported 1.5 ± 0.8 Placebo, 1.14 ± 0.5 Hydrocortisone Not reported
Sodium Level (Na, mEq/L) Not reported 130.1 ± 3.71 Placebo, 131.9 ± 6 Hydrocortisone Not reported
Potassium Level (K, mEq/L) Not reported 3.63 ± 0.44 Placebo, 3.6 ± 0.46 Hydrocortisone Not reported

[1][2][3][4][5] Table1. Common Variables and Results Across [6], Nafae 2013, and Cape Cod 2023.

2. Meta-Analysis Table for Key Parameters and Outcomes

Table
Parameter/Outcome Placebo Hydrocortisone p-Value Interpretation
Demographics        
Male/Female 15/8 17/6 0.53 No significant difference in gender distribution
Age, years 66.6 ± 14.7 60.4 ± 17.3 0.20 No significant age difference
Smoking Habit See subgroup analysis See subgroup analysis NS Not significantly different
Severity Scores        
APACHE II Score 18.2 ± 4.0 17.2 ± 4.1 0.39 No significant difference in severity
MODS Score 1.2 ± 0.4 1.2 ± 0.5 0.75 No significant difference
Vital Signs and Laboratory Values        
Temperature (°C) 38.2 ± 1.2 38.3 ± 0.9 0.76 No significant difference
WBC Count (×10⁹/L) 13.9 ± 5.1 13.4 ± 5.5 0.73 No significant difference
PaO₂/FiO₂ Ratio 178 ± 58 141 ± 49 0.03 Significant difference; lower in hydrocortisone group
PaO₂/FiO₂ ≤ 200 13 (57%) 21 (91%) 0.02 Significant; worse oxygenation in hydrocortisone group
CRP (mg/dL) 29 (6–200) 55 (14–349) 0.04 Significant; higher CRP in hydrocortisone group
Respiratory Support and Ventilation        
On Mechanical Ventilation 19 (83%) 15 (65%) 0.18 Not significant
Mechanical Ventilation-Free Days 0 (0–6) 4 (0–7) 0.01 Significant; more vent-free days in hydrocortisone
PaO₂/FiO₂ Ratio (after treatment) 237 ± 92 332 ± 80 0.0008 Significant improvement with hydrocortisone
PaO₂/FiO₂ Improvement ≥ 100 8 (35%) 20 (87%) 0.0007 Significant improvement in oxygenation
Chest Radiograph and MODS        
Chest Radiograph Score 2.6 ± 1.3 1.1 ± 0.7 < 0.0001 Significant improvement with hydrocortisone
Improvement in Chest Radiograph Score 5 (22%) 21 (91%) < 0.0001 Significant improvement with hydrocortisone
Patients with MODS 16 (70%) 8 (35%) 0.02 Significant reduction in MODS with hydrocortisone
Shock and Complications        
Delayed Septic Shock by Day 8 9 (43%) 0 (0%) 0.001 Significant reduction in delayed septic shock
New ARDS by Day 8 3 (13%) 0 (0%) 0.23 Not significant
Major Complications        
Major Complications 18 (78%) 6 (26%) < 0.001 Significant reduction in complications
Delayed Septic Shock 10 (52%) 0 (0%) < 0.001 Significant reduction with hydrocortisone
Shock Not Related to Sepsis 2 (9%) 0 (0%) 0.5 Not significant
ARDS 4 (17%) 0 (0%) 0.11 Not significant
Nosocomial Infection 4 (18%) 0 (0%) 0.11 Not significant
Ventilator-Associated Pneumonia 3 (13%) 0 (0%) 0.23 Not significant
Acute Renal Failure 3 (13%) 0 (0%) 0.23 Not significant
Mortality and Survival        
ICU Mortality 7 (30%) 0 (0%) 0.009 Significant reduction in ICU mortality
Hospital Mortality 7 (30%) 0 (0%) 0.009 Significant reduction in hospital mortality
60-day Mortality 8 (38%) 0 (0%) 0.001 Significant reduction in 60-day mortality
Length of Stay and Mechanical Ventilation        
Length of ICU Stay, days 18 (3–45) 10 (4–33) 0.01 Significant reduction in ICU stay
Length of Hospital Stay, days 21 (3–72) 13 (10–53) 0.03 Significant reduction in hospital stay
Duration of Mechanical Ventilation, days 10 (2–44) 4 (1–27) 0.007 Significant reduction in duration of ventilation

3. Pathophysiology and Purpose

Q: Why might steroids be beneficial in treating pneumonia?
A: Steroids may help control an excessive inflammatory response associated with infection, which can contribute to disease severity and complications in pneumonia.

Q: What are the main side effects of steroids in pneumonia treatment?
A: Major side effects include hyperglycemia, GI bleeding, increased risk of infections, and neuropsychiatric symptoms.

4. RCTs of Steroids in Pneumonia

Q: What did early RCTs (2005–2015) suggest about the impact of steroids on pneumonia outcomes?
A: Early RCTs showed mixed results:

  • Some trials showed reductions in mortality, time to clinical stability, and length of stay, while others did not affect mortality.
  • Steroids were generally associated with faster clinical improvement but increased hyperglycemia.

Q: What were limitations of early RCTs on steroids in pneumonia?
A: Limitations included small sample sizes, varied inclusion/exclusion criteria, differences in steroid types and dosing protocols, and potential inclusion of patients with pneumonia mimics.

5. Meta-Analyses Insights

Q: What did meta-analyses reveal about steroid benefits in pneumonia?
A: Meta-analyses suggested that steroids may reduce mortality in severe CAP (community-acquired pneumonia), reduce mechanical ventilation need, shorten ICU stays, and increase clinical stability time. However, steroids consistently increased hyperglycemia.

Q: Are there different guidelines regarding steroids in pneumonia?
A: Yes, the European guidelines (ESICM/SCCM) recommend steroids for severe CAP, while the American (ATS/IDSA) guidelines recommend against them, reflecting ongoing debate.

6. CAPE COD Trial (2023)

Q: What was the main question of the CAPE COD trial?
A: The CAPE COD trial asked if IV hydrocortisone reduces mortality in patients hospitalized with severe CAP.

Q: What were the results of the CAPE COD trial?
A: The trial found:

  • A reduction in 28-day mortality (6.2% in the steroid group vs. 11.9% in placebo).
  • Lower 90-day mortality and reduced need for intubation or vasopressors in the steroid group.
  • Higher insulin requirements in the steroid group, with no increase in GI bleeds or hospital-acquired infections.

Q: Why did the CAPE COD trial show a larger benefit with steroids?
A: Possible reasons include:

  • The steroid group had fewer cases of shock compared to placebo.
  • The strict inclusion criteria targeted severely ill patients who are more likely to benefit.
  • Some patients may have had concurrent ARDS, a condition where steroids are known to be beneficial.

7. Practical Takeaways and Remaining Questions

Q: In which patients with pneumonia might steroids be most beneficial?
A: Steroids appear to benefit patients with severe pneumonia, especially those with high levels of inflammation (e.g., elevated CRP).

Q: What questions remain about the best way to use steroids in CAP?
A: Unanswered questions include:

  • Optimal route of administration (IV vs. PO).
  • Ideal duration and timing of steroid initiation.
  • Best type of steroid for pneumonia treatment.

Q: What is the clinical recommendation regarding steroids in CAP?
A: Clinicians should carefully select patients with severe CAP for steroid treatment, considering the mixed evidence and the potential for side effects like hyperglycemia.

References

  1. Tyler Pitre; Daniyal Abdali; Dipayan Chaudhuri; Stephen M. Pastores; Andrea M. Nei; Djillali Annane; Bram Rochwerg; Dena Zeraatkar; Corticosteroids in Community-Acquired Bacterial Pneumonia: a Systematic Review, Pairwise and Dose-Response Meta-Analysis. J. Gen. Intern. Med.. 2023, 38, 2593-2606.
  2. Marco Confalonieri; Rosario Urbino; Alfredo Potena; Marco Piattella; Piercarlo Parigi; Giacomo Puccio; Rossana Della Porta; Carbone Giorgio; Francesco Blasi; Reba Umberger; G. Umberto Meduri; Hydrocortisone Infusion for Severe Community-acquired Pneumonia. Am. J. Respir. Crit. Care Med.. 2005, 171, 242-248.
  3. Pierre-François Dequin; Ferhat Meziani; Jean-Pierre Quenot; Toufik Kamel; Jean-Damien Ricard; Julio Badie; Jean Reignier; Nicholas Heming; Gaëtan Plantefève; Bertrand Souweine; Guillaume Voiriot; Gwenhaël Colin; Jean-Pierre Frat; Jean-Paul Mira; Nicolas Barbarot; Bruno François; Guillaume Louis; Sébastien Gibot; Christophe Guitton; Christophe Giacardi; Sami Hraiech; Sylvie Vimeux; Erwan L’her; Henri Faure; Jean-Etienne Herbrecht; Camille Bouisse; Aurélie Joret; Nicolas Terzi; Arnaud Gacouin; Charlotte Quentin; Mercé Jourdain; Marie Leclerc; Carine Coffre; Hélène Bourgoin; Céline Lengellé; Caroline Caille-Fénérol; Bruno Giraudeau; Amélie Le Gouge; Hydrocortisone in Severe Community-Acquired Pneumonia. New Engl. J. Med.. 2023, 388, 1931-1941.
  4. Ramadan M. Nafae; Mostafa I. Ragab; Fawzy M. Amany; Shimaa B. Rashed; Adjuvant role of corticosteroids in the treatment of community-acquired pneumonia. Egypt. J. Chest Dis. Tuberc.. 2013, 62, 439-445.
  5. Matthias Briel; Simone M C Spoorenberg; Dominic Snijders; Antoni Torres; Silvia Fernandez-Serrano; G Umberto Meduri; Albert Gabarrús; Claudine A Blum; Marco Confalonieri; Benjamin Kasenda; Reed Ac Siemieniuk; Wim Boersma; Willem Jan W Bos; Mirjam Christ-Crain; Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis. Clin. Infect. Dis.. 2017, 66, 346-354.
  6. M. Confalonieri; M. Kodric; M. Santagiuliana; C. Longo; M. Biolo; R. Cifaldi; C. Torregiani; M. Jevnikar; To use or not to use corticosteroids for pneumonia? A clinician’s perspective. Monaldi Arch. Chest Dis.. 2012, 77, 94-101.
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Samuel Huang
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