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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
| 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
| 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
- 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, .
- Marco Confalonieri; Rosario Urbino; Alfredo Potena; Marco Piattella; Piercarlo Parigi; Giacomo Puccio; Rossana Della Porta; Carbone Giorgio; Francesco Blasi; Reba Umberger; et al. Hydrocortisone Infusion for Severe Community-acquired Pneumonia. Am. J. Respir. Crit. Care Med. 2005, 171, 242-248, .
- Pierre-François Dequin; Ferhat Meziani; Jean-Pierre Quenot; Toufik Kamel; Jean-Damien Ricard; Julio Badie; Jean Reignier; Nicholas Heming; Gaëtan Plantefève; Bertrand Souweine; et al. Hydrocortisone in Severe Community-Acquired Pneumonia. New Engl. J. Med. 2023, 388, 1931-1941, .
- 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, .
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- 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, .
