Introduction
- Sepsis is a systemic inflammatory response (SIRS) with associated organ dysfunction as a result of an infection.
- Sepsis is defined as ≥2 of the criteria:
- Temperature >38 ºC or <36 ºC
- Heart rate of >90 bpm
- Respiratory rate of >20 breaths/minute or pCO2 of <32 mmHg
- WBC >12,000 cells/mL or <4000 cells/mL
- Initial management of sepsis includes:
- Intravenous fluids (LR/NS) 30 mL/kg (based on total body weight) administered within the first 3 hours.
- Empiric antibiotic therapy based on the common bacteria and site of infection initiated within the first hour.
- Per the Surviving Sepsis guidelines, IV hydrocortisone is recommended for patients at least 4 hours after initiation of norepinephrine/epinephrine ≥0.25 mcg/kg/min to maintain a MAP of ≥65 mmHg.
Pharmacology
| Hydrocortisone | Methylprednisolone | Fludrocortisone | |
| Dose | IV: 50 mg Q6H or 100 mg Q8H x 5-7 days | IV (succinate): 40 to 125 mg/day (maximum of 1 to 2 mg/kg/day) | PO (in addition to another glucocorticoid): 0.05 mg/day x 7 days |
| Administration | IV: over ≥30 seconds | IV: over several minutes or over 15 to 60 minutes as an infusion | Administer by NG tube |
| PK/PD | -Onset of action (IV): 1 hour -T ½ elimination (IV): 2 +/- 0.3 hours | -Onset of action (IV): 1 hour -T ½ elimination (IV): 0.25 +/- 0.1 hour | -Onset of action (PO): 1-2 hours -T ½ elimination (PO): ~3.5 hours |
| Mechanism of Action | -Anti-inflammatory (decreased synthesis and release of inflammatory mediators) -Immunosuppressive (decreased response to hypersensitivity reactions) -Antiproliferative: vasoconstriction and decreased permeability of WBC to the injury | -Same mechanism of action as hydrocortisone with a 4-5x greater potency | – Mineralocorticoid activity > hydrocortisone or methylprednisolone |
| Adverse Effects | -Cardiovascular: increased blood pressure -Endocrine: fluid retention, hyperglycemia, weight gain -Gastrointestinal: increased appetite -Psychiatric: altered behavior | -Similar adverse effects as hydrocortisone | -Higher risk of fluid retention, hypertension, and decreased electrolyte concentrations |
| Drug Interactions and warnings | –Warnings: adrenal suppression, immunosuppression (higher doses for increased duration of therapy), psychiatric changes -Drug Interactions: antacids (separate by 2 hours), live vaccinations, DDAVP (risk of hyponatremia), succinylcholine | -Warnings: adrenal suppression, acute hepatitis (rare) -Drug Interactions: similar to hydrocortisone and fludrocortisone | -Warnings: patients with underlying hepatic dysfunction, myasthenia gravis, systemic sclerosis, or thyroid disease -Drug Interactions: similar to hydrocortisone and methylprednisolone |
| Compatibility | Drug in Solution: None tested | Drug in Solution: -Compatible: D5W- ½ NS, NS -Incompatible: D5W, D5NS, LR | N/A |
Overview of Evidence
| Author, year | Design/ sample size | Intervention & Comparison | Outcome | |
| French Trial Annane D, 2002. | RCT (n = 300) | hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days. | 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events. | |
| Teng-Jen Yu, 2009. | RCT (n = 40) | Hydrocortisone 50 mg IV Q6H or methylprednisolone 20 mg Q12H x 7 days | -Higher survival rates with hydrocortisone vs methylprednisolone | |
| VANISH Gordan, 2016 | RCT (n = 1400) | Vasopressin vs. norepinephrine plus hydrocortisone vs. placebo | No significant difference in mortality at 28 days, but vasopressin plus hydrocortisone was associated with faster reversal of shock and reduced need for renal replacement therapy | |
| Gibbison B, 2017. | Systematic review & meta-analysis (n = 33 clinical trials) | Systemic treatment with any corticosteroids | -Decreased septic shock reversal with methylprednisolone vs hydrocortisone -Increased 28-day mortality with methylprednisolone vs dexamethasone -Decreased risk of superinfections with methylprednisolone –Decreased ICU mortality and LOS with methylprednisolone | |
| CORTICUS Sprung, 2018 |
RCT, (n=499) | Hydrocortisone 50 mg every 6 hours vs. placebo | The study found no significant difference between the two groups in 28-day mortality, but hydrocortisone was associated with a higher rate of shock reversal and a lower rate of progression to multiple organ dysfunction syndrome. | |
| HYPRESS Key, 2018 | RCT (n = 380) | Infusion of hydrocortisone 200 mg daily for five days followed by tapering until day 11 vs placebo | The study found no significant difference between the two groups in the primary outcome of time alive and free of vasopressor support by day 7 The study also found no significant difference between the two groups in secondary outcomes such as mortality at 28 days, ICU-free days, and hospital-free days | |
| ADRENAL Venkatesh B, 2018. | RCT (n = 3800) | Hydrocortisone 200 mg IV daily | -No difference in 28 or 90-day mortality with hydrocortisone –Decreased time to resolution of septic shock and discharge from the ICU with hydrocortisone -Decreased number of patients received a blood transfusion with hydrocortisone -Higher number of adverse events with hydrocortisone | |
| APROCCHHSAnnane D, 2018. | RCT (n = 1280) | -Hydrocortisone 50 mg IV Q6H + fludrocortisone 50 mcg PO daily in AM x 7 days -Drotrecogin alfa -Combination therapy of the three medications | –Decreased 90-day mortality with hydrocortisone + fludrocortisone -Decreased mortality with hydrocortisone + fludrocortisone at ICU and hospital discharge -Decreased time to discontinue vasopressor therapy and mechanical ventilation and achieve a SOFA score of <6 with hydrocortisone + fludrocortisone | |
Conclusions
- Per the Surviving Sepsis guidelines, hydrocortisone is recommended first-line for the treatment of septic shock in patients that are refractory to fluid (volume) resuscitation.
- Hydrocortisone portrayed greater efficacy in clinical trials than methylprednisolone.
- There are no clinical trials for the comparison of hydrocortisone monotherapy versus hydrocortisone + fludrocortisone; however, it is hypothesized that hydrocortisone provides sufficient mineralocorticoid activity as monotherapy without the increased risks of adverse effects with the addition of fludrocortisone.
- Necessary to avoid fludrocortisone in specific patient populations (i.e. congestive heart failure, hepatic and renal disease, etc.)
References
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