The Controversies of Corticosteroids in Sepsis
- Oct 10th, 2016
- Brit Long
Author: Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Jamie Santistevan, MD (@Jamie_Rae_EMdoc, Admin and Quality Fellow at UW, Madison, WI) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Medical Center / Parkland Memorial Hospital)
A 54-year-old male with a history of recent antibiotic therapy is currently being managed for pneumonia with IV antibiotics including cefepime, levofloxacin, and vancomycin. Despite 6L of IV fluids and norepinephrine at 20 micrograms/minute IV infusion, his blood pressure remains at 70/42, with a heart rate of 112. Bedside US reveals a hyperdynamic heart and IVC 2 cm in size. His electrolytes reveal a sodium of 135 and potassium of 4.9. What could you be missing? Should you start corticosteroids? What about the side effects?
Sepsis is a condition emergency providers manage daily, with over 750,000 septic patients seen in the emergency department (ED) per year.1-4 Septic shock is severe, with mortality ranging from 20% to 70%.1-4
Sepsis management requires rapid diagnosis, early administration of intravenous (IV) fluids with broad-spectrum antimicrobials, and source control. Early Goal-Directed Therapy (EGDT) first brought these elements to the forefront of emergency medicine,5 with further modifications in the ProCESS, ARISE, and ProMISe trials.6-9 Specific components of sepsis management remain essential including fluid resuscitation, broad-spectrum antimicrobials, and vasopressors.6-9
The systemic response of sepsis includes pro-inflammatory pathways and cytokines. Corticosteroids can act to attenuate these inflammatory molecules, suggesting a possible role for corticosteroid use.3,10 Vasomotor tone may decrease in septic shock, and corticosteroids can improve vascular function and organ perfusion.3,10
Septic shock can be associated with relative adrenal insufficiency, in which a patient’s endogenous cortisol levels are not sufficient to maintain hemodynamic status. Studies demonstrate conflicting results with steroid use in these patients. The role of corticosteroid therapy in patients with vasopressor-resistant septic shock remains controversial, specifically whether corticosteroids reduce mortality or reduce time of shock and vasopressor need. Despite recent meta-analyses, no clear guidance exists on corticosteroid indications and which patients truly benefit.11-17
Sepsis and the Hypothalamic–Pituitary–Adrenal (HPA) Axis
Sepsis has many effects on the body, including the HPA axis. The hypothalamus is responsible for stimuli integration and secretion of corticotropin-releasing hormone (CRH) during times of stress.10,11,16,17 This secretion of CRH results in initiation of adrenal corticotropin hormone (ACTH) synthesis in the anterior pituitary. ACTH results in cortisol production from the adrenals, with the entire system regulated through feedback. Severe sepsis and septic shock result in decreased albumin and corticosteroid binding proteins, which decrease total cortisol.16,17
Normal serum cortisol levels vary based on stress and time of day, ranging from 5 to 24 mcg/dL. Levels may reach 50 mcg/dL during periods of peak stress.16-21 Critical illness affects cortisol through multiple mechanisms.17,20-23
|Physiologic Stress and Cortisol Effects|
|– Reduced cortisol breakdown, resulting in increased levels and decreased production.
– Increased cortisol due to decreased breakdown in the setting of renal dysfunction.
– Cortisol binding globulin and albumin decrease, increasing free cortisol.
– Cytokines with inflammatory effects increase steroid receptor affinity, decrease steroid inactivation, and increase peripheral production of cortisol.
Relative adrenal insufficiency is based on several factors. First, stress results in cortisol increase, and as stress increases, cortisol level increases. The incidence of relative adrenal malfunction can approach 50% in severe sepsis and septic shock, due to impaired glucocorticoid and vasopressin production and dysregulated cortisol response.11-17 Medications such as etomidate, antifungals, and chronic steroid use act to decrease intrinsic corticosteroid production and affect protein binding.24,25
Septic Shock and Steroids
Steroids have been utilized in the treatment of septic shock for over 50 years.26-33 From the 1950s to the 1980s, high-dose steroids such as methylprednisolone 30 mg/kg or dexamethasone 3-6 mg/kg were used to treat patients in septic shock.30-33 Schumer et al. compared high dose corticosteroids versus normal saline, finding patients in the normal saline group experienced higher mortality.28 However, the mid-1980s ushered in several trials that did not demonstrate improved mortality in high-dose steroids.34-36 Cronin et al. found increased rate of morbidity and mortality in the high-dose steroid groups.37 Specific subpopulations in these studies experienced harm with high-dose steroids, bringing to a close this therapy.
In the 1990s, physiologic-dose steroids for patients in septic shock demonstrated trends towards improved mortality. Two of the most commonly quoted studies include the Annane and CORTICUS trials. Annane et al. randomized 300 patients with septic shock within 8 hours of diagnosis to hydrocortisone 50 mg IV every 6 hours with fludrocortisone 50 micrograms for 7 days versus placebo.38 All patients underwent a 250 microgram IV ACTH stimulation to evaluate for adrenal dysfunction, which the investigators defined as < 9 microgram/dL increase in total cortisol at 60 minutes. The primary endpoint included 28-day survival for the ACTH nonresponders, with secondary outcomes of total mortality, length of vasopressor requirements, and adverse events from steroid treatment. Low-dose steroid therapy was associated with improved mortality (28-day mortality 53% in steroid group versus 63%), which is based on an adjusted analysis, with no change in adverse events between groups. However, analysis of the complete data set suggests no mortality benefit for steroids. The 28-day mortality rate was not significantly decreased in ACTH stimulation test nonresponders.38 Median time to vasopressor withdrawal was decreased in the steroid group (7 versus 10 days). Oppert et al. suggested improved shock reversal and decreased cytokines in patients treated with hydrocortisone 50 mg IV, followed by 0.18 mg/kg/hr IV infusion.39
These studies were followed by meta-analyses suggesting reduced mortality with physiologically dosed steroids, which found improved hemodynamic effects with corticosteroids at physiologic-doses.40-42 The CORTICUS trial released in 2008 slowed the momentum of support for low-dose steroids.43 This study was a multicenter, prospective, double-blind trial of patients randomized to receive hydrocortisone 50 mg IV every 6 hours versus placebo. Patients were included only if they experienced hypotension for > 1 hour, with primary outcome 28-day mortality in ACTH nonresponders. Investigators in this study found no difference between hydrocortisone and placebo groups in 28-day mortality (39% versus 36%, respectively).43 Similar to Annane et al., the CORTICUS trial found reduced time to shock reversal with hydrocortisone, but higher rates of hyperglycemia, hypernatremia, and superinfection were found in the steroid group.38,43,44
|Study||Patients Included||Definition of shock||Intervention||Outcome||Secondary Outcome|
|Annane||300 adults with onset of shock within 8 hours, higher illness severity (SAPS II score)
All had short corticotropin test
|Sepsis with SBP < 90 mm Hg despite fluid replacement, >5ug/kg dopamine or current treatment with epinephrine/ norepinephrine, lactate > 2 mmol/L, need for mechanical ventilation, within 3 hours of onset||Hydrocortisone 50 mg IV every 6 hours for 1 week with fludrocortisone 50 mcg once daily for 1 week vs. placebo||Improved 28-day survival distribution from randomization in nonresponder short corticotropin test: median time to death 12 vs 24 days,
hazard ratio 0.67; 95% C.I. 0.47-0.95, P=0.02, NNT 7 (95% C.I. 4-49)
No statistical difference mortality in ACTH responders, 53% vs. 61% P=0.96, or all patients, 61% vs. 55%
|Median time to vasopressor withdrawal in nonresponders: 7 days in treated group, 10 days in placebo group|
|CORTICUS||499 adults with onset of shock within 72 hours, lower illness severity||Sepsis and shock defined by SBP < 90 mm Hg despite 1 hour of fluid resuscitation or need for vasopressors, organ dysfunction attributable to shock||Hydrocortisone 50 mg IV every 6 hr, tapering from day 6 to day 12 vs. placebo||No change in 28-day mortality in nonresponders: 39.2% in hydrocortisone vs. 36.1% in placebo group, not statistically different.
|No difference in 28-day mortality in short corticotropin responders or all patients.
Reduction in time to shock reversal with hydrocortisone. 3.3 days vs. 5.8 days
Nonsignificant increase in superinfections in hydrocortisone group: 33% vs. 26% (95% CI 0.96-1.68)
Corticosteroids may not decrease mortality at physiologic doses, but they do possess important effects. Patients with septic shock given corticosteroids demonstrate decreased need for vasopressors, which has the potential benefit of improving peripheral vascular recovery and organ function.11-15,38,42 Sligl et al. in 2009 found no statistical difference in mortality (42.2% [369 of 875 patients] vs. 38.4% [384 of 1001]; RR, 1.00; 95% CI, 0.84-1.18), but did find a change in incidence of shock reversal at 7 days in the steroid versus placebo groups (64.9% [314 of 484 patients] vs. 47.5% [228 of 480]; RR, 1.41; 95% CI, 1.22-1.64) and no increase in superinfection.14 Wang et al. in a 2014 meta-analysis found low dose hydrocortisone therapy decreased shock at 7 and 28 days, with no change in mortality.45 Faster time to shock reversal but no mortality benefit has been observed in another meta-analysis.46
Steroid Adverse Events
Corticosteroids affect multiple organ systems, and excess amounts are associated with adverse events including hyperglycemia, secondary infection from immunosuppression, delayed healing, skin breakdown, and muscle weakness.14,43,46-48 The CORTICUS trial suggested an increase in infection, with relative risk 1.27 (95% CI 0.96-1.68).43 However, this risk is not statistically different among the groups. Other meta-analyses do not suggest any increase in superinfection with corticosteroids.43
Elevated blood sugar is common, specifically as the dose of steroids increases.47,48 Episodes of hyperglycemia may cause harm, but treating hyperglycemia with insulin increases risk of hypoglycemia. Other issues with steroids include decreased skin integrity and delayed healing, though these are seen in high-doses. ICU patients may experience increased risk of critical illness myoneuropathy, prolonged weakness, increased length of stay, and prolonged mechanical ventilation.47,48
Many of these risks are not significant with physiologic-dose steroids, and they are more relevant to critical care physicians, rather than the ED.
What about evaluating adrenal function?
A great deal of controversy surrounds measuring adrenal function. Cortisol levels drastically change hour to hour due to corticosteroid-binding protein levels and activity, albumin production, and cortisol production during illness.21,49-52 Total cortisol levels are usually measured, though only free cortisol is active. Thus, total cortisol levels are difficult to interpret.49-52 Literature repeatedly demonstrates random serum cortisol is not beneficial due to wide range of baseline levels. Free cortisol may accurately reflect HPA axis activity, but studies do not support correlation of plasma levels with true tissue levels.
Evaluating adrenal function classically entails drawing baseline cortisol levels, administration of cosyntropin (or corticotropin), and reassessment of cortisol at 30 and 60 minutes. Low dose stimulation test uses cosyntropin 1 microgram IV, while high dose uses 250 micrograms IV. However, patients undergoing high dose testing demonstrate response even if they possess adrenal insufficiency due to the high dose of cosyntropin.50 Studies suggest the low dose testing may be more sensitive in diagnosing adrenal insufficiency, though sensitivities for diagnosing adrenal insufficiency approximate 50%. Patients with less than 9 mcg/dL response have greater mortality, along with those with higher baseline levels (34 mcg/dL).56,57
However, testing adrenal function via ACTH stimulation tests in critically ill patients is not reliable. Some patients demonstrate cortisol response > 9 mcg/dL with no cosyntropin administration, questioning this threshold.50,57-61 Many laboratories use immunoassay tests that are not available in many institutions and take days to result, along with poor correlation with gold standard mass spectrometry. At this time, these tests are not reliable for ED use and are even questionable for the ICU.57-60
Steroid Considerations in the ED
The Surviving Sepsis Guidelines advise consideration of corticosteroids for septic shock refractory to fluids and vasopressors.2 They do not recommend the use of corticotropin testing.2 Steroids can improve hemodynamic status, but literature does not support mortality benefit.11-15,38,40,43 Steroids can be used to reduce duration of septic shock in fluid and vasopressor-resistant hypotension.11-15,38,43 However, steroids are associated with side effects including hyperglycemia, myopathy, and electrolyte derangements.47,48
In septic shock, rapid diagnosis and management is integral with antimicrobials, source control, and IV fluid resuscitation. Vasopressors should be used when fluids do not increase MAP above 65 mm Hg.2,10 If the patient does not respond to these treatments, providers should evaluate for steroid indications including patient chronic baseline steroid use, chronic adrenal insufficiency, and refractory hypotension. Patients responsive to fluids and/or vasopressors receive little benefit, if any, from steroids. Contraindications should be considered including potential risk of worsening myopathy, DKA, HIV, TB, recent surgery or open wounds, and active peptic ulcer disease. If these are present, steroids should be avoided if possible. Other considerations include patient physiologic reserve (presence of other comorbidities, response to treatment, and exposure to other adrenal-suppressing agents such as etomidate).
Regimens for corticosteroids include hydrocortisone 100 mg IV every 8 hours or 50 mg IV every 6 hours. Another option is 100 mg IV bolus followed by infusion of 0.18 mg/kg/hr IV. These regimens have not been compared directly. Fludrocortisone is not advised at this time, as the COIITSS study demonstrated increased risk of infection with fludrocortisone in conjunction with corticosteroids.61 The ADRENAL study is currently underway, comparing low-dose corticosteroids in ICU septic shock, with primary outcome of mortality at 90 days.62
– Sepsis management requires early recognition, fluid resuscitation, source control, broad spectrum antimicrobials, and vasopressors for those not responsive to IV fluids.
– Patients with septic shock unresponsive to fluid and vasopressor resuscitation warrant further management and consideration of other disease states.
– The pathophysiology of sepsis may include loss of vasomotor tone and relative adrenal insufficiency.
– High-dose corticosteroids may result in patient harm, but physiologic, or low-dose, corticosteroids may be used to decrease the need for vasopressors.
– Most current meta-analyses do not demonstrate a mortality benefit with steroids. The Surviving Sepsis Guidelines advise consideration of corticosteroids in patients with vasopressor and fluid resistant septic shock.
– Corticosteroids may decrease need for vasopressors and improve perfusion.
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