What is the current role for corticosteroids in critical care?

73 What is the Current Role for Corticosteroids in Critical Care? Craig Lyons and Leo G. Kevin

INTRODUCTION Corticosteroids are commonly used in critical care. The merits of these drugs are fully established in some disease states, such as an adrenal crisis, anaphylaxis and vasculitic crises; however, there are several conditions that are regularly seen in the critical care unit where corticosteroid treatment is the subject of debate, controversy and ongoing clinical trials. In this chapter, we examine the evidence-base in those critical illnesses for which corticosteroid use is particularly contested, namely septic shock, acute respiratory distress syndrome, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, acute severe asthma, and traumatic spinal cord injury (TSCI).

SEPTIC SHOCK In 1976, William Schumer published the first trial comparing use of methylprednisolone (30 mg/kg) or dexamethasone (3 mg/kg) with placebo.1 Both regimens were associated with a substantial reduction in mortality (methylprednisolone— 1.6%; dexamethasone—9.3%; placebo—38.4%). In the 1980s however, four randomized controlled trials of varying design failed to validate a mortality benefit and instead suggested potential for harm. All used high-dose regimens, typically methylprednisolone 30 mg/kg.2–5 In the 1990s, with growing interest in the phenomenon of relative adrenocortical insufficiency during critical illness, and in use of “low-dose” corticosteroids to mitigate this, four small randomized controlled trials totaling 165 patients, demonstrated faster shock reversal with use of low-dose hydrocortisone.6–9 These findings reignited the debate regarding the merits of corticosteroids in septic shock and prompted a number of large-scale trials for the new millennium. The first of these, from Annane et al., randomized 300 patients with septic shock to receive either placebo or 50mg hydrocortisone every 6 hours, plus fludrocortisone 50 µg daily for 7 days.10 Twenty-eight day mortality was reduced in those patients who received corticosteroids (55 vs. 61%). A subgroup analysis isolated the mortality benefit to those patients with inadequate adrenal reserve on the basis of their response to an ACTH stimulation test. This prompted the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.11

CORTICUS randomized 499 patients with septic shock to receive 50 mg hydrocortisone or placebo every 6 hours for 5 days, after which the dose was tapered. Corticosteroid administration did not reduce 28-day mortality, irrespective of the response to ACTH stimulation. 2018 saw the publication of two large randomized controlled trials, the “Hydrocortisone plus Fludrocortisone for Adults with Septic Shock” (APROCCHSS) trial,12 and the “Adjunctive Glucocorticoid Therapy in Patients with Septic Shock” (ADRENAL) trial.13 These offer the most informative evidence to date of corticosteroid use in septic shock, but their divergent results fail to offer a definitive direction for clinical practice. In APROCCHSS, a combination of hydrocortisone 50 mg every 6 hours and 50 mcg enteral fludrocortisone were administered for 7 days without tapering. The intervention arm had a reduction in 90-day mortality compared to placebo (43 vs. 49.1%). Secondary outcomes were also in favor of corticosteroid use, with patients weaned more quickly from mechanical ventilation and vasopressor therapies. Hyperglycemia was more commonly observed in the steroid arm but other side effects occurred at a similar rate in both groups. ADRENAL randomized 3800 patients with septic shock who required mechanical ventilation to receive 200 mg hydrocortisone per day by continuous infusion, or placebo, for 7 days. Ninety-day mortality was 27.9% in the hydrocortisone group and 28.8% in the placebo group (OR 0.9; 95% confidence interval 0.82–1.10, P 5 .50). No mortality difference was observed in six prespecified groups: admission type (medical vs. surgical), gender, APACHE II score (,25 vs. 25), duration of shock at time of randomization, and dose of catecholamine infusions (norepinephrine or epinephrine at doses of ,15 µg/min or .15 µg/min). Interestingly, however, there were advantages of hydrocortisone in some secondary outcomes: resolution of shock occurred more rapidly (median 3 days vs. 4 days), there was a lower incidence of blood transfusion (37.0 vs. 41.7%) and there was a shorter time to discharge from the intensive care unit (10 days vs. 12 days), although time to hospital discharge was not different between groups. Based on current evidence, chiefly the ADRENAL trial by magnitude of patient enrolment, and a 2018 metaanalysis,14 it can be concluded that corticosteroids do not reduce 529

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mortality in patients with septic shock. There are some caveats, however. Patients in APROCCHSS were sicker, requiring much higher doses of vasopressors at enrolment, perhaps pointing to a specific subgroup that does benefit. The role for fludrocortisone remains unclear and it is not widely used. Where these two trials agree is in the finding that corticosteroid treatment favorably alters the course of disease and does not appear to increase the risk of myopathy, infections or wound dehiscence. Some clinicians may reasonably seek to justify corticosteroid administration for the reported secondary benefits, all of which may improve resource utilization. A separate question is whether corticosteroids have the potential to prevent the development of shock in septic patients. This was examined in the HYPRESS trial, where 200mg hydrocortisone was given for 5 days and then tapered.15 No difference was found in rates of progression to septic shock (21.2 vs. 22.9%) or 28-day mortality (8.8 vs. 8.2%).

ACUTE RESPIRATORY DISTRESS SYNDROME The first report of acute respiratory distress syndrome (ARDS) in 1967 proposed a role for corticosteroids,16 but more than 50 years later, their role in this condition remains unresolved. Several trials have been performed, some focusing on preventing the development of ARDS in at-risk patients, others on improving outcomes in the early phase of the disease, and still others at preventing lung fibrosis later on. Interpretation of this literature is complicated by differences in selected corticosteroid, in the duration and dose of corticosteroid treatment, and in the variable inclusion of patients with septic shock. Moreover, since the publication of many of these trials, there have been major changes in the definition of ARDS and in many aspects of critical care management, particularly mechanical ventilation strategies.

Prevention of ARDS Four randomized controlled trials have tested methylprednisolone in the prevention of ARDS in at-risk patients. When subjected to metaanalysis they pointed to an increased, rather than a decreased, risk of ARDS, and a higher risk of mortality in those who subsequently developed ARDS.17

Treatment of Established ARDS In 1987 Bernard et al. randomized 99 patients with ARDS to a short course of high-dose methylprednisolone (30 mg/kg every 6 hours for 4 doses) or placebo.18 The mean interval between the clinical onset of ARDS and entry to the trial was 31 hours. At 45 days, there were no differences between the groups in measures of gas exchange, lung mechanics or mortality. Importantly, there was also no evidence of increased infection in the corticosteroid group. Interest in use of high dose corticosteroids to treat ARDS waned, although the question of longer treatments and lower doses remained to be tested. In 2006, a retrospective analysis of patients with ARDS in a sepsis trial, where patients were treated with hydrocortisone, pointed to improved survival and an increase in ventilator-free days10,19; however, these benefits occurred only in

those patients who had failed a corticotropin stimulation test. Furthermore, patients in the treatment group were given fludrocortisone in addition to hydrocortisone. Meduri et al. then reported a randomized controlled trial in which a long course of low-dose methylprednisolone was given to patients within 72 hours of disease onset.20 Intensive care mortality was 20.6% in the treatment group vs. 42.9% in the placebo group (P 5 .03); however, the trial comprised only 91 patients, and there were striking between-group differences at baseline, most notably in the rate of catecholamine-dependent shock which was much higher in the placebo group.

Late Treatment in Persistent ARDS Meduri et al. administered methylprednisolone 2 mg/kg per day (tapered from day 14) or placebo to patients with ARDS who had been ventilated for at least 7 days without evidence of improvement.21 The trial was stopped early after only 24 patients, when none of 16 patients in the methylprednisolone group had died compared to 5 out of 8 patients in the placebo group. There were also improvements in oxygenation and lung mechanics, and less organ dysfunction. The NIH NHLBI ARDS Network then trialed the same protocol in 180 patients.22 Once again, compared to patients in the placebo group, those in the methylprednisolone group showed improvements in oxygenation and lung mechanics. Moreover, they liberated from mechanical ventilation sooner (14 days vs. 23 days), although they were later more likely to need a return to assisted ventilation (28 vs. 9%). Most importantly however, on this occasion methylprednisolone gave survival benefit. Also of note, in the subset of patients randomized 14 or more days after the onset of ARDS, those in the methylprednisolone group had a higher mortality, suggesting that corticosteroid treatment might be harmful if started late in the course of the disease.

COMMUNITY ACQUIRED PNEUMONIA Corticosteroids are widely used in the treatment of community acquired pneumonia (CAP) albeit without a strong evidence base. Blum et al. published the largest RCT on steroid use in CAP in 2015, randomizing 785 patients to receive either 50mg prednisolone daily or placebo for 7 days.23 The primary endpoint, time to attainment of stable vital signs, was achieved more quickly in the corticosteroid group (3 days vs. 4.4 days). Median time to discharge from hospital was 1 day shorter but there was no reduction in mortality. Patients with severe disease were inadequately represented, limiting generalizability of results to critically ill patients with CAP. Indeed, there is little data pertaining specifically to severe CAP. Torres et al. assessed benefit of a 5-day course of methylprednisolone in patients with CAP, 73% of whom were classified with Pneumonia Severity Index class IV or V, a larger representation of such patients than in most studies.24 A composite primary outcome of treatment failure, which was typically diagnosed by radiographic progression of pneumonia, occurred less commonly in those patients receiving methylprednisolone (13 vs. 31%).

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A metaanalysis of relevant trials of CAP of all grades did not demonstrate a mortality benefit, although there were reductions in time to clinical stability and in lengths of critical care and hospital stay.25 A further metaanalysis isolated a survival benefit to the subgroup of patients with severe pneumonia.26 Corticosteroid benefits, if they exist, may be partly dependent on the infecting pathogen. Although the evidence is of low-grade, corticosteroid therapy is standard at treatment initiation for Pneumocystis jiroveci pneumonia,27,28 whereas potential harm is reported in viral pneumonia.29,30 In summary, corticosteroid therapy does not have an established place in treatment of pneumonia although there is some evidence of benefits in those with severe disease. The Extended Steroids in CAPe (ESCAPEe) trial (NCT01283009), currently in progress, aims to provide more clarity to this question.

ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Corticosteroid administration during acute exacerbations of chronic obstructive pulmonary disease (COPD) improves indices of pulmonary function in the first 72 hours of therapy and shortens hospital stay, but there is little evidence that it reduces mortality.31 Of note, the majority of patients in trials of corticosteroid therapy for COPD exacerbation do not have an illness severity sufficient to warrant critical care admission. Indeed, some trials regard it as an exclusion criterion. There is conflicting evidence from the few trials that focused specifically on critically ill patients. Some have found less progression to invasive mechanical ventilation and shorter duration of invasive ventilation in corticosteroid treated patients,32 whereas others have not.33 Guidelines issued by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) advise the use of 40 mg prednisolone daily or equivalent for 5 days.34 The American Thoracic Society recommends therapy up to 14 days in duration.35 Evidence for a short course comes from the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial, which compared 40 mg prednisolone daily for 5 vs. 14 days.36 No difference was observed in measures of lung function or in the likelihood of further exacerbation within 6 months. Patients with a higher eosinophil count may represent a subpopulation more likely to derive benefit from steroid therapy.37

ACUTE SEVERE ASTHMA Systemic corticosteroid administration accelerates improvements in airflow limitation in patients with acute asthma who are failing to respond to standard bronchodilator therapy, although published studies are underpowered to detect a mortality benefit.38,39 Administration within 1 hour of emergency department admission is recommended. Patients who have not been receiving steroids preadmission seem to derive greater benefit.40

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High doses provide no advantage over lower doses,41 whilst oral and intravenous routes of administration are equally effective.42,43 Likelihood of relapse appears similar for 5 and 10 day courses.44 In practice, patients with severe or life-threatening exacerbations typically receive corticosteroids intravenously and for a longer duration. This is at least partly related to concerns that these groups have been underrepresented in controlled trials. Various recommendations exist, including hydrocortisone 100 mg 6-hourly and prednisolone 40–50 mg daily for 5 days.45

TRAUMATIC SPINAL CORD INJURY Evidence for corticosteroids in TSCI comes largely from the National Acute Spinal Cord Injury Studies (NASCIS) II and III, published in 1990 and 1997, respectively.46,47 NASCIS II randomized 487 acute TSCI patients to receive methylprednisolone or placebo. Methylprednisolone was administered as a 30 mg/kg bolus followed by maintenance infusion of 5.4 mg/kg per hour for 23 hours. There was no significant difference in neurological outcomes between the groups46; however, a posthoc analysis showed improved motor function in those patients who had received methylprednisolone within 8 hours of injury.48 In response to this, NASCIS III randomized 499 patients to receive methylprednisolone within 8 hours of injury and then for either 24 or 48 hours. For patients that received their steroid bolus within 3 hours of injury, there was no difference in outcomes at 1 year between groups. For patients treated between 3 and 8 hours after injury, those who received 48 hours of methylprednisolone attained greater motor but not functional recovery. They also had a higher incidence of severe pneumonia, whilst mortality was unchanged.47 There was some, but not universal adoption of corticosteroids for spinal cord injuries. Much skepticism remains. Major problems concerning the statistical analysis of the NASCIS data have been identified,49 and there is the obvious lack of a placebo group in NASCIS III. Recent metaanalyses provide no support for routine use of corticosteroids and indeed raise concerns about serious adverse effects.50 Current US guidelines expressly discourage use of corticosteroids in TSCI.51

CONCERNS REGARDING CORTICOSTEROID USE Accepted adverse effects of corticosteroids in critically ill patients include hyperglycemia and electrolyte disorders. Less certain, but more concerning, adverse effects include gastrointestinal bleeding, muscle weakness and increased secondary infections. An early report of severe muscle weakness in asthmatic patients treated with corticosteroids and muscle relaxants52 had a profound impact on the use of both these drug classes in critically ill patients, particularly in combination. Animal studies confirm an effect of corticosteroids on skeletal muscle.53 The recent, large trials of corticosteroids in critically ill patients offer inconclusive and sometimes conflicting results on the question of these adverse events.

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For example, in both CORTICUS11 and ADRENAL,13 there were insufficient cases of neuromuscular weakness reported to allow a firm conclusion while there were increased rates of secondary infections in CORTICUS but not in ADRENAL. Accepted practice is to limit duration of corticosteroid administration to as short a time as possible, particularly when muscle relaxants are coadministered.

AUTHORS’ RECOMMENDATIONS • Corticosteroids can be considered in septic shock, to aid reversal of shock. • Corticosteroids should not be given late in the course of ARDS (from 14 days). • Corticosteroids are recommended in acute severe asthma and acute exacerbations of COPD. Evidence does not indicate a mortality benefit but does support more rapid resolution of bronchospasm and there may be benefits in other outcomes. • Although widely used, there is no clear evidence of benefit from corticosteroids in community acquired pneumonia. • After much controversy, corticosteroids are not recommended in traumatic acute spinal cord injury. • Due to concerns about secondary infections and ICUacquired weakness, corticosteroid treatment duration should be limited, especially in patients also receiving muscle relaxants.

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10. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871. 11. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. 12. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008; 358(2):111-124. 13. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018; 378(9):797-808. 14. Rygård SL, Butler E, Granholm A, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2018;44(7):1003-1016. 15. Keh D, Trips E, Marx G. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016;316(17):1775-1785. 16. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967;2(7511):319-323. 17. Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ. 2008;336(7651):1006-1009. 18. Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med. 1987;317(25):1565-1570. 19. Annane D, Sébille V, Bellissant E, Ger-Inf-05 Study Group. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med. 2006;34(1):22-30. 20. Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. 21. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998; 280(2):159-165. 22. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684. 23. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385(9977):1511-1518. 24. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313(7): 677-686. 25. Wan YD, Sun TW, Liu ZQ, Zhang SG, Wang LX, Kan QC. Efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis. Chest. 2016;149(1):209-219. 26. Nie W, Zhang Y, Cheng J, Xiu Q. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLoS One. 2012;7(10):e47926. 27. Montaner JS, Lawson LM, Levitt N, Belzberg A, Schechter MT, Ruedy J. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1990;113(1):14-20.

CHAPTER 73 28. Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A double-blind, placebo-controlled trial. N Engl J Med. 1990; 323(21):1444-1450. 29. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. 30. Moreno G, Rodríguez A, Reyes LF, et al. Corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study. Intensive Care Med. 2018; 44(9):1470-1482. 31. Walters JA, Tan DJ, White CJ, Gibson PG, Wood-Baker R, Walters EH. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(9):CD001288. 32. Alía I, de la Cal MA, Esteban A, et al. Efficacy of corticosteroid therapy in patients with an acute exacerbation of chronic obstructive pulmonary disease receiving ventilatory support. Arch Intern Med. 2011;171(21):1939-1946. 33. Abroug F, Ouanes-Besbes L, Fkih-Hassen M, et al. Prednisone in COPD exacerbation requiring ventilatory support: an open-label randomised evaluation. Eur Respir J. 2014;43(3): 717-724. 34. Gold: UpToDate: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. 2018. Available at: http://www.goldcopd.org. Accessed September 24, 2018. 35. Wedzicha JA Ers Co-Chair, Miravitlles M, Hurst JR. Management of COPD exacerbations: a European Respiratory Society/ American Thoracic Society guideline. Eur Respir J. 2017;49(3): pii: 1600791. 36. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs. conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309(21):2223-2231. 37. Bafadhel M, Davies L, Calverley PM, Aaron SD, Brightling CE, Pavord ID. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J. 2014;44(3):789-791. 38. Lin RY, Pesola GR, Bakalchuk L, et al. Rapid improvement of peak flow in asthmatic patients treated with parenteral methylprednisolone in the emergency department: a randomized controlled study. Ann Emerg Med. 1999;33(5):487-494. 39. Fanta CH, Rossing TH, McFadden Jr ER. Glucocorticoids in acute asthma. A critical controlled trial. Am J Med. 1983; 74(5):845-851. 40. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with

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e1 Abstract: Corticosteroids are commonly used in critical care. The merits of these drugs are fully established in some disease states, such as an adrenal crisis, anaphylaxis and vasculitic crises; however, there are several conditions that are regularly seen in the critical care unit where corticosteroid treatment is the subject of debate, controversy and ongoing clinical trials. In this chapter, we examine the

evidence-base in those critical illnesses for which corticosteroid use is particularly contested, namely septic shock, acute respiratory distress syndrome, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, acute severe asthma, and traumatic spinal cord injury. Keywords: corticosteroids, critical illness, outcome