Name the potential indications for endogenous steroid administration in the critically ill patient population.
Describe the rationale for steroid administration in a given condition, based on the underlying pathophysiology.
Evaluate the evidence base for steroid administration and discuss existing controversies in the literature.
Appraise the benefits and potential harmful effects of steroid administration for a particular indication.
Steroids may be beneficial for a broad spectrum of critically ill patients, including those with cardiovascular, respiratory, and neurological conditions.
Clinicians should be aware of the potential indications for steroids and the properties of the agent selected.
Steroids may have significant adverse effects.When evidence is equivocal, clinicians must evaluate the benefits and risks to an individual patient before administering exogenous steroids.
Future research will clarify the role of exogenous steroids in current areas of controversy.Corticosteroids are a group of hormones produced by the cortex of the adrenal gland. Thomas Addison first attributed the deficiency of these steroid hormones to a disease process in 1855 when he described the physical symptoms related to the destruction of the adrenal gland secondary to tuberculosis.
The first documented therapeutic use of a corticosteroid was in 1948, when Philip Hench used synthetically produced cortisone (compound E) to treat a patient with rheumatoid arthritis. Over the subsequent 60 years the use of corticosteroids in medicine, including critical care, has become widespread. Interest in the potential benefits of the profound anti-inflammatory and immunosuppressant effects of exogenous corticosteroids has led to the exploration of their role across a broad spectrum of clinical scenarios.
However, steroid administration remains controversial within modern critical care. Whilst there are many postulated benefits of corticosteroids, the evidence is frequently lacking. It must be remembered that steroids are potent hormones with diverse physiological effects and adverse consequences; they can have a significant impact, both positive and negative, on a critically ill patient.
The adrenal cortex produces mineralocorticoids (e.g. aldosterone) and glucocorticoids (e.g. cortisol). Mineralocorticoids are involved in the control of water and electrolyte balance, whilst glucocorticoids have anti-inflammatory, immunosuppressive, and metabolic effects.
Cortisol is released as a function of the hypothalamic–pituitary–adrenal (HPA) axis. In health, the hypothalamus releases corticotrophin-releasing hormone (CRH) in a diurnal pattern, stimulating the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH, in turn, causes the release of cortisol from the zona fasciculata of the adrenal cortex. Cortisol has a subsequent negative-feedback effect on CRH and ACTH release. In times of stress, the HPA axis is activated, and the circulating ACTH and cortisol concentrations increase markedly. Prolonged exogenous steroid administration impairs the HPA axis, with suppression of endogenous cortisol release in patients who have been treated with the equivalent of 5 mg or more of prednisolone for over 4 weeks. 1 Tapering of exogenous steroids is required to allow the HPA axis to recover. Prolonged courses of steroids should not be suddenly stopped, as absolute steroid deficiency manifesting as an Addisonian crisis may result.
Exogenous corticosteroids have both glucocorticoid and mineralocorticoid effects to a varying degree of potency ( Table 1 ). 2 The properties of each individual therapeutic preparation should inform its use in critical care. Administered corticosteroids enter target cells, bind to glucocorticoid receptors in the cytoplasm, and then migrate into the nucleus where the activated receptor complex binds to DNA. This complex alters the proteins produced by the nucleus, changing the functions of the cell in a number of ways, including down-regulating the release of inflammatory mediators. The anti-inflammatory effects of glucocorticoids underlie the majority of their therapeutic uses ( Table 2 ).
Equivalent doses and comparison of glucocorticoid and mineralocorticoid potency of commonly used steroid preparations.
| Agent | Equivalent glucocorticoid dose (mg) | Relative glucocorticoid potency | Relative mineralocorticoid potency |
|---|---|---|---|
| Hydrocortisone | 100 | 1 | 1 |
| Prednisolone | 25 | 4 | 0.6 |
| Methylprednisolone | 20 | 5 | 0.25 |
| Betamethasone | 3.75 | 25 | 0 |
| Dexamethasone | 3.75 | 25 | 0 |
| Fludrocortisone | n/a | 10 | 125 |
| Aldosterone | n/a | 0 | 400 |
Indications for steroid administration in critical care
| Indication | Dose | Duration |
|---|---|---|
| Septic shock | Hydrocortisone 200 mg 24 h −1 i.v. | Taper when vasopressors no longer required |
| Anaphylaxis | Hydrocortisone 200 mg i.v. | Stat |
| Airway oedema | Methylprednisolone 40 mg i.v. | At least 4 h before extubation |
| Exacerbation of asthma | Prednisolone 40–50 mg daily oral or hydrocortisone 100 mg QDS i.v. | At least 5 days |
| Exacerbation of COPD | Prednisolone 30 mg daily oral | 7–14 days |
| Pneumocystis pneumonia in HIV-positive individuals | Prednisolone 40 mg BD oral or methylprednisolone 60 mg daily i.v. | Taper after Day 5 as guided by local expertise |
| Streptococcus pneumoniae bacterial meningitis | Dexamethasone 10 mg i.v. QDS | Four days |
| Raised ICP caused by cerebral tumour | Dexamethasone 16 mg oral daily | Taper when symptoms improve as per local guidance |
| Adrenal crisis | Hydrocortisone 100 mg i.v. then 200 mg 24 h −1 | Guided by endocrinologist |
| Myxoedema coma | Hydrocortisone 100 mg i.v. | Stat then guided by endocrinologist |
| Organ donor optimisation | Methylprednisolone 15 mg kg −1 (maximum 1 g) | Stat dose |
Patients receiving chronic corticosteroid therapy who undergo major surgery may require additional ‘stress dose’ steroids (i.e. their regular corticosteroid dose is supplemented with extra steroid). The use of stress dosing arises from the concept of patients being in a state of relative adrenal insufficiency because of exogenous steroid administration, so the HPA axis is unable to generate sufficient endogenous steroid to meet the physiological demands of a stressful situation. The benefits of the stress dose in preventing the complications of steroid insufficiency (cardiovascular collapse, electrolyte disorders, and hypoglycaemia) must be weighed against the risks of impaired wound healing and fluid retention that may worsen the surgical outcome.
Whilst many hospitals produce their own guidance, the British National Formulary advises perioperative steroid replacement for any patient that has been taking more than 10 mg prednisolone daily within the last 3 months. 2 The magnitude of the proposed surgery dictates the dose of steroid supplementation. Minor procedures may require hydrocortisone 25–50 mg i.v. on induction alone, whereas major surgery may require hydrocortisone at induction of anaesthesia, followed by ongoing supplementation over the next 48–72 h. The perioperative team should produce an individualised plan for steroid supplementation in all patients when relevant and any unexplained perioperative hypotension should prompt consideration of steroid replacement if this has not already occurred.
Corticosteroids have been used in septic shock to improve cardiovascular function in the hope of reducing patient mortality. The benefits and adverse effects of steroid use in septic shock have been a controversial subject for many years. The role of relative adrenal insufficiency has also been closely examined with attempts to stratify patients into those with adequate adrenal reserve and those without, despite the difficulty in assessing the physiology of cortisol in critically ill patients.
Two major trials examined the role of corticosteroids in septic shock in the early 2000s with differing results. Annane and colleagues found that early administration of steroids in vasopressor-unresponsive septic shock reduced mortality, specifically in the subset of patients with relative adrenal insufficiency 3 . Conversely, the Corticosteroid Therapy of Septic Shock study described no difference in mortality in any of the patient groups, despite faster reversal of shock. 4 There were, however, significant differences in recruitment patterns and severity of illness between the two trials, and issues highlighted over the methodology used. A third trial in 2016 (Hydrocortisone for Prevention of Septic Shock) found that the administration of hydrocortisone to patients with severe sepsis did not prevent the progression to septic shock. 5
The inconsistent results of these and other trials have led to difficulty in consequent meta-analysis, with contradictory conclusions on the benefits of steroid administration. Whilst acknowledging the conflicting data, the 2016 Surviving Sepsis Campaign guidelines recommend the daily administration of hydrocortisone 200 mg i.v. when adequate fluid resuscitation and vasopressor therapy do not restore haemodynamic stability; steroids should then be tapered when vasopressors are no longer required. The guidelines also state that steroids should not be administered if haemodynamic variables are maintained by conventional measures, and that attempting to identify inadequate adrenal reserve by measuring plasma cortisol concentrations and the response to a test dose of ACTH is not useful. 6
The results of the much anticipated Adjunctive Glucorticoid Therapy in Patients with Septic Shock (ADRENAL) trial were published in January 2018. This was the largest randomised controlled trial to date of steroid administration in patients with septic shock undergoing mechanical ventilation. Patients received either hydrocortisone 200mg/24 hours as an infusion or a placebo. There was no difference in mortality between the 2 groups at 90 days. However, the patients who received hydrocortisone had a faster resolution of shock and a shorter duration of mechanical ventilation so the debate regarding steroid use is likely to continue. 7
An intense systemic inflammatory response can occur after cardiopulmonary bypass caused by circulating blood coming into direct contact with the artificial surface of the extracorporeal circuit. Subsequent complications, including vasodilatory shock, organ dysfunction, and arrhythmias, can contribute markedly to morbidity and mortality. The administration of corticosteroids to suppress the inflammatory response has been proposed as a possible therapy to reduce the incidence of complications after surgery that requires cardiopulmonary bypass.
Two large trials reviewing the use of perioperative steroids in cardiac surgery have been completed in the past 5 yr: Dexamethasone for Cardiac Surgery 8 and Steroids in Cardiac Surgery. 9 Neither trial found an improvement in mortality or significant morbidity when steroids were administered as compared to placebo.
Corticosteroid administration is a cornerstone of treatment in anaphylaxis. It is used to shorten protracted reactions and to help prevent a biphasic reaction. A dose of hydrocortisone 200 mg i.v. is recommended by the Resuscitation Council (UK) and The Association of Anaesthetists of Great Britain & Ireland as part of the secondary treatment for anaphylaxis after adrenaline and i.v. fluid have been administered.
The presence of a tracheal tube may result in laryngeal oedema caused by irritation of the glottis and the subsequent inflammatory response. This can result in upper airway obstruction after tracheal extubation with symptoms of stridor and respiratory distress, and reintubation may be required which may in turn necessitate reintubation. Certain risk factors make severe laryngeal oedema more likely, such as prolonged intubation and recurrent airway instrumentation. In such patients, corticosteroid administration significantly reduces the risk of post-extubation stridor and consequent reintubation. 10
Of note, steroids must be administered at an appropriate time before planned tracheal extubation to allow for adequate effect; the American Thoracic Society recommends methylprednisolone 40 mg at least 4 h before extubation in patients who have failed a cuff-leak test. 11
Corticosteroids can be administered in acute exacerbations of both asthma and chronic obstructive pulmonary disease (COPD); they act to reduce the extent of airway inflammation and mucus plugging that complicates bronchospasm not relieved by beta-agonist therapy. Oral administration is as effective as i.v. injection.
The British Thoracic Society guidelines recommend that steroids are given as soon as possible to patients with an acute exacerbation of asthma. The dose is prednisolone 40–50 mg daily or hydrocortisone 100 mg i.v. every 6 h. This should be continued for at least 5 days.2, 12 In patients admitted to hospital with an exacerbation of COPD, the National Institute for Health and Care Excellence (NICE) CG101 advocates that prednisolone 30 mg once daily should be given for a duration of 7–14 days.
Acute respiratory distress syndrome (ARDS) is an inflammatory lung condition that results from either direct (e.g. pneumonia) or indirect (e.g. pancreatitis) lung injury. The pathophysiology is described as having three phases: exudative, proliferative, and fibrotic. Inflammation is central to the development of ARDS, and so the anti-inflammatory properties of steroids have been investigated extensively in an attempt to halt progression through these pathophysiological phases. The results have been mixed, with many studies showing no significant improvement in mortality or long-term outcomes. The timing of administration, duration of therapy, and type of steroid used have all been studied, with some recent data suggesting that prolonged methylprednisolone treatment reduces hospital mortality and increases ventilator-free days. 13 Despite this, the use of steroids in ARDS remains controversial and is not commonplace. The mortality from ARDS has declined in recent years and may in part be attributable to the use of strategies such as lung-protective ventilation. The ongoing multicentre Dexamethasone to Treat the Acute Respiratory Distress Syndrome trial, comparing dexamethasone with placebo in patients with ARDS receiving lung-protective ventilation, may help to clarify whether steroids are useful in these circumstances.
Nevertheless, corticosteroids should be given in patients of ARDS where steroid treatment is required to treat the primary underlying pathology, such as pulmonary vasculitic disease.
Pneumonia is a common condition in critical care, and despite advances in modern medicine, morbidity and mortality remain high: up to 30% of patients admitted to the Intensive Care Unit (ICU) with pneumonia will die. The anti-inflammatory properties of corticosteroids have long been proposed as a therapy for reducing the pulmonary and systemic inflammation in severe pneumonia. However, the available evidence is conflicting.
The current NICE guidelines (CG191, 2014) do not recommend routine corticosteroid administration to adult patients with community-acquired pneumonia (CAP). Since the publication of these guidelines, the results of further research have reignited debate in the respiratory and critical-care communities. Several meta-analyses published over the last 2 years have suggested that corticosteroid use reduces mortality and the incidence severe complications including the requirement for invasive ventilation and the development of ARDS. 14 However, these meta-analyses have included trials with low numbers of patients and significant heterogeneity, leading to the view that the evidence is currently inadequate for the routine use of steroids in CAP. 15 In addition, because the pathogenic aetiology of pneumonia is so varied, it is possible that the subsequent disease processes may not respond in a consistent fashion, making any beneficial effect of steroids extremely difficult to elucidate.
Several trials are ongoing in this area; studies are currently underway in France (Community Acquired Pneumonia: Evaluation of Corticosteroids), The Netherlands (Dexamethasone in Community Acquired Pneumonia), and the USA (Extended Steroid in Community Acquired Pneumonia), including specifically patients admitted to critical care that have been administered steroids after diagnosis of CAP.
Pneumocystis jirovecii pneumonia (PJP) is a type of pulmonary infection caused by the yeast-like fungus Pneumocystis jirovecii. The infection has a slow and indolent course, and may present with severe hypoxaemia that requires admission to a critical-care unit.
It is generally associated with patients who are immunocompromised and has typically been seen in Human Immunodeficiency Virus (HIV)-positive adults. Despite a decrease in infection rates in HIV patients, the incidence of PJP in the UK has increased over the last decade. This increase has been attributed to patients with haematological malignancy or who had received organ transplantation.
A meta-analysis has shown significantly reduced rates of mechanical ventilation and mortality in HIV-positive patients with PJP who are treated with adjuvant corticosteroids. 16 This is thought to be a consequence of a reduction in the inflammatory damage sustained as the organism undergoes necrosis. The data in non-HIV-infected patients are inconclusive and consist of retrospective cohort studies; consequently, international guidelines do not recommend the routine administration of corticosteroids to these patients, advising consideration on a case-by-case basis. 17 Furthermore, many of these patients may already be on high-dose corticosteroids for another indication.
Acute bacterial meningitis causes severe inflammation of the meninges and carries a mortality of over 10% of adult patients. In survivors, it can result in significant neurological damage, including hearing loss, cognitive impairment, and focal neurological deficits.
A Cochrane report in 2015 reviewed the effect of corticosteroids for bacterial meningitis, and concluded that the use of steroids reduced mortality when the condition was caused by Streptococcus pneumoniae, but not when attributed to Haemophilus influenzae or Neisseria meningitidis. In addition, hearing loss and neurological sequelae were significantly reduced in bacterial meningitis of any cause. 18 Consequently, in 2016, the UK joint specialist societies (including the Intensive Care Society) issued guidelines recommending that dexamethasone 10 mg i.v. QDS be commenced shortly before or simultaneously with antibiotics for the treatment of bacterial meningitis. 19 This should be continued for 4 days if the meningitis is suspected or proved to be caused by S. pneumoniae, and discontinued if another cause other than S. pneumoniae is found.
Traumatic brain injury (TBI) remains a leading cause of death and disability, particularly in young adults. Steroids have been used to treat patients with a TBI for many years in an attempt to reduce the deleterious effects of secondary cerebral oedema and swelling that occur after such an injury.
After years of controversy regarding the proposed benefit of steroid administration in TBI, the Corticosteroid Randomisation After Significant Head Injury trial results were published in 2005. 20 This study enrolled over 10 000 patients with a brain injury who were admitted to hospital with a Glasgow Coma Scale of 14 or less. The patients were randomised to receive a 48 h infusion of either methylprednisolone or placebo. The trial showed a significantly higher mortality at both 2 weeks and 6 months in patients in the intervention arm, and was stopped early after the interim analysis. Consequently, corticosteroid administration is not recommended after TBI.
The evidence regarding the use of steroids for spinal-cord injury is controversial. The series of National Acute Spinal Cord Injury Studies concluded with NASCIS III in the 1990s and recommended that methylprednisolone should be used to treat acute non-penetrating spinal-cord injury, leading to their widespread use. 21 Concerns have been raised, however, regarding the validity of these data. The lead author of NASCIS completed a Cochrane review in 2012 on the same subject and concluded that ‘high-dose methylprednisolone steroid therapy is the only pharmacological therapy shown to have efficacy in a phase 3 randomised trial when administered within 8 h of injury’. 22
Despite this, many international guidelines, including NICE CG41, specifically state that methylprednisolone should not be administered in acute spinal-cord injury, as the side-effects (particularly infection) are thought to outweigh any weak evidence of benefit.
In addition to concerns about the harmful effects of high-dose methylprednisolone in this setting, many patients with spinal-cord injury have concurrent TBI and as such steroids may be contraindicated.
Corticosteroids have been proposed as a treatment for Guillain–Barré Syndrome (GBS) by modulating the inflammatory polyneuropathy that is pathognomonic of the disease, reducing the extent of complications, and hastening recovery. A comprehensive Cochrane review in 2016 found that corticosteroid administration has no significant effect on the time to recovery and does not alter the long-term outcome in GBS. Steroids are not, therefore, recommended in the treatment of GBS. 23
Steroid administration is harmful when intracranial pressure (ICP) is raised because of trauma. Similarly, in spontaneous intracerebral haemorrhage, steroids do not improve mortality and can cause significant complications. 24 In contrast, oedema surrounding intracerebral tumours that causes a symptomatic rise in ICP is well controlled by steroid administration; dexamethasone (16 mg day −1 ) is generally prescribed, as it has minimal mineralocorticoid effect, and hence, reduces the risk of worsening the oedema caused by potential water and sodium retention. Similarly, dexamethasone is used to reduce the mass effect of vasogenic oedema and improve neurological symptoms in patients with brain abscesses.
The exacerbation of many autoimmune conditions and inflammatory diseases, and the rejection of transplanted organs can result in critical-care admission. Suppression of the immune response with glucocorticoid therapy is often a vital tenet of management. The broad presentations of these conditions require specialist input, and local advice should be sought on route and dosage of steroid administration.
Acute adrenal insufficiency is a life-threatening condition that may present with cardiovascular collapse, neurological deterioration, and electrolyte disturbance.
Adrenal failure can result from failure of any part of the HPA axis. Primary adrenal insufficiency (Addison's disease) has a number of aetiologies, including autoimmune disease, infections such as tuberculosis, and surgery. Secondary insufficiency is caused by reduced release of pituitary ACTH; causes include exogenous steroid use, pituitary tumours, and Sheehan's syndrome. The UK Society for Endocrinology guidance mandates hydrocortisone 100 mg i.v. immediately, followed by 200 mg 24 h −1 alongside fluid resuscitation in the event of an acute adrenal crisis regardless of cause. 1
Patients presenting with myxoedema coma may have simultaneous adrenal insufficiency, which may be either primary (caused by an autoimmune condition) or secondary to hypopituitarism. Resuscitation should, therefore, include corticosteroid administration, such as hydrocortisone 100 mg i.v.
Corticosteroids form an important part of the optimisation bundle that aims to improve the viability of donor organs. The National Health Service Blood and Transplant guidelines advocate the administration of methylprednisolone 15 mg kg −1 (maximum dose 1 g) to the donor as a means of suppressing the harmful inflammatory response to brainstem death; it may also have a role in attenuating the increase in extravascular lung water.
Whilst the effects of chronic steroid use are well described, many are not relevant to a short course in the critically ill population. Steroid administration, however, is not a benign undertaking—side effects may have a deleterious effect on the critically ill patient, which must be considered whenever steroids are prescribed.
Exogenous steroid administration is a controversial area of modern critical care practice; there is evidence of benefit in only a small number of well-defined clinical situations. Clinicians should decide whether the potential benefit of steroid use outweighs the harms that may result for individual conditions. The expanding body of current research will help to inform this area over the coming years.
The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.
Sarah Marsh FRCA FFICM is a Consultant in Anaesthesia and Intensive Care Medicine at Harrogate District Hospital. She is the Course Director of the FICM's exam preparatory course and is part of their newly formed Women in Intensive Care group. She is also the Deputy National Clinical Lead for e-Learning for Health's new e-ICM programme.
Adam Young BSc (Hons) is a specialty trainee in Anaesthesia at Leeds General Infirmary.
Matrix codes: 1A01, 2C03, 3C00
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