MCC ICU Deep dive: Steroids in the icu
MCC ICU Topic Deep Dive: All Things Steroids
Types:
Mineralocorticoid Steroids: The primary agent that we manipulate is aldosterone. Aldosterone causes water retention as well as potassium excretion. We occasionally block this (spironolactone) as part of goal directed therapy for heart failure patients to promote both diuresis and potassium retention.
Occasionally, fludrocortisone is used in the Neuro ICU. Fludrocortisone can be used as an aldosterone replacement, resulting in water and sodium retention.
Corticosteroids (or Glucocorticoids): These are synthetic hormones that replicate the effect of cortisol, a hormone that is regulated by the adrenal glands. Release of cortisol causes a multitude of effects including increased blood pressure, increased blood sugar, decreased inflammation (low dose), immunosuppression (high dose), occasionally tachycardia (as a result of arterial constriction), increased mental acuity and increased metabolic activity.
Pharmacology: Common ICU Steroids
First off, an important concept to know for steroids is biological half life. This is very different than the pharmacological half life.
Pharmacological Half life: Amount of time it takes for the amount of drug’s active substance in your body to reduce by half.
Biological Half Life: The amount of time it takes for half of the drug’s effect on the body to wear off.
Think of a hurricane going over land. The hurricane itself moves through very fast, but the effects of the hurricane linger long past the storm. Steroids cause a reaction that often lingers far past the actual half life of the drug itself.
For example, we commonly use 40 mg of prednisone PO as a “steroid burst for COPD. The dose is 40 mg daily for 5 days. Prednisone’s pharmacological half life is only about 3 hours, but the biological half life is about 24 hours.
Dexamethasone (Decadron): IV or PO available. Drug half life is 3-4 hours for a 20 mg tablet. Biological half life of 36-54 hours.
Hydrocortisone: IV or PO available Drug half life 80-100 minutes. Biological half life of 8-12 hours. This also has some mineralocorticoid effect.
Methylprednisolone (Solu-medrol): IV or PO available. Drug half life 2.5-3.5 hours. Biological half life of about 12-36 hours
Prednisone: PO only. Drug half life 2-3.5 hours. Biological half life of 12-36 hours
Steroid Indications: In ICU we see a wide range of both which steroid is being chosen, how long they are used for, and under what circumstances they are being used. Selection, dose, and duration should be based on evidence.
Dexamethasone: Brain Tumors.
Generally 4 mg QID is used initially and then tapered down to a lower dose or even off steroids if the patient is asymptomatic. Dexamethasone is known to decrease vasogenic edema around malignancy, thus reducing ICP and symptoms of brain tumor. This is also used in conjunction with chemotherapy for other cancers due to the anti-nausea effect it produces.
Use of dexamethasone in patients with high grade glioma: A clinical practice guideline
Curr Oncol. 2014 Jun;21(3):e493–e503. doi: 10.3747/co.21.1769
There are many studies ongoing to find “the perfect dose” and even several studies that suggest dexamethasone is associated with harm, especially in patients with glioblastoma.
ICU Team Takeaway: For a new brain tumor, start dexamethasone 4 mg QID. Further titration or discontinuation is a neurosurgery or oncology decision
Dexamethasone: ARDS
There was also a large trial completed in Spain called Dexa-ARDS that came out just as Covid started where patients with a P/F ratio < 200 were randomized to standard care VS Dexamethasone 20 mg for 5 days followed by 10 mg for 5 days with dexamethasone discontinued upon extubation.
In the steroid group, 21% of the patients died compared to 36% of the standard care group. There was also an association with vent free days in the steroid group (14.3 vent days VS 20.2 vent days)
Further dexamethasone evidence is a reflection of the Covid 19 pandemic. An early trial, called RECOVERY, used 6 mg of dexamethasone daily for up to 10 days with a mortality benefit at 28 days. While the actual percentage (22.9% of the dexamethasone group died at 28 days and 25.7% of the standard of care group died at 28 days), doesn’t sound amazing, if you multiply that out to the several billion people that contracted Covid-19, you are saving a lot of lives.
Dexamethasone in Hospitalized Patients with COVID-19
N Engl J Med 2021;384:693-704 DOI: 10.1056/NEJMoa2021436 VOL. 384 NO. 8
ICU Team Takeaway: For patients in ARDS, there is evidence to use the above doses of dexamethasone for either ARDS or Covid infection.
Dexamethasone: Meningitis
A 2002 study compared standard of care with placebo VS standard of care with dexamethasone for adult patients with confirmed bacterial meningitis. 301 patients were randomized to either 10 mg dexamethasone QID for 4 days VS placebo with end point goals of both morbidity and mortality being measured. Further, there was a subanalysis of the bacteria that were cultured. With pneumococcal meningitis especially, there was a significant morbidity and mortality.
Dexamethasone in Adults with Bacterial Meningitis
N Engl J Med 2002;347:1549-1556 DOI: 10.1056/NEJMoa021334 VOL. 347 NO. 20
ICU Team Takeaway: For patients with or suspected of bacterial meningitis, there is evidence to use the above doses of dexamethasone
Dexamethasone: Post Extubation Airway Edema
A 2007 study compared dexamethasone to placebo in patients that had been intubated for greater than 48 hours and had a minimal cuff leak. 86 patients were randomized to either 24 hours of dexamethasone 5 mg every 6 hours for 24 hours prior to extubation VS placebo. Patients were monitored for 48 hours for stridor post extubation. 10 % of the dexamethasone group developed stridor while 27% of the placebo group developed stridor. However, there was no significant difference in the re-intubation rate for either group (One of the dexamethasone group and two of the placebo group ended up re-intubated).
Dexamethasone to prevent postextubation airway obstruction in adults: a prospective, randomized, double-blind, placebo-controlled study
Crit Care. 2007 Jul 2;11(4):R72. doi: 10.1186/cc5957
This was clarified to some degree by the American Thoracic Society guidelines released in 2017 .
•We suggest performing a cuff leak test in mechanically ventilated adults who meet extubation criteria and are deemed high risk for postextubation stridor. (Conditional recommendation, Very low certainty in the evidence)•For adults who have failed a cuff leak test but are otherwise ready for extubation, we suggest administering systemic steroids for at least 4 hours before extubation. (Conditional recommendation, Moderate certainty in the evidence)
Postextubation stridor resulting from airway edema increases the risk for reintubation. A cuff leak test can detect airway edema and prompt steroid therapy to increase successful extubation rates. There were no randomized controlled trials comparing management based on a cuff leak test with management without a cuff leak test. However, 14 observational studies evaluated management based on a cuff leak test with bedside assessments, with variable definitions of a failed test (e.g., absent or insufficient cuff leak). A recent meta-analysis indicated that the likelihood ratio of reintubation is 4.04 (95%, CI 2.21–7.40) for failed cuff leak tests and 0.46 (95% CI, 0.26–0.82) for successful cuff leak tests. Given the small absolute decrease in reintubation rate (1.8%) and the large absolute increase in delayed extubation rate (9.2%) with cuff leak test-guided management, it should be reserved for patients at high risk for upper airway edema (e.g., traumatic intubation, intubated >6 days, large endotracheal tubes, female, or reintubation).
In a pooled analysis of 3 randomized trials (214 patients), the use of pre-extubation systemic steroids reduced the reintubation rate in patients who failed a cuff leak test (RR, 0.32; 95% CI, 0.14–0.76). The potential adverse effects of systemic steroids are limited in this setting by the short duration of therapy.
Liberation from Mechanical Ventilation in Critically Ill Adults. An Official ATS/ACCP Clinical Practice Guideline
https://doi.org/10.1513/AnnalsATS.201612-993CME
ICU Team Takeaway: For patients with concern for airway edema related to endotracheal tube placement, there is some evidence and a guideline to use the above doses of dexamethasone
Methylprednisolone: ARDS
There is a meta analysis of 9 trials that enrolled a total of 816 patients. Because this is a compilation of studies, various doses were used. As with other steroids, there was a significant benefit with both an improvement in vent free days as well as mortality. The conclusion was to use 1 mg/ kg/ day with an escalation to 2 mg/kg/day for persistent ARDS. The meta analysis did include multiple steroids and the benefit of alternate choices was also present.
Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS
J Intensive Care 2018 Aug 24:6:53. doi: 10.1186/s40560-018-0321-9. eCollection 2018.
A much older double blind study (2006) with less patients (180) came to similar conclusions. The dosage here was 2 mg/kg bolus on day one followed by 0.5mg/kg given four times daily. This was used for 21 days and then wean off with a taper. Again, both a mortality benefit and ventilator free days were observed in the treatment group.
Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome
N Engl J Med 2006;354:1671-1684DOI: 10.1056/NEJMoa051693 VOL. 354 NO. 16
Chest published a study a year later observing a similar effect using 1 mg/kg/day methylprednisolone. The goals of this study were reduced lung injury based on a scoring system as well as vent free days. Once again, the steroid group showed benefit over the placebo group.
Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.
Chest. 2007;131(4):954-963. doi:10.1378/chest.06-2100
ICU Team Takeaway: For patients in ARDS, there is evidence to use the above doses of methylprednisolone for ARDS
Hydrocortisone: Septic Shock
A 2018 study (APROCCHSS) that randomized 1241 patients to either placebo, hydrocortisone and fludrocortisone, or hydrocortisone with drotecogin alfa. Multiple aspects were analyzed with the following results. Hydrocortisone was not associated with a significant reduction in ventilator days. Hydrocortisone WAS associated with a reduction in vasopressor days. There was a slight mortality benefit at 90 days, but this is hotly debated and its validity is questionable.
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock
N Engl J Med 2018;378:809-818 DOI: 10.1056/NEJMoa1705716 VOL. 378 NO.
Also in 2018, the ADRENAL trial came out. This was a huge study (3800 patients) with septic shock that were randomized into a 200 mg hydrocortisone per day CONTINUOUS INFUSION vs placebo. This was stopped at 7 days, or if the patient transferred out of the ICU or died. The primary outcome was mortality at 90 days. Adrenal concluded that a slow infusion of hydrocortisone does not change mortality in septic shock.
Adjunctive Glucocorticoid Therapy in Patients with Septic Shock
N Engl J Med 2018;378:797-808 DOI: 10.1056/NEJMoa1705835 VOL. 378 NO. 9
ICU Team Takeaway: For patients in septic shock, 200 mg of hydrocortisone per day in divided doses may decrease the amount of vasopressor needed by a patient in septic shock. There is no proven mortality benefit.
FYI: If your patient has severe CAP, specifically, new guidelines and data show a mortality benefit. See below
Hydrocortisone: Severe Community Acquired Pneumonia
The critical care community has gone back and forth on steroids in community acquired pneumonia. A Cochrane review in 2017 found both a morbidity and mortality benefit for patients with severe CAP only, but the review looked at multiple studies using multiple steroids and doses.
Cochrane review non-specific glucocorticoid
https://doi.org/10.1002/14651858.CD007720.pub3
More recently, the New England Journal of Medicine published a study specifically looking at hydrocortisone in severe CAP. A dose of 200 mg of hydrocortisone daily in divided doses was compared to placebo. This was continued for 4-7 days based on how the patient was doing clinically and then tapered off over a total of 14 days. The primary outcome measured was death at 28 days. 25 of the 400 patients in the steroid group died as compared to 47 of the 395 patients in the placebo group.
Hydrocortisone in Severe Community-Acquired Pneumonia
N Engl J Med 2023;388:1931-1941 DOI: 10.1056/NEJMoa2215145 VOL. 388 NO. 21
ICU Team Takeaway: For patients with severe community acquired pneumonia, there is evidence that the above dosing of hydrocortisone has a mortality benefit.
Prednisone: COPD Exacerbation
Prednisone use for COPD has been standard of care for a long time. Two studies, one published in the Lancet and one published in the New England Journal of Medicine. In the Lancet trial 30 mg of prednisolone was used for 2 weeks with both predicted FEV1 and length of hospital stay being measured in the steroid and nonsteroid groups. The steroid group had significantly better outcomes in both areas.
The New England study, also in 1999, used a combination of systemic corticosteroids as well as multiple lengths of treatment, ranging for a couple weeks to 6 weeks. As with the Lancet study, COPD patients that were given steroids had shorter length of stay in the hospital and a mortality benefit was proven in the short term (at 6 month from the NEJM study, no mortality benefit was noted).
With both of these trials, the main takeaway was that systemic steroid treatment was of benefit to patients with COPD exacerbation. However, we have since changed the length of treatment based on further evidence.
The more common 40 mg of prednisone for 5 days was the result of a 2013 trial that was published in JAMA called REDUCE. By this time treatment had been scaled down to 2 weeks of steroids and REDUCE compared 5 days of prednisone at 40 mg per day VS courses of 14 days of steroid treatment. The results were the same and the 5 day treatment course was deemed “non-inferior”.
On a more up to date note, In 2023 the Global Initiative for Chronic Obstructive Lung Disease released an updated guideline for COPD patients.
“Systemic glucocorticoids in COPD exacerbations improve lung function, oxygenation, and risk of early relapse, and reduce treatment failures and length of hospitalization (126–128). A dose of 40 mg prednisone-equivalent per day for 5 days is recommended (129). Longer courses increase the risk of pneumonia and mortality (130). Therapy with oral prednisolone is equally effective to intravenous administration (131). Nebulized budesonide may be a suitable alternative to systemic corticosteroids in some patients (127, 132). Recent studies suggest that glucocorticoids may be less efficacious to treat COPD exacerbations in patients with lower blood eosinophil levels (133).”
Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial
Lancet Volume 354, Issue 9177p456-460August 07, 1999
Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease.
N Engl J Med 1999;340:1941-1947
Short- term VS conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial
DOI: 10.1001/jama.2013.5023
American Journal of Respiratory and Critical Care Medicine
https://www.atsjournals.org/doi/10.1164/rccm.202301-0106PP
ICU Team Takeaway: For patients with COPD Exacerbation there is evidence that the above dosing of prednisone has both a morbidity and mortality benefit.
Summary: First off, there are a lot more indications for steroids beyond what is mentioned above. Asthma, for example, is discussed in a completely different MCC deep dive (go to MCCICUtrainer.com and find the asthma deep dive if you are interested). There are autoimmune diseases, provoked adrenal insufficiency, myxedema coma, encephalitis, pericarditis, just to name a few. The goal of the above was to try and talk about the more common issues that we encounter in ICU. There are a lot more studies out there as well, even for the topics above, if anyone is interested. Again, the goal of this was to hit the major studies and major common diagnoses. Please let me know if there were other areas of interest that you would like me to explore.
Also, there are more steroids out there than the ones listed above. If you google "corticosteroids" there will be 24 listed glucocorticoids. My advice is to get comfortable with the several we use often and worry about alternatives only if new evidence comes out or we have a drug shortage that pushes you in newer directions.
When this topic was suggested to me, the gist of the request was “I am seeing a lot of variation in steroid use and it is difficult to know what to use”. The bottom line is that most of these drugs are probably equivalent to each other to some degree. The data above tells us what we know for sure, but the correct dose of steroid realistically is probably “whatever makes the patient better”. For example, would 10 mg of prednisone daily work for COPD exacerbation? The evidence we have now says that 40 mg works and until a trial is completed that says 10 mg is equivalent to 40 mg, all science can tell you for sure is that we know 40 mg po prednisone has a proven benefit. If your attending physician is using a different dose than you were expecting but the patient is clinically improving, I would hesitate to make a change. Online (I use MDcalc) there are steroid converters to give you equivalent doses.
The following are all the same dose of steroid.
3 mg dexamethasone
16 mg methylprednisolone
20 mg prednisone
80 mg hydrocortisone
Use the evidence we have to start. If a clinician sees the need to change the steroid, dose, or the duration, please ask questions for your own knowledge. As always, this will be posted to the website (MCCICUtrainer.com) for your reference.
