Hello, everyone. Today, I'll be presenting on To Stress or Not to Stress, Controversies and Updates in Steroid Use. My name is Mohamed Abdaifi. I'm a clinical assistant professor at the College of Pharmacy, Howard University in Washington, D.C., and I'm also the coronary care unit's clinical pharmacy specialist and the PGY-1 pharmacy residency coordinator at Howard University Hospital. I have no relevant financial relationships pertains to this presentation to disclose. During this presentation, I will describe the evolving role of steroid therapy in severe community-acquired pneumonia, sepsis, and COVID-19 infection. Then I will evaluate the optimal steroid regimens for a given patient cases and opportunities how to minimize adverse effects. Then lastly, I will discuss strategies for corticosteroids alternative in case of drug shortages. First of all, I will start by describing the pharmacology review of all corticosteroids that are currently being used in clinical practice. We naturally produce cortisol, which is an indigenous glucocorticoid that we utilize for glucose metabolism and also has many immunological effects. Corticosteroids that are commercially available, those are synthetic analogs of our naturally produced cortisol. Our indigenous steroids are produced by our adrenal cortex, and those include the mineralocorticoids, such as aldosterone, and also the glucocorticoids, such as cortisol and cortisone. The synthetic commercially available corticosteroids have different degrees of glucocorticoids and mineralocorticoid potency and efficacy. Looking closer at the glucocorticoids, they're mainly involved in metabolism, immunosuppressive, and also they have anti-inflammatory and vasoconstructive effects. However, the mineralocorticoids are mainly involved in regulation of the electrolytes and fluid balances in our body. Now I would like to introduce a basic concept that will help us understand the entirety of this presentation. This concept is the hypothalamus-pituitary-adrenal axis physiology. The natural activation and suppression of cortisol production is a continuous process that takes over 24 hours. Upon experiencing any stress, this could be physical or emotional, corticotropin-releasing hormone gets produced, which activates the hypothalamus to produce adrenocorticotropic hormone. The ACTH activates the pituitary and adrenal cortex, which results in cortisol production. The negative pathway mechanism mainly involves higher cortisol levels, suppresses the hypothalamus, and the pituitary gland activation. Our naturally produced cortisol reaches its highest concentration typically in the morning, at this level normally between 10 to 25 micrograms per deciliter. On the other hand, the lowest concentration can be found during nighttime. Again, any stress can stimulate and increases the production of our naturally produced steroids, such as infection, trauma, or even mental emotional stress. Now let's take a closer look at the pharmacology of corticosteroids. Corticosteroids have two major physiological effects on our bodies. Number one, anti-inflammatory response. Number two, blood pressure support. By binding to the glucocorticoid receptors, they result in inhibition of gene expression and translation of leukocytes. This inhibition of leukocytes results in huge reduction of cytokines and chemokines. Lastly, they also result in inhibition of phospholipase A2. All those are major and important pro-inflammatory markers that whenever they are reduced, this results in a huge anti-inflammatory response. Secondly, the way they produce blood pressure support by reducing the effect of naturally produced nitric oxide, and also they enhance the effect of the catecholamines. Normally patients, they respond better to catecholamines whenever they're being administered steroids at the same time. Also, they produce an increase in vasopressin that we naturally produce, which results in vasoconstriction and blood pressure support. Lastly, they also enhance cardiac contractility and cardiac output. In this table, I have summarized the mineralocorticoid and the anti-inflammatory potency of all glucocorticoids and also the mineralocorticoids. It is important to note that hydrocortisone has the strongest mineralocorticoid potency among all glucocorticoids, and it is also important to note that fluorocortisone, which is considered to be a mineralocorticoid steroid, has no anti-inflammatory potency. Now shifting gears towards critical illness-related corticosteroid insufficiency and how could a critical illness result in adrenal and corticosteroid insufficiency. This corticosteroid insufficiency has been around for years, and you might have heard this disease states with other terminologies such as relative adrenal insufficiency and adrenal insufficiency of critical illness. Any acute illness such as sepsis or septic shock, severe chemoacquired pneumonia, ARDS, or even burns could result in inhibition of the hypothalamus pituitary adrenal axis. And this inhibition results in glucocorticoid resistance, so we are able to produce glucocorticoids. However, we're not utilizing those glucocorticoids properly. Or even worse, this could result in lower production of glucocorticoids. Ultimately, whenever this inhibition takes place, it presents and shows clinically with hypertension, patients become unresponsive to cuticulamines, delirium, and sometimes confusion. Now let's take a closer look at the use of steroid therapy in severe chemoacquired pneumonia. By looking at what the guidelines say regarding the use of steroids in severe chemoacquired pneumonia, starting from 2017, the ATS IDSA guidelines made no comments regarding corticosteroid use among patients with severe chemoacquired pneumonia. However, in 2019 and 2023, new guidelines came out, and they recommended the use of corticosteroids only if septic shock or refractory septic shock presents in addition to severe chemoacquired pneumonia. However, recently in 2024, the Society of Critical Care Medicine-Focused Guidelines was published, and they did mention that they recommend the administration of corticosteroids to adult patients who are hospitalized for severe bacterial chemoacquired pneumonia. As we just discussed, many guidelines do actually recommend and suggest the use of corticosteroids only for severe chemoacquired pneumonia. One of the major ways that we use and utilize in clinical practice to define severe chemoacquired pneumonia is per the 2007 IDSA ATS guidelines, and this was also endorsed in the 2019 guidelines as well. This criteria includes one major criteria or three or more minor criteria. Major criteria includes any septic shock patient that is requiring vasopressors to keep their blood pressure at goal, and also any respiratory failure patients that is requiring mechanical ventilation. Another major way that is used currently also in clinical practice to define severe chemoacquired pneumonia is what was published in the SMART-COP trial. Following the SMART-COP trial method, we basically assess our patient vital signs. You look at their blood pressure, and you look at their respiratory status, and also you look at their opium level, and you look at the chest x-ray, and you evaluate how many loops are involved in their pneumonia. And lastly, you assess their mental status, and also you look at their pH and P2F ratio. Whenever you have a score of five or more, this is considered to be high-risk and severe chemoacquired pneumonia. The same European guidelines that did recommend in 2023 the use of steroids among patients with severe chemoacquired pneumonia only if they also have shock defined severe chemoacquired pneumonia as any chemoacquired pneumonia that is requiring ICU level of care and admission. Of course, the reason of this ICU admission should be considered if it's related to the CAP or if it's related to something else. One of the first studies that I would like to discuss for the use of steroids among patients with severe chemoacquired pneumonia is the CAPE-COD trial. This trial was done in Europe and France among 31 ICUs. They included any patients with severe chemoacquired pneumonia. They defined severe chemoacquired pneumonia as the mechanical ventilation with PEEP of at least five and P2F ratio of 300 or less. And lastly, patient had to have PSI of more than or equal to 130. They excluded any patients with influenza, septic shock, or they're currently on 15 milligram of prednisone at baseline or more. In this trial, they used hydrocortisone continuous of 200 milligram daily, and they used as a competitor placebo that was also provided and administered in the same methodology as hydrocortisone. And their primary outcome was 28 day or cause mortality. Unfortunately, this trial was stopped early primarily due to COVID-19 outbreak. However, they were able to successfully recruit 800 patients. And as you can see clearly on the right side, they found a significant reduction in their primary outcome, which again was 28 day or cause mortality among patients with severe chemoacquired pneumonia and receiving hydrocortisone in comparison to patients receiving placebo. Few things we should be aware of from the KF-CLA trial that about 45% of patients included in this study were on mechanical ventilation at baseline, and they were almost equal distributed between invasive and non-invasive ventilation. However, the subsequent mechanical ventilation was lower among patients receiving steroids. Lastly, and most importantly, they excluded from this study any patients with septic shock. So we cannot really generalize the outcomes of this study among patients with severe chemoacquired pneumonia and septic shock at the same time. Another major study that looked at the steroid use among patients with severe chemoacquired pneumonia is the ESCAPE trial. This study was done in the United States among 42 ICUs. They included any patients with severe chemoacquired pneumonia, and they actually used the IDSA-ATS definition. For interventions, they utilized methylpyridazolone as a continuous infusion for 20 days, and also they converted to placebo that was given in a similar fashion as the methylpyridazolone. Their primary outcome was 60 day or cause mortality. They were able to include in the ESCAPE trial almost 600 patients, and this trial unfortunately was stopped early due to predetermined stop dates. And looking closer at the outcomes, they failed to find any difference in mortality in their primary outcome, which was defined as 60 day or cause mortality. They also tested all cause mortality at 180 days, which also was no difference between methylpyridazolone and placebo among patients with severe chemoacquired pneumonia. We have to note that this study was not powered to find any difference between methylpyridazolone and placebo, and also about 96% of patients included in this trial were male. So all these two considered together could possibly limit the external validity of this trial. I have listed here and summarized suggested steroid regimens that could be utilized for patients who are experiencing severe chemoacquired pneumonia. Mainly hydrocortisone and methylpyridazolone could be utilized if steroids are deemed necessary and appropriate for those patients. In conclusion, corticosteroid could be beneficial and helpful among patients who are experiencing severe chronic acquired pneumonia and requiring ICU level of care, or if they have septic shock in addition to their severe chronic acquired pneumonia for hemodynamic support. We should effectively screen and rule out any contraindication prior to steroid initiation. Lastly, clinical parameters and scales such as pneumonia severity index could be utilized for clinical guidance. Now moving to another major area where we utilize corticosteroids, which is in the management of sepsis and septic shock. Similar to the severe chronic acquired pneumonia approach, let's first of all go over what do the guidelines say and mention in terms of steroid use for the management of sepsis and septic shock. Expert opinions do recommend and suggest the use of steroids for those patients who are experiencing sepsis and septic shock and requiring continuous vasopressor support and therapy for hemodynamics. Even the SCCM 2024 focus guidelines do actually recommend the use of corticosteroids among patients with septic shock. However, they recommend against using higher doses of corticosteroids. Higher doses were defined as any dose of hydrocortisone more than 400 milligram a day. The major studies and trials that looked at the use of steroids in the management of sepsis was the adrenal trial. In this trial, they included any adult patients with septic shock that is requiring vasopressors and mechanical ventilation. And they utilized here hydrocortisone 200 milligram a day that was given as a continuous infusion for at least seven days or until ICU discharge. They also utilized matching placebo that was administered in the same fashion. And their primary outcome was 90-day all-cause mortality. In the adrenal trial, they found no significant difference in terms of mortality among patients receiving hydrocortisone versus placebo as the p-value was 0.42. Few major points to be aware of from the adrenal trial that neuromuscular weakness, which is a major side effect of steroid that was not assessed. And also about 8% of both groups received open-label steroids. Lastly, a probe use of antibiotic was not assessed. And as we all know, that a probe use of antibiotic is a major cornerstone of sepsis management. Another major study that looked at the steroid use in the management of sepsis in the ICU is the approaches trial. In this trial, they included adult patients with confirmed or possible septic shock for less than 24 hours. They also utilized hydrocortisone. However, they utilized hydrocortisone here in terms of boluses. They utilized 50 milligram ibuproles every six hours plus fludrocortisone 50 microgram tablet once daily by mouth in the morning for seven days without tabor. They also utilized two matching placebos. They were given in the same fashion as the intervention. And here they assessed for 90-day all-cause mortality as their primary outcome. Their major primary finding here was completely different from the adrenal trial. In this trial, authors were able to identify a significant reduction among patients receiving hydrocortisone plus fludrocortisone with septic shock confirmed or possible diagnosis. And they found this reduced mortality was significant with a B value of 0.02. A few things to be aware of from the approach to this trial. Their patient SOFA score median was about 11 in both groups and this reflects very high acuity level. So this could possibly limit the external validity of this trial. Lastly, this trial was stopped twice and in total it was taught about almost two years. If steroids are deemed necessary, effective and safe to be used among patients with septic shock, then hydrocortisone plus fludrocortisone combination therapy can be utilized and used for seven days or until ICU discharge. Or hydrocortisone alone can be also utilized. When using hydrocortisone either with combination of fludrocortisone or alone, it is not recommended to exceed 200 milligram per day and this can be given as a continuous infusion or divided every six hours. If fludrocortisone is deemed necessary to be used in addition to hydrocortisone, then 50 microgram orally can be also utilized. In conclusion, corticosteroids should be highly considered when fluid resuscitation and vasopressor therapy have been initiated. However, hemodynamics parameters are not a goal yet and whenever hypoperfusion persists. Similar to the severe community acquired or a temporary approach, effective screening for contraindication and side effects must be done prior to initiation of corticosteroids for sepsis and septic shock management. Now moving to the third disease stage that we'll be discussing today, which is the role of steroid therapy in the management of COVID-19 infection. Briefly looking at the NIH 2023 guidelines, you will see that in this guidelines corticosteroids is actually recommended against the use of steroid if COVID is being treated as an outpatient without the need of supplemental oxygen. However, whenever COVID is being treated as an inpatient with the need of supplemental oxygen, then dexamethasone is recommended to be used as corticosteroids for the management of COVID-19. One of the main and early trials that looked at steroids role in the management of COVID-19 was the recovery trial. In this trial they included hospitalized with suspected or confirmed COVID-19 infection and they used and utilized dexamethasone six milligram either IV or orally for 10 days or until discharge. They utilized a placebo that was also given and administered in a similar fashion and their primary outcome was 28 day all cause mortality. In this trial they found patients with severe COVID-19 who required supplemental oxygen, dexamethasone significantly reduced their mortality at 28 days. And looking closer at those patients, the greater benefit of mortality reduction was seen among those patients receiving mechanical ventilation at randomization. However, patients who were not on any supplemental oxygen, they had no mortality reduction benefits. Here from the recovery trial, they found a significant reduction in mortality among patients receiving dexamethasone versus usual care for COVID-19. And you can see this clearly in graph A. Also on the right side on graph B, looking just on the invasive mechanical ventilation, similar outcome were found and they found significant reduction in terms of mortality for patients receiving dexamethasone versus usual care. What I really wanted to look closer at is the rates ratio of mortality reduction. On the B side, the invasive mechanical ventilation, you see clearly greater reduction with a rate ratio of 0.64 versus only 0.83 among all participants. Another major study that looked at the steroid use for the management of COVID-19 was the CODIX trial. Similar to the other study, they included hospitalized patients with suspected or confirmed COVID-19 and received mechanical ventilation within 48 hours of meeting the criteria for moderate to severe ARDS. They also utilized dexamethasone. However, the dose was different here. Dexamethasone was given as 20 milligram IV once daily for five days. Then the dose was lower to 10 milligram IV for five days or until ICU discharge. Their primary outcome was number of days alive and free from mechanical ventilation at day 28. Consistent findings were found in the CODIX trial. They also detected that dexamethasone had increased significantly the number of days alive and free of mechanical ventilation over 28 days. In patients with COVID-19 and moderate to severe ARDS. In conclusion, corticosteroids should be highly considered when managing COVID-19, patients who are hospitalized and requiring supplemental oxygens. Patients who have ARDS on top of their COVID-19 infection, those could be your optimal or most beneficial patients of receiving steroids. Similar to sepsis and severe community-acquired pneumonia, effective screening of safe and effective steroids prior to initiation must be done. Lastly, I would like to discuss strategies for steroid utilization during medication shortages. Corticosteroids are currently being utilized for a variety of indications in and outside of the ICU. Dealing with medication shortages could result in therapeutic challenges and lack of access to standard of care therapies. And that ultimately could be harmful to patient care. When thinking about a steroid alternative for managing patient care, we have to think about the desirable effect of this particular steroids that we are trying to use. For example, you should think about, are we using it for the glucocorticoid effect or is it for the mineralocorticoid effect? As a reminder, the glucocorticoid effect revolves around the metabolism, inflammation, immunity, wound healing, and also the muscle contractility. However, the mineralocorticoid effect normally revolves around salt and water reabsorption and retention, and also the mineral metabolism. Now taking a closer look at the steroid use in septic shock management. Whenever we are trying to use any steroid for sepsis and septic shock management, the desirable effect of this steroid is the mineralocorticoid property. Mineralocorticoid, again, is where you have the hemodynamic support by providing salt and water retention. And if you remember, hydrocortisone has the highest mineralocorticoid properties. However, in case of hydrocortisone shortages, which was recently happening in healthcare, metharpidinazolone and dexamethasone IV could be an acceptable alternative to hydrocortisone. If you also remember correctly, metharpidinazolone have a minimal mineralocorticoid potency. About 50% of that you find you get from hydrocortisone. Unfortunately, dexamethasone has no mineralocorticoid potency whatsoever. Now assuming hydrocortisone is shortage or you are unable to use hydrocortisone for sepsis and septic shock management, to overcome this low mineralocorticoid to non-mineralocorticoid property of metharpidinazolone and dexamethasone, you could utilize flutricortisone 50 microgram once daily by mouth as an add-on therapy to your metharpidinazolone or dexamethasone to supplement and augment the mineralocorticoid effects. On the other hand, whenever you are utilizing steroids for the severe community acquired pneumonia and COVID-19 infection, you are utilizing steroids for their glucocorticoid effect to reduce inflammation. If you remember dexamethasone then followed by metharpidinazolone, they have the highest and they carry the highest glucocorticoid properties out of all corticosteroids and should be your number one and two whenever you are utilizing steroids for the glucocorticoid as an anti-inflammatory drugs. To conclude this presentation, the role of corticosteroids use in the ICU has gained interest and has expanded significantly over the past years. When corticosteroids use among patients with septic shock, severe community acquired pneumonia and COVID-19 might be beneficial. And as we discussed previously, effective patient screening to identify optimal candidates for corticosteroids prior to initiation to ensure safety and efficacy is required. Thank you for listening and I hope this was helpful.

steroid use

community-acquired pneumonia

sepsis

COVID-19 infection

pharmacology

corticosteroids