Abstract
Objectives
Critical illness-related corticosteroid insufficiency (CIRCI) is a common complication among critically ill patients, often stemming from hypothalamic-pituitary-adrenal axis impairment. This study aimed to determine the incidence and characteristics of CIRCI, focusing on Circi Diagnosis, in patients with severe COVID-19, and to evaluate the clinical outcomes in this vulnerable population.
Methodology
This retrospective cohort study, conducted at a single center, investigated the prevalence of CIRCI and approaches to CIRCI diagnosis in critically ill patients diagnosed with COVID-19.
Results
Out of 145 COVID-19 positive patients with refractory shock, 22.94% were identified as having probable CIRCI, highlighting the significant incidence of CIRCI in this cohort. Patients treated with corticosteroids exhibited statistically significant longer durations of mechanical ventilation (p=0.001). Furthermore, this group presented with a higher burden of morbidity and mortality, and a greater incidence of organ dysfunction. Multivariable logistic regression analysis identified the SOFA score as a significant predictor of mortality in patients with CIRCI (p=0.013), underscoring the importance of severity of illness in prognosis.
Conclusion
CIRCI in COVID-19 patients presents unique diagnostic challenges due to the profound inflammatory response associated with this infection. Accurate CIRCI diagnosis is crucial as it appears to be a significant indicator of increased mortality risk in this patient population. Further research is warranted to optimize CIRCI diagnosis and management strategies in COVID-19.
Keywords: CIRCI diagnosis, adrenal insufficiency, COVID-19, critical illness, shock
INTRODUCTION
The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, emerged from Wuhan, China, in late 2019, rapidly becoming a global health crisis. This novel betacoronavirus, distinct from SARS and MERS viruses, manifests with symptoms ranging from fever and cough to severe pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ dysfunction.1 The sheer scale of the pandemic and the severity of illness in a significant proportion of patients have placed immense strain on healthcare systems worldwide.
In the Philippines, as of the time of this study, the impact of COVID-19 was substantial, with over 36,000 cases and a significant number requiring hospitalization at the Philippine General Hospital (PGH).2 Severe COVID-19 frequently leads to organ dysfunction, including shock, ARDS, cardiac complications, and acute kidney injury. Data from Wuhan indicated that over a quarter of hospitalized patients required intensive care unit (ICU) admission due to these complications.1 Global data reveals that a considerable percentage of COVID-19 patients experience severe or fatal outcomes, with septic shock occurring in a notable proportion (4-8.7%). Mortality rates among critically ill patients are alarmingly high, reaching over 60% at 28 days.3,4 International studies further emphasize the severity, with shock reported in 23-31% of ICU patients and septic shock contributing to mortality in 70% of fatal COVID-19 cases.1,5,6 These statistics underscore the critical need to address complications arising from severe COVID-19, including conditions like critical illness-related corticosteroid insufficiency (CIRCI).
CIRCI is a well-recognized complication in critically ill patients, characterized by an inadequate corticosteroid response to the physiological stress of severe illness. This condition leads to refractory hypotension, often accompanied by other metabolic disturbances such as hypoglycemia, electrolyte imbalances, metabolic acidosis, and eosinophilia.7 The incidence of CIRCI is substantial in septic shock, reaching up to 60%, and varies widely from 12% to 75% in sepsis cohorts.8,9 The resulting dysregulated inflammation in CIRCI contributes to organ dysfunction, prolonged dependence on vasopressors and mechanical ventilation, and increased mortality. CIRCI is prevalent across various critical illnesses, including sepsis, septic shock, severe pneumonia, ARDS, cardiac arrest, trauma, burns, and post-major surgery states.10 Prolonged ICU stays, common in severe COVID-19, further increase the risk of symptomatic adrenal insufficiency, with a twenty-fold higher incidence observed in patients in ICU for over two weeks.11
CIRCI diagnosis relies on clinical findings, primarily refractory hypotension unresponsive to fluid resuscitation and requiring escalating vasopressor support. Guidelines from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine suggest confirming CIRCI diagnosis with a random cortisol measurement, although specific cut-offs remain debated.12
Glucocorticoid therapy forms the cornerstone of CIRCI management. Stress-dose glucocorticoids, such as hydrocortisone (200-300 mg/day), have demonstrated hemodynamic benefits and improved survival in septic shock patients by mitigating organ dysfunction, reducing ventilator dependence, and shortening ICU stays.13 While potential adverse effects like hyperglycemia and myopathy are recognized, they are less common with short-term stress-dose administration in critical care settings. Current evidence supports the use of low-dose corticosteroids (hydrocortisone 200-300 mg/day for at least three days) to improve survival and hemodynamic stability in critically ill patients without significant adverse event risks.12
Data regarding glucocorticoid use, the primary treatment for CIRCI, in viral pneumonia is limited and mixed. Studies in influenza A/H1N1 have shown both benefits (reduced lung injury, organ dysfunction, mortality) and no benefit or even potential harm (increased mortality trend) with glucocorticoids. However, confounding factors, such as disease severity in treatment arms, complicate interpretation.13,15 In SARS pneumonia, preliminary data suggested lower mortality and shorter hospital stays with glucocorticoid treatment, but these findings require further validation. Importantly, much of the research on glucocorticoids in viral pneumonia focuses on ARDS rather than septic shock, highlighting the need for investigations in viral pneumonia patients with septic shock.13
In the context of COVID-19, glucocorticoids have been used for specific indications like septic shock and ARDS. Early data from Wuhan indicated high glucocorticoid usage (44.9%) in hospitalized COVID-19 patients, but outcome analyses were limited.1 A small study suggested potential early benefits of glucocorticoids in improving oxygenation and reducing organ dysfunction, but the small sample size necessitates cautious interpretation.3 A larger study in Wuhan showed reduced mortality with methylprednisolone in ARDS patients, but the overlap with septic shock was unclear.16 The RECOVERY trial established the benefit of dexamethasone in oxygen-requiring COVID-19 patients, demonstrating reduced 28-day mortality.5,17
Currently, there is a significant gap in understanding the incidence of CIRCI in COVID-19 patients, particularly in local settings. The role of CIRCI as a risk factor for adverse outcomes and the effectiveness of glucocorticoid treatment in this context remain critical questions. Investigating CIRCI in COVID-19 is essential for improving intensive care management. Accurate and timely CIRCI diagnosis is crucial as glucocorticoid treatment, when appropriately indicated, can be life-saving. Addressing this knowledge gap is vital for optimizing clinical decision-making and improving outcomes for critically ill COVID-19 patients.
This study aimed to: (1) describe the incidence and characteristics of probable and definite CIRCI among COVID-19 patients, emphasizing CIRCI diagnosis criteria; (2) evaluate clinical outcomes (morbidity, mortality, ventilator days, shock duration, vasopressor dependence, ICU stay, hospital length of stay, recovery rate) in critically ill COVID-19 patients with shock, comparing those treated with and without glucocorticoids; and (3) assess the incidence of adverse events associated with glucocorticoid use.
METHODOLOGY
Study Design
This single-center, retrospective cohort study investigated the occurrence of CIRCI and approaches to CIRCI diagnosis in critically ill patients with confirmed COVID-19. The study involved a review of medical records of patients admitted to designated COVID-19 inpatient units.
Study Duration
Patient records were reviewed from March 31, 2020, to June 30, 2020, encompassing the first three months after the Philippine General Hospital became a designated COVID-19 referral center.
Inclusion Criteria
The study included patients aged 19 years and older with confirmed COVID-19 infection (positive rRT-PCR assay) and an admitting diagnosis of shock or development of refractory hypotension during hospitalization. Refractory hypotension was defined as persistent systolic blood pressure <90 mmHg despite adequate fluid resuscitation, requiring vasopressor support (≥0.5 mcg/kg/min norepinephrine or equivalent, or increasing vasopressor requirements). Elevated lactate levels (>2 mmol/L) further supported shock diagnosis.18
CIRCI diagnosis criteria were defined as follows:
- Probable CIRCI: Clinical manifestations of CIRCI, including refractory hypotension poorly responsive to fluids and vasopressors or increasing vasopressor needs, potentially with other signs of adrenal insufficiency (weakness, fatigue, anorexia, abdominal pain, nausea, vomiting, hypoglycemia, hyperkalemia, hyponatremia, metabolic acidosis, eosinophilia), but without documented hypocortisolism (random cortisol level) during critical illness.
- Definite CIRCI: Clinical findings of CIRCI as above, and a random serum cortisol level of <10 mcg/dL.
Serum cortisol levels were measured using the cortisol (125I) RIA kit (Ref: RK-240CT). The ACTH stimulation test utilized Synacthen (tetracosactide acetate, 250 mcg/ampule). Analytical validity standards were met. The conversion factor for serum cortisol (nmol/L to mcg/dL) was 1 mcg/dL = 27.59 nmol/L.19
COVID-19 confirmation was based on WHO Global Surveillance for Disease Interim Guidance.20 A confirmed case was defined as a patient with or without COVID-19 symptoms, with laboratory-confirmed SARS-CoV-2 infection by rRT-PCR assay from nasal/pharyngeal swabs, sputum, bronchoalveolar lavage fluid, or other bodily fluids.4
Exclusion Criteria
Patients initially suspected of COVID-19 but testing negative and not diagnosed with COVID-19 were excluded. Patients who rapidly responded to initial fluid resuscitation or antibiotics and were weaned off vasopressors within 4 hours of shock onset were also excluded, as CIRCI was deemed unlikely. Further exclusion criteria were: pre-admission systemic glucocorticoid use (≥40 mg prednisolone equivalent daily for >1 week), use of etomidate, ketoconazole, or other adrenal insufficiency-inducing agents,21 pre-existing adrenal disease, adrenalectomy, pituitary surgery/irradiation, and pregnancy.
Outcomes
The study assessed clinical characteristics (median age, sex distribution, median blood pressure, shock etiologies, vasopressor dose, vasopressor duration, ventilator days, ICU and hospital length of stay, morbidity and mortality rates) of patients with refractory shock and probable CIRCI. Laboratory values, including serum cortisol levels, were examined. Corticosteroid utilization rates, types, and doses were also collected.
A detailed analysis compared clinical outcomes of patients with refractory shock who received corticosteroids versus those who did not. Outcomes included vasopressor days, ventilator days, vasopressor requirements, ICU and hospital length of stay, morbidity and mortality rates, and ICU severity of illness scores (Mortality Probability Model – MPM).
In the corticosteroid group, outcomes were compared between patients receiving hydrocortisone and those receiving other corticosteroids (dexamethasone, prednisone, methylprednisolone). Outcomes were also analyzed based on hydrocortisone dosage (exactly 200 mg/day vs. >200 mg/day), comparing to the recommended dose for CIRCI.10
Statistical Methods
Data analysis was performed using Stata Version 15.1. Non-normally distributed quantitative variables were summarized using medians and ranges (Shapiro-Wilk test). Qualitative variables were presented as counts and proportions. Group comparisons (corticosteroid vs. no corticosteroid, hydrocortisone vs. non-hydrocortisone) utilized the Mann-Whitney U test for medians and the Z test for proportions.
Comparisons across hydrocortisone dosage groups employed the Kruskal-Wallis test for medians and the Chi-square test for proportions. Statistical significance was set at α = 0.05.
Multivariable logistic regression analysis was used to identify mortality predictors in COVID-19 patients with CIRCI. Based on literature review, covariates included severity of illness score, shock etiology, timing of steroid initiation relative to shock onset, hypoglycemia presence, and steroid duration, as these factors were hypothesized to influence outcomes in COVID-19.16,18 All variables were included in the model as potential risk factors for mortality in CIRCI and of clinical interest.
Ethical Issues
This research was a sub-study of a larger project (“The Development and Pilot Testing of a Protocol for the Initiation and Use of Corticosteroids for Critical Illness-Related Corticosteroid Insufficiency for Patients Admitted with Shock at the Philippine General Hospital”), approved by the University of the Philippines Manila Research Ethics Review Board (Registration Number 2020-297-01).
RESULTS
Study Population Characteristics
The final analysis included 145 COVID-19 patients, representing 22.94% of all COVID-19 admissions (N=632) at PGH during the study, who presented with refractory shock and met criteria for probable CIRCI. Among these, 22 patients had serum cortisol results available. In the steroid group (n=13), median baseline cortisol was 25.4 mcg/dL, and in the non-steroid group (n=9), median baseline cortisol was 25.08 mcg/dL. Four patients met definite CIRCI criteria based on initial cortisol or ACTH stimulation testing. Two patients with indeterminate cortisol levels underwent ACTH stimulation testing for further CIRCI diagnosis.
The median age was 63 years, and the majority (57.24%) were male. Septic shock was the primary etiology in 72.22%. The average lactate level was 2.887 mmol/L, consistent with vasopressor-dependent shock.22 Norepinephrine was the primary vasopressor, sometimes supplemented with dopamine, epinephrine, or dobutamine, for a median duration of 2 days (range 0-49 days). The median SOFA score was 13, indicating a 40-50% mortality risk.23 High APACHE II and MPM scores further reflected this elevated risk. Acute respiratory failure was common, with 85.42% requiring ventilation and 81.12% diagnosed with ARDS. High rates of organ dysfunction were observed: acute kidney injury (67.59%) and central nervous system (CNS) dysfunction (79.17%). The overall mortality rate was 90.34% (Table 1).
Alt text: Table 1 presents baseline characteristics and outcomes of COVID-19 patients diagnosed with CIRCI. Key data includes median age (63 years), sex distribution (57.24% male), top shock etiologies (septic 72.22%), median SOFA score (13), APACHE II score (29), MPM score (82.7), ventilator use (85.42%), ARDS (81.12%), acute kidney injury (67.59%), CNS dysfunction (79.17%), hypoglycemia (8.97%), metabolic acidosis (11.11%), eosinophilia (2.10%), median baseline cortisol level (696.06 nmol/L), vasopressor doses, days on vasopressors (median 2), days on ventilator (median 4), ICU length of stay (median 5), hospital length of stay (median 9), morbidity (86.90%), and mortality (90.34%). The table provides a comprehensive overview of the clinical profile and poor prognosis of COVID-19 patients with CIRCI.
The median random cortisol level for the entire cohort was 25.26 mcg/dL, below the 34 mcg/dL threshold where CIRCI is considered unlikely,10 supporting the high probability of CIRCI in this population. Among patients with indeterminate cortisol levels who underwent ACTH stimulation testing, 50% exhibited a cortisol increase >9 mcg/dL, while 50% did not.
Laboratory findings suggestive of adrenal insufficiency were also prevalent. Hyponatremia (<135 mEq/L) was present in 26.9%, and hyperkalemia (>5.5 mEq/L) in 16.55%. Hypoglycemia (<70 mg/dL) occurred in 8.97%, metabolic acidosis in 11.11%, and eosinophilia in 2.10% (Table 1).
Use of Corticosteroids for COVID-19 Patients with CIRCI
Corticosteroid utilization was high (70.83%) in COVID-19 patients with refractory shock. Hydrocortisone (200 mg/day), the recommended regimen for CIRCI, was used in half of the treated patients. Other corticosteroids, primarily dexamethasone (71.57% of non-hydrocortisone steroids), were used in 68.63%. One patient received methylprednisolone. Corticosteroids were initiated early, at a median of less than one day after shock onset (range 0-31 days), and administered for a median of 4 days. Blood pressure improvement post-corticosteroid initiation was observed in 70.45% (Table 2).
Alt text: Table 2 details corticosteroid use in COVID-19 patients with CIRCI. It shows that 70.83% received corticosteroids. Among these, 31.37% received hydrocortisone (with dose breakdown: <200mg/day 9.38%, 200mg/day 50.00%, >200mg/day 40.62%). 68.63% received non-hydrocortisone steroids. Corticosteroids were initiated at a median of 0 days after shock onset and continued for a median of 4 days. Blood pressure improved in 70.45% of patients after corticosteroid initiation. The table summarizes the high utilization of corticosteroids and the types used in this patient cohort.
Use of Corticosteroids and Patient Outcomes
Patients receiving corticosteroids had significantly longer median ventilator days (p=0.001). They also exhibited higher morbidity and mortality risk, indicated by significantly higher APACHE II scores (p=0.0233), MPM scores (p=0.0006), and a greater proportion with acute kidney injury (p=0.028), oliguria (p=0.020), and CNS dysfunction (p=0.019). No significant differences were found in hospital length of stay, morbidity, or mortality rates between steroid and non-steroid groups (Table 3).
Alt text: Table 3 compares clinical characteristics and outcomes of COVID-19 patients with CIRCI, stratified by corticosteroid use. Patients receiving steroids had significantly higher APACHE II (p=0.0233) and MPM scores (p=0.0006), and longer ventilator days (p=0.0001). They also had a higher incidence of acute kidney injury (p=0.028), oliguria (p=0.020), and CNS dysfunction (p=0.019). No significant differences were found in SOFA score, ARDS, hypoglycemia, baseline cortisol, vasopressor days, ICU stay, hospital stay, morbidity, or mortality. The table highlights that while steroid use was associated with longer ventilation and greater illness severity, it did not significantly impact overall mortality in this cohort.
Two of three patients with baseline cortisol <10 mcg/dL died. Ten of fourteen patients with indeterminate cortisol levels (11-34 mcg/dL) also died. Of the two patients undergoing ACTH stimulation testing, the non-responder died, while the responder (cortisol increase >9 mcg/dL) survived.
No significant differences were seen in morbidity (p=0.062) and mortality (p=0.376) rates between patients receiving hydrocortisone and those receiving other steroids. However, the hydrocortisone group had a slightly longer median hospital stay (13 vs. 7.5 days, p=0.0231), potentially reflecting greater shock severity (Table 5). Similarly, no significant morbidity (p=0.279) or mortality (p=0.125) differences were found across varying hydrocortisone doses (Appendix).
Alt text: Table 5 compares characteristics and outcomes of COVID-19 CIRCI patients treated with hydrocortisone versus other steroids. The hydrocortisone group had a significantly longer hospital stay (p=0.0231) and a lower incidence of ventilator use (p=0.032) and ARDS (p=0.014). No significant differences were observed in SOFA score, APACHE II score, MPM score, acute kidney injury, oliguria, CNS dysfunction, hypoglycemia, baseline cortisol, vasopressor days, ventilator days, ICU stay, morbidity, or mortality. The table suggests potential differences in disease presentation and resource utilization between the two steroid treatment groups, despite similar mortality outcomes.
Steroid-induced hyperglycemia occurred in only 7 patients (6.8%) in the corticosteroid group. One patient developed hypernatremia post-corticosteroid initiation. No cases of steroid-induced myopathy, secondary infection, or bleeding were detected, indicating a low incidence of adverse events.
Predictors of Mortality Among COVID-19 Patients with CIRCI
Univariable analysis identified higher ICU risk scores, specifically SOFA (OR=1.37, CI 1.15-1.63, p=0.002) and MPM (OR=1.03, CI 1.01-1.06, p=0.002), as predictors of mortality in COVID-19 patients with CIRCI (Table 4). Multivariable analysis confirmed SOFA score as a significant independent predictor (OR=1.31, CI 1.06-1.62, p=0.013). Each 1% increase in MPM score was associated with a 31% increase in mortality odds. Days in shock at steroid initiation was a significant predictor in unadjusted analysis (OR=0.82, CI 0.68-0.99, p=0.041), with mortality odds decreasing by 18% per day in shock before steroid initiation. Duration of steroid use showed an association with mortality in logistic regression.
Alt text: Table 4 presents a multiple logistic regression analysis of mortality predictors in COVID-19 patients with CIRCI. Multivariable analysis identified SOFA score as a significant predictor of mortality (OR=1.31, p=0.013). Univariable analysis also showed MPM score (p=0.002) and APACHE II score (p=0.001) as significant predictors. Hypovolemic shock etiology was associated with lower mortality compared to septic shock (p=0.012). Days in shock when steroids were started was significant in univariable analysis (p=0.041). Steroid use, days on steroids, etiology of cardiogenic and multifactorial shock, and hypoglycemia were not significant predictors in multivariable analysis. The table highlights the SOFA score as a key independent predictor of mortality in this patient population.
DISCUSSION
COVID-19 is a complex systemic disease often leading to multi-organ dysfunction. Shock is a frequent complication, with 22-67% of patients requiring vasopressors.24 This study found a substantial 22.94% of COVID-19 admissions at PGH meeting criteria for probable CIRCI, highlighting a significant disease burden.
This cohort represented a high-risk population with critical COVID-19, as evidenced by elevated MPM and APACHE II scores, consistent with poor outcomes. Patients receiving steroids had significantly longer ventilator days, likely due to higher rates of ARDS and multiple organ dysfunction, hindering ventilator weaning. The steroid group also presented with significantly higher rates of baseline acute kidney injury, oliguria, and CNS dysfunction, further contributing to prolonged ventilation.
While no statistically significant differences in overall morbidity and mortality were observed between steroid and non-steroid groups, logistic regression suggested a potential association between longer steroid duration and decreased mortality. However, the study’s power analysis indicated that the sample size might be slightly insufficient to definitively demonstrate steroid use as a significant mortality predictor. The relatively small sample size may have limited the detection of stark outcome differences between groups.
This study, conducted early in the pandemic, reflected treatment approaches based on clinical presentation. While some patients presented with refractory shock and CIRCI signs like weakness and fatigue, a significant proportion also had acute respiratory failure (85.42%). Consequently, dexamethasone, recommended for oxygen-requiring severe COVID-19,25 was widely used. One patient received methylprednisolone for ARDS. However, compared to hydrocortisone, dexamethasone and methylprednisolone lack significant mineralocorticoid activity. This may explain why some patients remained in shock despite corticosteroid treatment and the lack of statistically significant mortality reduction in this cohort. Furthermore, the median corticosteroid duration in this study (4 days) was shorter than in the RECOVERY trial (7 days), potentially due to high early mortality in critical COVID-19, and may have contributed to the lack of mortality benefit.
Findings from this Philippine cohort align with trends from China, where studies also showed high non-hydrocortisone steroid use and high organ dysfunction rates in non-survivors.26
CIRCI diagnosis in COVID-19 presents unique challenges. Patients may exhibit refractory shock, but cortisol levels can be higher than in non-COVID-19 CIRCI due to intense inflammation.27 In this cohort, median cortisol was 25.26 mcg/dL, compared to 24.15 mcg/dL in a non-COVID subgroup at the same institution.28 However, cortisol levels were not consistently measured, and the small sample with cortisol results may have limited the detection of significantly low cortisol levels. Elevated cortisol levels in COVID-19 CIRCI may reflect the stress response to massive inflammation, potentially masking true adrenal insufficiency. CIRCI diagnosis should not solely rely on cortisol levels. Inter-individual cortisol variability and tissue glucocorticoid resistance in critical illness further complicate interpretation.24,27 Despite limitations, random cortisol levels remain valuable for guiding therapy and future management.
The pathophysiology of CIRCI in COVID-19 is complex and multifactorial. While cortisol levels may be elevated, the response is often insufficient to meet the demand in severe COVID-19. Profound inflammation with cytokines like IL-1, IL-6, and TNF-α disrupts the hypothalamic-pituitary-adrenal (HPA) axis. TNF-α blunts ACTH release, inhibiting ACTH and angiotensin II action on adrenal cells.32–34 Thus, the cytokine storm itself impairs the HPA axis. Another proposed mechanism involves SARS viruses producing ACTH-mimicking amino acid sequences, leading to antibody production and central adrenal insufficiency.35
CIRCI in COVID-19 is associated with significant morbidity and mortality. Consensus on optimal management, including CIRCI diagnosis and treatment, is crucial. Hydrocortisone, with mineralocorticoid activity, may be particularly beneficial for hypotension in this context. Evidence suggests hydrocortisone may offer similar anti-inflammatory and mortality benefits to dexamethasone and methylprednisolone due to a class effect.36,[37](#cit0037] Hydrocortisone also demonstrates endothelial protection in severe inflammation.[35](#cit0035] The REMAP-CAP trial indicated an 80% probability of benefit with hydrocortisone 200 mg/day.[38](#cit0038] Liu et al. also found hydrocortisone reduced 28-day mortality in ARDS patients, supporting a class effect.39
Hydrocortisone use in COVID-19 shock aligns with recommendations from Surviving Sepsis Guidelines for COVID-19,40 China National Commission,[39](#cit0039] and Philippine Living Clinical Practice Guidelines for COVID-19.25 Corticosteroid use in COVID-19 is deemed safe, without significant impact on secondary infection rates41 or SARS-CoV-2 viral clearance.26
This study characterized CIRCI in COVID-19 at a tertiary referral center. Limitations include the small number of cortisol measurements and ACTH stimulation tests due to resource constraints. The impact of steroid use on mortality was not fully demonstrated, possibly due to the limited sample size. The study period was during the early implementation of a CIRCI protocol, contributing to inconsistent cortisol testing. These findings highlight the need to integrate CIRCI diagnosis and management into institutional protocols for critically ill COVID-19 patients, as early detection and treatment can be life-saving.
CONCLUSION
CIRCI represents a significant disease burden in COVID-19 patients. CIRCI diagnosis in this population is uniquely challenging due to the intense inflammatory response. CIRCI is likely a marker of increased risk for adverse outcomes and mortality in COVID-19.
Acknowledgments
The authors express gratitude to Dr. Abraham Hermoso, Dr. Riza Paula Labagnoy, the staff of the Medical Records Division of the Philippine General Hospital, and Dr. Emilio Q. Villanueva III for their contributions. They also acknowledge the support of the Department of Medicine of the Philippine General Hospital, led by Dr. John Añonuevo and Dr. Jubert Benedicto.
APPENDIX
Appendix.
Comparison of patient characteristics and outcomes of patients given different doses of hydrocortisone
Alt text: Appendix Table compares characteristics and outcomes of COVID-19 CIRCI patients based on different hydrocortisone dosages: <200mg/day, 200mg/day, and >200mg/day. No significant differences were found in SOFA score, APACHE II score, MPM score, ventilator use, ARDS, acute kidney injury, oliguria, CNS dysfunction, hypoglycemia, baseline cortisol, vasopressor days, ventilator days, vasopressor requirements, ICU stay, morbidity, or mortality across the dosage groups, except for a statistically significant difference in hospital length of stay (p=0.0112). The appendix table suggests that varying hydrocortisone doses within this cohort did not significantly impact most clinical outcomes, except for hospital length of stay.
Statement of Authorship
All authors certified fulfillment of the ICJME authorship criteria.
CRediT Author Statement
AEA: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft preparation, Writing – review and editing, Visualization, Project administration, Funding acquisition; KWL: Validation, Formal analysis, Investigation, Data curation, Writing – original draft preparation, Writing – review and editing, Visualization; MA: Validation, Formal analysis, Investigation, Data curation, Writing – original draft preparation, Writing – review and editing, Visualization; CJ: Conceptualization, Methodology, Software, Validation, Formal analysis, Data curation, Writing – original draft preparation, Writing – review and editing, Visualization, Supervision.
Author Disclosure
Dr. Anna Arcellana is a junior manuscript editor at JAFES. Dr. Cecilia Jimeno is the Vice Editor-in-Chief of JAFES. The other authors did not declare any conflicts of interest.
Funding Source
This study is part of a research project on critical illness-related corticosteroid insufficiency funded by the Philippine College of Endocrinology, Diabetes, and Metabolism and the Expanded Health Research Office of the Philippine General Hospital.
References
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