Patients aged above 18 years (males and females) were recruited from the intensive care unit at the Bagcilar Training and Research Hospital, Istanbul, Turkey. A total of 119 patients with documented COVID-19 were included in the study.
Patients were admitted to critical care unit mostly for severe pneumonia and related ARDS. Other indications were MODS and myocardial infarction. Indications for admission to critical care were determined by advisory board committee of ministry of health in Turkey . According to that in addition to pulmonary infiltrates on thorax computerized tomography, patients with (a) respiratory rate >30/minute, (b) dyspnea and respiratory failure, (c) patient with oxygen saturation <90% and PaO2 <70mmHg (despite nasal oxygen supply of 5 liters/minutes), (d) Pa02/Fi02 <300, (e) lactate>4mmol/L, (f) bilateral infiltration or multilobar involvement in lung CT, (g) hypotension, (h) skin perfusion disorder, (i) kidney and liver function test disorder, thrombocytopenia and organ dysfunction, (j) immunosuppressive patients, (k) uncontrolled comorbidity, (l) elevated troponin, arrhythmia.
All of the patients needed assisted ventilation either by intubation (n=60) or noninvasive mechanical ventilation (NIMV) (n=59). MODS was described as change in consciousness, respiratory failure, low oxygen saturation, low urine output, increase in creatinine, increase in heart rate, filiform pulses, cold extremities, low blood pressure, coagulopathy, thrombocytopenia, acidosis, increase in lactate level and hyperbilirubinemia.
According to national COVID-19 treatment protocol(12), besides standard supportive care, all of the patients received hydroxychloroquine at a dose of 200mg/day, 98.3% favipiravir 200 mg/day, 37.8% azithromycin 500 mg/day, 17.6% oseltamivir 200 mg/day, 97.4% antibiotics either as piperacillin-tazobactam, meropenem, linezolid or daptomycin. Also, all patients received enoxaparin sodium 6000 IU twice daily and 15-gram parenteral vitamin C infusion every day.
Concomitant diseases were recorded. Subjects with any disease that can affect cortisol secretion such as brain tumors, pituitary diseases, and adrenal diseases were excluded. Patients who were pregnant or have alcohol abuse were also not included. Patients on treatment with drugs that can directly or indirectly cause or affect cortisol metabolism were also excluded. But, medications that patient on treatment for chronic diseases were recorded and included into the study such as antihypertensive medications, antidiabetics etc.
This study was conducted in accordance with the guidelines proposed in the Declaration of Helsinki and was approved by the ethical committee of Bagcilar Training and Research Hospital (2020.05.1.10.042). All subjects or legal representative gave informed consent before entrance into the study.
All patients were seen in intensive care units. After collection of demographic data, laboratory results used in evaluation and follow-up of a COVID-19 was recorded from patient file e.g. complete blood count, lymphocyte count, C-reactive protein (CRP), fibrinogen, D-dimer, lactate dehydrogenase (LDH), ferritin, triglyceride, troponin-I, creatine kinase (CK), blood urea, creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). These laboratory tests were a part of routine assessment and we did not add any other test than those.
Assessment of Adrenal Function
For the diagnosis of adrenal insufficiency in patients in critical care, Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 recommendations were used . The task force recommended delta cortisol (change in baseline cortisol at 60 min of < 9 μg/dL) after cosyntropin (250 μg) administration and a random plasma cortisol of < 10 μg/dL to be used for diagnosis.
Initially blood drawn from all patients for random cortisol. Patients with random cortisol level below 10 μg/dL were directly accepted as adrenal insufficiency and values above 34 μg/dL were accepted as intact adrenal gland. If random cortisol was between 10-34 μg/dL, patients were directed to cosyntropin stimulation test. But instead of 250 μg which is thought to be supra-physiologic for assessment of these patients, we used 1 μg test. Both tests are equally accurate to identify mortality and time of vasopressor therapy (14). Delta cortisol (change in baseline cortisol at 30 or 60 min of < 9 μg/dL) after cosyntropin (1 μg) administration was accepted as adrenal insufficiency.
Patients who had diagnosed as CIRCI were administered intravenous hydrocortisone at a dose of 100 mg three times daily during ICU stay. If patient recovered from COVID-19 and clinically stabilized hydrocortisone dose was steadily tapered to maintenance dose of 30 mg/day and until reassessment of adrenal function they were suggested to continue hydrocortisone after discharge. Other patients who had initial cortisol level above 34 μg/dL or patients who had > 9 μg/dL increase in cosyntropin test were not given any corticosteroid therapy. All patients also received standard supportive care and COVID-19 specific medications.
Assessment of Pulmonary Involvement
All patients presenting with dyspnea or symptoms like coughing were directed to computerized tomography of thorax . In order to assess the severity of pulmonary involvement, we stratified patients into three groups: patients who had involved pulmonary surface area on CT scan less than 25% were accepted as mild, 25-50% moderate, >50% severe. All scans were assessed by same radiologist.
Treatment of Comorbidities
If patients were stable in concomitant diseases, we did not change their therapy unless clinical condition created a contraindication for the use of medications such renal dysfunction or hepatic failure. For the treatment of diabetes, oral antidiabetics were stopped, and insulin infusion was introduced to control glycaemia. Antihypertensive treatment was continued unless contraindicated or patient becomes hypotensive. All other medications were continued.
Assessment of mortality
In-hospital mortality was recorded with the exact reason.
All laboratory assays were studied at the central laboratory of Bagcilar Training and Research Hospital. Serum LDH, AST, ALT, Urea, creatinine, CRP, CK, triglyceride was studied with photometric method in Beckman Coulter AU4800, Fibrinogen, D-dimer, was studied in Succeeder sf-8200. Complete blood count was studied with absorption photometry and flow cytometry in Sysmex XN-900.
Statistical analyses were performed using SPSS software version 25. Descriptive analyses were presented using means and standard deviations for continuous data and frequencies and percentages for categorical data. Since the variables were normally distributed, independent samples t-test was used to compare the groups. The Chi-Square and Fisher’s exact test, where appropriate, were used to compare the percentages in the groups. For the multivariate analysis, the possible risk factors identified statistically significant with the univariate analyses were further entered into lineer regression analysis to determine independent predictors of adrenal insufficiency. A 5% type-I error level was used to infer a statistical significance.