Variable Levels of Oxytocin During Sepsis: The Role of Oxytocin in Sepsis Pathophysiology.

BACKGROUND: Although the role of oxytocin in the pathophysiology of sepsis is still unknown, rising preclinical evidence suggests that oxytocin is possibly involved. However, no direct clinical studies have measured the levels of oxytocin during sepsis. In this preliminary study, the serum oxytocin levels were evaluated throughout the duration of sepsis. METHOD: Twenty-two male patients over 18 years of age with a SOFA score of 2 points or more who were admitted to the ICU were included. Patients with a history of neuroendocrine, psychiatric, and neurologic disorders, cancer, an infection caused by COVID-19, shock due to reasons other than sepsis, a history of psychiatric or neurologic medication use, and those who died during the study were excluded. The main endpoint included the measurement of serum oxytocin levels using radioimmunoassay at 6, 24, and 48 h of the ICU admission. RESULTS: Mean serum oxytocin level was higher at 6 h of ICU admission (41.27 ± 13.14 ng/L) than after 24 and 48 h of ICU admission (22.63 ± 5.75 and 20.97 ± 7.61 ng/L respectively) (P-value < .001). CONCLUSION: Our study, while reporting increased serum oxytocin levels in the initial phase of sepsis and decline afterward, supports the possible contribution of oxytocin in the pathophysiology of sepsis. Given that oxytocin seems to modulate the innate immune system, future investigations are necessary to assess the potential role of oxytocin in the pathophysiology of sepsis.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Serum level of Vitamin D is associated with COVID-19 mortality rate in hospitalized patients.

BACKGROUND: Due to widespread of coronavirus disease 2019 (COVID-19) infection, identification of its risk factors and clinical characteristics are important. The aim of the present study was to assess Vitamin D levels in individuals with severe acute respiratory syndrome coronavirus-19 infection and to report on its potential as a predictive marker. MATERIALS AND METHODS: All patients, diagnosed with COVID-19 infection from February 16 to March 21, 2020, and referred to Firoozgar Hospital, Tehran, Iran, were enrolled in this study. Vitamin D analysis was undertaken on patient serum samples using a commercial kit (Pars Azmoon Co., Tehran, Iran). SPSS v. 22 was used for statistical analysis. RESULTS: Vitamin D serum concentration was analyzed in a total of 317 patients whose mean age ± standard deviation was 62.05 ± 15 years and with 62.5% being male. A significant association of Vitamin D level and death was observed. Higher levels of serum Vitamin D had protection against death (odds ratio = 0.955 [95% confidence interval = 0.923-0.988], P = 0.008). CONCLUSION: As a preliminary study in the Iranian population who suffered COVID-19 disease, we identified that Vitamin D deficiency was associated with a higher death rate and intensive care unit admission.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

The predictive power of serum vitamin D for poor outcomes in COVID-19 patients.

Considering the high prevalence of vitamin D deficiency worldwide and its relationship with immune response to viral infections, this study attempted to identify the predictive power of serum vitamin D for poor outcomes among the COVID-19 patients. This retrospective cohort study included all patients with confirmed COVID-19 hospitalized between February 20, 2020, and April 20, 2020, at a designated COVID-19 hospital, located in Tehran province, Iran. General characteristics, medical history and clinical symptoms were recorded by trained physicians. Blood parameters including complete blood count, creatinine, lactate dehydrogenase, creatine phosphokinase, erythrocyte sedimentation rate, C-reactive protein and vitamin D were tested. This study included 290 hospitalized patients with COVID-19 (the mean age [SD]: 61.6 [16.9], 56.6% males), of whom 142 had vitamin D concentrations less than 20 ng/ml, defined as vitamin D deficiency. COVID-19 patients with vitamin D deficiency were more likely to die (Crude OR [95% CI]: 2.30 [1.25-4.26]), require ICU (2.06 [1.22-3.46]) and invasive mechanical ventilation (2.03 [1.04-3.93]) based on univariate logistic regression results. Although, after adjusting for potentials confounders such as gender and age, the association between vitamin D and need to invasive mechanical ventilation lost its significance, adjusted values for the risk of death and ICU requirement were still statistically significant. Vitamin D deficiency can be considered as a predictor of poor outcomes and mortality in COVID-19 patients. Therefore, checking serum 25 (OH) D on admission and taking vitamin D supplements according to the prophylactic or treatment protocols is recommended for all COVID-19 patients.

Infliximab and Intravenous Gammaglobulin in Hospitalized Severe COVID-19 Patients in Intensive Care Unit.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) may lead to the cytokine storm syndrome which may cause acute respiratory failure syndrome and death. Our aim was to investigate the therapeutic effects of infliximab, intravenous gammaglobulin (IVIg) or combination therapy in patients with severe COVID-19 disease admitted to the intensive care unit (ICU). METHODS: In this observational research, we studied 104 intubated adult patients with severe COVID-19 infection (based on clinical symptoms, and radiographic or CT scan parameters) who were admitted to the ICU of a multispecialty hospital during March 2020 in Tehran, Iran. All cases received standard treatment regimens as local protocol (Oseltamivir + hydroxychloroquine + lopinavir/ritonavir or sofosbuvir or atazanavir ± ribavirin). The cases were grouped as controls (n = 43), infliximab (n = 27), IVIg (n = 23) and combination (n = 11). RESULTS: There was no significant difference between controls and treatment groups in terms of underlying diseases or the number of underlying diseases. The mean age (SD) of cases was 72.42 (16.06) in the control group, 64.52 (12.965) in IVIg, 63.40 (17.57) in infliximab and 64.00 (11.679) in combination therapy; (P = 0.047, 0.031 and 0.11, respectively). Also, 37% in the infliximab group, 26.1% in IVIg, 45.5% in combination therapy, and 62.8% in the control group expired (all P < 0.05). Hazard ratios were 0.31 in IVIg (95% CI: 0.12-0.76, P = 0.01), 0.30 in infliximab (95% CI: 0.13-0.67, P = 0.004), 0.39 in combination therapy (95% CI: 0.12-1.09, P = 0.071). CONCLUSION: According to the findings of this study, it seems that infliximab and IVIg, alone or together, in patients with severe COVID-19 disease can be considered an effective treatment.

Troponin is a useful marker in clinical decision making in hospitalized patients with COVID-19 infections.

BACKGROUND: COVID-19 was introduced by the World Health Organization (WHO) as a global pandemic. The disease manifestations ranges from a mild common cold to severe disease and death. It has a higher mortality rate in people with a history of comorbidities, including cardiovascular disease (CVD) and can also contribute to cardiac injury. This study was conducted to evaluate the relationship between troponin levels as a cardiac marker and adverse outcomes in this disease. METHODS: The study sample included 438 patients hospitalized with COVID-19; however, the troponin data of 6 patients were not available. The need to be admitted to the intensive care unit (ICU), and death were considered the adverse outcome in patients with COVID-19. Troponin levels were checked in all patients on day 1 and day 3 of hospitalization. Multiple logistic regression analysis was performed to determine whether there was an independent association between the adverse outcomes and troponin enzyme in hospitalized patients with COVID-19. RESULTS: The mean age of patients was 61.29 ± 15.84 years. Among the 432 patients tested on day 1 of hospitalization, 24 patients (5.6%) tested positive (Troponin 1), and among the 303 patients tested on day 3, 13 patients (4.3%) tested positive (Troponin 2). Based on our results, Troponin 1 showed an independent association with both death (3.008 [95%CI = 1.091-8.290]; P = 0.033) and need for ICU admission (8.499 [95%CI = 3.316-21.788]; P < 0.001) in multiple logistic regression analysis. Moreover, the status of Troponin 2 had an independent significant association with both death (4.159 [95%CI = 1.156-14.961]; P = 0.029) and ICU admission (7.796 [95%CI = 1.954-31.097]; P = 0.004). CONCLUSION: Troponin showed a significant association with adverse outcomes in people who were hospitalized with COVID-19. The periodical assessment of this enzyme from the time of hospitalization may improve the clinical decision making of clinicians.

Angiotensin Converting Enzyme Inhibitors, A Risk Factor of Poor Outcome in Diabetic Patients with COVID-19 Infection.

INTRODUCTION: Diabetes mellitus and hypertension are described as the most common comorbidities among COVID-19 patients. We investigated the adverse effect of ACEIs in diabetic and nondiabetic patients with COVID-19. METHODS: This prospective study consisted of 617 RT-PCR-confirmed COVID-19 inpatients. Demographic and baseline characteristics, underlying comorbid diseases, and antihypertensive drugs were evaluated. Study outcome (in-hospital death) was evaluated with the Kaplan-Meyer method and Cox regression model. Statistical analyses were performed with SPSS software for Windows. P values < .05 were considered significant. RESULTS: Mean ± SD age was 58.49 ± 15.80 (range: 18 to 94) years old. Cox regression analysis revealed that age (adjusted hazard ratio [HR] = 1.04, 95% CI: 1.03 to 1.06), diabetes mellitus (adjusted HR = 2.07, 95% CI: 1.32 to 3.26), immunocompromised patients (adjusted HR = 2.33, 95% CI: 1.29 to 4.21), acute kidney injury (AKI) (adjusted HR = 3.23, 95% CI: 2.01 to 5.19), ICU admission (adjusted HR = 2.48, 95% CI: 1.46 to 4.21), Asthma and COPD (adjusted HR = 2.13, CI:1.6 to 4.28) and ACEI (adjusted HR = 3.08, 95% CI: 1.56 to 6.06), respectively were associated with in-hospital death. Among diabetic patients, ACEI (adjusted HR = 3.51, 95% CI: 1.59 to 7.75), AKI (adjusted HR = 3.32, 95% CI: 1.76 to 6.45) and ICU admission (adjusted HR = 3.64, 95% CI: 1.530 to 8.65) were associated with increased mortality. The Kaplan-Meier survival curve showed a lower survival rate in diabetic patients with ACE inhibitor (adjusted HR = 3.36, 95% CI: 2.25 to 7.71). CONCLUSION: ACEIs may harm the diabetic patient's outcome with COVID-19. Further studies can confirm if ACE inhibitors have an adverse effect on COVID-19 diabetic patient's mortality.

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

BACKGROUND: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.

Abdominal Compartment Syndrome in Critically Ill Patients.

BACKGROUND: Abdominal compartment syndrome patients suffer severe obstacles such as kidney failure and shock. To evade further complications, identifying the abdominal compartment syndrome (ACS) and Intra-abdominal hypertension (IAH), in critically ill individuals and hospitalised in the intensive care unit (ICU) is obligated. AIM: The current study intended to study the abdominal compartment syndrome and the concomitant risk factors among hospitalised patients in ICU, by using the Intra-abdominal pressure test. MATERIAL AND METHODS: One hundred and twenty-five hospitalised patients at ICU entered the current survey. Abdominal pressure was measured by standard intravesical technique. The SPSS 21 analysed the preoperative and intraoperative factors such as demographic records and comorbidities. RESULTS: Seventy-three (58.4%) participants were males and 52 (41.6%) were women in the mean age of 55.1 ± 18.3 years. Eighty-nine patients (71.2%) showed normal intra-abdominal pressure since 31 patients (24.8%), and 5 patients (4%) developed IAH and ACS. The intra-abdominal pressure (IAP) applied to Glasgow Coma Scale (GCS), Acute Physiology, shock, Systemic Inflammatory Response Syndrome (SIRS), central venous oxygen saturation and Chronic Health Evaluation (APACHE II) score (P < 0.05). Patients with high IAP have shown a higher mortality frequency, compared to others (P < 0.05). CONCLUSION: Current findings showed a correlation between IAP hospitalised patients in ICU and shock, SIRS, APACHE II, central venous oxygen saturation and GCS. Intra-abdominal pressure test, as a valuable prognosis test for the abdominal compartment syndrome (ACS) and Intra-abdominal hypertension (IAH), may offer better results when added to the routine medical checkup of ICU patients.

Procalcitonin and Proinflammatory Cytokines in Early Diagnosis of Bacterial Infections after Bronchoscopy.

BACKGROUND: Fiberoptic bronchoscopy (FOB) guided bronchoalveolar lavage (BAL) remains as the chief diagnostic tool in respiratory disorders. 1.2-16% of patients frequently experience fever after bronchoscopy. To exclude the need for multiple antibiotic prescribing in patients with post-bronchoscopy fever, the presence of the self-limiting inflammatory responses should be excluded. AIM: The current study was conducted to test the serum of patients undergoing bronchoscopy for some proinflammatory cytokines including Tumor Necrosis Factor-alpha (TNF-ɑ), Interleukin-1beta (IL-1ß), Interleukin-8 (IL-8) and Interleukin-6 (IL-6) and the value of Procalcitonin (PCT). MATERIAL AND METHODS: Current case-control study was conducted at the National Research Institute of Tuberculosis and Lung Disease in Iran. Nineteen patients (48.72%) that attended with a reasonable sign for a diagnostic bronchoscopy from January 2016 to December 2017 were included in the case group. The control group consisted of 20 patients who underwent a simple bronchoscopy and without FOB-BAL. The laboratory findings for PCT concentrations and cytokine levels in the three serum samples (before FOB-BAL (t0), after 6 hr. (t1), and at 24 hr. past (t2) FOB-BAL) were compared between two groups. RESULTS: The frequency of post-bronchoscopy fever was 5.12, and the prevalence of post-bronchoscopy infectious fever was 2.56%. PCT level was considerably higher in the patient with a confirmed bacterial infection when compared to other participants (p-value < 0. 05). Interestingly, IL-8 level in the bacterial infection proven fever patient was higher than in other patients (p < 0.001). IL-8 levels displayed a specificity of 72.7% and a sensitivity of 100%, at the threshold point of 5.820 pg/ml. PCT levels had a specificity of 84% and a sensitivity of 81%, at the threshold point of 0.5 ng/ml. CONCLUSION: The present findings show that in patients with fever after bronchoscopy, PCT levels and IL-8 levels are valuable indicators for antibiotic therapy, proving adequate proof for bacterial infection. The current findings also illustrate that to monitor the serum levels of PCT and proinflammatory cytokines in the patients undergoing FOB-BAL, the best time is the 24-hour postoperative bronchoscopy.

Successful treatment of Chronic Myelogenic Leukemia (CML) with imatinib after renal transplantation.

Chronic Myelogenic Leukemia (CML) is a rare malignant disorder after solid organ transplantation, especially in renal transplant recipients. Imatinib Mesylate is currently approved as first line treatment of CML. Most reports on CML are from kidney recipients who received azathioprine  in combination with cyclosporine and prednisolone as immunosuppressive therapy. We report a case with CML who was treated with Mycophenolate Mofetil.