Possible Role of Selective Serotonin Reuptake Inhibitors (SSRIs) in Clinical Outcome of COVID-19 Patients

In February 2020, the World Health Organization officially named the disease caused by the new corona virus as COVID-19 (Corona Virus Disease 2019). For COVID-19 patients, there are usually four phases of the disease. The first one is virus reproduction phase. The second phase is accompanied with mild symptoms and usually includes flu-like symptoms. The third phase is associated with the development of acute respiratory distress syndrome (ARDS) and is characterized by its symptoms. The fourth phase is associated with high fever, systemic inflammatory responses, especially in the lungs, and eventual respiratory failure. COVID-19 is associated with upregulations of inflammatory cytokines. In the acute phase of COVID-19, the function of TCD4+ cells are impaired and the production of interferon-gamma (IFN-γ) and Tumor Necrosis Factor-alpha (TNF-α) in these cells is reduced. With impaired immune function, virus replication continues, and damaged lung cells induce excessive inflammatory responses and overproduction of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 from immune cells. This eventually induce cytokine storm with systemic inflammatory responses and end organ damage. The level of inflammatory cytokines such as IL-1β, IL-6 and IL-10 in COVID-19 patients has been reported to be higher in COVID-19 patients admitted in ICU. The lack of effective treatment for the severe infection caused by COVID-19 has led scientists and physicians to repurpose popular medications that are indicated for other similar conditions. No effective modality to successful management of this viral disease has yet been identified. Immunosuppressive and anti-inflammatory drugs have been suggested for acute patients with cytokine storms and severe lung involvement. Recently, due to the anti-inflammatory effects of selective serotonin reuptake inhibitors (SSRIs), their therapeutic effects have been proposed for COVID-19 patients. This group of drugs are usually prescribed to treat depressive disorders. SSRIs have been shown to reduce inflammation and the expression of inflammatory cytokines such as TNF⍺ and IL-1β. The decrease in inflammatory cytokines such as IL-1β and TNF-α in the cerebral tissue has been shown as a result of sertraline administration, indicating the anti-inflammatory effects of this drug. In another study, Fluvoxamine could lower IL-1β, IL-6, and TNFα expression in the striatum in depressed mice. Much attention is paid to sertraline due to its very low anticholinergic activity which is especially desirable for the elderly with coronary heart diseases. Moreover, the anti-inflammatory properties of this compound is attributed to prevention of the expression of pro-inflammatory cytokines. Recently, it was demonstrated that treatment of patients with major depression with SSRIs could reduce the expression of inflammatory cytokines, such as IL-10, TNF-α, and IL-6 in these patients. The expression of these inflammatory mediators increase in critically ill COVID-19 patients. Therefore, the use of this class of medications in the management of COVID-19 patients could be considered, especially for acute patients with cytokine storms. In a recently published study, the use of antidepressants SSRI and paroxetine and SNRI venlafaxine in hospitalized patients due to COVID-19 reduced the risk of intubation and death. This therapeutic effect on COVID-19 could be attributed to the inhibition of acid sphingomyelinase activity, which prevents epithelial cell from being infection by SARS-CoV2. It has also been suggested that S1A (σ-1- receptor) agonists can prevent cytokine storms in severe COVID-19. SSRIs, especially fluvoxamine and to a lesser extent sertraline have a moderate to high affinity for this receptor. Antidepressants are associated with decreased plasma levels of pro-inflammatory cytokines which elevate in COVID-19. Furthermore, the antiviral activity of some antidepressants such as fluoxetine has been reported in COVID-19 patients. In a randomized clinical trial on adult outpatients with COVID-19, administration of 100 mg of fluvoxamine reduced the likelihood of clinical deterioration over 15 days. This has been attributed to the high affinity of fluvoxamine for S1R, which reduces the inflammatory responses. It seems that SSRIs are potential candidates for COVID-19 due to their anti-inflammatory properties. Future clinical studies will determine the exact role of this class of medications in clinical outcomes of COVID-19 patients

A Comparison of inflammatory markers in two different CLP procedures in murine polymicrobial sepsis model

Introduction: Sepsis, a common and costly cause of inpatient mortality in both sexes and all age groups (particularly in intensive care units), ensues an inflammatory process involving a variety of pathogen-expressed conserved structures called pathogen associated molecular pattern (PAMP) which are considered the main cause of oxidative stress and increase in inflammatory markers. Methods and Results: In this murine model study, male Wistar rats were assigned into three groups: CLP with gauge 18, CLP with gauge 21, and a sham group (a group without CLP). Subsequently, 24 hours following the surgery, all animals were sacrificed and inflammatory markers such as myeloperoxidase (MPO), reactive oxygen species (ROS) and lipid peroxidation (LPO) were measured in their cardiac tissues. In CLP group with gauge 18, LPO, ROS, and MPO were significantly increased in comparison with the other two groups. Moreover, although lower in comparison with the gauge 18 CLP group, LPO, ROS, and MPO were significantly higher in gauge 21 CLP group compared to the sham group. Conclusions: In murine models of sepsis, the gauge size can be influential in study outcomes and inflammatory changes observed in gauge 18 CLP mice can be considered as the most reliable and clinically-relevant indicators of sepsis-induced inflammation in humans.&nbsp

Porównanie wpływu leczenia metforminą i insuliną na kontrolę glikemii u krytycznie chorych pacjentów

Introduction: It is accepted that preventing hyperglycaemia during critical illness while assuring adequate caloric intake can reduce mortality and morbidity. The aim of this study was to compare the metabolic effects of metformin and insulin on hyperglycaemia in ICU patients. Methods: This double-blind randomised clinical trial was performed on 24 patients who were admitted to the intensive care unit (ICU) from 20 March to 20 September 2007. All patients with serious injuries or with major non-abdominal surgeries were included if they met the inclusion criteria, and were assigned randomly to one of the study groups. Patients in Group 1 received intensive insulin therapy, and patients in Group 2 were treated with metformin. Moreover, the Acute Physiology And Chronic Health Evaluation (APACHE) II scoring system was used to grade disease severity. Results: Both glycaemic management protocols led to significantly improved glucose levels without any report of hypoglycaemia. The mean initial glucose levels for the insulin group decreased significantly after the intravenous infusion of insulin (p < 0.001). Additionally, the blood glucose concentration was significantly lower after two weeks of metformin administration compared to baseline measurements (p < 0.001). Moreover, the blood glucose concentration decrease during these two weeks was significantly higher in the insulin group (p = 0.01). Besides, APACHE II score was lower than baseline at the end of the study for both therapeutic groups (score of 10 vs. 15 [insulin] and 16 [metformin]). Finally, new renal dysfunction (maximum serum creatinine level at least double the initial value) was observed in three of the patients (two patients from the metformin group and one from the insulin group) in the last days of the protocol, although none of the patients showed lactic acidosis after ICU admission. Conclusions: Both metformin and intensive insulin therapy significantly decreased hyperglycaemia in ICU patients. Insulin caused a greater reduction in blood glucose concentration but required more attention and trained personnel.Wstęp: Dowody naukowe wskazują, że zapobieganie hiperglikemii u osób w stanie krytycznym przy zapewnieniu odpowiedniego poboru kalorii może zmniejszyć śmiertelność i chorobowość. Celem niniejszego badania było porównanie wpływu metforminy i insuliny na występowanie hiperglikemii u pacjentów leczonych na oddziale intensywnej opieki medycznej (OIOM). Materiał i metody: Badanie z randomizacją przeprowadzone metodą podwójnie ślepej próby obejmowało 24 chorych przyjętych na OIOM w okresie od 20 marca do 20 października 2007 roku. Wszystkich pacjentów z ciężkimi obrażeniami lub po poważnych zabiegach chirurgicznych niedotyczących jamy brzusznej, którzy spełniali kryteria włączenia, przydzielono losowo do jednej z grup terapeutycznych. U chorych przydzielonych do grupy 1. stosowano intensywną insulinoterapię, natomiast chorym z grupy 2. podawano metforminę. Do oceny ciężkości stanu chorych wykorzystano skalę APACHE (Acute Physiologic Assessment and Chronic Health Evaluation) II. Wyniki: Oba protokoły leczenia hipoglikemizującego spowodowały istotną poprawę wyrównania glikemii, przy czym nie odnotowano żadnego przypadku hipoglikemii. W grupie stosującej insulinoterapię średnie stężenie glukozy obniżyło się istotnie w stosunku do wartości wyjściowych po dożylnym wlewie insuliny (p < 0, 001). U osób leczonych metforminą po 2 tygodniach przyjmowania leku stężenie glukozy we krwi było istotnie niższe od poziomu wyjściowego (p < 0,001). Redukcja stężenia glukozy w ciągu tych 2 tygodni była istotnie większa w grupie przyjmującej insulinę (p = 0,01). W obu grupach terapeutycznych punktacja w skali APACHE II w momencie zakończenia badania była niższa od wartości wyjściowych (10 punktów v. 15 [insulina] i 16 [metformina]). U 3 chorych (2 osoby przydzielone do leczenia metforminą i 1 osoba przydzielona do insulinoterapii) zaobserwowano rozwój niewydolności nerek de novo (maksymalne stężenie kreatyniny w surowicy co najmniej 2-krotnie większe od wartości wyjściowych) w ostatnich dniach stosowania protokołu leczenia hipoglikemizującego, chociaż u żadnego z pacjentów nie stwierdzono kwasicy mleczanowej po przyjęciu na OIOM. Wnioski: Zarówno leczenie metforminą, jak i intensywna insulinoterapia istotne zmniejszają hiperglikemię u pacjentów na OIOM. Insulina powoduje większą redukcję stężenia glukozy, jednak jej stosowanie wymaga większej uwagi, a personel medyczny musi być odpowiednio przeszkolony

Effect of vitamin C on coagulation factors and endothelium function in patients with sepsis

Objective: Sepsis is one of the leading causes of mortality in intensive care unit. Despite advances in its management, its mortality rate remains high. Recently, high dose of vitamin C in sepsis treatment has attracted the attention of researchers. In the current study, the impacts of 25 mg/kg of vitamin C every 6 hours as a bolus for 3 days were assessed in septic patients in intensive care unit (ICU).&nbsp;Methods: This was a prospective cohort study that was performed on adult patients with diagnosis of sepsis. Patients were assigned to control group (administration of placebo) or intervention group, i.e., those receiving a 25 mg/kg dose of vitamin C every 6 hours as a bolus for 3 days. Clinical data were recorded before and after the experiment. Also, plasma levels of antithrombin III, syndecan-1, fibrin degradation product (FDP), D-dimer, and C-reactive protein (CRP) were measured at 0, 24, 48, and 72 hours.&nbsp;Results: In septic patients receiving vitamin C, a significant upregulation of antithrombin III and significant decreases in the levels of syndecan-1 (at 48 hours; P-value=0.046 and at 72 hours; P-value=0.007), D-dimer and CRP were observed compared to the control. Reductions in sequential organ failure assessment (SOFA) score, in-hospital mortality, and ICU length of stay were seen in septic patients receiving vitamin C.&nbsp;Conclusion: Prescribing high dose of intravenous vitamin C can reduce the mortality of sepsis patients and reduce the length of stay in the ICU

Is Albumin-based Resuscitation in Severe Sepsis and Septic Shock Justifiable? An Evidence from a Cost-effectiveness Evaluation

BACKGROUND: Fluid and antimicrobial therapy are the essential parts of sepsis management. The type of fluid to resuscitate with is an unsettled issue in the treatment of severe sepsis and septic shock. The objective of this study was to evaluate the cost effectiveness of albumin-based resuscitation over crystalloids.METHODS: A cost-effectiveness analysis was conducted by extracting data from a database of Sina Hospital, Islamic Republic of Iran. A decision tree was constructed by using Tree Age Pro2011. The patients were grouped based on the types of fluids used for resuscitation into crystalloid alone or crystalloid + albumin groups at the initial decision node. The patients were followed from the onset of severe sepsis and septic shock upto 28 days. The healthcare payers’ perspective was considered in constructing the model. The cost was measured in US dollars and the effectiveness was measured by life years gained.RESULTS: The addition of albumin during resuscitation of patients with severe sepsis and septic shock has an effectiveness gain of 0.09 life years and cost increment of 495.00 USD. The estimated ICER for this analysis was 5500.00 USD per life year gained. The probability that albumin is cost-effective at one GDP per capita is 49.5%.CONCLUSION: Albumin-based resuscitation is not cost-effective in Iran when a GDP per capita was considered for a life year gain. The cost-effectiveness was insensitive to the cost of standard care. We recomend the caustious use albumin as per the Surviving Sepsis Campaign guideline.

Metabolic Modeling-Based Drug Repurposing in Statin: An Overview of Mechanistic Approaches in the Management of Craniocerebral Trauma

Drug repurposing, known as drug repositioning, is considered a method for redeveloping a compound to utilize in a distinctive illness, which is now becoming a progressively critical procedure for industrial researchers and the scholarly community. A large number of repurposed medicines have been discovered by chance in the lab or through the careful monitoring of drug action in the clinic and retrospective analysis of clinical findings. Additionally, statins are broadly used to treat hyperlipidemia and prevent cardiovascular disease although their application as the neuroprotective agents weakening secondary neurological harm is yet limited in traumatic brain injury (TBI). Their other non-cholesterol-mediated (i.e., pleiotropic) mechanisms of action include upregulating endothelial nitric oxide synthase expression, and enhancing neurogenesis and synaptogenesis, as well as anti-apoptotic effects, increased angiogenesis, and various antioxidant and anti-inflammatory mechanisms. Almost all studies have supported the potential role of statins in neuroprotection, and a few have particularly focused on their effects in traumatic brain injury models. The sulfonylurea receptor 1 (SUR1) protein is a regulatory component linked with pore-forming ion channels. Thus, ATP-sensitive potassium (KATP) channels are created, which can be demonstrated in pancreatic islet cells and certain neurons. Further, transient receptor potential melastatin 4 (TRPM4) is the second pore-forming subunit of SUR1. Upregulating SUR1 and opening SUR1-TRPM4 opening have been observed in the different models related to central nervous system (CNS) injuries such as TBI. Sulfonylurea drugs may prevent neuronal degeneration and improve post-TBI cognitive results by inhibiting the SUR1-TRPM4 channel

Evaluation of the Effects of Melatonin Supplementation on Coagulation in Patients with Haemorrhagic Stroke; A Randomized, Double-Blind, Controlled Trial

Introduction: Considering that hemorrhagic stroke patients are at higher risk for bleeding, administration of higher doses of melatonin with a controversial coagulation profile is a serious concern.&nbsp;Objective: This study aimed to investigate the possible effects of high doses of melatonin on bleeding parameters and blood hemostasis in hemorrhagic stroke patients.&nbsp;Methods: This study is a randomized, double-blind, prospective, controlled trial. Confirmed hemorrhagic stroke patients were divided into two groups. Participants were randomly assigned into the melatonin group (30 mg daily via gastric tube gavage for 5 consecutive days) or the control group. Each patient was monitored for 5 days, and 2 blood samples were taken and the effect of the intervention on coagulation factors and blood hemostasis were investigated.&nbsp;Result: In total, 30 patients were randomly assigned to melatonin (n=15) or control groups (n=15). there was no significant difference between the two groups in demographic and clinical characteristics. There was a significant decline in prothrombin time (PT) and fibrinogen levels in the melatonin group (p=0.011 &amp; p&lt;0.001, respectively). P-values for VII and VWB factors showed a significant increment in these two factors in the melatonin group after the intervention (p=0.035 &amp; p=0.002, respectively). No significant changes in serum levels of D-dimer factor, APACHE II, and GCS scores were evident in the two groups after the intervention (p&gt;0.05).&nbsp;Conclusion: Considering the favorable changes in coagulation parameters observed in this study, it could be concluded that melatonin can have both procoagulant and antithrombin properties

Intensive care unit-acquired urinary tract infections in patients admitted with sepsis: etiology, risk factors, and patterns of antimicrobial resistance

SummaryObjectivesThe objective of the present study was to evaluate the etiology, risk factors, and patterns of antimicrobial resistance of intensive care unit (ICU)-acquired urinary tract infections (UTIs) in patients admitted with sepsis.MethodsIn this observational study, 100 septic patients hospitalized in a general ICU were selected. Demographic, clinical, and outcome data were obtained by chart review. Antibiotic resistance/susceptibility was determined using the minimal inhibitory concentration (MIC) technique.ResultsA UTI was present in 28 (28%) patients; the male to female ratio was 19:9 and the mean age of the patients was 58.71±19.45 years. From the total of 28 isolates, 27 were resistant to ciprofloxacin, 23 to amikacin, 27 to meropenem, 28 to cefepime, 26 to ceftazidime, and 27 to ceftriaxone.ConclusionsOn the basis of our results, the rate of multidrug-resistant UTIs may be very high in some ICUs in patients admitted with sepsis. This antimicrobial susceptibility/resistance should be determined, and a special antimicrobial treatment protocol should be planned based on the results for each ICU. The use of antibiotics for treating UTIs should be guided only through this protocol because of the different spectra of pathogens and susceptibility patterns in each ICU

The role of magnesium sulfate in the intensive care unit

Magnesium (Mg) has been developed as a drug with various clinical uses. Mg is a key cation in physiological processes, and the homeostasis of this cation is crucial for the normal function of body organs. Magnesium sulfate (MgSO4) is a mineral pharmaceutical preparation of magnesium that is used as a neuroprotective agent. One rationale for the frequent use of MgSO4 in critical care is the high incidence of hypomagnesaemia in intensive care unit (ICU) patients. Correction of hypomagnesaemia along with the neuroprotective properties of MgSO4 has generated a wide application for MgSO4 in ICU

The role of glutathione-S-transferase polymorphisms on clinical outcome of ALI/ARDS patient treated with N-acetylcysteine

SummaryOxidative stress has a proven role in pathophysiology of acute respiratory distress syndrome. The antioxidant drugs, especially N-acetylcysteine (NAC) have been used for years to overcome oxidative stress effects in patients. In the present study we have investigated the effects of NAC treatment (IV NAC in 150mg/kg at the first day followed by 50mg/kg/day for three days) on 27 ICU patients with ALI/ARDS considering the glutathione-S-transferase genetic variations, as an important enzyme contributing in oxidative stress pathways. The results indicated that NAC improved oxygenation (increase in PaO2/FiO2) and decreased mortality rate in treated patients compared to control group (p<0.05). Evaluation of three isoforms of glutathione-S-transferase (GST M1, P1 and T1), in these patients have showed an association between GST M1 null, and GST M1 and T1 double null polymorphisms with increased mortality in control group, suggesting antioxidant therapy critical for this group of patients