Early administration of norepinephrine in sepsis: Multicenter randomized clinical trial (EA-NE-S-TUN) study protocol.

One of the most important components of sepsis management is hemodynamic restoration. If the target mean arterial pressure (MAP) is not obtained, the first recommendation is for volume expansion, and the second is for norepinephrine (NE). We describe the methodology of a randomized multicenter trial aiming to assess the hypothesis that low-dose NE given early in adult patients with sepsis will provide better control of shock within 6 hours from therapy starting compared to standard care. This trial includes ICU septic patients in whom MAP decrease below 65 mmHg to be randomized into 2 groups: early NE-group versus standard care-group. The patient's attending clinician will determine how much volume expansion is necessary to meet the target of a MAP > 65 mm Hg. If this target not achieved, after at least 30 ml/kg and guided by the available indices of fluid responsiveness, NE will be used in a usual way. The latter must follow a consensual schedule elaborated by the investigating centers. Parameters to be taken at inclusion and at H6 are: lactates, cardiac ultrasound parameters (stroke volume (SV), cardiac output (CO), E/E' ratio), and P/F ratio. MAP and diuresis are recorded hourly. Our primary outcome is the shock control defined as a composite criterion (MAP > 65 mm Hg for 2 consecutive measurements and urinary output > 0.5 ml/kg/h for 2 consecutive hours) within 6 hours. Secondary outcomes: Decrease in serum lactate> 10% from baseline within 6 hours, the received fluid volume within 6 hours, variation of CO and E/E', and 28 days-Mortality. The study is ongoing and aims to include at least 100 patients per arm. This study is likely to contribute to support the indication of early initiation of NE with the aim to restrict fluid intake in septic patients. (ClinicalTrials.gov ID: NCT05836272).

Differences in leucocytes and inflammation-based indices among critically ill patients owing to SARS-CoV-2 variants during several successive waves of COVID-19 pandemic.

BACKGROUND/AIM: Inflammatory indices are useful informative markers in assessing the severity of the COVID-19 disease course; however, their involvements during series waves of SARS-CoV-2 virus outbreaks in critical patients with COVID-19 remain unclear. Hence, we aimed to ascertain the changing dynamics of the combined inflammatory indices (NLR, dNLR, CLR, LMR, PLR, SII, and SIRI) and their associations with clinical outcomes in severe COVID-19 patients during serial waves of SARS-CoV-2. PATIENTS AND METHODS: We retrospectively enrolled 163 severe COVID-19 patients admitted to the ICU during six SARS-CoV-2 waves. RESULTS: We found that most of patients admitted to the ICU were from the fourth wave. Patients in the fourth wave were considerably younger and had the highest percentage of ARDS than other waves. The highest CRP was found in the first wave, while the lowest in patients admitted in the sixth wave. Although most of the COVID-19 waves were marked with leukocytosis, neutrophilia, and lymphocytopenia, the lowest of both NLR and dNLR were found in the fourth wave "Delta wave" and the lowest of both CLR and SII were observed in "Omicron wave". Interestingly, during most of the COVID-19 waves, the derived combined inflammatory ratio NLR, dNLR, CLR, SII and SIRI were sustained at high levels in fatal cases at the last day of hospitalization, while these indices declined in the alive group at the end of ICU hospitalization. No major difference was identified in lymphocyte count between admission and the last day of hospitalization in both deceased and recovered COVID-19 patients during Delta and Omicron waves. Moreover, patients admitted in the Omicron wave had less severe disease compared to those admitted in the Delta wave. The Kaplan-Meier analysis revealed no significant difference in survival rates or the probability of respiratory failure between six successive COVID-19 waves. CONCLUSION: Taken together, our results showed marked differences in the alteration of nonspecific inflammation and damage in the adaptive immune response during the six serial SARS-CoV-2 waves. Considering the inflammatory response of infectious diseases, embedding inflammatory indices informative markers into routine clinical testing offers the potential to mitigate the impact of future pandemics of COVID-19 and other infectious diseases.

Evaluation of individual and combined NLR, LMR and CLR ratio for prognosis disease severity and outcomes in patients with COVID-19.

OBJECT: The study aimed to utilize the peripheral blood immunological parameters and resulting individual and combined inflammatory indices [neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR) and C-reactive protein/lymphocyte ratio (CLR)] in predicting the prognosis and mortality in COVID-19 patients. MATERIALS AND METHODS: The measurements of individual and combined inflammatory indices (NLR, LMR and CLR) were performed at hospital admission and at last day of hospitalization for COVID-19 patients. RESULTS: Prominent elevation of NLR and CLR among patients with refractory disease admitted to Intensive Care Unit (ICU) and deceased patients was found when compared with moderate ill patients and healthy controls. Interestingly, NLR and CLR typically returned to near normal value as patients recover from severe infection. By contrast, deceased patients had persistent increased NLR and CLR until last day of hospitalization in ICU. ROC obtained for the above parameters showed that NLR and CLR were the most associated immunological parameters with the severity of COVID-19 disease. Using multivariate logistic regression analysis, CLR > 69.46 is an independent prognostic factors in identifying critically ill COVID-19 cases. Study of the combined markers NLR and CLR showed that most of patients admitted in ICU were characterized with high NLR combined with high CLR, while most of healthy subjects and non-ICU group have low NLR combined with low CLR. CONCLUSION: The combination of NLR and CLR could improve the predictive efficacy compared to individual markers to segregate patients who will develop a severe disease from those with a mild pathology.

Case Report: Tropical sprue, diagnostic challenges of an old but unrecognized disease.

Tropical sprue (TS) is a post-infective disease of the small bowel characterized by a malabsorption syndrome affecting tropics inhabitants and visitors. Diagnosis of TS remains challenging since it can be confused with common diarrheal diseases, especially in non-endemic areas. We report a Tunisian case of latent TS. A 58-year-old male with a history of chronic watery diarrhea, was admitted to the intensive care unit for confusion which was related to a severe metabolic acidosis. Despite the neurological improvement after hydro-electrolytic resuscitation and acid-base disorders correction, the patient continued to have three to five loose stools daily. A nutritional assessment showed a malabsorption syndrome: iron, Vitamin B12and folate deficiencies; normochromic normocytic anemia and hypoalbuminemia. Gastrointestinal endoscopy showed duodenal villous atrophy and biopsy confirmed subtotal villous atrophy with increased intraepithelial lymphocytosis and a thickened hyalonalized sub-epithelial basal lamina. Celiac disease was evoked, however the patient did not improve on a gluten-free diet and the celiac serology was negative. On re-interviewing, we discovered that the patient had spent two months in India three years prior. Given the travel history, clinico-biological and histological data TS was highly considered and a good response to a five-month antibiotic course combined to nutritional supplementation supported this diagnosis. Clinico-biological, endoscopic and histological findings were overlapping between TS and other malabsorption diseases, explaining diagnosis difficulties. TS should be systematically discussed in tropics visitors presenting with chronic diarrhea. Improvement after micronutrient and vitamin deficiencies replacement combined to a prolonged antibiotic course supports the diagnosis of TS.

Impact of acetazolamide use in severe exacerbation of chronic obstructive pulmonary disease requiring invasive mechanical ventilation.

PURPOSE: To analyse the impact of acetazolamide (ACET) use in severe acute decompensation of chronic obstructive pulmonary disease requiring mechanical ventilation and intensive care unit (ICU) admission. PATIENTS AND METHODS: Retrospective pair-wise, case-control study with 1:1 matching. Patients were defined as cases when they had received acetazolamide (500 mg per day) and as controls when they did not received it. Patients were matched according to age, severity on admission (pH, PaO2/FiO2 ratio) and SAPSII score. Our primary endpoint was the effect of ACET (500 mg per day) on the duration of mechanical ventilation. Our secondary endpoints were the effect of ACET on arterial blood gas parameters, ICU length of stay (LOS) and ICU mortality. RESULTS: Seventy-two patients were included and equally distributed between the two studied groups. There were 66 males (92%). The mean age (± SD) was 69.7 ± 7.4 years ranging from 53 to 81 years. There were no differences between baseline characteristics of the two groups. Concomitant drugs used were also not significantly different between two groups. Mean duration of mechanical ventilation was not significantly different between ACET(+) and ACET(-) patients (10.6±7.8 days and 9.6±7.6 days, respectively; P = 0.61). Cases had a significantly decreased serum bicarbonate, arterial blood pH, and PaCO2 levels. We did not found any significant difference between the two studied groups in terms of ICU LOS. ICU mortality was also comparable between ACET(+) and ACET(-) groups (38% and 52%, respectively; P = 0.23). CONCLUSION: Although our study some limitations, it suggests that the use of insufficient acetazolamide dosage (500 mg/d) ACET (500 mg per day) has no significant effect on the duration of mechanical ventilation in critically ill COPD patients requiring invasive mechanical ventilation. Our results should be confirmed or infirmed by further studies.

Incidence and impact outcome of pulmonary embolism in critically ill patients with severe exacerbation of chronic obstructive pulmonary diseases.

PURPOSE: We aimed to determine the incidence and the prognostic impact [mortality and length of intensive care unit (ICU) stay (LOS)] of pulmonary embolism (PE) in critically ill patients with severe acute exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: This is a retrospective study performed during a 5-year period in the ICU of Habib Bourguiba University Hospital (Sfax, Tunisia). All patients with severe acute exacerbation of COPD were included. The diagnosis of PE is confirmed by spiral computed tomography scan showing one or more filling defects or obstruction in the pulmonary artery or its branches. RESULTS: During the study period, 131 patients with acute exacerbation of COPD were admitted in our ICU. The mean age (±standard deviation) was 68.6 ± 9.2 years, ranging from 39 to 99 years (median: 70 years). During their ICU stay, 23 patients (17.5%) developed PE. The diagnosis was confirmed within 48 h from ICU admission in all cases but one. The comparison between the two groups (with and without PE) showed that they had the same baseline characteristics. However, all PE group developed shock on ICU admission or during ICU stay. Signs of right heart failure were more observed in the PE group. ICU mortality was significantly higher in the PE group (69.5% vs 44%; P = 0.029). In addition, the ICU LOS was significantly higher in the PE group than the PE-free group (P = 0.007). Finally, PE was identified as an independent factor predicting poor outcome [odds ratio = 3.49, 95% CI (1.01-11.1); P = 0.035]. CONCLUSION: Our study showed that PE is common in patients with severe COPD exacerbation requiring ICU admission. Moreover, PE was significantly associated with higher mortality and ICU LOS in critically ill patients with severe COPD exacerbation.

The use of a low dose hydrocortisone to prevent pulmonary embolism in patients with multiple trauma.

BACKGROUND: Venous thromboembolism events are common in trauma patients. Immediate acute inflammation following injury triggers coagulation cascade and may increase the risk of pulmonary embolism (PE) in this population. OBJECTIVE: We aimed to evaluate whether early low-dose steroids prevent symptomatic PE onset in multiple trauma patients. SETTING: The medical surgical intensive care unit of Habib Bourguiba University Hospital (Sfax--Tunisia). METHODS: Comparative study of two cohorts: a retrospective cohort of patients who didn't receive early low-dose steroids (steroid (-) group) and a prospective cohort of patients who received hydrocortisone with a dose of 100 mg/8 h for a scheduled period of 7 days (steroid (+) group). All adult patients admitted in our intensive care unit (ICU) for multiple trauma with predicted duration of mechanical ventilation over 48 h were included. MAIN OUTCOME MEASURE: Evaluation of the impact of low-dose steroids on the incidence of symptomatic PE. RESULTS: We included 175 patients: 92 in the steroids (-) group and 83 in the steroids (+) group. PE was diagnosed in 15 patients (8.5 %). The incidence of PE was significantly lower in steroid (+) group (3.6 vs 13 %; p = 0.013). In multivariate analysis, independent factors predicting PE onset were meningeal hemorrhage [OR = 14.7; 95 % CI (2.2-96.3); p = 0.013] and pelvic ring trauma [OR = 8; 95 % CI (1.8-36.4); p = 0.007] whereas low-dose steroids were significantly associated with a protective effect [OR = 0.2; 95 % CI (0.05-0.77); p = 0.019]. There was no significant difference between steroids (+) and steroids (-) groups neither in terms of mean ICU length of stay (LOS) (respectively 11 ± 9.7 and 12.3 ± 10.7 days; p = 0.372) nor in terms of ICU mortality (respectively 29.3 and 24.1 %; p = 0.434). CONCLUSION: Steroids are effective in reducing the incidence of PE in multiple trauma patients. However, no significant benefice was found on ICU mortality.