Immunologic effect and clinical impact of erythromycin in septic patients: A randomized clinical trial.

To investigate the potential regulatory effect of erythromycin added to standard care in septic patients on sepsis biomarkers and clinical outcome. It was a single-blind randomized trial including critical septic patients. The primary endpoint was the change in the TNF/IL-10 ratio between days 0 and 6. Changes in other biomarkers, vasopressor use, and 28-day mortality were secondary endpoints. One hundred and ten patients were examined (erythromycin group, n = 55 versus placebo group, n = 55). Clinical features of the groups were well matched. Erythromycin addition had no beneficial effects on the TNF/IL-10 ratio or mortality (51% vs. 47%, p = 0.62). Both groups' serum TNF/IL-10 ratios did not significantly rise (from 0.48 [0.34-1.18] to 0.59 [0.21-1.10] vs. 0.65 [0.25-1.14] to 0.93 [0.24-1.88] in the erythromycin and placebo groups, respectively; p values = 0.86 and 0.12). Serum Procalcitonin (PCT) and CRP dropped considerably in the Erythromycin group, whereas only PCT showed a drop in the placebo group. On day 6, the non-survivors' serum TNF/IL-10 ratio was lower than that of the survivors (0.55 [0.17-1.04] vs 1.08 [0.4-2.28], p = 0.029). Neither the pro/anti-inflammatory imbalance nor the mortality were impacted by the addition of erythromycin to standard care in septic patients (ClinicalTrials.gov ID: NCT04665089 (11/12/2020)).

Beneficial of adding Tocilizumab to standard care in critical forms of Covid-19 pneumonia: Study on paired series.

INTRODUCTION: Tocilizumab (TCZ), a humanized monoclonal antibody directed against interleukin-6 (IL-6) receptors, has been tried in various studies as a Covid-19 therapy with controversial results. AIM: To evaluate the effectiveness of adding TCZ to standard care (SC) in critical Covid-19 patients. METHODS: it was designed retrospectively as a comparative study on two paired series of critical patients affected with Covid-19: the 1st group received TCZ plus SC versus a 2nd group which received only SC. The matching criteria were age, sex and severity score and the matching was based on the propensity score matching (PSM) by the nearest neighbor. Outcomes were: survival, mechanical ventilation (MV) and nosocomial infections. RESULTS: Ninety patients were included by pairing estimated successful (PSM > 0.5 in more than 50% in each group for all matching criteria). 55.5% of SC group progressed to stage 3-acute respiratory distress syndrome (ARDS) versus 31% of TCZ+SC patients (p=0.03). No effect of TCZ was found on mortality (49% in each group, p=1) nor on MV use (p=0.67). ICU stay was more prolonged in TCZ+SC group (16 versus 8 days, p<10-3). The administration of TCZ induced a significant decrease in CRP but not changed the IL-6 dosage. Nosocomial infections occurred in 18 (40%) of TCZ+SC group comparatively to 15 (33,5%) of SC group, p=0.66. CONCLUSION: Tocilizumab reduced the risk of progression to severe ARDS probably due to its immune-modulating properties. But no beneficial effect was found on survival or on the use of ventilation.

Shunt in critically ill Covid-19 ARDS patients: Prevalence and impact on outcome (cross-sectional study).

PURPOSE: To examine critical Covid-19-acute respiratory distress syndrome (C-ARDS) patients requiring mechanical ventilation (MV), using transthoracic echocardiography (TTE) coupled with bubble test (BT), in order to search a right/left shunt. METHODS: A Cross-sectional and comparative study comparing several parameters according to the presence or not of shunt. RESULTS: 75 patients were included. Twenty-three shunts (31%) were detected: patent foramen oval (PFO) type [n=11 (15%)] and trans-pulmonary transit of bubbles (TPBT) [n = 12 (16%)]. The shunt did not affect P/F ratio (P/F=77 vs 81, p=0.97), nor mortality. CONCLUSION: A right/left shunt was detected in a third of studied patients similarly between PFO and TPBT without significant impact on P/F ratio or outcome.

Ultrasound assessment of the diaphragm during the first days of mechanical ventilation compared to spontaneous respiration: a comparative study.

INTRODUCTION: In critically ill patients, the diaphragm is subject to several aggressions mainly those induced by mechanical ventilation (MV). Currently, diaphragmatic ultrasound has become the most useful bedside for the clinician to evaluate diaphragm contractility. AIM:   To examine the effects of MV on the diaphragm contractility during the first days of ventilation. METHODS: Two groups of subjects were studied: a study group (n=30) of adults receiving MV versus a control group (n=30) of volunteers on spontaneous ventilation (SV). Using an ultrasound device, we compared the diaphragmatic thickening fraction (DTF). Secondly, we analysed the relationship between DTF and weaning. RESULTS: comparatively to SV group, patients of MV group have a higher end expiratory diameter (EED) (2.09 ± 0.6 vs. 1.76 ± 0.32 mm, p=0.01) and a lower DTF (39.9 ± 12.5%  vs.  49.0 ± 20.5%, p=0.043). Fourteen among the 30 ventilated patients successfully weaned. No significant correlation was shown between DTF and weaning duration (Rho= - 0.464, p=0.09). A DTF value > 33% was near to be significantly associated with weaning success (OR=2; 95% CI= [1.07-3.7], p=0.05) with a sensitivity at 85.7%. CONCLUSIONS: diaphragmatic contractility was altered from the first days of MV. A DTF value >32,7% was associated to the weaning success and that may be useful to predict successful weaning with sensitivity at 85.7%.

Ultrasound variations of diaphragm activity between prone position versus supine position in ventilated patients: a cross-sectional comparative study.

PURPOSE: To evaluate the effect of the positioning from the supine position (SP) to the prone position (PP) on the diaphragm activity in ventilated patients; using the ultrasound (US) imaging. METHODS: A cross-sectional comparative study before/after PP was conducted on 40 ICU patients over 18 years who received invasive ventilation (IV) for at least 48 h. The considered ventilator modes were: assisted control volume with a low trigger flow (between - 2 and 2 L/mn) and pressure support mode. US diaphragmatic assessments were performed at SP and at 60 min of PP. Both End-inspiratory and End-expiratory diameters (EID/EED) were taken at 3 levels of axillary lines and determined by the average values of multiple measures. Diaphragmatic thickening fraction (DTF) was calculated as: DTF = (EID - EED/EED) × 100. Pairing and ANOVA tests were used for comparisons. RESULTS: Forty ventilated patients (42 years of median age) at 4 days [2-7] of median duration of ventilation were examined during the two positions: SP versus PP. EID decreased from the SP to the PP (2.8 mm in SP vs. 2.4 mm in PP, p = 0.001). No difference was showed regarding the expiratory thickness. Overall, DTF didn't change in PP (37.4 vs. 42.05%, p = 0.36). When the patient was placed in PP, the best DTF value was showed at the posterior part of diaphragm (posterior: 45%, median: 31% and anterior: 38%, p = 0.049). CONCLUSION: The ventral placement in ventilated patients reduced end-inspiratory diameter and tended to decrease DTF. In PP, the best contractile activity was detected at the posterior region of diaphragm.

Plasma 25-Hydroxyvitamin D Level at Admission Predicts Unfavorable Outcome in Intensive Care Unit Patients.

INTRODUCTION: Patients in intensive care units (ICUs) are at high risk of unfavorable outcomes. Considering the role of vitamin D (Vit D) in cardiovascular and immune functions, Vit D deficiency could affect ICU patients' outcomes. This study aimed to evaluate Vit D status and its predictive value for outcome in ICU patients. PATIENTS AND METHODS: A total of 169 ICU patients were followed during ICU stay. Primary outcome was the occurrence of at least one major adverse event; secondary outcomes were organ failure, septic shock, ICU-acquired infection, other adverse events, and ICU mortality. Plasma 25-hydroxyvitamin D (25(OH)D) was assessed by immunoassay. Multivariate Cox regression analyses were performed to test the associations of low 25(OH)D levels with poor outcomes. RESULTS: Around 75% of patients had 25(OH)D levels <12 ng/ml. During their ICU stay, 114 patients experienced a major adverse event, 85 patients presented an ICU-acquired infection, and 22 patients died. Plasma 25(OH)D levels <12 ng/ml were associated with higher risk of major adverse events, Hazard ratio [95% CI], 4.47 [1.77, 11.3], p = .020, and ICU-acquired infection, 2.67 [1.01, 7.42], p = .049, but not with increased risk of ICU mortality. CONCLUSIONS: Hypovitaminosis D is very common in ICU patients. Results of the present study show that low plasma 25(OH)D levels are associated with increased risk of unfavorable outcomes in these patients. Additional research is needed to investigate the impact of Vit D status and effect of Vit D supplementation in ICU patients.

Empiric antifungal and outcome in ICU patients.

BACKGROUND: The management of invasive candidiasis (IC) remains a major challenge in intensive care units (ICU). On the one hand, it becomes admitted that delayed antifungal is an independent mortality factor. In the other hand, the unreasonable administration of antifungal agents is implicated in emergence of resistant Candida strains.  Aim: to evaluate whether empirical antifungal therapy (EAFT) improves survival at day 28 and prevents a new episode of candidemia in septic patients without proven Candida infection. METHODS: a 8-years retrospective double cohort, monocentric study, comparing two arms of ICU non neutropenic septic patients without proven fungal infection according to administration or not of an EAFT. The primary outcome was the 28-day mortality and the second was the occurrence of candidemia. The analysis was adjusted on Acute Physiology And Chronic Health Evaluation II (APACHE II) score, Candida score, invasive ventilation and central catheterisation. RESULTS:   247 patients were included (EAFT group, n=125 and non EAFT group, n=122). No improvement of 28-day survival was found. These results were in accordance both in crude analysis and after adjusting on factors mentioned above. No preventing effect on a new episode of candidemia. Nevertheless, a beneficial effect of EAFT on survival was found in patients with an APACHE II score<16: OR=0.68; CI 95% [0.53-0.87]; p=0.002. CONCLUSIONS: no beneficial impact of an EAFT on 28- day survival neither in preventing the occurrence of candidemia in non neutropenic septic critically patients. In patients with APACHE II score less than 16, there was a beneficial effect on survival.

Appropriateness of empiric antimicrobial therapy with imipenem/colistin in severe septic patients: observational cohort study.

BACKGROUND: Empiric antimicrobial therapy (EAMT) using imipenem/colistin is commonly prescribed as a first line therapy in critically ill patients with severe sepsis. We aimed to assess the appropriateness of prescribing imipenem/colistin as EAMT in ICU patients. METHODS: A 3-year observational prospective study included ICU patients that required imipenem/colistin as EAMT. The EAMT was assessed according to microbiological and clinical outcomes. The outcomes were: delay in apyrexia, delay in the decrease of the biological inflammatory parameters (BIP), the requirement for vasoactive agents, bacteriological eradication, length of stay, ventilator days and 30-day mortality. RESULTS: 79 administrations of EAMT in 70 patients were studied. EAMT was appropriate in 52% of the studied cases. An ICU stay > 6 days was related to inappropriateness, and chronic respiratory failure was associated with appropriateness. In the appropriate EAMT group, we showed: earlier apyrexia, shorter delay in the decrease of the BIP and a reduced significant vasopressors requirement. Furthermore, EAMT improved survival with a median gain of 4 days. Inappropriate EAMT increased the mortality risk by six. The acquisition of NI in ICU was also an independent factor of mortality. CONCLUSIONS: EAMT using imipenem-colistin was appropriate in half of the cases and inappropriateness was associated with an increased ICU mortality risk.

Nosocomial infections: current situation in a resuscitation-unit.

BACKGROUND: The nosocomial infection (NI) is defined as an infection that is not present or incubating on admission in establishment of care. It can be caused by the patient's germs, care personnel or hospital environment. Multidrug resistant (MDR) bacteria are particularly common in intensive care units that lead to a serious infections and increase morbidity, mortality and cost of care. PURPOSE: To identify the epidemiological characteristics of NI, the predisposing factors, the antimicrobial sensitivity pattern of isolated bacteria and the impact on morbidity and mortality. METHODS: Observational study over the year 2013. All infected patients hospitalized for at least 48 hours were included unless infection has been documented at admission. The type of sampling and bacteriological analyzes were performed based on the infection site according to the classification of Coordination Committee for the Fight against Nosocomial Infection of 2012. Statistical analysis was performed using the SPSS software 20. A p value <0.05 was considered significant. RESULTS: 63 patients were included with an average age of 51 years and SAPS II at 38. 95% of included patients were ventilated and 100% had a central catheterization. 164 infectious episodes were documented. The number of infection episodes per patient was statistically correlated with the length of stay. The most common isolated microorganism was Acinetobacter baumannii. It remains sensitive to colistin in 87.5% of cases. It was noted an emergence of Carbapenemase Producing Enterobacteriaceae (12%). The major identified risk factors were: previous organ failure, sepsis and catecholamines use (respective OR at 2.72, 2.56 and 2.15). Death was attributed to nosocomial infection in 36.6% of cases. CONCLUSION: The incidence of nosocomial infections is constantly rising in intensive care units. Pneumonia remains the most common infectious site. Contributing factors are an anterior organ failure, sepsis and catecholamines use. Approximately, one infected patient among three died by nosocomial infection.

Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial.

BACKGROUND: Cases of ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) gram-negative bacilli (GNB) mainly Acinetobacter baumannii, Pseudomonas aeruginosa and enterobacteria are common in hospitalised patients of Tunisian intensive care units (ICUs). Parenteral colistin has been used for the therapy of VAP caused by MDR GNB at Tunisian hospitals over the past few years with a favourable clinical response. However, its use fell out of favour because of the reported drug-related nephrotoxicity and neurotoxicity. OBJECTIVES: To determine whether aerosolised (AS) colistin was beneficial and safe in therapy of gram-negative VAP. METHODS: This was a randomised, single-blind study, in 149 critically ill adults who developed gram-negative VAP. Included patients were divided into two groups whether they received AS colistin (intervention group; n = 73) or intravenous (IV) colistin (control group; n = 76). AS colistin was given as 4 million units (MU) by nebulisation three times per 24 h. IV colistin was given as a loading dose of 9 MU followed by 4.5 MU two times per 24 h. Patients were followed during 28 days. Primary outcome was cure of VAP assessed at day 14 of therapy and defined as resolution of clinical signs of VAP and bacteriological eradication. Secondary outcomes were incidence of acute renal failure (ARF), mechanical ventilation length, ICU length of stay and 28-day mortality. Results were analysed based on intention-to-treat concept. RESULTS: The patient's baseline characteristics and distribution of pathogens VAP in both groups were similar. The clinical cure rate was 67.1 % in AS group and 72 % in IV group (p = 0.59). When administered in monotherapy or in combination, the AS regimen was as effective as IV regimen. Patients in AS group had significantly lower incidence of ARF (17.8 vs 39.4 %, p = 0.004), more favourable improvement of P/F ratio (349 vs 316 at day 14, p = 0.012), shortened time to bacterial eradication (TBE) (9.89 vs 11.26 days, p = 0.023) and earlier weaning from ventilator in ICU survivors with a mean gain in ventilator-free days of 5 days. No difference was shown in the length of stay and the 28-day mortality. CONCLUSION: Aerosolised colistin seems to be beneficial. It provided a therapeutic effectiveness non-inferior to parenteral colistin in therapy of MDR bacilli VAP with a lower nephrotoxicity, a better improvement of P/F ratio, a shortened bacterial eradication time and earlier weaning from ventilator in ICU survivors. Trial registration ClinicalTrials.gov Identifier: NCT02683603.

Efficacy and Toxicity of High-Dose Colistin in Multidrug-Resistant Gram-Negative Bacilli Infections: A Comparative Study of a Matched Series.

BACKGROUND: Colistimethate sodium (CMS) is the commercialized form of colistin that is effective against multiresistant Gram-negative bacilli. Its main side effects are nephrotoxicity and neurotoxicity. Pharmacodynamic dosages showed that they were infratherapeutic. Therefore, strategies with higher doses were proposed. The aim of this study was to assess the efficiency and toxicity of higher-dose CMS by comparing two treatment strategies: high-dose CMS versus standard-dose CMS. METHODS: A prospective and comparative study of two matched groups was conducted. Fourty-six patients in each group were matched for age, severity and nature of infection. In the high-dose colistin group, CMS was administered at a loading dose of 9 MIU followed by a maintenance dose of 4.5 MIU/12 h. In the second group, retrospectively analyzed, colistin was administered at 6 MIU/day. For each group, clinical results, bacteriological eradication and daily creatinine clearance were recorded. Primary outcome measures were clinical cure defined as disappearance of infectious signs and eradication of microorganisms in all the follow-up cultures. Secondary outcome measures were incidence of acute renal failure and mortality. RESULTS: Ninety-two patients were analyzed by matching. There was a higher cure rate in the high-dose group (63 vs. 41.3%, p = 0.04). No higher risk of nephrotoxicity was found by increasing daily doses of colistin (32.2 versus 26%, p = 0.64). Similarly, there was no significant difference in the time to onset of renal failure (8.32 vs. 11 days, p = 1) or in the requirement of hemodialysis (26.6 vs. 41%, p = 1). CONCLUSION: The high-dose colistin regimen is more efficient, without significant renal or neurological toxicity.