Association of dynamics of anellovirus loads with hospital-acquired pneumonia in brain-injured patients during the intensive care unit stay.

BACKGROUND: Critical illness induces immune disorders associated with an increased risk of hospital-acquired pneumonia (HAP) and acute respiratory distress syndrome (ARDS). Torque Teno Virus (TTV), from the Anelloviridae family, are proposed as a biomarker to measure the level of immunosuppression. Our objective was to describe the kinetics of TTV DNA loads and their association with critical-illness related complications. METHODS: We performed a longitudinal study in 115 brain-injured patients from a prospective cohort, collected endotracheal and blood samples at three time points (T1, T2, T3) during the two weeks post-admission in intensive care unit, and measured viral DNA loads using the TTV R-gene® kit (Biomerieux) and a pan-Anelloviridae in house qRT-PCR. RESULTS: TTV DNA was detected in the blood of 69, 71, and 64% of brain-injured patients at T1, T2 and T3 respectively. Time-associated variations of TTV and Anellovirus (AV) DNA loads were observed. Using a linear mixed-effects model, we found that HAP and ARDS were associated with lower blood AV DNA loads. CONCLUSION: Our results show that HAP or ARDS in critically ill patients are associated to changes in AV DNA loads, and should be evaluated further as a biomarker of immune disorders leading to these complications.

Azithromycin regulates bacterial virulence and immune response in a murine model of ceftazidime-treated Pseudomonas aeruginosa acute pneumonia.

Pseudomonas aeruginosa (PA) remains one of the leading causes of nosocomial acute pneumonia. The array of virulence factors expressed by PA and the intense immune response associated with PA pneumonia play a major role in the severity of these infections. New therapeutic approaches are needed to overcome the high resistance of PA to antibiotics and to reduce the direct damage to host tissues. Through its immunomodulatory and anti-virulence effects, azithromycin (AZM) has demonstrated clinical benefits in patients with chronic PA respiratory infections. However, there is relatively little evidence in PA acute pneumonia. We investigated the effects of AZM, as an adjunctive therapy combined with ceftazidime (CAZ), in a murine model of PA acute pneumonia. We observed that the combined therapy (i) reduces the weight loss of mice 24 h post-infection (hpi), (ii) decreases neutrophil influx into the lungs at 6 and 24 hpi, while this effect is absent in a LPS-induced pneumonia or when PA is pretreated with antibiotics and mice do not receive any antibiotics, and that (iii) AZM, alone or with CAZ, modulates the expression of PA quorum sensing regulators and virulence factors (LasI, LasA, PqsE, PhzM, ExoS). Our findings support beneficial effects of AZM with CAZ on PA acute pneumonia by both bacterial virulence and immune response modulations. Further investigations are needed to clarify the exact underlying mechanisms responsible for the reduction of the neutrophils influx and to better discriminate between direct immunomodulatory properties of AZM, and indirect effects on neutrophilia resulting from bacterial virulence modulation.

New Insights in the Pathophysiology of Hospital- and Ventilator-Acquired Pneumonia: A Complex Interplay between Dysbiosis and Critical-Illness-Related Immunosuppression.

Both hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) have long been considered as diseases resulting from the invasion by pathogens of a previously sterile lung environment. Based on this historical understanding of their pathophysiology, our approaches for the prevention and treatment have significantly improved the outcomes of patients, but treatment failures remain frequent. Recent studies have suggested that the all-antimicrobial therapy-based treatment of pneumonia has reached a glass ceiling. The demonstration that the constant interactions between the respiratory microbiome and mucosal immunity are required to tune homeostasis in a state of symbiosis has changed our comprehension of pneumonia. We proposed that HAP and VAP should be considered as a state of dysbiosis, defined as the emergence of a dominant pathogen thriving at the same time from the catastrophic collapse of the fragile ecosystem of the lower respiratory tract and from the development of critical-illness-related immunosuppression. This multidimensional approach to the pathophysiology of HAP and VAP holds the potential to achieve future successes in research and critical care. Microbiome and mucosal immunity can indeed be manipulated and used as adjunctive therapies or targets to prevent or treat pneumonia.

Factors associated with an unfavourable outcome in elderly intensive care traumatic brain injury patients. a retrospective multicentre study.

BACKGROUND: Changes in the epidemiology of traumatic brain injury (TBI) in older patients have received attention, but limited data are available on the outcome of these patients after admission to intensive care units (ICUs). The aim of this study was to evaluate the outcomes of patients over 65 years of age who were admitted to an ICU for TBI. METHODS: This was a multicentre, retrospective, observational study conducted from January 2013 to February 2019 in the surgical ICUs of 5 level 1 trauma centres in France. Patients aged ≥ 65 years who were hospitalized in the ICU for TBI with or without extracranial injuries were included. The main objective was to determine the risk factors for unfavourable neurological outcome at 3 months defined as an Extended Glasgow Outcome Scale (GOSE) score < 5. RESULTS: Among the 349 intensive care patients analysed, the GOSE score at 3 months was ≤ 4 and ≥ 5 in 233 (67%) and 116 (33%) patients, respectively. The mortality rate at 3 months was 157/233 (67%), and only 7 patients (2%) fully recovered or had minor symptoms. Withdrawal or withholding of life-sustaining therapies in the ICU was identified in 140 patients (40.1%). Multivariate analysis showed that age (OR 1.09, CI 95% 1.04-1.14), male sex (OR 2.94, CI95% 1.70-5.11), baseline Glasgow Coma Scale score (OR 1.20, CI95% 1.13-1.29), injury severity score (ISS; OR 1.04, CI95% 1.02-1.06) and use of osmotherapy (OR 2.42, CI95% 1.26-4.65) were associated with unfavourable outcomes (AUC = 0.79, CI 95% [0.74-0.84]). According to multivariate analysis, the variables providing the best sensitivity and specificity were age ≥ 77 years, Glasgow Coma Scale score ≤ 9 and ISS ≥ 25 (AUC = 0.79, CI 95% [0.74-0.84]). CONCLUSIONS: Among intensive care patients aged ≥ 65 years suffering from TBI, age (≥ 77 years), male sex, baseline Glasgow coma scale score (≤ 9), ISS (≥ 25) and use of osmotherapy were predictors of unfavourable neurological outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04651803. Registered 03/12/2020. Retrospectively registered.

Factors associated with time to defecate and outcomes in critically ill patients: a prospective, multicentre, observational study.

Delayed defecation is common in patients on intensive care. We aimed to determine factors associated with time to defecation after admission to intensive care and in turn its association with length of stay and mortality. We studied 396 adults admitted to one of five intensive care units in whom at least 2 days' invasive ventilation was anticipated during an expected stay of at least 3 days. The median (IQR [range]) time to defecate by the 336 out of 396 (84%) patients who did so before intensive care discharge was 6 (4-8 [1-18]) days. Defecation was independently associated with five factors, hazard ratio (95%CI), higher values indicating more rapid defecation: alcoholism, 1.32 (1.05-1.66), p = 0.02; laxatives before admission, 2.35 (1.79-3.07), p < 0.001; non-invasive ventilation, 0.54 (0.36-0.82), p = 0.004; duration of ventilation, 0.78 (0.74-0.82), p < 0.001; laxatives after admission, 1.67 (1.23-2.26), p < 0.001; and enteral nutrition within 48 h of admission, 1.43 (1.07-1.90), p = 0.01. Delayed defecation was associated with prolonged intensive care stay but not mortality.

Cefazolin tissue concentrations with a prophylactic dose administered before sleeve gastrectomy in obese patients: a single centre study in 116 patients.

BACKGROUND: In obese patients undergoing sleeve gastrectomy, the blood and fatty-tissue concentrations of cefazolin required for adequate antibiotic prophylaxis are uncertain. METHODS: This was a single centre prospective study in obese (Group A: 40≤ BMI ≤50 kg m-2) and severely obese (Group B: 50< BMI ≤65 kg m-2) patients undergoing bariatric surgery. Blood and fatty-tissue samples were collected after a cefazolin 4 g i.v. injection. The primary aim was to compare cefazolin concentrations in subcutaneous fatty tissue with a targeted tissue concentration of 4 µg g-1 according to Staphylococcus aureus resistance breakpoint. RESULTS: One hundred and sixteen patients were included: 79 in Group A and 37 in Group B. At the beginning of the surgery, cefazolin concentration in subcutaneous fatty tissue was 12.2 (5.4) µg g-1 in Group A and 12 (6.1) µg g-1 in Group B (P=0.7). At the end, cefazolin concentrations in subcutaneous fatty tissue were 9.0 (4.9) and 7.8 (4.2) µg g-1 in Groups A and B, respectively (P=0.2). The plasma concentration of free cefazolin during surgery was higher in Group A than in Group B (P<0.0001). Fatty-tissue concentrations of 95% and 83% patients in Groups A and B, respectively, were above S. aureus resistance breakpoint. CONCLUSIONS: After a 4 g dose, the concentrations of cefazolin in fatty tissue were above the 4 µg g-1 tissue concentration target, providing adequate antibiotic tissue concentrations during bariatric surgery. As cefazolin concentration in fatty tissue is a surrogate endpoint, the results should be considered in conjunction with the results on free cefazolin concentrations in subcutaneous tissue. CLINICAL TRIAL REGISTRATION: NCT01537380.

Risk factors and pathogens involved in early ventilator-acquired pneumonia in patients with severe subarachnoid hemorrhage.

Ventilator-acquired pneumonia (VAP) is a common burden in intensive care unit (ICU) patients, but, to date, specific data are not available in patients with severe aneurysmal subarachnoid hemorrhage (SAH). A single neuro-ICU retrospective analysis of 193 patients with SAH requiring mechanical ventilation (MV) ≥48 h admitted from January 2005 to May 2010 was undertaken. The diagnosis of early VAP was prospectively upheld during a multidisciplinary staff meeting, according to the American Thoracic Society (ATS) 2005 guidelines with a threshold of 7 days after the onset of MV. Patients had a median age of 53 (44-62) years and 70 (36 %) were male. The median Glasgow coma scale (GCS) score before MV was 9 (5-14). 142 (74 %) patients had a World Federation of Neurosurgeons (WFNS) score ≥III. Aneurysm was secured with an endovascular coiling procedure in 162 (84 %) patients. 81 (48.7 %) patients declared an early VAP. On multivariate analysis, male sex (odds ratio [OR] 2.26, 95 % confidence interval [CI] [1.14-4.46]), use of mannitol before day 7 (OR 3.03, 95 % CI [1.54-5.95]), and achieving enteral nutrition ≥20 kcal kg(-1) day(-1) after day 7 (OR 2.91, 95 % CI [1.27-6.67]) remained independent risk factors of VAP. The main pathogens involved were methicillin-susceptible Staphylococcus aureus (MSSA) (34.9 %), Haemophilus influenzae (28.1 %), Streptococcus pneumoniae (15.5 %), and Enterobacteriaceae (10.7 %). Early VAP was associated with a longer duration of MV and ICU stay, but not with an excess of mortality. Early VAP bears significant morbidity in patients with severe SAH. Pathogens involved in early VAP are susceptible to antibiotics. Among modifiable risk factors of VAP, early enteral nutrition could be an easy and effective target.

Long-term survival of traumatic brain injury and intra-cerebral haemorrhage patients: A multicentric observational cohort.

PURPOSE: Mortality is often assessed during ICU stay and early after, but rarely at later stage. We aimed to compare the long-term mortality between TBI and ICH patients. MATERIALS AND METHODS: From an observational cohort, we studied 580 TBI patients and 435 ICH patients, admitted from January 2013 to February 2021 in 3 ICUs and alive at 7-days post-ICU discharge. We performed a Lasso-penalized Cox survival analysis. RESULTS: We estimated 7-year survival rates at 72.8% (95%CI from 67.3% to 78.7%) for ICH patients and at 84.9% (95%CI from 80.9% to 89.1%) for TBI patients: ICH patients presenting a higher mortality risk than TBI patients. Additionally, we identified variables associated with higher mortality risk (age, ICU length of stay, tracheostomy, low GCS, absence of intracranial pressure monitoring). We also observed anisocoria related with the mortality risk in the early stage after ICU stay. CONCLUSIONS: In this ICU survivor population with a prolonged follow-up, we highlight an acute risk of death after ICU stay, which seems to last longer in ICH patients. Several variables characteristic of disease severity appeared associated with long-term mortality, raising the hypothesis that the most severe patients deserve closer follow-up after ICU stay.

French recommendations for the management of patients with spinal cord injury or at risk of spinal cord injury.

OBJECTIVES: To update the French guidelines on the management of trauma patients with spinal cord injury or suspected spinal cord injury. DESIGN: A consensus committee of 27 experts was formed. A formal conflict-of-interest (COI) policy was developed at the outset of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding (i.e. pharmaceutical, medical devices). The authors were advised to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. METHODS: The committee studied twelve questions: (1) What are the indications and arrangements for spinal immobilisation? (2) What are the arrangements for pre-hospital orotracheal intubation? (3) What are the objectives of haemodynamic resuscitation during the lesion assessment, and during the first few days in hospital? (4) What is the best way to manage these patients to improve their long-term prognosis? (5) What is the place of corticosteroid therapy in the initial phase? (6) What are the indications for magnetic resonance imaging in the lesion assessment phase? (7) What is the optimal time for surgical management? (8) What are the best arrangements for orotracheal intubation in the hospital environment? (9) What are the specific conditions for weaning these patients from mechanical ventilation for? (10) What are the procedures for analgesic treatment of these patients? (11) What are the specific arrangements for installing and mobilising these patients? (12) What is the place of early intermittent bladder sampling in these patients? Each question was formulated in a PICO (Patients, Intervention, Comparison, Outcome) format and the evidence profiles were produced. The literature review and recommendations were made according to the GRADE® Methodology. RESULTS: The experts' work synthesis and the application of the GRADE method resulted in 19 recommendations. Among the recommendations formalised, 2 have a high level of evidence (GRADE 1+/-) and 12 have a low level of evidence (GRADE 2+/-). For 5 recommendations, the GRADE method could not be applied, resulting in expert advice. After two rounds of scoring and one amendment, strong agreement was reached on all the recommendations. CONCLUSIONS: There was significant agreement among experts on strong recommendations to improve practices for the management of patients with spinal cord injury.

Pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia.

Hospital-acquired pneumonia is a major cause of morbidity and mortality. The incidence of hospital-acquired pneumonia remains high globally and treatment can often be ineffective. Here, we review the available data and unanswered questions surrounding hospital-acquired pneumonia, discuss alterations of the respiratory microbiome and of the mucosal immunity in patients admitted to hospital, and explore potential approaches to stratify patients for tailored treatments. The lungs have been considered a sterile organ for decades because microbiological culture techniques had shown negative results. Culture-independent techniques have shown that healthy lungs harbour a diverse and dynamic ecosystem of bacteria, changing our comprehension of respiratory physiopathology. Understanding dysbiosis of the respiratory microbiome and altered mucosal immunity in patients with critical illness holds great promise to develop targeted host-directed immunotherapy to reduce ineffective treatment, to improve patient outcomes, and to tackle the global threat of resistant bacteria that cause these infections.

Ammonia plasma concentration and prolonged infusion of remifentanil in patients with acute kidney injury.

BACKGROUND: Glycine is an excipient of remifentanil and may induce side effects. To investigate glycine and ammonia concentration with the use of remifentanil in Intensive Care Unit patients with acute kidney injury (AKI) defined by a decrease in creatinine clearance above 50%. METHODS: Prospective open-label cohort study in three surgical Intensive Care Units. Thirty-three patients with AKI and requiring sedation for at least 72 hours. Sedation with remifentanil and midazolam or propofol was adapted every six hours according to ATICE. Glycine and ammonia plasma concentrations were measured at H0 (start of infusion) and every 12 hours during a continuous intravenous 72 hours remifentanil infusion, and 24 hours after the end of the infusion. Clinical and biological glycine or ammonia toxicity were evaluated. RESULTS: Fifteen patients required continuous veno-venous hemodiafiltration (CVVHDF). Glycine and ammonia plasma concentrations exceeded the normal value respectively for 11 (33%) and 15 (45%) patients before remifentanil infusion (H0). Accumulation of glycine or ammonia was observed neither for patients with or without CVVHDF. For patients without CVVHDF, the plasma ammonia concentration at the end of remifentanil infusion was significantly correlated with the creatinine clearance at H72 (P=0.03) and with the mean rate of remifentanil infusion (P=0.002). No side effect was reported. CONCLUSION: Remifentanil was not associated with an accumulation of glycine or ammonia in patients with AKI. Plasma ammonia concentration was correlated with the mean rate of remifentanil and creatinine clearance. A 72-hours remifentanil infusion appeared safe for sedation of patients with AKI.

Operative care and surveillance in severe trauma patients. Interference between resuscitation treatments and anaesthesiology, and consequence on immunity.

Major trauma remains a worldwide cause of morbi-mortality. Early mortality is the consequence of hemorrhagic shock and traumatic brain injury. During early resuscitation, anaesthesia is often mandatory to perform surgery. It is mandatory to master the hemodynamic effects of hypnotic drugs in order to anticipate their potential deleterious effects in the setting of hemorrhagic shock. After early resuscitation, trauma patients present a high prevalence of nosocomial pneumonia, which sustains major morbidity. Nosocomial pneumonia are the consequence of an overwhelming systemic inflammatory response syndrome (SIRS) as well as a trauma-related immunosuppression. The administration of hemisuccinate of hydrocortisone modulates the SIRS and reduces the risk of nosocomial pneumonia as well as the length of mechanical ventilation. Finally in the operating theatre, fighting against hypothermia and un-anatomical positions, which can aggravate rhabdomyolysis, are both mandatory.

[Brain injury, immunity and infections]. / Agressions cérébrales, immunité et infections.

Infections are a major cause of death and morbidity after acute injury of the central nervous system (CNS). Acute lesions of the CNS alter immune homeostasis contributing to the development of immunosuppression (IS), and making the bed of the infection. IS results in a decreased phagocytic functions of neutrophils and macrophages as well as monocyte deactivation (decreased capacity of antigen presentation to lymphocytes). The immune abnormalities occur very quickly and may last for weeks. The neurovegetative system is closely connected to the secondary lymphoid organs where cells of innate immunity receive information from injured organs inducing the long lasting adaptive immune response (immune synapse). The sympathetic system is critically involved in the IS through production of anti-inflammatory mediators like interleukin-10. This may prove important as all types of acute injury of the CNS can lead to direct damage to sympathetic centers. Specialized units of care for ischemic stroke, taking into account the risk of infection related to the IS, have improved the prognosis until 18th month after the initial damage of the SNC. It is now well recognized that the improved long-term prognosis is related with the secondary prevention of recurrent ischaemia as well as aggressive management of pulmonary infections. A better understanding of the pathophysiology of IS can be considered in the near future, opening the door to immunomodulatory therapeutic trials.

Risk factors of postoperative vomiting in children receiving continuous intravenous morphine.

BACKGROUND: Risk factors of postoperative vomiting (POV) have been less extensively explored in children compared to adults. We analyzed the risk factors of POV in children receiving continuous intravenous (i.v.) morphine in a standardized manner without POV prophylaxis after major surgery. METHODS: This observational retrospective study included 235 children aged from 2 to 216 months (91 F:144 M, 11.5% <6 months, 31.5% 6-11 months). The primary end point was the occurrence of at least one episode of POV recorded on the nursing chart. The independent predictors of POV were determined by univariate analysis followed by a multivariate analysis by logistic regression. The data are presented as either medians (25th-75th percentile) or as values with a 95% confidence interval. RESULTS: Continuous i.v. morphine was administered over 42 (22-60) h with an initial infusion rate of 20 µg x kg(-1) x h(-1) in 63% of cases, which was increased in 31.5% of cases and was accompanied by an additional bolus in 39.2% of children. At least one episode of POV occurred in 22.6% of children. The following three independent factors were associated with POV: female gender (OR 3.324 [1.695-6.519], P=0.0005), urological surgery (OR 5.605 [1.291-24.340], P=0.0214) and age (OR 1.012 [1.006-1.018], P<0.0001). The discriminating characteristics of the model were good with an ROC curve AUC of 0.778, sensitivity of 71.7% and specificity of 71.4% for a 0.22 cut-off value of POV incidence. The positive predictive value was 42.2%, and the negative predictive value was 89.6%. CONCLUSION: Female gender, which is usually considered a risk factor after puberty, should be taken into account independent of age to guide the POV prophylaxis in children receiving a postoperative continuous i.v. morphine infusion.