Raphaël Cinotti

Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study

IntroductionWe sought to investigate whether the use of balanced solutions reduces the incidence of hyperchloraemic acidosis without increasing the risk for intracranial hypertension in patients with severe brain injury.MethodsWe conducted a single-centre, two-arm, randomised, double-blind, pilot controlled trial in Nantes, France. Patients with severe traumatic brain injury (Glasgow Coma Scale score ≤8) or subarachnoid haemorrhage (World Federation of Neurosurgical Society grade III or higher) who were mechanically ventilated were randomised within the first 12 hours after brain injury to receive either isotonic balanced solutions (crystalloid and hydroxyethyl starch; balanced group) or isotonic sodium chloride solutions (crystalloid and hydroxyethyl starch; saline group) for 48 hours. The primary endpoint was the occurrence of hyperchloraemic metabolic acidosis within 48 hours.ResultsForty-two patients were included, of whom one patient in each group was excluded (one consent withdrawn and one use of forbidden therapy). Nineteen patients (95%) in the saline group and thirteen (65%) in the balanced group presented with hyperchloraemic acidosis within the first 48 hours (hazard ratio = 0.28, 95% confidence interval [CI] = 0.11 to 0.70; P = 0.006). In the saline group, pH (P = .004) and strong ion deficit (P = 0.047) were lower and chloraemia was higher (P = 0.002) than in the balanced group. Intracranial pressure was not different between the study groups (mean difference 4 mmHg [-1;8]; P = 0.088). Seven patients (35%) in the saline group and eight (40%) in the balanced group developed intracranial hypertension (P = 0.744). Three patients (14%) in the saline group and five (25%) in the balanced group died (P = 0.387).ConclusionsThis study provides evidence that balanced solutions reduce the incidence of hyperchloraemic acidosis in brain-injured patients compared to saline solutions. Even if the study was not powered sufficiently for this endpoint, intracranial pressure did not appear different between groups.Trial registrationEudraCT 2008-004153-15 andNCT00847977The work in this trial was performed at Nantes University Hospital in Nantes, France.

Implementation of an evidence-based extubation readiness bundle in 499 brain-injured patients. a before-after evaluation of a quality improvement project.

RATIONALE Mechanical ventilation is associated with morbidity in patients with brain injury. OBJECTIVES This study aims to assess the effectiveness of an extubation readiness bundle to decrease ventilator time in patients with brain injury. METHODS Before-after design in two intensive care units (ICUs) in one university hospital. Brain-injured patients ventilated more than 24 hours were evaluated during two phases (a 3-yr control phase followed by a 22-mo intervention phase). Bundle components were protective ventilation, early enteral nutrition, standardization of antibiotherapy for hospital-acquired pneumonia, and systematic approach to extubation. The primary endpoint was the duration of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS A total of 299 and 200 patients, respectively, were analyzed in the control and the intervention phases of this before-after study. The intervention phase was associated with lower tidal volume (P < 0.01), higher positive end-expiratory pressure (P < 0.01), and higher enteral intake in the first 7 days (P = 0.01). The duration of mechanical ventilation was 14.9 ± 11.7 days in the control phase and 12.6 ± 10.3 days in the intervention phase (P = 0.02). The hazard ratio for extubation was 1.28 (95% confidence interval [CI], 1.04-1.57; P = 0.02) in the intervention phase. Adjusted hazard ratio was 1.40 (95% CI, 1.12-1.76; P < 0.01) in multivariate analysis and 1.34 (95% CI, 1.03-1.74; P = 0.02) in propensity score-adjusted analysis. ICU-free days at Day 90 increased from 50 ± 33 in the control phase to 57 ± 29 in the intervention phase (P < 0.01). Mortality at Day 90 was 28.4% in the control phase and 23.5% in the intervention phase (P = 0.22). CONCLUSIONS The implementation of an evidence-based extubation readiness bundle was associated with a reduction in the duration of ventilation in patients with brain injury.

An in vitro model of mycobacterial granuloma to investigate the immune response in brain-injured patients.

Objective:We investigated the overall immune response to pathogens in brain-injured patients, and assessed its relationship to nosocomial pneumonia. Design:Observational study. Setting:Two surgical ICUs of a single institution. Patients:Severe brain-injured patients (n = 32) requiring mechanical ventilation and sex- and age-matched healthy donors (n = 25). Interventions:None. Measurements and Main Results:We evaluated, ex vivo, the ability of peripheral blood mononuclear cells from brain injury patients to develop an effective granulomatous response to mycobacteria. Thirty-two consecutive patients (25 traumatic brain injured and seven subarachnoid hemorrhage) were included. Median Glasgow Coma Scale was 7 (5–8). Thirteen (41%) patients developed nosocomial pneumonia. Peripheral blood mononuclear cells from brain-injured patients with nosocomial pneumonia generated significantly fewer mature granulomas compared with brain-injured patients without nosocomial pneumonia and with healthy donors. The percentage of multinucleated giant cells was lower in brain-injured patients without nosocomial pneumonia (1% [range: 0%–7%]) and in brain-injured patients with nosocomial pneumonia (4% [range: 2%–5%]) compared with healthy donors (20% [range: 15%–28%]). The blood levels of &ggr;&dgr; T cells were significantly increased in brain-injured patients without nosocomial pneumonia (66% [range: 34%–69%]) compared with healthy donors (23% [range: 8%–61%]) and was not altered in brain-injured patients with nosocomial pneumonia (31% [range: 12%–44%]). The percentage of &ggr;&dgr; T cells in granulomas was significantly decreased in brain injury patients with nosocomial pneumonia (5% [range: 4%–43%]) compared with healthy donors (43% [range: 19%–54%]) and was not significantly altered in brain-injured patients without nosocomial pneumonia (26% [range: 10%–41%]). The blood levels of natural killer cells were not altered in brain-injured patients. The percentage of natural killer cells in granulomas was significantly decreased in brain-injured patients with nosocomial pneumonia (3% [range: 1%–9%]) compared with brain-injured patients without nosocomial pneumonia (16% [range: 6%–29%]) and with healthy donors (17% [range: 10%–29%]). Conclusions:Brain-injured patients experienced a maturation defect of the ex vivo granulomatous response involving monocytes as well as natural killer cells and &ggr;&dgr; T cells.

Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections

Summary Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen‐presentation capacity and secretion of immunogenic cytokines. Development of these “paralyzed” DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF‐&bgr;. Paralyzed DCs secreted TGF‐&bgr; and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen‐presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis‐ and trauma‐induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention. Graphical Abstract Figure. No Caption available. HighlightsMacrophages and DCs produced after severe primary pneumonia are functionally impairedTGF‐&bgr; and Treg cells induce a tolerogenic differentiation program in these DCsThese “paralyzed” DC express high amounts of Blimp 1 and low amounts of IRF4Expression of Blimp 1 in human DC correlates with outcome in ICU patients &NA; Following a severe primary infection, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis‐induced immunosuppression. Roquilly et al. show that resolution of the primary infection changed the local environment, leading to the development of DCs and macrophages that are functionally impaired in terms of T cell activation, and instead exhibit tolerogenic properties that contribute to immune suppression.

The Microbiology of Community-acquired Peritonitis in Children.

Background: Microbiologic data are lacking regarding pediatric community-acquired peritonitis (CAP). Methods: We conducted a 2-year retrospective single center study. Consecutive children undergoing CAP surgery were included. Microbiology and antimicrobial susceptibility of peritoneal isolates were analyzed. Results: A total of 70 children from 3 months to 14 years of age were included. A total of 123 bacterial isolates were analyzed. Escherichia coli was the predominant aerobic organism (51% of isolates); 54.8% were susceptible to amoxicillin whereas 90.3% were susceptible to amoxicillin-clavulanate. Anaerobes accounted for 29% of isolates, and 94.3% of strains were susceptible to amoxicillin-clavulanate and 68.5% were susceptible to clindamycin. Pseudomonas aeruginosa was present in 6% of isolates and in 10% of children. The presence of E. coli resistant to amoxicillin or to amoxicillin-clavulanate was the only independent risk factor associated with postoperative peritonitis. Conclusion: Microbiology of pediatric CAP is similar to adult CAP with a predominancy of E. coli and anaerobes. P. aeruginosa in peritoneal samples had no apparent influence on the outcome.

Severe and multiple hypoglycemic episodes are associated with increased risk of death in ICU patients

IntroductionIn a randomized controlled trial comparing tight glucose control with a computerized decision support system and conventional protocols (post hoc analysis), we tested the hypothesis that hypoglycemia is associated with a poor outcome, even when controlling for initial severity.MethodsWe looked for moderate (2.2 to 3.3 mmol/L) and severe (<2.2 mmol/L) hypoglycemia, multiple hypoglycemic events (n ≥3) and the other main components of glycemic control (mean blood glucose level and blood glucose coefficient of variation (CV)). The primary endpoint was 90-day mortality. We used both a multivariable analysis taking into account only variables observed at admission and a multivariable matching process (greedy matching algorithm; caliper width of 10−5 digit with no replacement).ResultsA total of 2,601 patients were analyzed and divided into three groups: no hypoglycemia (n =1,474), moderate hypoglycemia (n =874, 34%) and severe hypoglycemia (n =253, 10%). Patients with moderate or severe hypoglycemia had a poorer prognosis, as shown by a higher mortality rate (36% and 54%, respectively, vs. 28%) and decreased number of treatment-free days. In the multivariable analysis, severe (odds ratio (OR), 1.50; 95% CI, 1.36 to 1.56; P =0.043) and multiple hypoglycemic events (OR, 1.76, 95% CI, 1.31 to 3.37; P <0.001) were significantly associated with mortality, whereas blood glucose CV was not. Using multivariable matching, patients with severe (53% vs. 35%; P <0.001), moderate (33% vs. 27%; P =0.029) and multiple hypoglycemic events (46% vs. 32%, P <0.001) had a higher 90-day mortality.ConclusionIn a large cohort of ICU patients, severe hypoglycemia and multiple hypoglycemic events were associated with increased 90-day mortality.Trial registrationClinicaltrials.gov Identifier: NCT01002482. Registered 26 October 2009.

Effects of tight computerized glucose control on neurological outcome in severely brain injured patients: a multicenter sub-group analysis of the randomized-controlled open-label CGAO-REA study

IntroductionHyperglycemia is a marker of poor prognosis in severe brain injuries. There is currently little data regarding the effects of intensive insulin therapy (IIT) on neurological recovery.MethodsA sub-group analysis of the randomized-controlled CGAO-REA study (NCT01002482) in surgical intensive care units (ICU) of two university hospitals. Patients with severe brain injury, with an expected ICU length of stay ≥48 hours were included. Patients were randomized between a conventional glucose management group (blood glucose target between 5.5 and 9 mmol.L−1) and an IIT group (blood glucose target between 4.4 and 6 mmol.L−1). The primary outcome was the day-90 neurological outcome evaluated with the Glasgow outcome scale.ResultsA total of 188 patients were included in this analysis. In total 98 (52%) patients were randomized in the control group and 90 (48%) in the IIT group. The mean Glasgow coma score at baseline was 7 (±4). Patients in the IIT group received more insulin (130 (68 to 251) IU versus 74 (13 to 165) IU in the control group, P = 0.01), had a significantly lower morning blood glucose level (5.9 (5.1 to 6.7) mmol.L−1 versus 6.5 (5.6 to 7.2) mmol.L−1, P <0.001) in the first 5 days after ICU admission. The IIT group experienced more episodes of hypoglycemia (P <0.0001). In the IIT group 24 (26.6%) patients had a favorable neurological outcome (good recovery or moderate disability) compared to 31 (31.6%) in the control group (P = 0.4). There were no differences in day-28 mortality. The occurrence of hypoglycemia did not influence the outcome.ConclusionsIn this sub-group analysis of a large multicenter randomized trial, IIT did not appear to alter the day-90 neurological outcome or ICU morbidity in severe brain injured patients or ICU morbidity.

Impaired blood dendritic cell numbers and functions after aneurysmal subarachnoid hemorrhage.

Previous Presentation Portions of this study were presented at the Annual Congress of Société Française d’Anesthésie et de Réanimation in Paris, September 2012. Background Toll-like receptor (TLR) agonists are promising therapy for the prevention of nosocomial infections in critical ill patients. We aimed to analyze the TLR-reactivity of circulating dendritic cells (DC) as assessed by cytokine production after an ex vivo challenge with TLR agonists in aneurysmal subarachnoid hemorrhage (SAH) patients. Methods and Findings A single-center prospective observational study took place in one intensive care unit of a teaching hospital. Blood samples were harvested on days 2, 5 and 10 in 21 severe SAH patients requiring mechanical ventilation and 17 healthy controls. DC production of cytokines (Tumour Necrosis Factor, TNF-α; Interleukin, IL-12; and Interferon, IFN-α) was assessed by intracellular immunostaining on TLR-3, 4, 7/8 and 9 stimulations. SAH patients had decreased numbers of blood myeloid (mDCs) and plasmacytoid DCs (pDCs) on days 2, 5 and 10. Compared with the healthy controls, the frequency of mDCs producing TNF-α after TLR-3 stimulation was decreased in the SAH patients. The frequency of myeloid DCs producing IL-12 after TLR-3 and 4 stimulations was also decreased in the SAH patients. In contrast, the mDCs response to TLR-7/8 was not impaired in the SAH patients. The frequency of pDCs producing TNF-α+ and IFN-α+ on TLR-7/8 stimulation were reduced at all of the tested times in the SAH patients, whereas reactivity to TLR-9 was preserved. On day 2, the pDCs from non-survivor patients (n = 8) had a decreased ability to produce IFN-α on TLR-9 stimulation compared with the survivors. Conclusions These data suggest functional abnormalities of circulating pDCs and mDCs that could be important for immunomodulation after SAH.

Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury

Issues regarding recommendations on empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) have emerged in specific populations. To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients. The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy ≥48 h (p<0.001) and VAP onset ≥10 days (p<0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770–0.883) in the learning cohort and 0.805 (95% CI 0.732–0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596–0.751). Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts <48 h. To stop spread of resistant bacteria, we should limit broad antimicrobial therapy in brain-injured pneumonia patients http://ow.ly/UL3pS

Extubation Success Prediction in a Multicentric Cohort of Patients with Severe Brain Injury

BACKGROUND Patients with brain injury are at high risk of extubation failure. METHODS We conducted a prospective observational cohort study in four intensive care units of three university hospitals. The aim of the study was to create a score that could predict extubation success in patients with brain injury. RESULTS A total of 437 consecutive patients with brain injury were included, and 338 patients (77.3%) displayed successful extubation. In the multivariate analysis, four features were associated with success the day of extubation: age less than 40 yr, visual pursuit, swallowing attempts, and a Glasgow coma score greater than 10. In the score, each item counted as one. A score of 3 or greater was associated with 90% extubation success. The area under the receiver-operator curve was 0.75 (95% CI, 0.69 to 0.81). After internal validation by bootstrap, the area under the receiver-operator curve was 0.73 (95% CI, 0.68 to 0.79). Extubation success was significantly associated with shorter duration of mechanical ventilation (11 [95% CI, 5 to 17 days] vs. 22 days [95% CI, 13 to 29 days]; P < 0.0001), shorter intensive care unit length of stay (15 [95% CI, 9 to 23 days] vs. 27 days [95% CI, 21 to 36 days]; P < 0.0001), and lower in-intensive care unit mortality (4 [1.2%] vs. 11 [11.1%]; P < 0.0001). CONCLUSIONS Our score exploring both airway functions and neurologic status may increase the probability of successful extubation in patients with severe brain injury.