Pierre Moine

Protective versus Conventional Ventilation for Surgery: A Systematic Review and Individual Patient Data Meta-analysis.

Background:Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end–expiratory pressure (PEEP) level and occurrence of PPC. Methods:Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression. Results:Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 patients (8.9%) assigned to ventilation with low VT and high PEEP levels and 63 cases in 525 patients (12%) assigned to ventilation with low VT and low PEEP levels (adjusted relative risk, 0.93; 95% CI, 0.64 to 1.37; P = 0.72). A dose–response relationship was found between the appearance of PPC and VT size (R2 = 0.39) but not between the appearance of PPC and PEEP level (R2 = 0.08). Conclusions:These data support the beneficial effects of ventilation with use of low VT in patients undergoing surgery. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during nonopen abdominal surgery.

Determinants of postintensive care unit mortality: a prospective multicenter study.

ObjectiveSix to 25 percent of patients discharged alive from the intensive care unit (ICU) die before hospital discharge. Although this post-ICU mortality may indicate premature discharge from a full ICU or suboptimal management in the ICU or ward, another factor may be discharge from the ICU as part of a decision to limit treatment of hopelessly ill patients. We investigated determinants of post-ICU mortality, with special attention to this factor. DesignProspective, multicenter, database study. SettingSeven ICUs in or near Paris, France. PatientsA total of 1,385 patients who were discharged alive from an ICU after a stay of ≥48 hrs; 150 (10.8%) died before hospital discharge. Decisions to withhold or withdraw life-sustaining treatments were implemented in the ICUs in 80 patients, including 47 (58.7%) who died before hospital discharge. InterventionsNone. Measurements and Main ResultsIn the univariate analysis, post-ICU mortality was associated with advanced age, poor chronic health status, severe comorbidities, severity and organ failure scores (Simplified Acute Physiology Score II, sepsis-related organ failure assessment, and Logistic Organ Dysfunction at admission and at ICU discharge), decisions to withhold or withdraw life-sustaining treatments, and Omega score (reflecting ICU resource utilization and length of ICU stay). Multivariate stepwise logistic regression identified five independent determinants of post-ICU mortality: McCabe class 1 (odds ratio, 0.388 [95% confidence interval, 0.26–0.58]), transfer from a ward (odds ratio, 1.89 [95% confidence interval, 1.27–2.80]), Simplified Acute Physiology Score II score at admission >36 (odds ratio, 1.57 [95% confidence interval, 1.6–2.33]), decisions to withhold or withdraw life-sustaining treatments (odds ratio, 9.64 [95% confidence interval, 5.75–16.6]), and worse sepsis-related organ failure assessment score at discharge (odds ratio, 1.11 [95% confidence interval, 1.03–1.18] per point). ConclusionsMore than 10% of ICU survivors died before hospital discharge. Determinants of post-ICU mortality included variables reflecting patient status before and during the ICU stay. However, the most powerful predictor of post-ICU mortality was the decision to withhold or withdraw life-sustaining treatments in the ICU, suggesting that the decision has been made not to use the unique services of the ICU for these patients.

Cortisol response to corticotropin stimulation in trauma patients: influence of hemorrhagic shock.

Background An abnormal adrenocortical function and a vasopressor dependency have been demonstrated during septic shock. Because trauma and hemorrhage are the leading causes of noninfectious inflammatory syndromes, the goal of this study was to assess the adrenal reserve of trauma patients and its relation with clinical course. Methods Cortisol response to an intravenous corticotropin bolus was obtained in 34 young trauma patients (Injury Severity Score =29.1 ± 7.3) at the end of the resuscitative period (“early phase”) and at the end of the first posttraumatic week (“late period”). Cortisol response less than +9 g/dl defined an impaired adrenal function, and the corresponding patient was called a nonresponder. According to the early response, hemorrhagic shock, circulating interleukin-6, need for vasopressor therapy, subsequent organ dysfunction and infection, and outcomes were studied. Results Sixteen patients (47%) were nonresponders at the end of the early phase. Hemorrhagic shock was more frequent (69 vs. 28%;P = 0.037) and interleukin-6 concentrations were higher (728 ± 589 vs. 311 ± 466 pg/ml;P = 0.048) in these patients. The early cortisol responses were negatively correlated with the concomitant interleukin-6 serum concentrations (r2 = 0.298;P = 0.003). Four early nonresponders (and shock patients) remained nonresponders during the late phase (25%). Morbidity and mortality were similar in early nonresponders and responders. The duration of norepinephrine treatment and the total amount of infused drug were significantly higher in early nonresponders. Conclusions A sustained impairment of adrenal reserve is frequently observed in trauma patients. This abnormal cortisol response to corticotropin stimulation is related with the inflammatory consequences of hemorrhagic shock and is followed by a prolonged vasopressor dependency.

Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data.

BACKGROUND Protective mechanical ventilation strategies using low tidal volume or high levels of positive end-expiratory pressure (PEEP) improve outcomes for patients who have had surgery. The role of the driving pressure, which is the difference between the plateau pressure and the level of positive end-expiratory pressure is not known. We investigated the association of tidal volume, the level of PEEP, and driving pressure during intraoperative ventilation with the development of postoperative pulmonary complications. METHODS We did a meta-analysis of individual patient data from randomised controlled trials of protective ventilation during general anesthaesia for surgery published up to July 30, 2015. The main outcome was development of postoperative pulmonary complications (postoperative lung injury, pulmonary infection, or barotrauma). FINDINGS We included data from 17 randomised controlled trials, including 2250 patients. Multivariate analysis suggested that driving pressure was associated with the development of postoperative pulmonary complications (odds ratio [OR] for one unit increase of driving pressure 1·16, 95% CI 1·13-1·19; p<0·0001), whereas we detected no association for tidal volume (1·05, 0·98-1·13; p=0·179). PEEP did not have a large enough effect in univariate analysis to warrant inclusion in the multivariate analysis. In a mediator analysis, driving pressure was the only significant mediator of the effects of protective ventilation on development of pulmonary complications (p=0·027). In two studies that compared low with high PEEP during low tidal volume ventilation, an increase in the level of PEEP that resulted in an increase in driving pressure was associated with more postoperative pulmonary complications (OR 3·11, 95% CI 1·39-6·96; p=0·006). INTERPRETATION In patients having surgery, intraoperative high driving pressure and changes in the level of PEEP that result in an increase of driving pressure are associated with more postoperative pulmonary complications. However, a randomised controlled trial comparing ventilation based on driving pressure with usual care is needed to confirm these findings. FUNDING None.

Long‐term‐impaired expression of nuclear factor‐κB and IκBα in peripheral blood mononuclear cells of trauma patients

Nuclear factor (NF)‐κB expression and dimer characteristics were studied in peripheral blood mononuclear cells (PBMCs) of major‐trauma patients and healthy controls. Analysis of PBMCs on days 1, 3, 5, and 10 after trauma revealed that expression of both p65p50 heterodimers and p50p50 homodimers was significantly reduced compared with that in controls. In vitro lipopolysaccharide (LPS) stimulation of PBMCs induced NF‐κB translocation. However, throughout the survey, p65p50 activation remained significantly lower in trauma patients than in controls. After LPS stimulation in vitro, the p65p50/p50p50 ratio was significantly lower in PBMCs from trauma patients than from healthy controls. The ex vivo expression of IκBα was higher in PBMCs of controls than of trauma patients. LPS did not induce IκB expression in PBMCs from trauma patients, but strong induction was obtained with staphylococci, suggesting that this defect is not universal and depends on the nature of the activating signal. Although no direct correlation was found between levels of interleukin‐10 or transforming growth factor‐β and NF‐κB, these immunosuppressive cytokines were significantly elevated in trauma patients by 10 days after admission. The long‐term low‐basal and LPS‐induced nuclear translocation of NF‐κB recalled long‐term immunoparalysis observed in patients with severe inflammatory stress such as trauma.

Relationship between Capsular Type, Penicillin Susceptibility, and Virulence of Human Streptococcus pneumoniae Isolates in Mice

ABSTRACT We examined the relationship between penicillin susceptibility, peritoneal virulence in Swiss mice, and capsular type in a selection of 122 clinical Streptococcus pneumoniae isolates belonging to 24 serotypes. Regardless of the serotype, all 32 virulent strains were susceptible to penicillin, and all 41 strains with diminished susceptibility or resistance to penicillin were avirulent. The remaining 49 strains were both susceptible to penicillin and avirulent, irrespective of the serotype. On the basis of their capsular type and pathogenic behavior, strains fell into one of four groups. In the group consisting of serotypes 1, 3, and 4 (n = 16), strains were predominantly virulent (81.3%), and all were penicillin susceptible. In the serotype 6 group (n = 32), the frequency of virulence was significantly lower (34.4 versus 81.3%, P = 0.002), and strains were predominantly penicillin susceptible (71.9%). In the group composed of serotypes 9, 14, 19, and 23 (n = 50), all strains were avirulent, and 56% had decreased susceptibility (n = 12) or resistance to (n = 16) penicillin. The fourth group was heterogenous, as it pooled 24 strains of 15 different serotypes; in this group the frequency of virulence was 33.3%, and strains were predominantly penicillin susceptible (83.3%). These data point to a complex relationship between penicillin susceptibility and virulence in mice but do not entirely separate these characteristics from the role of the capsular type. The possibility that the mechanisms conferring penicillin resistance are related to those leading to a loss of virulence is supported by these findings.

Practices in non-neutropenic ICU patients with Candida-positive airway specimens

Objective: To examine practices of French intensivists regarding the management of mechanically ventilated patients with Candida-positive airway specimens but no major risk factors for immunodepression. Design: Closed-item questionnaire with a clinical vignette. Setting: 564 French intensive care units (ICUs). Participants: 198 intensivists who have a special interest in infectious diseases and who answered the questionnaire (response rate, 35.1%). Intervention: None. Measurements and results: The respondents recommended bronchoalveolar lavage (62.6% of respondents), protected distal sampling and protected specimen brush (59.1%), transbronchial biopsy (38.9%), and tracheal aspiration (12.1%) for the diagnosis of candidal pneumonia. A positive airway specimen was felt by most respondents (83.3%) to indicate colonisation; 66.7% of respondents recommended tests for systemic candidiasis in this situation, and 56.5% serial sampling to compute the colonisation index. Azole derivatives were the preferred antifungal medications. The clinical vignette described a patient with chronic obstructive lung disease who required mechanical ventilation for an acute exacerbation and who had a tracheal aspirate positive for Candida. Responses varied widely, with 37.8% of respondents diagnosing clinically insignificant colonisation but 24.2% recommending antifungal treatment and 61.6% serial testing to assess the Candida colonisation index. Intensivists with greater experience with severely immunocompromised patients were more aggressive in their diagnostic management. Conclusions: Wide variations occur among practices of French intensivists regarding Candida-positive airway specimens in patients without major risk factors for immunodepression. Additional studies are needed to improve our understanding of the links between Candida colonisation and infection and to determine the indications for pre-emptive antifungal treatment in non-neutropenic critically ill patients.

Bupivacaine's action on the carrageenan-induced inflammatory response in mice: cytokine production by leukocytes after ex-vivo stimulation.

We aimed to study the effect of bupivacaine on the systemic response elicited by intraplantar injection of carrageenan. To that purpose, we studied the effects of carrageenan, bupivacaine, or both on the production of tumor necrosis factor (TNF)-&agr;, interleukin (IL)-1&bgr;, and IL-10 by whole blood cultured in the presence of lipopolysaccharide (LPS) and of heat-killed Staphylococcus Aureus Cowan (SAC). Mice received a hindpaw injection of carrageenan with or without encapsulated IM bupivacaine given contralaterally. Whole blood was sampled 15 h later and cultured for 24 h with LPS or SAC. The amounts of TNF-&agr;, IL-1&bgr;, and IL-10 in the supernatants were measured. In the presence of LPS or SAC, proinflammatory cytokine (TNF-&agr; and IL-1&bgr;) production was increased after carrageenan. Bupivacaine prevented this inflammatory response: 992 ± 102 versus 2146 ± 338 versus 919 ± 116 pg/mL for TNF-&agr; (bupivacaine + carrageenan versus carrageenan versus control after LPS stimulation). This effect of bupivacaine was less after SAC stimulation. Moreover, IL-10 was not involved in the inhibition of proinflammatory cytokine production observed after treatment by bupivacaine alone. These experiments show that carrageenan-induced hindpaw inflammation modifies the blood cell reactivity to LPS and SAC and that bupivacaine regulates the systemic response elicited by carrageenan. Furthermore, IL-10 does not seem to be a factor of the antiinflammatory response induced by bupivacaine. The precise mechanism underlying this effect of bupivacaine remains to be clarified.

Nuclear factor-kappaB activation in mouse lung lavage cells in response to Streptococcus pneumoniae pulmonary infection.

ObjectivesTo assess the state and activation kinetics of the nuclear transcription regulatory protein nuclear factor-&kgr;B (NF-&kgr;B) in lung lavage cells in a murine pneumococcal pneumonia model and to determine how the virulence of the infecting organisms altered the activation state of NF-&kgr;B. DesignExperimental, comparative study of three Streptococcus pneumoniae strains that induced three distinct pulmonary diseases. SettingExperimental laboratory in a university-based medical center. SubjectsFemale BALB/cby mice, 8–10 wks of age. InterventionsWe randomly divided the mice into the following five groups: a) the control group; b) animals infected by virulent encapsulated S. pneumonia e P4241 strain; c) animals infected by avirulent encapsulated S. pneumoniae P15986 strain; d) animals infected by avirulent unencapsulated S. pneumoniae R6 strain; e) animals infected by virulent lysed S. pneumoniae P4241 strain. Animals were anesthetized and infected by intratracheal delivery of 4 × 105 colony-forming units (CFU) of S. pneumoniae per mouse or bacterial components equivalent to 4 × 105 CFU for lysed S. pneumoniae challenge. After intratracheal challenge with virulent encapsulated strain P4241, mice developed acute pneumonia, became bacteremic, and died within 3 to 5 days. None of the mice infected with the avirulent encapsulated strain P15986 or the avirulent unencapsulated strain R6 died. After collection of lung lavage cells and nuclear extraction, NF-&kgr;B activation was determined 1 hr, 4 hrs, 6 hrs and 24 hrs after pneumococcal infection. At the same time, pulmonary and blood clearance, bronchoalveolar lavage cells population, and tumor necrosis factor-&agr; production were assessed (six mice per time point). Measurements and Main ResultsNF-&kgr;B was constitutively expressed within nuclear extracts of lung lavage cells from uninfected control mice. A significant increase in NF-&kgr;B activation was detected within 1 hr after injection of virulent lysed S. pneumoniae P4241 strain (bacterial components equivalent to 4 × 105 CFU), and was still present 24 hrs after the injection. After live pneumococcal challenge, significant NF-&kgr;B activation was detected within 4 hrs with a peak at 24 hrs. Responses to all three strains (P4241, P15986 and R6) were time-dependent (p < .0001), as NF-&kgr;B activation gradually increased during the first 24 hrs. Moreover, compared with the control uninfected mice, the intensity of the retarded &kgr;B oligonucleotide, as determined by densitometry, was increased approximately four- to five-fold and seven-fold in reactions containing nuclear extracts isolated 24 hrs after infection with the avirulent strains P15986 or R6 and the virulent strain P4241, respectively. With the virulent strain P4241, responses were significantly stronger than with the avirulent strains P15986 and R6 (p < .01). Responses were of similar order with avirulent strains P15986 and R6 (p > .05). ConclusionPulmonary infection by S. pneumoniae induced delayed and time-dependent activation of NF-&kgr;B in mouse lung lavage cells. The degree of NF-&kgr;B activation in lung lavage cells correlated with the virulence of the infecting organisms. Our results suggest that the more severe the infection, the higher the rise in NF-&kgr;B.

Short-term effect of inhaled nitric oxide and prone positioning on gas exchange in patients with severe acute respiratory distress syndrome.

Objective: To compare the short‐term effects of inhaled nitric oxide (NO) and prone positioning in improving oxygenation in acute respiratory distress syndrome (ARDS). Methods: Charts of consecutive ARDS patients (lung injury score >2) during a 2‐yr period, tested for both inhaled NO and prone positioning efficacy were retrospectively reviewed. Variations in the PaO2/FIO2 ratio induced by inhaled NO and prone positioning were evaluated. Measurements and Main Results: Twenty‐seven patients (age, 42 ± 17 yrs) were included. Simplified Acute Physiology Score II was 45 ± 14. Mortality rate in the intensive care unit was 63%. The causes of ARDS were pneumonia (n = 14), extra‐lung infection (n = 5), and noninfectious systemic inflammatory response syndrome (n = 8). Lung injury score was 2.7 ± 0.3. At baseline, before the initiation of inhaled NO, the PaO2/FIO2 ratio was 97 ± 46 torr and before prone positioning, 92 ± 26 torr. Variations in the PaO2/FIO2 ratio were lower at start of NO therapy (11 ± 4 ppm) than that observed at prone positioning initiation (23 ± 31 vs. 62 ± 78 torr, p < .05). An increase in variations in the PaO2/FIO2 ratio of > 15 torr was associated with prone positioning in 16 patients (59%) and with NO inhalation in 13 patients (48%) (not significant). An increase in variations in the PaO2/FIO2 ratio of > 15 torr was associated with both techniques in only six patients (22%). There was no correlation between the response to prone positioning and the response to inhaled NO (r2 = .005; p = .73). Conclusions: Prone positioning improves hypoxemia significantly better than does inhaled NO. The response to one technique is not predictive of the response to the other technique.