Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Gentamicin in hemodialyzed critical care patients: early dialysis after administration of a high dose should be considered.

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. We performed Monte Carlo simulations (MCS) to determine the best gentamicin pharmacokinetic profile (high peak and low trough concentrations). Then, 6 mg/kg of gentamicin was infused into 10 ICU patients over a period of 30 min. A 4-h-long hemodialysis session was started 30 min after the end of the infusion. Pharmacokinetic samples were regularly collected over 24 h. A one-compartment model with zero-order input and first-order elimination was developed in Nonmem version VI to analyze patients' measured gentamicin concentration-versus-time profiles. Finally, additional MCS were performed to compare the regimen chosen with the FDA-approved gentamicin regimen. High peak concentrations (C(max), 31.8 ± 16.8 mg/liter) were achieved. The estimated C(24) and C(48) values (concentrations 24 and 48 h, respectively, after the beginning of the infusion) were 4.1 ± 2.3 and 1.8 ± 1.2 mg/liter, respectively. The volume of distribution was 0.21 ± 0.06 liter/kg. MCS confirmed that the dosing regimen chosen achieved the target C(max) whereas the FDA-approved regimen did not (31.0 ± 10.9 versus 8.8 ± 3.1 mg · liter(-1)). Moreover, the C(24) values were similar while the AUC(0-24) values were moderately increased (190.8 ± 65.0 versus 135 ± 42.2 mg · h · liter(-1)). Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high C(max) and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.

High risk of pulmonary embolism in acute respiratory distress syndrome related to COVID-19: an observational controlled-cohort study.

BACKGROUND: COVID-19 may induce endovascular injury of pulmonary vessels and could be associated with increased risk of pulmonary embolism. The main objective was to compare the incidence of pulmonary embolism in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 versus patients with pulmonary ARDS unrelated to COVID-19. METHODS: This is an observational controlled-cohort study performed at a single center of a university teaching hospital in France. The incidence of pulmonary embolism was prospectively assessed using computed tomography pulmonary angiography (CTPA) in patients with ARDS related to COVID-19 and compared to patients from a 3-year historical cohort of patients with pulmonary ARDS unrelated to COVID-19. In patients with ARDS related to COVID-19, CTPA was performed approximately 7 days after intubation or earlier in case of respiratory or hemodynamic worsening. RESULTS: CTPA was performed in 29 out of the 42 patients (69%) with ARDS related to COVID-19 and in 51 out of the 156 patients (33%) from the historical cohort of patients with pulmonary ARDS unrelated to COVID-19. Incidence of pulmonary embolism was 40% (17/42) in patients with ARDS related to COVID-19 and 3% (5/156) in the historical cohort (P=0.001). The proportion of patients with pulmonary embolism among all patients who had CTPA was 59% (17/29) in patients with ARDS related to COVID-19 and 10% (5/51) in the historical cohort (P=0.0001). After adjustment on the interval between ICU admission and computed tomography, COVID-19 remained independently associated with pulmonary embolism. CONCLUSIONS: Pulmonary embolism was particularly frequent in patients with ARDS related to COVID-19, thereby suggesting that CTPA should be systematically performed in these patients.

Comparison of prognostic factors between bacteraemic and non-bacteraemic critically ill immunocompetent patients in community-acquired severe pneumococcal pneumonia: a STREPTOGENE sub-study.

BACKGROUND: The presence of bacteraemia in pneumococcal pneumonia in critically ill patients does not appear to be a strong independent prognostic factor in the existing literature. However, there may be a specific pattern of factors associated with mortality for ICU patients with bacteraemic pneumococcal community-acquired pneumonia (CAP). We aimed to compare the factors associated with mortality, according to the presence of bacteraemia or not on admission, for patients hospitalised in intensive care for severe pneumococcal CAP. METHODS: This was a post hoc analysis of data from the prospective, observational, multicentre STREPTOGENE study in immunocompetent Caucasian adults admitted to intensive care in France between 2008 and 2012 for pneumococcal CAP. Patients were divided into two groups based on initial blood culture (positive vs. negative) for Streptococcus pneumoniae. The primary outcome was hospital mortality, which was compared between the two groups using odds ratios according to predefined variables to search for a prognostic interaction present in bacterial patients but not non-bacteraemic patients. Potential differences in the distribution of serotypes between the two groups were assessed. The prognostic consequences of the presence or not of initial bi-antibiotic therapy were assessed, specifically in bacteraemic patients. RESULTS: Among 614 included patients, 274 had a blood culture positive for S. pneumoniae at admission and 340 did not. The baseline difference between the groups was more frequent leukopaenia (26% vs. 14%, p = 0.0002) and less frequent pre-hospital antibiotic therapy (10% vs. 16.3%, p = 0.024) for the bacteraemic patients. Hospital mortality was not significantly different between the two groups (p = 0.11). We did not observe any prognostic factors specific to the bacteraemic patient population, as the statistical comparison of the odds ratios, as an indication of the association between the predefined prognostic parameters and mortality, showed them to be similar for the two groups. Bacteraemic patients more often had invasive serotypes but less often serotypes associated with high case fatality rates (p = 0.003). The antibiotic regimens were similar for the two groups. There was no difference in mortality for patients in either group given a beta-lactam alone vs. a beta-lactam combined with a macrolide or fluoroquinolone. CONCLUSION: Bacteraemia had no influence on the mortality of immunocompetent Caucasian adults admitted to intensive care for severe pneumococcal CAP, regardless of the profile of the associated prognostic factors.

Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol.

INTRODUCTION: Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia. METHODS AND ANALYSIS: Academic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee. ETHICS AND DISSEMINATION: The protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2016-001054-17 and NCT03149640.

Disseminated invasive aspergillosis in patients with severe influenza infection.

A female 66 year-old patient, not immunocompromised, was admitted in ICU for severe influenza complicated by severe acute respiratory distress syndrome (ARDS) leading to extra-corporeal membrane oxygenation (ECMO). During ICU hospitalization, she developed a disseminated invasive aspergillosis with cerebral access and coronary occlusion which lead to cardiac arrest. Despite a successful revascularization procedure, the patient died of refractory shock.

A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock.

INTRODUCTION: We aimed to establish whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during evolving bacterial community-acquired infection in adults is associated with severe sepsis or septic shock. METHODS: We conducted a multicentre case-control study in eight intensive care units. Cases were all adult patients admitted for severe sepsis or septic shock due to a bacterial community-acquired infection. Control individuals were patients hospitalized with a mild community-acquired infection. Each case was matched to one control for age, presence of diabetes and site of infection. RESULTS: The main outcome measures were the proportions of cases and controls exposed to NSAIDs or aspirin during the period of observation. In all, 152 matched pairs were analyzed. The use of NSAIDs or aspirin during the observation period did not differ between cases and controls (27% versus 28; odds ratio = 0.93, 95% confidence interval [CI] = 0.52 to 1.64). If aspirin was not considered or if a distinction was made between acute and chronic drug treatment, there remained no difference between groups. However, the median time to prescription of effective antibiotic therapy was longer for NSAID users (6 days, 95% CI = 3 to 7 days) than for nonusers (3 days, 95% CI = 2 to 3 days; P = 0.02). CONCLUSIONS: In this study, the use of NSAIDs or aspirin during evolving bacterial infection was frequent and occurred in one-quarter of the patients with such infection. Although the use of NSAIDs by patients with severe sepsis or septic shock did not differ from their use by those with mild infection at the same infected site, we observed a longer median time to prescription of effective antibiotic therapy in NSAID users.

Predictors of successful separation from high-flow nasal oxygen therapy in patients with acute respiratory failure: a retrospective monocenter study.

BACKGROUND: High-flow nasal oxygen therapy (HFOT) is a promising first-line therapy for acute respiratory failure. However, its weaning has never been investigated and could lead to unnecessary prolonged intensive-care unit (ICU) stay. The aim of this study is to assess predictors of successful separation from HFOT in critically ill patients. We performed a retrospective monocenter observational study over a 2-year period including all patients treated with HFOT for acute respiratory failure in the ICU. Those who died or were intubated without prior HFOT separation attempt, who were treated with non-invasive ventilation at the time of HFOT separation, or who received HFOT as a preventive treatment during the post-extubation period were excluded. RESULTS: From the 190 patients analyzed, 168 (88%) were successfully separated from HFOT at the first attempt. Patients who failed separation from HFOT at the first attempt had longer ICU length of stay than those who succeeded: 10 days (7-12) vs. 5 (4-8), p < 0.0001. Fraction of inspired oxygen (FiO2) ≤ 40% and a respiratory rate-oxygenation (ROX) index (calculated as the ratio of SpO2/FiO2 to the respiratory rate) ≥ 9.2 predicted successful separation from HFOT with sensitivity of 85% and 84%, respectively. CONCLUSIONS: FiO2 ≤ 40% and ROX index ≥ 9.2 were two predictors of successful separation from HFOT at the bedside. Prospective multicenter studies are needed to confirm these results.

Host-pathogen interactions and prognosis of critically ill immunocompetent patients with pneumococcal pneumonia: the nationwide prospective observational STREPTOGENE study.

PURPOSE: To assess the relative importance of host and bacterial factors associated with hospital mortality in patients admitted to the intensive care unit (ICU) for pneumococcal community-acquired pneumonia (PCAP). METHODS: Immunocompetent Caucasian ICU patients with PCAP documented by cultures and/or pneumococcal urinary antigen (UAg Sp) test were included in this multicenter prospective study between 2008 and 2012. All pneumococcal strains were serotyped. Logistic regression analyses were performed to identify risk factors for hospital mortality. RESULTS: Of the 614 patients, 278 (45%) had septic shock, 270 (44%) had bacteremia, 307 (50%) required mechanical ventilation at admission, and 161 (26%) had a diagnosis based only on the UAg Sp test. No strains were penicillin-resistant, but 23% had decreased susceptibility. Of the 36 serotypes identified, 7 accounted for 72% of the isolates, with different distributions according to age. Although antibiotics were consistently appropriate and were started within 6 h after admission in 454 (74%) patients, 116 (18.9%) patients died. Independent predictors of hospital mortality in the adjusted analysis were platelets ≤ 100 × 109/L (OR, 7.7; 95% CI, 2.8-21.1), McCabe score ≥ 2 (4.58; 1.61-13), age > 65 years (2.92; 1.49-5.74), lactates > 4 mmol/L (2.41; 1.27-4.56), male gender and septic shock (2.23; 1.30-3.83 for each), invasive mechanical ventilation (1.78; 1-3.19), and bilateral pneumonia (1.59; 1.02-2.47). Women with platelets ≤ 100 × 109/L had the highest mortality risk (adjusted OR, 7.7; 2.8-21). CONCLUSIONS: In critically ill patients with PCAP, age, gender, and organ failures at ICU admission were more strongly associated with hospital mortality than were comorbidities. Neither pneumococcal serotype nor antibiotic regimen was associated with hospital mortality.

Protected telescopic catheter also allows anaerobic bacteria isolation in patients with ventilatory-acquired pneumonia.

OBJECTIVE: To analyze the possibility of isolating anaerobic bacteria using protected telescopic catheter (PTC) in patients with ventilatory-associated pneumonia. DESIGN AND SETTING: A prospective epidemiological study in a 12-bed intensive care unit. PATIENTS: 104 patients with suspected ventilatory-associated pneumonia undergoing PTC for microbiological determination including specific methods for anaerobic bacteria identification (mean age 59.3, range 17-82; SAPS II 44.6+/-17.9). MEASUREMENTS AND RESULTS: We performed 156 PTC procedures. Of the 14 cases ventilatory-associated pneumonia occurred early in 6 and in 8 late. In 52 samples at least one bacteria was isolated (33.3%). Of the 156 samples 14 yielded with anaerobic bacteria, representing 26.9% of the positive samples and 9% of all the samples. CONCLUSION: Considering the potential pathogenic role of anaerobic bacteria in patients with ventilatory-associated pneumonia, the possibility of isolating these bacteria using PTC and taking into account its easiness and limited side effects should be underlined.

Validation of an algorithm based on direct examination of specimens in suspected ventilator-associated pneumonia.

BACKGROUND: The management of suspected ventilator-associated pneumonia (VAP) is traditionally based on either a clinical or a "bacteriological" approach. Direct examination of specimens may provide a valuable help to both approaches. OBJECTIVE: The objective was to test an algorithm for the management of suspected pneumonia based on severity criteria and Gram stains of specimens, including early treatment of patients with a positive Gram stain of a protected telescoping catheter specimen and awaiting culture results in patients with either Gram stains of endotracheal aspirate and protected specimen both being negative, or only positive endotracheal aspirate (EA), except in the presence of the severity criteria. METHODS: Observational study including 76 first episodes of suspected pneumonia in 4 units. We assessed the rates of correctly diagnosed episodes and of those treated empirically (i.e., ultimately confirmed pneumonia), or appropriately not receiving such therapy (non-confirmed pneumonia), based on protected specimen culture results. RESULTS: When adhered to, the algorithm allowed early appropriate management in 80% of patients, including 83% of those with confirmed pneumonia, and 74% of those without confirmed infection. The rate of appropriately managed episodes using this algorithm was significantly higher than that using a strategy based on the modified clinical pulmonary infection score (CPIS) alone (80 vs. 50%, p<0.001). The empiric regimen was adequate in 86% of confirmed episodes. CONCLUSION: A strategy based on severity criteria and Gram stain examination of respiratory tract specimens allows correct identification and appropriate management of more than 80% of mechanically ventilated patients who need or do not need therapy for suspected pneumonia.

Sequential application of oxygen therapy via high-flow nasal cannula and noninvasive ventilation in acute respiratory failure: an observational pilot study.

BACKGROUND: The aim of this study was to evaluate the clinical efficacy of humidified oxygen via high-flow nasal cannula (HFNC) alternating with noninvasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF). METHODS: We performed a prospective observational study in a 12-bed ICU of a university hospital. All subjects with a PaO2 /FIO2 of ≤300 mm Hg with standard mask oxygen and a breathing frequency of > 30 breaths/min or signs of respiratory distress were included and treated with HFNC first and then NIV. Ventilatory parameters, blood gases, and tolerance were recorded during 2 consecutive sessions of NIV and HFNC. Outcome was assessed after continuation of this noninvasive strategy. RESULTS: Twenty-eight subjects with AHRF were studied, including 23 (82%) with ARDS. Compared with standard oxygen therapy, PaO2 significantly increased from 83 (68-97) mm Hg to 108 (83-140) mm Hg using HFNC and to 125 (97-200) mm Hg using NIV (P<.01), whereas breathing frequency significantly decreased. HFNC was significantly better tolerated than NIV, with a lower score on the visual analog scale. The non-intubated subjects received HFNC for 75 (27-127) h and NIV for 23 (8-31) h. Intubation was required in 10 of 28 subjects (36%), including 8 of 23 subjects with ARDS (35%). After HFNC initiation, a breathing frequency of ≥30 breaths/min was an early factor associated with intubation. CONCLUSIONS: HFNC was better tolerated than NIV and allowed for significant improvement in oxygenation and tachypnea compared with standard oxygen therapy in subjects with AHRF, a large majority of whom had ARDS. Thus, HFNC may be used between NIV sessions to avoid marked impairment of oxygenation.

Incidence and impact of skin mottling over the knee and its duration on outcome in critically ill patients.

PURPOSE: Skin mottling is frequent and can be associated with an increased mortality rate in ICU patients with septic shock. Its overall incidence in ICU and its impact on outcome is unknown. We aimed to assess the incidence of skin mottling over the knee among all critically ill patients admitted in ICU and its role on their outcome. METHODS: An observational study over a 1-year period in a 15-bed medical ICU of a teaching hospital. Skin mottling over the knee was prospectively and qualitatively assessed by trained nurses. RESULTS: Incidence of skin mottling was 29% (230 of 791 patients) in overall, and 49% (32 of 65 patients) in the subset of patients admitted for septic shock. Skin mottling was present on the day on admission in 65% of patients and persisted more than 6 h in 59% of cases. In-ICU mortality was 8% in patients without mottling, 30% in patients with short skin mottling and 40% in patients with persistent skin mottling (p < 0.01 between all groups). In the overall population, skin mottling over the knee was associated with in-ICU mortality independently from SAPS II (aOR 3.29 [95% CI, 2.08-5.19], p < 0.0001). Among patients with skin mottling over the knee, persistence of skin mottling remained associated with increased in-ICU mortality independently of organ dysfunctions at the mottling onset (OR 2.77 [95% CI, 1.34-5.72], p = 0.004). CONCLUSIONS: Skin mottling is frequent in the general population of patients admitted in ICU. Occurrence and persistence of skin mottling are independently associated with in-ICU mortality.