Physiological changes after fluid bolus therapy in cardiac surgery patients: A propensity score matched case-control study.

Objective: Fluid bolus therapy (FBT) is ubiquitous in intensive care units (ICUs) after cardiac surgery. However, its physiological effects remain unclear. Design: : We performed an electronic health record-based quasi-experimental ICU study after cardiac surgery. We applied propensity score matching and compared the physiological changes after FBT episodes to matched control episodes where despite equivalent physiology no fluid bolus was given. Setting: The study was conducted in a multidisciplinary ICU of a tertiary-level academic hospital. Participants: The study included 2,736 patients who underwent Coronary Artery Bypass Grafting and/or heart valve surgery. Main Outcome Measures: Changes in cardiac output (CO) and mean arterial pressure (MAP) during the 60 minutes following FBT. Results: We analysed 3572 matched fluid bolus (FB) episodes. After FBT, but not in control episodes, CO increased within 10 min, with a maximum increase of 0.2 l/min (95%CI 0.1 to 0.2) or 4% above baseline at 40 min (p < 0.0001 vs. controls). CO increased by > 10% from baseline in 60.6% of FBT and 49.1% of control episodes (p < 0.0001). MAP increased by > 10% in 51.7% of FB episodes compared to 53.4% of controls. Finally, FBT was not associated with changes in acid-base status or oxygen delivery. Conclusion: In this quasi-experimental comparative ICU study in cardiac surgery patients, FBT was associated with statistically significant but numerically small increases in CO. Nearly half of FBT failed to induce a positive CO or MAP response.

Low tidal volume ventilation for patients undergoing laparoscopic surgery: a secondary analysis of a randomised clinical trial.

BACKGROUND: We recently reported the results for a large randomized controlled trial of low tidal volume ventilation (LTVV) versus conventional tidal volume (CTVV) during major surgery when positive end expiratory pressure (PEEP) was equal between groups. We found no difference in postoperative pulmonary complications (PPCs) in patients who received LTVV. However, in the subgroup of patients undergoing laparoscopic surgery, LTVV was associated with a numerically lower rate of PPCs after surgery. We aimed to further assess the relationship between LTVV versus CTVV during laparoscopic surgery. METHODS: We conducted a post-hoc analysis of this pre-specified subgroup. All patients received volume-controlled ventilation with an applied PEEP of 5 cmH2O and either LTVV (6 mL/kg predicted body weight [PBW]) or CTVV (10 mL/kg PBW). The primary outcome was the incidence of a composite of PPCs within seven days. RESULTS: Three hundred twenty-eight patients (27.2%) underwent laparoscopic surgeries, with 158 (48.2%) randomised to LTVV. Fifty two of 157 patients (33.1%) assigned to LTVV and 72 of 169 (42.6%) assigned to conventional tidal volume developed PPCs within 7 days (unadjusted absolute difference, - 9.48 [95% CI, - 19.86 to 1.05]; p = 0.076). After adjusting for pre-specified confounders, the LTVV group had a lower incidence of the primary outcome than patients receiving CTVV (adjusted absolute difference, - 10.36 [95% CI, - 20.52 to - 0.20]; p = 0.046). CONCLUSION: In this post-hoc analysis of a large, randomised trial of LTVV we found that during laparoscopic surgeries, LTVV was associated with a significantly reduced PPCs compared to CTVV when PEEP was applied equally between both groups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry no: 12614000790640.

Impact of renal-replacement therapy strategies on outcomes for patients with chronic kidney disease: a secondary analysis of the STARRT-AKI trial.

PURPOSE: To assess whether pre-existing chronic kidney disease (CKD) modified the relationship between the strategy for renal-replacement theraphy (RRT) initiation and clinical outcomes in the STARRT-AKI trial. METHODS: This was a secondary analysis of a multi-national randomized trial. We included patients who had documented pre-existing estimated glomerular filtration rate (eGFR) data prior to hospitalization, and we defined CKD as an eGFR ≤ 59 mL/min/1.73 m2. The primary outcome was all-cause mortality at 90 days. Secondary outcomes included RRT dependence and RRT-free days at 90 days. We used logistic and linear regression and interaction testing to explore the effect of RRT initiation strategy on outcomes by CKD status. RESULTS: We studied 1121 patients who had pre-hospital measures of kidney function. Of these, 432 patients (38.5%) had CKD. The median (IQR) baseline serum creatinine was 130 (114-160) and 76 (64-90) µmol/L for those with and without CKD, respectively. Patients with CKD were older and more likely to have cardiovascular comorbidities and diabetes mellitus. Patients with CKD had higher 90-day mortality (47% vs. 40%, p < 0.001) compared to those without CKD, though this was not significant after covariate adjustment (adjusted odds ratio [aOR], 1.05; 95% CI, 0.79-1.41). Patients with CKD were more likely to remain RRT dependent at 90 days (14% vs. 8%; aOR, 1.89; 95% CI, 1.05-3.43). CKD status did not modify the effect of RRT initiation strategy on 90-day mortality. Among patients with CKD, allocation to the accelerated strategy conferred more than threefold greater odds of RRT dependence at 90 days (aOR 3.18; 95% CI, 1.41-7.91) compared with the standard strategy, whereas RRT initiation strategy had no effect on this outcome among those without CKD (aOR 0.71; 95% CI, 0.34-1.47, p value for interaction, 0.009). CONCLUSION: In this secondary analysis of the STARRT-AKI trial, an accelerated strategy of RRT initiation conferred a higher risk of 90-day RRT dependence among patients with pre-existing CKD; however, no effect was observed in the absence of CKD.

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications.

BACKGROUND: Low tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications. METHODS: This is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated. RESULTS: We studied 1206 patients (median age of 64 [55-72] years, 59.0% males, median ARISCAT of 26 [19-37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery. CONCLUSION: In adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12614000790640 .

Geo-economic variations in epidemiology, ventilation management and outcome of patients receiving intraoperative ventilation during general anesthesia- posthoc analysis of an observational study in 29 countries.

BACKGROUND: The aim of this analysis is to determine geo-economic variations in epidemiology, ventilator settings and outcome in patients receiving general anesthesia for surgery. METHODS: Posthoc analysis of a worldwide study in 29 countries. Lower and upper middle-income countries (LMIC and UMIC), and high-income countries (HIC) were compared. The coprimary endpoint was the risk for and incidence of postoperative pulmonary complications (PPC); secondary endpoints were intraoperative ventilator settings, intraoperative complications, hospital stay and mortality. RESULTS: Of 9864 patients, 4% originated from LMIC, 11% from UMIC and 85% from HIC. The ARISCAT score was 17.5 [15.0-26.0] in LMIC, 16.0 [3.0-27.0] in UMIC and 15.0 [3.0-26.0] in HIC (P = .003). The incidence of PPC was 9.0% in LMIC, 3.2% in UMIC and 2.5% in HIC (P < .001). Median tidal volume in ml kg- 1 predicted bodyweight (PBW) was 8.6 [7.7-9.7] in LMIC, 8.4 [7.6-9.5] in UMIC and 8.1 [7.2-9.1] in HIC (P < .001). Median positive end-expiratory pressure in cmH2O was 3.3 [2.0-5.0]) in LMIC, 4.0 [3.0-5.0] in UMIC and 5.0 [3.0-5.0] in HIC (P < .001). Median driving pressure in cmH2O was 14.0 [11.5-18.0] in LMIC, 13.5 [11.0-16.0] in UMIC and 12.0 [10.0-15.0] in HIC (P < .001). Median fraction of inspired oxygen in % was 75 [50-80] in LMIC, 50 [50-63] in UMIC and 53 [45-70] in HIC (P < .001). Intraoperative complications occurred in 25.9% in LMIC, in 18.7% in UMIC and in 37.1% in HIC (P < .001). Hospital mortality was 0.0% in LMIC, 1.3% in UMIC and 0.6% in HIC (P = .009). CONCLUSION: The risk for and incidence of PPC is higher in LMIC than in UMIC and HIC. Ventilation management could be improved in LMIC and UMIC. TRIAL REGISTRATION: Clinicaltrials.gov , identifier: NCT01601223.

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies.

BACKGROUND: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. METHODS: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. FINDINGS: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p<0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p<0·0001). INTERPRETATION: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. FUNDING: No funding.

Ventilation practices in burn patients-an international prospective observational cohort study.

BACKGROUND: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28). METHODS: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume (V T) was defined as V T ≤ 8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma. RESULTS: A total of 160 patients from 28 ICUs in 16 countries were included. Low V T was used in 74% of patients, median V T size was 7.3 [interquartile range (IQR) 6.2-8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma (p = 0.58). Median VFD-28 was 17 (IQR 0-26), without a difference between ventilation with low or high V T (p = 0.98). All patients were ventilated with PEEP levels ≥5 cmH2O; 80% of patients had maximum airway pressures <30 cmH2O. CONCLUSION: In this international cohort study we found that lung-protective ventilation is used in the majority of burn patients, irrespective of the presence of inhalation trauma. Use of low V T was not associated with a reduction in VFD-28. TRIAL REGISTRATION: Clinicaltrials.gov NCT02312869. Date of registration: 9 December 2014.

Postoperative hypothermia following non-cardiac high-risk surgery: A prospective study of temporal patterns and risk factors.

BACKGROUND AND OBJECTIVES: Hypothermia occurs commonly during surgery and can cause postoperative complications. We aimed to describe the characteristics and outcomes of hypothermia in patients undergoing major surgeries. METHODS: This prospective, observational, multicenter study of a nationally representative sample included all patients over 18 years of age admitted to an intensive care unit (ICU). Thirty ICUs were selected randomly at national level. The main outcome measure was the proportion of patients who developed postoperative hypothermia in the first 24 hours of ICU admission. Patients were divided into three groups based on temperature: <35°C, <36°C, and ≥36°C (no hypothermia). Patients' characteristics, postoperative complications, and risk factors were evaluated in all groups. To verify whether hypothermia was a strong risk factor for postoperative complications, a Kaplan-Meier curve was generated and adjusted using a Cox regression model. RESULTS: In total, 738 patients had their temperatures measured. The percentage of patients with temperature <35°C (median [Q1-Q3], 34.7°C [34.3-34.9°C]) was 19.1% (95% confidence interval [CI] = 16.1-22.5) and that of patients with temperature <36°C (median [Q1-Q3], 35.4°C [35.0-35.8°C]) was 64% (95% CI = 58.3-70.0). The percentage of surgical complications was 38.9%. Patients with hypothermia were older, had undergone abdominal surgeries, had undergone procedures of longer duration, and had more comorbidities. A postoperative temperature ≤35°C was an independent risk for composite postoperative complications (hazard ratio = 1.523, 95% CI = 1.15-2.0), especially coagulation and infection. CONCLUSIONS: Inadvertent hypothermia was frequent among patients admitted to the ICU and occurred more likely after abdominal surgery, after a long procedure, in elderly patients, and in patients with a higher number of comorbidities. Low postoperative temperature was associated with postoperative complications.

Fully automated postoperative ventilation in cardiac surgery patients: a randomised clinical trial.

BACKGROUND: Ensuring that lung-protective ventilation is achieved at scale is challenging in perioperative practice. Fully automated ventilation may be more effective in delivering lung-protective ventilation. Here, we compared automated lung-protective ventilation with conventional ventilation after elective cardiac surgery in haemodynamically stable patients. METHODS: In this single-centre investigator-led study, patients were randomly assigned at the end of cardiac surgery to receive either automated (adaptive support ventilation) or conventional ventilation. The primary endpoint was the proportion of postoperative ventilation time characterised by exposure to predefined optimal, acceptable, and critical (injurious) ventilatory parameters in the first three postoperative hours. Secondary outcomes included severe hypoxaemia (Spo2 <85%) and resumption of spontaneous breathing. Data are presented as mean (95% confidence intervals [CIs]). RESULTS: We randomised 220 patients (30.4% females; age: 62-76 yr). Subjects randomised to automated ventilation (n=109) spent a 29.7% (95% CI: 22.1-37.4) higher mean proportion of postoperative ventilation time receiving optimal postoperative ventilation after surgery (P<0.001) compared with subjects receiving conventional postoperative ventilation (n=111). Automated ventilation also reduced the proportion of postoperative ventilation time that subjects were exposed to injurious ventilatory settings by 2.5% (95% CI: 1-4; P=0.003). Severe hypoxaemia was less likely in subjects randomised to automated ventilation (risk ratio: 0.26 [0.22-0.31]; P<0.01). Subjects resumed spontaneous breathing more rapidly when randomised to automated ventilation (hazard ratio: 1.38 [1.05-1.83]; P=0.03). CONCLUSIONS: Fully automated ventilation in haemodynamically stable patients after cardiac surgery optimised lung-protective ventilation during postoperative ventilation, with fewer episodes of severe hypoxaemia and an accelerated resumption of spontaneous breathing. CLINICAL TRIAL REGISTRATION: NCT03180203.

Effectiveness of prothrombin complex concentrate for the treatment of bleeding: A systematic review and meta-analysis.

Prothrombin complex concentrate (PCC) is increasingly being used as a treatment for major bleeding in patients who are not taking anticoagulants. The aim of this systematic review and meta-analysis is to evaluate the effectiveness of PCC administration for the treatment of bleeding in patients not taking anticoagulants. Studies investigating the effectivity of PCC to treat bleeding in adult patients and providing data on either mortality or blood loss were eligible. Data were pooled using Mantel-Haenszel random effects meta-analysis or inverse variance random effects meta-analysis. From 4668 identified studies, 17 observational studies were included. In all patient groups combined, PCC administration was not associated with mortality (odds ratio = 0.83; 95% confidence interval [CI], 0.66-1.06; P = .13; I2  = 0%). However, in trauma patients, PCC administration, in addition to fresh frozen plasma, was associated with reduced mortality (odds ratio = 0.64; CI, 0.46-0.88; P = .007; I2  = 0%). PCC administration was associated with a reduction in blood loss in cardiac surgery patients (mean difference: -384; CI, -640 to -128, P = .003, I2  = 81%) and a decreased need for red blood cell transfusions when compared with standard care across a wide range of bleeding patients not taking anticoagulants (mean difference: -1.80; CI, -3.22 to -0.38; P = .01; I2  = 92%). In conclusion, PCC administration was not associated with reduced mortality in the whole cohort but did reduce mortality in trauma patients. In bleeding patients, PCC reduced the need for red blood cell transfusions when compared with treatment strategies not involving PCC. In bleeding cardiac surgery patients, PCC administration reduced blood loss.

Intraoperative mechanical ventilation practice in thoracic surgery patients and its association with postoperative pulmonary complications: results of a multicenter prospective observational study.

BACKGROUND: Intraoperative mechanical ventilation may influence postoperative pulmonary complications (PPCs). Current practice during thoracic surgery is not well described. METHODS: This is a post-hoc analysis of the prospective multicenter cross-sectional LAS VEGAS study focusing on patients who underwent thoracic surgery. Consecutive adult patients receiving invasive ventilation during general anesthesia were included in a one-week period in 2013. Baseline characteristics, intraoperative and postoperative data were registered. PPCs were collected as composite endpoint until the 5th postoperative day. Patients were stratified into groups based on the use of one lung ventilation (OLV) or two lung ventilation (TLV), endoscopic vs. non-endoscopic approach and ARISCAT score risk for PPCs. Differences between subgroups were compared using χ2 or Fisher exact tests or Student's t-test. Kaplan-Meier estimates of the cumulative probability of development of PPC and hospital discharge were performed. Cox-proportional hazard models without adjustment for covariates were used to assess the effect of the subgroups on outcome. RESULTS: From 10,520 patients enrolled in the LAS VEGAS study, 302 patients underwent thoracic procedures and were analyzed. There were no differences in patient characteristics between OLV vs. TLV, or endoscopic vs. open surgery. Patients received VT of 7.4 ± 1.6 mL/kg, a PEEP of 3.5 ± 2.4 cmH2O, and driving pressure of 14.4 ± 4.6 cmH2O. Compared with TLV, patients receiving OLV had lower VT and higher peak, plateau and driving pressures, higher PEEP and respiratory rate, and received more recruitment maneuvers. There was no difference in the incidence of PPCs in OLV vs. TLV or in endoscopic vs. open procedures. Patients at high risk had a higher incidence of PPCs compared with patients at low risk (48.1% vs. 28.9%; hazard ratio, 1.95; 95% CI 1.05-3.61; p = 0.033). There was no difference in the incidence of severe PPCs. The in-hospital length of stay (LOS) was longer in patients who developed PPCs. Patients undergoing OLV, endoscopic procedures and at low risk for PPC had shorter LOS. CONCLUSION: PPCs occurred frequently and prolonged hospital LOS following thoracic surgery. Proportionally large tidal volumes and high driving pressure were commonly used in this sub-population. However, large RCTs are needed to confirm these findings. TRIAL REGISTRATION: This trial was prospectively registered at the Clinical Trial Register (www.clinicaltrials.gov; NCT01601223 ; registered May 17, 2012.).

Low tidal volume ventilation during anaesthesia for major surgery: protocol and statistical analysis plan.

BACKGROUND: Mechanical ventilation is mandatory in patients undergoing general anaesthesia for major surgery. Tidal volumes higher than 10 mL/kg of predicted body weight have been advocated for intraoperative ventilation, but recent evidence suggests that low tidal volumes may benefit surgical patients. To date, the impact of low tidal volume compared with conventional tidal volume during surgery has only been assessed in clinical trials that also combine different levels of positive end-expiratory pressure (PEEP) in each arm. We aimed to assess the impact of low tidal volume compared with conventional tidal volume during general anaesthesia for surgery on the incidence of postoperative respiratory complications in adult patients receiving moderate levels of PEEP. STUDY DESIGN AND METHODS: Single-centre, two-arm, randomised clinical trial. In total, 1240 adult patients older than 40 years scheduled for at least 2 hours of surgery under general anaesthesia and routinely monitored with an arterial line were included. Patients were ventilated intraoperatively with a moderate level of PEEP (5 cmH2O) and randomly assigned to tidal volume of 6 mL/kg predicted body weight (low tidal volume) or 10 mL/kg predicted body weight (conventional tidal volume in Australia). MAIN OUTCOME MEASURE: The primary outcome is the occurrence of postoperative respiratory complications, recorded as a composite endpoint of adverse respiratory events during the first 7 postoperative days. RESULTS AND CONCLUSIONS: This is the first well powered study comparing the effect of low tidal volume ventilation versus high tidal volume ventilation during surgery on the incidence of postoperative respiratory complications in adult patients receiving moderate levels of PEEP. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12614000790640).

The LAS VEGAS risk score for prediction of postoperative pulmonary complications: An observational study.

BACKGROUND: Currently used pre-operative prediction scores for postoperative pulmonary complications (PPCs) use patient data and expected surgery characteristics exclusively. However, intra-operative events are also associated with the development of PPCs. OBJECTIVE: We aimed to develop a new prediction score for PPCs that uses both pre-operative and intra-operative data. DESIGN: This is a secondary analysis of the LAS VEGAS study, a large international, multicentre, prospective study. SETTINGS: A total of 146 hospitals across 29 countries. PATIENTS: Adult patients requiring intra-operative ventilation during general anaesthesia for surgery. INTERVENTIONS: The cohort was randomly divided into a development subsample to construct a predictive model, and a subsample for validation. MAIN OUTCOME MEASURES: Prediction performance of developed models for PPCs. RESULTS: Of the 6063 patients analysed, 10.9% developed at least one PPC. Regression modelling identified 13 independent risk factors for PPCs: six patient characteristics [higher age, higher American Society of Anesthesiology (ASA) physical score, pre-operative anaemia, pre-operative lower SpO2 and a history of active cancer or obstructive sleep apnoea], two procedure-related features (urgent or emergency surgery and surgery lasting ≥ 1 h), and five intra-operative events [use of an airway other than a supraglottic device, the use of intravenous anaesthetic agents along with volatile agents (balanced anaesthesia), intra-operative desaturation, higher levels of positive end-expiratory pressures > 3 cmH2O and use of vasopressors]. The area under the receiver operating characteristic curve of the LAS VEGAS risk score for prediction of PPCs was 0.78 [95% confidence interval (95% CI), 0.76 to 0.80] for the development subsample and 0.72 (95% CI, 0.69 to 0.76) for the validation subsample. CONCLUSION: The LAS VEGAS risk score including 13 peri-operative characteristics has a moderate discriminative ability for prediction of PPCs. External validation is needed before use in clinical practice. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, number NCT01601223.

Effect of On-Demand vs Routine Nebulization of Acetylcysteine With Salbutamol on Ventilator-Free Days in Intensive Care Unit Patients Receiving Invasive Ventilation: A Randomized Clinical Trial.

Importance: It remains uncertain whether nebulization of mucolytics with bronchodilators should be applied for clinical indication or preventively in intensive care unit (ICU) patients receiving invasive ventilation. Objective: To determine if a strategy that uses nebulization for clinical indication (on-demand) is noninferior to one that uses preventive (routine) nebulization. Design, Setting, and Participants: Randomized clinical trial enrolling adult patients expected to need invasive ventilation for more than 24 hours at 7 ICUs in the Netherlands. Interventions: On-demand nebulization of acetylcysteine or salbutamol (based on strict clinical indications, n = 471) or routine nebulization of acetylcysteine with salbutamol (every 6 hours until end of invasive ventilation, n = 473). Main Outcomes and Measures: The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for a difference between groups of -0.5 days. Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events. Results: Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54-75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0-26) ventilator-free days (1-sided 95% CI, -0.00003 to ∞). There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, -15.5% [95% CI, -20.7% to -10.3%]; P < .001) were more frequent with routine nebulization and mainly related to tachyarrhythmia (12.5% vs 25.9%; difference, -13.4% [95% CI, -18.4% to -8.4%]; P < .001) and agitation (0.2% vs 4.3%; difference, -4.1% [95% CI, -5.9% to -2.2%]; P < .001). Conclusions and Relevance: Among ICU patients receiving invasive ventilation who were expected to not be extubated within 24 hours, on-demand compared with routine nebulization of acetylcysteine with salbutamol did not result in an inferior number of ventilator-free days. On-demand nebulization may be a reasonable alternative to routine nebulization. Trial Registration: clinicaltrials.gov Identifier: NCT02159196.

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.

Cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: a systematic review and meta-analysis.

CONTEXT: A recently published meta-analysis of randomized clinical trials (RCT) showed that androgen deprivation therapy (ADT) did not significantly increase cardiovascular mortality in prostate cancer patients. However, cardiovascular morbidity, which can impact quality of life, was not evaluated. OBJECTIVE: To evaluate the risk of cardiovascular morbidity associated with ADT in patients with prostate cancer. METHODS: We conducted a literature search from January 1960 to June 2012. RCT and large cohort studies that evaluated first-line endocrine therapy and ADT longer than 6 months were screened for inclusion. RESULTS: In total, 126,898 patients were included in four cohort studies, and 10,760 patients were included in nine RCTs. Analysis of the RCTs showed no differences in the development of acute myocardial infarction (AMI) (OR 1.23; 95 % CI 0.92-1.64; I (2): 0 %) among the patients receiving ADT or not. The analysis of randomized studies that reported other nonfatal cardiovascular events demonstrated a significant increase in such events in the group receiving ADT (OR 1.55; 95 % CI 1.09-2.20; I (2): 0 %). When the large cohort studies were included in the analysis, an increased risk of AMI among men with ADT was found (OR 2.01, 95 % CI 1.90-2.13; I (2): 91,3 %). CONCLUSION: The use of ADT in prostate cancer patients corresponded with a significant increase in cardiovascular morbidity associated with AMI and with nonfatal events. Therefore, ADT is linked to a significant negative impact on quality of life. Periodic cardiovascular evaluation is required for these patients.