Cerebral Hemodynamics and Levosimendan Use in Patients with Cerebral Vasospasm and Subarachnoid Hemorrhage: An Observational Perfusion CT-Based Imaging Study.

BACKGROUND: Delayed cerebral ischemia associated with cerebral vasospasm (CVS) in aneurysmal subarachnoid hemorrhage significantly affects patient prognosis. Levosimendan has emerged as a potential treatment, but clinical data are lacking. The aim of this study is to decipher levosimendan's effect on cerebral hemodynamics by automated quantitative measurements of brain computed tomography perfusion (CTP). METHODS: We conducted a retrospective analysis of a database of a neurosurgical intensive care unit. All patients admitted from January 2018 to July 2022 for aneurysmal subarachnoid hemorrhage and treated with levosimendan for CVS who did not respond to other therapies were included. Quantitative measurements of time to maximum (Tmax), relative cerebral blood volume (rCBV), and relative cerebral blood flow (rCBF) were automatically compared with coregistered CTP before and after levosimendan administration in oligemic regions. RESULTS: Of 21 patients included, CTP analysis could be performed in 16. Levosimendan improved Tmax from 14.4 s (interquartile range [IQR] 9.1-21) before treatment to 7.1 s (IQR 5.5-8.1) after treatment (p < 0.001). rCBV (94% [IQR 79-103] before treatment and 89% [IQR 72-103] after treatment, p = 0.63) and rCBF (85% [IQR 77-90] before treatment and 87% [IQR 73-98] after treatment, p = 0.98) remained stable. The subgroup of six patients who did not develop cerebral infarction attributed to delayed cerebral ischemia showed an approximately 10% increase (rCBV 85% [IQR 79-99] before treatment vs. 95% [IQR 88-112] after treatment, p = 0.21; rCBF 81% [IQR 76-87] before treatment vs. 89% [IQR 84-99] after treatment, p = 0.4). CONCLUSIONS: In refractory CVS, levosimendan use was associated with a significant reduction in Tmax in oligemic regions. However, this value remained at an abnormal level, indicating the presence of a persistent CVS. Further analysis raised the hypothesis that levosimendan causes cerebral vasodilation, but other studies are needed because our design does not allow us to quantify the effect of levosimendan from that of the natural evolution of CVS.

Myocardial dysfunction assessed by speckle-tracking in good-grade subarachnoid hemorrhage patients (WFNS 1-2): a prospective observational study.

BACKGROUND: Cardiac complications due to non-traumatic subarachnoid hemorrhage (SAH) are usually described using classical echocardiographic evaluation. Strain imaging appears to have better sensitivity than standard echocardiographic markers for the diagnosis of left ventricular dysfunction. The aim of this study was to determine the prevalence of cardiac dysfunction defined as a Global Longitudinal Strain (GLS) ≥ - 20% in patients with good-grade SAH (WFNS 1 or 2). METHODS: Seventy-six patients with good-grade SAH were prospectively enrolled and analyzed at admission for neurocritical care. Transthoracic echocardiography was performed on days 1, 3, and 7 after hemorrhage. Routine measurements, including left ventricular ejection fraction (LVEF), were performed, and off-line analysis was performed by a blinded examiner, to determine 2-, 3-, and 4-cavity longitudinal strain and left ventricular GLS. GLS was considered altered if it was ≥ - 20%, we also interested the value of ≥ - 17%. LVEF was considered altered if it was < 50%. RESULTS: On day 1, 60.6% of patients had GLS ≥ - 20% and 21.2% of patient had GLS ≥ - 17%. In comparison, alteration of LVEF was present in only 1.7% of patients. The concordance rate between LVEF < 50% and GLS ≥ - 20% and LVEF ≥ 50% and GLS < - 20% was 46%. CONCLUSION: Strain imaging showed a higher prevalence (60.6%) of left ventricular dysfunction during the acute phase of good-grade SAH (WFNS 1 or 2) than previously described.

Early non-invasive ventilation and high-flow nasal oxygen therapy for preventing endotracheal intubation in hypoxemic blunt chest trauma patients: the OptiTHO randomized trial.

BACKGROUND: The benefit-risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O2) during the early stage of blunt chest trauma remains controversial because of limited data. The main objective of this study was to compare the rate of endotracheal intubation between two NIV strategies in high-risk blunt chest trauma patients. METHODS: The OptiTHO trial was a randomized, open-label, multicenter trial over a two-year period. Every adult patients admitted in intensive care unit within 48 h after a high-risk blunt chest trauma (Thoracic Trauma Severity Score ≥ 8), an estimated PaO2/FiO2 ratio < 300 and no evidence of acute respiratory failure were eligible for study enrollment (Clinical Trial Registration: NCT03943914). The primary objective was to compare the rate of endotracheal intubation for delayed respiratory failure between two NIV strategies: i) a prompt association of HFNC-O2 and "early" NIV in every patient for at least 48 h with vs. ii) the standard of care associating COT and "late" NIV, indicated in patients with respiratory deterioration and/or PaO2/FiO2 ratio ≤ 200 mmHg. Secondary outcomes were the occurrence of chest trauma-related complications (pulmonary infection, delayed hemothorax or moderate-to-severe ARDS). RESULTS: Study enrollment was stopped for futility after a 2-year study period and randomization of 141 patients. Overall, 11 patients (7.8%) required endotracheal intubation for delayed respiratory failure. The rate of endotracheal intubation was not significantly lower in patients treated with the experimental strategy (7% [5/71]) when compared to the control group (8.6% [6/70]), with an adjusted OR = 0.72 (95%IC: 0.20-2.43), p = 0.60. The occurrence of pulmonary infection, delayed hemothorax or delayed ARDS was not significantly lower in patients treated by the experimental strategy (adjusted OR = 1.99 [95%IC: 0.73-5.89], p = 0.18, 0.85 [95%IC: 0.33-2.20], p = 0.74 and 2.14 [95%IC: 0.36-20.77], p = 0.41, respectively). CONCLUSION: A prompt association of HFNC-O2 with preventive NIV did not reduce the rate of endotracheal intubation or secondary respiratory complications when compared to COT and late NIV in high-risk blunt chest trauma patients with non-severe hypoxemia and no sign of acute respiratory failure. CLINICAL TRIAL REGISTRATION: NCT03943914, Registered 7 May 2019.

Ability of the Analgesia Nociception Index variations to identify a response to a volume expansion of 250 mL of crystalloids in the operating room (REVANI): a prospective observational study.

BACKGROUND: Analgesia Nociception Index (ANI) is a device based on analysis of the R-R interval and respiratory sinus arrhythmia to assess the balance between sympathetic and parasympathetic activity. The autonomic system is directly affected by load changes. Therefore, monitoring sympathetic tone and its change could theoretically allow tracking of load changes during volume expansion. The aim of the present study was to determine whether changes in ANI are able to track the increase in stroke volume caused by volume expansion (SV). METHODS: This prospective observational study included mechanically ventilated patients undergoing neurosurgery and benefiting from SV monitoring. Exclusion criteria were cardiac dysfunction, arrhythmias, beta-blockade therapy, and dysautonomia. SV was optimized by fluid administration of 250 ml of crystalloid fluid. A positive fluid increase was defined as a SV increase of 10% or more from baseline. Changes in SV and medium ANI (ANIm) were recorded before and 4 to 5 min after volume expansion. RESULTS: Sixty-nine patients had 104 fluid challenges (36 positive and 68 negative). Volume expansion resulted in a greater ANI increase in responders than in nonresponders. The change in ANIm > 5 predicted fluid responsiveness with a sensitivity of 68.4% (95% CI: 67.4% to 69.5%) and a specificity of 51.2% (95% CI: 50.1% to 52.3%). The area under the receiver operating characteristic curve was 0.546 (95% CI: 0.544 to 0.549) and appeared to be affected by remifentanil dose and baseline ANI. CONCLUSION: Changes in ANIm induced by fluid challenge is not able to predict fluid responsiveness in mechanically ventilated patients undergoing neurosurgery. TRIAL REGISTRATION: Clinical trial registration: NCT04223414.

Relationship Between Brain Tissue Oxygen and Near-Infrared Spectroscopy in Patients with Nontraumatic Subarachnoid Hemorrhage.

BACKGROUND: Continuous monitoring of cerebral oxygenation is one of the diagnostic tools used in patients with brain injury. Direct and invasive measurement of cerebral oxygenation with a partial brain oxygen pressure (PbtO2) probe is promising but invasive. Noninvasive assessment of regional transcranial oxygen saturation using near-infrared spectroscopy (NIRS) may be feasible. The aim of this study was to evaluate the interchangeability between PbtO2 and NIRS over time in patients with nontraumatic subarachnoid hemorrhage. METHODS: This retrospective study was performed in a neurocritical care unit. Study participants underwent hourly PbtO2 and NIRS measurements over 72 h. Temporal agreement between markers was described by their pointwise correlation. A secondary analysis assessed the structure of covariation between marker trajectories using a bivariate linear mixed model. RESULTS: Fifty-one patients with subarachnoid hemorrhage were included. A total of 3362 simultaneous NIRS and PbtO2 measurements were obtained. The correlation at each measurement time ranged from - 0.25 to 0.25. The global correlation over time was - 0.026 (p = 0.130). The bivariate linear mixed model confirmed the lack of significant correlation between the PbtO2 and NIRS measurements at follow-up. NIRS was unable to detect PbtO2 values below 20 mm Hg (area under the receiver operating characteristic curve 0.539 [95% confidence interval 0.536-0.542]; p = 0.928), and percentage changes in NIRS were unable to detect a decrease in PbtO2 ≥ 10% (area under the receiver operating characteristic curve 0.615 [95% confidence interval 0.614-0.616]; p < 0.001). CONCLUSIONS: PbtO2 and NIRS measurements were not correlated. There is no evidence that NIRS could be a substitute for PbtO2 monitoring in patients with nontraumatic subarachnoid hemorrhage.

Effects of capnometry monitoring during recovery in the post-anaesthesia care unit: a randomized controlled trial in adults (CAPNOSSPI).

PURPOSE: Continuous capnography should be used on patients admitted to post-anaesthesia care units (PACUs) with endotracheal tubes, but this monitoring is not always performed. Optimized ventilation in the PACU could be part of the global standards of practice to maintain the benefits of perioperative ventilation. The main objective was to study the rate of patients with alveolar hypoventilation before tracheal extubation or Laryngeal Mask Airway (LMA) removal upon the measurement of continuous capnography. METHODS: In this prospective, parallel-group, randomized controlled study, we enrolled adult patients admitted to the PACU after general anaesthesia with an endotracheal tube or LMA in place. Patients were randomly assigned to two groups: in the Capno + group, nurses managed the patients with access to the capnometer and end-tidal carbon dioxide pressure (PETCO2) measurements; in the Capno- group, nurses monitored the patients without seeing PETCO2 measurements. The primary outcome was the percentage of patients with PETCO2 measurements above 45 mm Hg during the minute before extubation. Secondary endpoints included the delay in recovering spontaneous breathing, rate of hypoxemia, delay before extubation, and length of stay in the PACU. RESULTS: Forty-eight patients were randomized into the two groups. The percentage of patients with PETCO2 > 45 mm Hg the minute before extubation was significantly decreased in the Capno + group (83.3% versus 54,1% in the Capno- and Capno + groups respectively, p = 0.029). There were no significant differences concerning secondary endpoints. CONCLUSIONS: The use of PETCO2 monitoring improves patient safety by decreasing the incidence of CO2 retention during recovery from general anaesthesia. This study suggests that this monitoring should be integrated in the PACU. The risk of hypoxemia can also be prevented through the early recognition of apnoea. CLINICAL TRIAL REGISTRY: clinicaltrial.gov. identifier: NCT03370081.

May the neutrophil-to-lymphocyte ratio at admission predict the occurrence and the severity of ARDS after blunt chest trauma patients? A retrospective study.

INTRODUCTION: In blunt chest trauma patients, the activation of inflammatory response is thought to be one of the pathophysiological pathways leading to delayed acute respiratory distress syndrome(ARDS). The main objective of the study was to assess the performance of the neutrophil-lymphocyte ratio(NLR) for prediction of delayed ARDS. The secondary objective was to compare NLR in patients with traumarelated focal and non-focal ARDS. METHODS: Over a 2-year period, every adult patient triaged to our level 1 trauma center with multiple rib fractures and PaO 2 /FiO 2 ratio > 200 at admission were retrospectively included. The NLR was recorded at admission in the Emergency Department(ED). The main study outcome was the occurrence of moderate to severe ARDS within 5 days after admission according to Berlin criteria. Two phenotypes (focal and non-focal ARDS) were determined based on the closest chest CT regarding the ARDS onset. RESULTS: 216 patients were included and 42(19%) underwent moderate to severe ARDS within 5 days after ED admission (focal, N = 26 [12%] and non-focal, N = 16 [7%]). The NLR at ED admission was not statistically different between patients who developed or not a delayed ARDS (14 ± 13 vs. 11 ± 8,p = 0.095), although patients with non-focal ARDS presented higher NLR ratio than focal ARDS (21 ± 18 p < 0.0001). The AUC for NLR at ED in predicting delayed ARDS was 0.53. CONCLUSION: In blunt chest trauma patients, the NLR at ED admission was unable to predict delayed ARDS over the five first days post-injury. Although not clinically relevant, the NLR was higher in patients with non focal ARDS.

Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy.

The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0-24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

Salt wasting syndrome in brain trauma patients: a pathophysiologic approach using sodium balance and urinary biochemical analysis.

BACKGROUND: To explore the underlying mechanisms leading to the occurrence of hyponatremia and enhanced urinary sodium excretion in brain trauma patients using sodium balance and urinary biochemical analysis. METHODS: We conducted a retrospective analysis of a local database prospectively collected in 60 brain trauma patients without chronic renal dysfunction. Metabolic and hemodynamic parameters were averaged over three consecutive periods over the first seven days after admission. The main outcome investigated in this study was the occurrence of at least one episode of hyponatremia. RESULTS: Over the study period, there was a prompt decrease in sodium balance (163 ± 193 vs. -12 ± 154 mmol/day, p < 0.0001) and free water clearance (- 0.7 ± 0.7 vs. -1.8 ± 2.3 ml/min, p < 0.0001). The area under the ROC curves for sodium balance in predicting the occurrence of hyponatremia during the next period was 0.81 [95% CI: 0.64-0.97]. Variables associated with averaged urinary sodium excretion were sodium intake (R2 = 0.26, p < 0.0001) and fractional excretion of urate (R2 = 0.15, p = 0.009). Urinary sodium excretion was also higher in patients with sustained augmented renal clearance over the study period (318 ± 106 vs. 255 ± 135 mmol/day, p = 0.034). CONCLUSION: The decreased vascular volume resulting from a negative sodium balance is a major precipitating factor of hyponatremia in brain trauma patients. Predisposing factors for enhanced urinary sodium excretion were high sodium intake, high fractional excretion of urate and augmented renal clearance over the first seven days after ICU admission.

Utility of changes in end-tidal carbon dioxide after volume expansion to assess fluid responsiveness in the operating room: a prospective observational study.

BACKGROUND: From a physiological viewpoint, changes in end-tidal carbon dioxide (EtCO2) could be a simple, noninvasive, and inexpensive way to monitor changes in cardiac index. This study aimed to assess the utility of changes in EtCO2 as a marker of fluid responsiveness after volume expansion in the operating room. METHODS: A prospective observational study was conducted in a tertiary university teaching hospital, from August 2018 to February 2019. A total of 109 non-consecutive, mechanically ventilated adults undergoing neurosurgery in the supine position with cardiac output monitors were included. Patients with major respiratory disease, arrhythmia, or heart failure were excluded. Volume expansion with 250 ml of saline 0.9% was performed over 10 min to maximise cardiac output during surgery, according to current guidelines. A positive fluid challenge was defined as an increase in stroke volume index of more than 10% from baseline. Changes in stroke volume index (monitored using pulse contour analysis) and EtCO2 were recorded before and after infusion. RESULTS: A total of 242 fluid challenges in 114 patients were performed, of which 26.9% were positive. Changes in EtCO2 > 1.1% induced by infusions had utility for identifying fluid responsiveness, with a sensitivity of 62.9% (95% confidence interval [CI], 62.5-63.3%) and a specificity of 77.8% (95% CI, 77.6-78.1%). The area under the receiver operating characteristic curve for changes in EtCO2 after volume expansion was 0.683 (95% CI, 0.680-0.686). CONCLUSIONS: Changes in EtCO2 induced by rapid infusion of 250 ml saline 0.9% lacked accuracy for identifying fluid responsiveness in mechanically ventilated patients in the operating room. CLINICAL TRIAL REGISTRATION: NCT03635307.

Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial.

Importance: It is not known if use of colloid solutions containing hydroxyethyl starch (HES) to correct for intravascular deficits in high-risk surgical patients is either effective or safe. Objective: To evaluate the effect of HES 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery. Design, Setting, and Participants: Multicenter, double-blind, parallel-group, randomized clinical trial of 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery at 20 university hospitals in France from February 2016 to July 2018; final follow-up was in October 2018. Interventions: Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9% saline (n = 389) or 0.9% saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day, defined as ending at 7:59 am the following day. Main Outcomes and Measures: The primary outcome was a composite of death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, durations of intensive care unit and hospital stays, and all-cause mortality at postoperative days 28 and 90. Results: Among 826 patients enrolled (mean age, 68 [SD, 7] years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group (difference, 3.3% [95% CI, -3.3% to 10.0%]; relative risk, 1.10 [95% CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (interquartile range, 750-2000 mL) in the HES group and 1500 mL (interquartile range, 750-2150 mL) in the saline group (median difference, 250 mL [95% CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3% of patients had died in the HES and saline groups, respectively (difference, 1.8% [95% CI, -0.7% to 4.3%]; relative risk, 1.76 [95% CI, 0.79-3.94]; P = .17). Conclusions and Relevance: Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9% saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02502773.

Do changes in perfusion index reflect changes in stroke volume during preload-modifying manoeuvres?

Changes in stroke volume (deltaSV) induced by a lung recruitment manoeuvre (LRM) have been shown to accurately predict fluid responsiveness during protective mechanical ventilation. Cardiac output monitors are used in a limited number of surgical patients. In contrast, all patients are monitored with a pulse oximeter, that may enable the continuous monitoring of a peripheral perfusion index (PI). We postulated that changes in PI (deltaPI) may reflect deltaSV during brief modifications of cardiac preload. We studied 47 patients undergoing neurosurgery and ventilated with a tidal volume of 6-8 ml/kg. All patients were monitored with a pulse contour system enabling the continuous monitoring of SV and with a pulse oximeter enabling the continuous monitoring of PI. LRMs were performed by increasing airway pressure up to 30 cmH20 for 30 s. Fluid loads (250 ml of saline 0.9% in 10 min) were performed only in patients who experienced a deltaSV > 30% during LRMs (potential fluid responders). LRMs induced a 26% decrease in SV (p < 0.05) and a 27% decrease in PI (p < 0.05). We observed a fair relationship between deltaPI and deltaSV (r2 = 0.34). A deltaPI ≥ 26% predicted a deltaSV > 30% with a sensitivity of 83% and a specificity of 78%  (AUC  =  0.84, 95%CI 0.71-0.93). 24 patients experienced a deltaSV > 30% and subsequently received fluid. Fluid loads induced a 16% increase in SV and a 17% increase in PI, but fluid-induced deltaPI and deltaSV were weakly correlated (r2 = 0.19). In neurosurgical patients, we conclude that deltaPI may be used as a surrogate for deltaSV during LRMs but not during fluid loading.

Are Standard Dosing Regimens of Ceftriaxone Adapted for Critically Ill Patients with Augmented Creatinine Clearance?

The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

Increased ß-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study.

BACKGROUND: Augmented renal clearance (ARC) is recognized as a leading cause of ß-lactam subexposure when conventional dosing regimens are used. The main objective was to compare the clinical outcome of ARC patients treated by conventional or increased ß-lactam dosing regimens for a first episode of hospital or ventilator-acquired pneumonia (HAP-VAP). METHODS: In this single-center, retrospective study, every ARC patient treated by ß-lactam for a first episode of HAP-VAP was included during two 15-month periods, before (Control period) and after (Treatment period) the modification of a local antibiotic therapy protocol. ARC was defined by a 24-h measured creatinine clearance ≥ 150 ml/min. The primary endpoint was defined as a therapeutic failure of the antimicrobial therapy or a HAP-VAP relapse within 28 days. Inverse probability of treatment weight (IPTW) was derived from a propensity score model. Cox proportional hazard models were used to evaluate the association between treatment period and clinical outcome. RESULTS: During the study period, 177 patients were included (control period, N = 88; treatment period, N = 89). Therapeutic failure or HAP-VAP relapse was significantly lower in the treatment period (10 vs. 23%, p = 0.019). The IPTW-adjusted hazard ratio of poor clinical outcome in the treatment period was 0.35 (95% CI 0.15-0.81), p = 0.014. No antibiotic side effect was reported during the treatment period. CONCLUSIONS: Higher than licensed dosing regimens of ß-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill augmented renal clearance (ARC) patients.

Fibrinolysis in trauma patients: wide variability demonstrated by the Lysis Timer.

Hyperfibrinolysis contributes to the pathophysiology of trauma-induced coagulopathy. At present, systematic administration of tranexamic acid (TXA) is recommended in all patients in the early phase of trauma. However, there is some debate regarding whether TXA is beneficial in all trauma patients. A rapid and accurate tool to diagnose hyperfibrinolysis may be useful for tailoring TXA treatment. We conducted a proof-of-concept study of consecutive adult trauma patients. A first blood sample was obtained at the time of pre-hospital care (T1). Patients received 1 g of TXA after T1. A second sample was obtained on arrival at the emergency unit (T2). We examined coagulation, fibrin and fibrinogen formation and degradation. Fibrinolysis was assessed by determining tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor 1 (PAI-1) activity and global fibrinolysis capacity assay using a device developed by Hyphen BioMed: the Lysis Timer (GFC/LT). The study population consisted of 20 patients (42 ± 21 years, index of severity score 32 ± 21). Both coagulation and fibrinolysis were altered at T1. GFC/LT values exhibited hyperfibrinolysis only in five patients. Principal component analysis carried out at T1 showed two main axes of alteration. The major axis was related to coagulation, altered in all patients, while the second axis was related to fibrinolysis. GFC/LT was mainly influenced by PAI-1 activity while fibrin monomers were related to the severity of trauma. At T2, GFC/LT exhibited the marked effect of TXA on clot lysis time. In conclusion, GFC/LT demonstrated huge variation in the fibrinolytic response to trauma.

End-expiratory occlusion maneuver to predict fluid responsiveness in the intensive care unit: an echocardiographic study.

BACKGROUND: In mechanically ventilated patients, an increase in cardiac index during an end-expiratory-occlusion test predicts fluid responsiveness. To identify this rapid increase in cardiac index, continuous and instantaneous cardiac index monitoring is necessary, decreasing its feasibility at the bedside. Our study was designed to investigate whether changes in velocity time integral and in peak velocity obtained using transthoracic echocardiography during an end-expiratory-occlusion maneuver could predict fluid responsiveness. METHODS: This single-center, prospective study included 50 mechanically ventilated critically ill patients. Velocity time integral and peak velocity were assessed using transthoracic echocardiography before and at the end of a 12-sec end-expiratory-occlusion maneuver. A third set of measurements was performed after volume expansion (500 mL of saline 0.9% given over 15 minutes). Patients were considered as responders if cardiac output increased by 15% or more after volume expansion. RESULTS: Twenty-eight patients were responders. At baseline, heart rate, mean arterial pressure, cardiac output, velocity time integral and peak velocity were similar between responders and non-responders. End-expiratory-occlusion maneuver induced a significant increase in velocity time integral both in responders and non-responders, and a significant increase in peak velocity only in responders. A 9% increase in velocity time integral induced by the end-expiratory-occlusion maneuver predicted fluid responsiveness with sensitivity of 89% (95% CI 72% to 98%) and specificity of 95% (95% CI 77% to 100%). An 8.5% increase in peak velocity induced by the end-expiratory-occlusion maneuver predicted fluid responsiveness with sensitivity of 64% (95% CI 44% to 81%) and specificity of 77% (95% CI 55% to 92%). The area under the receiver operating curve generated for changes in velocity time integral was significantly higher than the one generated for changes in peak velocity (0.96 ± 0.03 versus 0.70 ± 0.07, respectively, P = 0.0004 for both). The gray zone ranged between 6 and 10% (20% of the patients) for changes in velocity time integral and between 1 and 13% (62% of the patients) for changes in peak velocity. CONCLUSIONS: In mechanically ventilated and sedated patients in the neuro Intensive Care Unit, changes in velocity time integral during a 12-sec end-expiratory-occlusion maneuver were able to predict fluid responsiveness and perform better than changes in peak velocity.

Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room.

BACKGROUND: Mini-fluid challenge of 100 ml colloids is thought to predict the effects of larger amounts of fluid (500 ml) in intensive care units. This study sought to determine whether a low quantity of crystalloid (50 and 100 ml) could predict the effects of 250 ml crystalloid in mechanically ventilated patients in the operating room. METHODS: A total of 44 mechanically ventilated patients undergoing neurosurgery were included. Volume expansion (250 ml saline 0.9%) was given to maximize cardiac output during surgery. Stroke volume index (monitored using pulse contour analysis) and pulse pressure variations were recorded before and after 50 ml infusion (given for 1 min), after another 50 ml infusion (given for 1 min), and finally after 150 ml infusion (total = 250 ml). Changes in stroke volume index induced by 50, 100, and 250 ml were recorded. Positive fluid challenges were defined as an increase in stroke volume index of 10% or more from baseline after 250 ml. RESULTS: A total of 88 fluid challenges were performed (32% of positive fluid challenges). Changes in stroke volume index induced by 100 ml greater than 6% (gray zone between 4 and 7%, including 19% of patients) predicted fluid responsiveness with a sensitivity of 93% (95% CI, 77 to 99%) and a specificity of 85% (95% CI, 73 to 93%). The area under the receiver operating curve of changes in stroke volume index induced by 100 ml was 0.95 (95% CI, 0.90 to 0.99) and was higher than those of changes in stroke volume index induced by 50 ml (0.83 [95% CI, 0.75 to 0.92]; P = 0.01) and pulse pressure variations (0.65 [95% CI, 0.53 to 0.78]; P < 0.005). CONCLUSIONS: Changes in stroke volume index induced by rapid infusion of 100 ml crystalloid predicted the effects of 250 ml crystalloid in patients ventilated mechanically in the operating room.