Objective: The objectives of this study are to determine what is the minimal volume required to perform an effective fluid challenge and to investigate how different doses of IV fluids in an fluid challenge affect the changes in cardiac output and the proportion of responders and nonresponders. Design: Quasi-randomized controlled trial. Setting: Cardiothoracic ICU, tertiary university hospital. Patients: Eighty postcardiac surgery patients. Intervention: IV infusion of 1, 2, 3, or 4 mL/Kg (body weight) of crystalloid over 5 minutes. Measurements and Main Results: Mean systemic filling pressure measured using the transient stop-flow arm arterial-venous equilibrium pressure, arterial and central venous pressure, cardiac output (LiDCOplus; LiDCO, Cambridge, United Kingdom), and heart rate. The groups were well matched with respect to demographic and baseline physiologic variables. The proportion of responders increased from 20% in the group of 1 mL/kg to 65% in the group of 4 mL/kg (p = 0.04). The predicted minimal volume required for an fluid challenge was between 321 and 509 mL. Only 4 mL/Kg increases transient stop-flow arm arterial-venous equilibrium pressure beyond the limits of precision and was significantly associated with a positive response (odds ratio, 7.73; 95% CI, 1.78–31.04). Conclusion: The doses of fluids used for an fluid challenge modify the proportions of responders in postoperative patients. A dose of 4 mL/Kg increases transient stop-flow arm arterial-venous equilibrium pressure and reliably detects responders and nonresponders.

Transient stop-flow arm arterial–venous equilibrium pressure (Pmsf-arm) is a validated technique for measuring the mean systemic filling pressure (Pmsf). Pmsf is a functional measure of the effective intravascular volume status. This study aims to assess the precision of the Pmsf-arm measurement. Pmsf-arm was measured by inflating a pneumatic tourniquet around the upper arm 50 mmHg above systolic pressure for 60 s, four times consecutively, with an interval of 5 min. Arterial (Pa) and venous pressure (Pv) were recorded every 10 s. Pa–Pv difference was calculated to determine the stop-flow time. The coefficient error (CE) was determined and used to derive the least significant change (LSC) in Pmsf-arm that this technique could reliably detect. The rANOVA test was used to compare repeated measurements of the four determinations of Pmsf-arm. 80 measurements of Pmsf-arm were studied in 20 patients. Pa and Pv equalised after 60 s of inflation (Pa–Pv difference 0 ± 0.01 mmHg). There were no significant differences of Pmsf-arm values among determinations. For a single measurement, the CE was 5 % (±2 %) and the LSC was 14 % (±5 %). Averaging two, three and four measurements the CE improves to 4 % (±1 %), 3 % (±1 %) and 3 % (±1 %) respectively, and the LSC was reduced to 10 % (±4 %), 8 % (±3 %) and 7 % (±3 %) respectively. One measurement of Pmsf-arm can reliably detect changes on Pmsf-arm of 14 %. The precision of Pmsf-arm technique improves when averaging two or three measurements.

OBJECTIVE:This study aims to describe the pharmacodynamics of a fluid challenge over a 10-minute period in postoperative patients. DESIGN:Prospective observational study. SETTING:General and cardiothoracic ICU, tertiary hospital. PATIENTS:Twenty-six postoperative patients. INTERVENTION:Two hundred and fifty-milliliter fluid challenge performed over 5 minutes. Data were recorded over 10 minutes after the end of fluid infusion MEASUREMENTS AND MAIN RESULTS:Cardiac output was measured with a calibrated LiDCOplus (LiDCO, Cambridge, United Kingdom) and Navigator (Applied Physiology, Sydney, Australia) to obtain the Pmsf analogue (Pmsa). Pharmacodynamics outcomes were modeled using a Bayesian inferential approach and Markov chain Monte Carlo estimation methods. Parameter estimates were summarized as the means of their posterior distributions, and their uncertainty was assessed by the 95% credible intervals. Bayesian probabilities for groups' effect were also derived. The predicted maximal effect on cardiac output was observed at 1.2 minutes (95% credible interval, -0.6 to 2.8 min) in responders. The probability that the estimated area under the curve of central venous pressure was smaller in nonresponders was 0.12. (estimated difference, -4.91 mm Hg·min [95% credible interval, -13.45 to 3.3 mm Hg min]). After 10 minutes, there is no evidence of a difference between groups for any hemodynamic variable. CONCLUSIONS:The maximal change in cardiac output should be assessed 1 minute after the end of the fluid infusion. The global effect of the fluid challenge on central venous pressure is greater in nonresponders, but not the change observed 10 minutes after the fluid infusion. The effect of a fluid challenge on hemodynamics is dissipated in 10 minutes similarly in both groups.

To determine the effects of fluid administration on arterial load in critically ill patients with septic shock.Analysis of septic shock patients monitored with an oesophageal Doppler and equipped with an indwelling arterial catheter in whom a fluid challenge was performed because of the presence of systemic hypoperfusion. Measures of arterial load [systemic vascular resistance, SVR = mean arterial pressure (MAP)/cardiac output (CO); net arterial compliance, C = stroke volume (SV)/arterial pulse pressure; and effective arterial elastance, Ea = 90 % of systolic arterial pressure/SV] were studied both before and after volume expansion (VE).Eighty-one patients were analysed, 54 (67 %) increased their CO by at least 10 % after VE (preload responders). In the whole population, 29 patients (36 %) increased MAP by at least 10 % from preinfusion level (pressure responders). In the preload responder group, only 24 patients (44 %) were pressure responders. Fluid administration was associated with a significant decrease in Ea [from 1.68 (1.11-2.11) to 1.57 (1.08-1.99) mmHg/mL; P = 0.0001] and SVR [from 1035 (645-1483) to 928 (654-1452) dyn s cm(-5); P < 0.01]. Specifically, in preload responders in whom arterial pressure did not change, VE caused a reduction in Ea from 1.74 (1.22-2.24) to 1.55 (1.24-1.86) mmHg/mL (P < 0.0001), affecting both resistive [SVR: from 1082 (697-1475) to 914 (624-1475) dyn s cm(-5); P < 0.0001] and pulsatile [C: from 1.11 (0.84-1.49) to 1.18 (0.99-1.44) mL/mmHg; P < 0.05] components. There was no relationship between preinfusion arterial load parameters and VE-induced increase in arterial pressure.Fluid administration significantly reduced arterial load in critically patients with septic shock and acute circulatory failure, even when increasing cardiac output. This explains why some septic patients increase their cardiac output after fluid administration without improving blood pressure.

There is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m2).

Functional assessment of arterial load by dynamic arterial elastance (Eadyn), defined as the ratio between pulse pressure variation (PPV) and stroke volume variation (SVV), has recently been shown to predict the arterial pressure response to volume expansion (VE) in hypotensive, preload-dependent patients. However, because both SVV and PPV were obtained from pulse pressure analysis, a mathematical coupling factor could not be excluded. We therefore designed this study to confirm whether Eadyn, obtained from two independent signals, allows the prediction of arterial pressure response to VE in fluid-responsive patients.

Objective Severe trauma can be associated with significant hemorrhagic shock and impaired organ perfusion. We hypothesized that goal-directed therapy would confer morbidity and mortality benefits in major trauma. Methods The MedLine, Embase and Cochrane Controlled Clinical Trials Register databases were systematically searched for randomized, controlled trials of goal-directed therapy in severe trauma patients. Mortality was the primary outcome of this review. Secondary outcomes included complication rates, length of hospital and intensive care unit stay, and the volume of fluid and blood administered. Meta-analysis was performed using RevMan software, and the data presented are as odds ratios for dichotomous outcomes and as mean differences (MDs) and standard MDs for continuous outcomes. Results Four randomized, controlled trials including 419 patients were analyzed. Mortality risk was significantly reduced in goal-directed therapy-treated patients, compared to the control group (OR=0.56, 95%CI: 0.34-0.92). Intensive care (MD: 3.7 days 95%CI: 1.06-6.5) and hospital length of stay (MD: 3.5 days, 95%CI: 2.75-4.25) were significantly shorter in the protocol group patients. There were no differences in reported total fluid volume or blood transfusions administered. Heterogeneity in reporting among the studies prevented quantitative analysis of complications. Conclusion Following severe trauma, early goal-directed therapy was associated with lower mortality and shorter durations of intensive care unit and hospital stays. The findings of this analysis should be interpreted with caution due to the presence of significant heterogeneity and the small number of the randomized, controlled trials included.

Introduction The reliability of pulse pressure analysis to estimate cardiac output is known to be affected by arterial load changes. However, the contribution of each aspect of arterial load could be substantially different. In this study, we evaluated the agreement of eight non-commercial algorithms of pulse pressure analysis for estimating cardiac output (PPCO) with esophageal Doppler cardiac output (EDCO) during acute changes of arterial load. In addition, we aimed to determine the optimal arterial load parameter that could detect a clinically significant difference between PPCO and the EDCO. Methods We included mechanically ventilated patients monitored with a prototype esophageal Doppler (CardioQ-Combi™, Deltex Medical, Chichester, UK) and an indwelling arterial catheter who received a fluid challenge or in whom the vasoactive medication was introduced or modified. Initial calibration of PPCO was made with the baseline value of EDCO. We evaluated several aspects of arterial load: total systemic vascular resistance (TSVR = mean arterial pressure [MAP]/EDCO * 80), net arterial compliance (C = EDCO-derived stroke volume/pulse pressure), and effective arterial elastance (Ea = 0.9 * systolic blood pressure/EDCO-derived stroke volume). We compared CO values with Bland-Altman analysis, four-quadrant plot and a modified polar plot (with least significant change analysis). Results A total of 16,964-paired measurements in 53 patients were performed (median 271; interquartile range: 180-415). Agreement of all PPCO algorithms with EDCO was significantly affected by changes in arterial load, although the impact was more pronounced during changes in vasopressor therapy. When looking at different parameters of arterial load, the predictive abilities of Ea and C were superior to TSVR and MAP changes to detect a PPCO-EDCO discrepancy ≥ 10% in all PPCO algorithms. An absolute Ea change > 8.9 ± 1.7% was associated with a PPCO-EDCO discrepancy ≥ 10% in most algorithms. Conclusions Changes in arterial load profoundly affected the agreement of PPCO and EDCO, although the contribution of each aspect of arterial load to the PPCO-EDCO discrepancies was significantly different. Changes in Ea and C mainly determined PPCO-EDCO discrepancy.

Introduction Goal-directed perioperative therapy (GDT) is now part of a number of international perioperative protocols and, to some extent, seems to have come of age, but no research takes place in isolation and it is valuable to retrospectively look at influential papers to understand the context and influences of the time the research was undertaken. Methods One of the earliest publication of a randomised trial of GDT was a study we published 20 years ago in 1993, with co-author Professor E. David Bennett. In this article we describe the work leading up to our research, and look at the historical context of our study and choices we made in designing a protocol. Conclusion With 20 years of hindsight we consider the issues that have arisen following our study and place this into the whole of the debate around the use of GDT.

The difference between mean systemic filling (Pmsf) and central venous pressure (CVP) is the venous return gradient (dVR). The aim of this study is to assess the significance of the Pmsf analogue (Pmsa) and the dVR during a fluid challenge.

Patients with limited cardiac reserve are less likely to survive and develop more complications following major surgery. By augmenting oxygen delivery index (DO2I) with a combination of intravenous fluids and inotropes (goal directed therapy (GDT)), postoperative mortality and morbidity of high-risk patients may be reduced. However, although most studies suggest that GDT may improve outcome in high-risk surgical patients, it is still not widely practiced. We set out to test the hypothesis that GDT results in greatest benefit in terms of mortality and morbidity in patients with the highest risk of mortality and have undertaken a systematic review of the current literature to see if this is correct. We performed a systematic search of Medline, Embase and CENTRAL databases for randomized controlled trials (RCTs) and reviews of GDT in surgical patients. To minimize heterogeneity we excluded studies involving cardiac, trauma, and paediatric surgery. Extremely high risk, high risk and intermediate risks of mortality were defined as >20%, 5 to 20% and <5% mortality rates in the control arms of the trials, respectively. Meta analyses were performed and Forest plots drawn using RevMan software. Data are presented as odd ratios (OR; 95% confidence intervals (CI), and P-values). A total of 32 RCTs including 2,808 patients were reviewed. All studies reported mortality. Five studies (including 300 patients) were excluded from assessment of complication rates as the number of patients with complications was not reported. The mortality benefit of GDT was confined to the extremely high-risk group (OR = 0.20, 95% CI 0.09 to 0.41; P < 0.0001). Complication rates were reduced in all subgroups (OR = 0.45, 95% CI 0.34 to 0.60; P < 0.00001). The morbidity benefit was greatest amongst patients in the extremely high-risk subgroup (OR = 0.27, 95% CI 0.15 to 0.51; P < 0.0001), followed by the intermediate risk subgroup (OR = 0.43, 95% CI 0.27 to 0.67; P = 0.0002), and the high-risk subgroup (OR 0.56, 95% CI 0.36 to 0.89; P = 0.01). Despite heterogeneity in trial quality and design, we found GDT to be beneficial in all high-risk patients undergoing major surgery. The mortality benefit of GDT was confined to the subgroup of patients at extremely high risk of death. The reduction of complication rates was seen across all subgroups of GDT patients.

SEDATION IN INTENSIVE CARE PAtients is assumed to reduce discomfort from care interventions, increase tolerance of mechanical ventilation, prevent accidental removal of instrumentation, and reduce metabolic demands during cardiovascular and respiratory instability. Long-term sedation may have serious adverse effects, such as prolonged mechanical ventilation, coma, delirium, delusional memories and posttraumatic stress disorder, impaired cognitive function, prolonged hospitalization, increased costs, and mortality. Daily sedation stops, sedation protocols, spontaneous breathing trials and early mobilization, or primary use of opiates without other sedation may help reduce these complications. Current sedatives are problematic in long-term sedation. Benzodiazepines and propofol accumulate unpredictably. High-dose or prolonged propofol use may cause potentially fatal propofol infusion syndrome. Dexmedetomidine, a sedative with high

CONTEXT:Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.OBJECTIVE:To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care.DESIGN, SETTING, AND PATIENTS:Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).INTERVENTIONS:Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.MAIN OUTCOME MEASURES:For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).RESULTS:Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).CONCLUSIONS:Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.TRIAL REGISTRATION:clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.

Goal-directed therapy in the perioperative setting has been shown to be associated with short-term improvements in outcome. This study assesses the longer-term survival of patients from a previous randomized controlled trial of goal-directed therapy in high-risk surgical patients.

OBJECTIVE:Critical illness and associated sequelae can cause severe metabolic disturbances. The effects these have on hepatic drug metabolism are poorly understood. In vivo, enzyme specific drug probes are used to measure changes in hepatic drug metabolism but they require multiple blood sampling and are time consuming. We suggest that a single measurement, 4 h after intravenous administration of midazolam is a reliable indicator of integral plasma midazolam exposure or area under the curve (AUC) in critically ill patients. We also explore the hypothesis that acute kidney injury (AKI) directly impairs hepatic metabolism of drugs in critically ill patients.METHODS:A prospective study in 20 critically ill patients who were not taking specific enzyme inhibitors or inducers or benzodiazepines. Correlation between 4 h midazolam concentration and AUC was calculated. We also assessed the difference in metabolism between the patients with normal renal function and those with AKI.RESULTS:Four hour midazolam concentration correlated with AUC r = 0.956 (p < 0.0001). In addition, the 4 h midazolam concentration was greater in critically ill patients with AKI than those with normal renal function p = 0.023.CONCLUSION:A single-time-point determination of plasma midazolam concentration is a reliable predictor of integral plasma midazolam exposure in critically ill patients. This tool can now be used to assess the effects of critical illness on hepatic drug metabolism. Using this method, we suggest that AKI reduces the hepatic metabolism of midazolam in critically ill patients.

Bland-Altman analysis is used for assessing agreement between two measurements of the same clinical variable. In the field of cardiac output monitoring, its results, in terms of bias and limits of agreement, are often difficult to interpret, leading clinicians to use a cutoff of 30% in the percentage error in order to decide whether a new technique may be considered a good alternative. This percentage error of +/- 30% arises from the assumption that the commonly used reference technique, intermittent thermodilution, has a precision of +/- 20% or less. The combination of two precisions of +/- 20% equates to a total error of +/- 28.3%, which is commonly rounded up to +/- 30%. Thus, finding a percentage error of less than +/- 30% should equate to the new tested technique having an error similar to the reference, which therefore should be acceptable. In a worked example in this paper, we discuss the limitations of this approach, in particular in regard to the situation in which the reference technique may be either more or less precise than would normally be expected. This can lead to inappropriate conclusions being drawn from data acquired in validation studies of new monitoring technologies. We conclude that it is not acceptable to present comparison studies quoting percentage error as an acceptability criteria without reporting the precision of the reference technique.

BACKGROUND:Pulmonary vein thrombosis represents a potentially fatal disease. This syndrome may clinically mimic pulmonary embolism but has a different investigation strategy and prognosis. Pulmonary vein thrombosis is difficult to diagnose clinically and usually requires a combination of conventionally used diagnostic modalities.CASE PRESENTATION:The authors report a case of a 78-year-old previously healthy female presenting with collapse and shortness of breath. Serum biochemistry revealed acute kidney injury, positive D-dimmer's and increased C reactive protein. Chest radiography demonstrated volume loss in the right lung. The patient was started on antibiotics and also therapeutic doses of low molecular weight heparin. The working diagnosis included community acquired pneumonia & pulmonary embolism. A computed tomography pulmonary angiogram was performed to confirm the clinical suspicions of pulmonary embolism. This demonstrated a thrombus in the pulmonary vein, with associated fibrosis and volume loss of the right lower lobe. A subsequent thrombophilia screen revealed a positive lupus anticoagulant antibody and rheumatoid factor and also decreased anti thrombin III and protein C levels. The urine protein/creatinine ratio was found to be 553 mg/mmol.CONCLUSION:The diagnosis of this patient was therefore of idiopathic pulmonary fibrosis associated with pulmonary vein thrombosis. Whether or not the pulmonary vein thrombosis was a primary cause of the fibrosis or a consequence of it was unclear. There are few data on the management of pulmonary vein thrombosis, but anticoagulation, antibiotics, and, in cases of large pulmonary vein thrombosis, thrombectomy or pulmonary resection have been used.