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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. [ABSTRACT FROM AUTHOR]

Background: Recent work suggests that increased plasma concentrations of cardiac troponin I (cTnI) are common in critically ill patients and are associated with poor outcome. We measured the frequency of increased plasma cTnI concentrations during patients' stay in a mixed medical/surgical intensive care unit (ICU) and compared our findings with hospital mortality.Methods: Basic details, organ support, and hospital mortality were recorded for all patients treated in ICU during a 6 month period. cTnI concentrations were sampled daily for all patients, using 0.04 µg litre(-1) as the upper limit of normal, and 0.12 µg litre(-1) as an additional stratification point.Results: Of 663 patients, 54% were male, with a mean (sd) age of 60 (18) yr, 65% were surgical patients, and the median Acute Physiology and Chronic Ill Health II (APACHE II) score was 15 (inter-quartile range 12-20). Increased cTnI concentrations were found in 345 patients (52%) while in ICU. One hundred and twenty patients (18%) died in hospital. cTnI concentration >0.04 µg litre(-1) was associated with reduced odds of hospital survival, independent of age, medical admission, unplanned admission, APACHE II score, mechanical ventilation, and haemofiltration (adjusted odds ratio 0.25, 95% confidence interval 0.08-0.75, P=0.014). Stratification by the degree of cTnI increase revealed an incremental trend towards a lower odds of hospital survival, including for patients with 'minor' elevations of cTnI (0.05-0.12 µg litre(-1)).Conclusions: Increased serum cTnI concentrations during ICU stay independently predicts hospital mortality, even when the threshold is low. We found a trend towards an association between 'minor' elevations in cTnI and higher in-hospital mortality. [ABSTRACT FROM AUTHOR]

Background.: Dynamic arterial elastance (Ea dyn ), the relationship between pulse pressure variation (PPV) and stroke volume variation (SVV), has been suggested as a functional assessment of arterial load. The aim of this study was to evaluate the impact of arterial load changes during acute pharmacological changes, fluid administration, and haemorrhage on Ea dyn ., Methods.: Eighteen anaesthetized, mechanically ventilated New Zealand rabbits were studied. Arterial load changes were induced by phenylephrine ( n =9) or nitroprusside ( n =9). Thereafter, animals received a fluid bolus (10 ml kg -1 ), followed by stepwise bleeding (blood loss: 15 ml kg -1 ). The influence of arterial load and cardiac variables on PPV, SVV, and Ea dyn was analysed using a linear mixed-effects model analysis., Results.: After phenylephrine infusion, mean ( sd ) Ea dyn decreased from 0.89 (0.14) to 0.49 (0.12), P <0.001; whereas after administration of nitroprusside, Ea dyn increased from 0.80 (0.23) to 1.28 (0.21), P <0.0001. Overall, the fluid bolus decreased Ea dyn [from 0.89 (0.44) to 0.73 (0.35); P <0.01], and haemorrhage increased it [from 0.78 (0.23) to 0.95 (0.26), P =0.03]. Both PPV and SVV were associated with similar arterial factors (effective arterial elastance, arterial compliance, and resistance) and heart rate. Furthermore, PPV was also related to the acceleration and peak velocity of aortic blood flow. Both arterial and cardiac factors contributed to the evolution of Ea dyn throughout the experiment., Conclusions.: Acute modifications of arterial load induced significant changes on Ea dyn ; vasodilatation increased Ea dyn , whereas vasoconstriction decreased it. The Ea dyn was associated with both arterial load and cardiac factors, suggesting that Ea dyn should be more properly considered as a ventriculo-arterial coupling index., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

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.

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.

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.

Purpose: To determine the effects of fluid administration on arterial load in critically ill patients with septic shock., Methods: 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)., Results: 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., Conclusion: 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.

Introduction: 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 m(2))., Methods: We randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined., Results: Mean PC was 76.7 ± 28.5 mL/min/1.73 m(2) (SBI), and 78.9 ± 28.6 mL/min/1.73 m(2) (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p < 0.0001). Bias was 2.2 mL/min/1.73 m(2) (limits of agreement -8.2 to 12.6 mL/min/1.73 m(2)) for CILDI. PC overestimated RC by 7.1 ± 7.3 mL/min/1.73 m(2). Mean intra-individual variation in GFR (CILDI) was 10.3% (p < 0.003). Mean ± SD Css was 172 ± 185 min., Conclusion: We hypothesise that changes in GFR >10.3% depict evolving AKI. If this were applicable to AKI, this is less than the 50% change in serum creatinine currently required to define AKI. CILDI is now ready for testing in patients with AKI., Trial Registration: This trial was registered with the European Union Clinical Trials Register ( https://www.clinicaltrialsregister.eu/ ), registration number: 2010-019933-89 .

Background: Dynamic arterial elastance (Eadyn), defined as the pulse pressure variation (PPV) to stroke volume variation (SVV) ratio, has been suggested as a predictor of the arterial pressure response to fluid administration. In this study, we assessed the effectiveness of Eadyn to predict the arterial blood pressure response to a fluid challenge (FC) in preload-dependent, spontaneously breathing patients., Methods: Patients admitted postoperatively and monitored with the Nexfin monitor (BMEYE, Amsterdam, The Netherlands) were enrolled in the study. Patients were included in the analysis if they were spontaneously breathing and had an increase in cardiac output ≥10% during an FC. Patients were classified according to the increase in mean arterial blood pressure (MAP) after FC into MAP-responders (MAP increase ≥10%) and MAP-nonresponders (MAP increase <10%). Eadyn was continuously calculated from the PPV and SVV values obtained from the monitor., Results: Thirty-four FCs from 26 patients were studied. Seventeen FCs (50%) induced a positive MAP response. Preinfusion Eadyn was significantly higher in MAP-responders (1.39 ± 0.41 vs 0.85 ± 0.23; P = 0.0001). Preinfusion Eadyn predicted a positive MAP response to FC with an area under the receiver-operating characteristic curve of 0.92 ± 0.04 of standard error (95% confidence interval, 0.78-0.99; P < 0.0001). A preinfusion Eadyn value ≥1.06 (gray zone: 0.9-1.15) discriminated MAP-responders with a sensitivity and specificity of 88.2% (approximate 95% confidence interval, 64%-99%), respectively., Conclusions: Noninvasive Eadyn, defined as the PPV to SVV ratio, predicted the arterial blood pressure increase to fluid administration in spontaneously breathing, preload-dependent patients.

Introduction: 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., Methods: We analyzed the response of arterial pressure to an intravenous infusion of 500 ml of normal saline in 53 mechanically ventilated patients with acute circulatory failure and preserved preload dependence. Eadyn was calculated as the simultaneous ratio between PPV (obtained from an arterial line) and SVV (obtained by esophageal Doppler imaging). A total of 80 fluid challenges were performed (median, 1.5 per patient; interquartile range, 1 to 2). Patients were classified according to the increase in mean arterial pressure (MAP) after fluid administration in pressure responders (≥ 10%) and non-responders., Results: Thirty-three fluid challenges (41.2%) significantly increased MAP. At baseline, Eadyn was higher in pressure responders (1.04 ± 0.28 versus 0.60 ± 0.14; P < 0.0001). Preinfusion Eadyn was related to changes in MAP after fluid administration (R (2) = 0.60; P < 0.0001). At baseline, Eadyn predicted the arterial pressure increase to volume expansion (area under the receiver operating characteristic curve, 0.94; 95% confidence interval (CI): 0.86 to 0.98; P < 0.0001). A preinfusion Eadyn value ≥ 0.73 (gray zone: 0.72 to 0.88) discriminated pressure responder patients with a sensitivity of 90.9% (95% CI: 75.6 to 98.1%) and a specificity of 91.5% (95% CI: 79.6 to 97.6%)., Conclusions: Functional assessment of arterial load by Eadyn, obtained from two independent signals, enabled the prediction of arterial pressure response to fluid administration in mechanically ventilated, preload-dependent patients with acute circulatory failure.

Patients with limited cardiopulmonary reserve are at risk of mortality and morbidity after major surgery. Augmentation of oxygen delivery index (DO2I) with i.v. fluids and inotropes (goal-directed therapy, GDT) has been shown to reduce postoperative mortality and morbidity in high-risk patients. Concerns regarding cardiac complications associated with fluid challenges and inotropes may prevent clinicians from performing GDT in patients who need it most. We hypothesized that GDT is not associated with an increased risk of cardiac complications in high-risk, non-cardiac surgical patients. We performed a systematic search of Medline, Embase, and CENTRAL databases for randomized controlled trials (RCTs) of GDT in high-risk surgical patients. Studies including cardiac surgery, trauma, and paediatric surgery were excluded. We reviewed the rates of all cardiac complications, arrhythmias, myocardial ischaemia, and acute pulmonary oedema. Meta-analyses were performed using RevMan software. Data are presented as odds ratios (ORs), [95% confidence intervals (CIs)], and P-values. Twenty-two RCTs including 2129 patients reported cardiac complications. GDT was associated with a reduction in total cardiovascular (CVS) complications [OR=0.54, (0.38-0.76), P=0.0005] and arrhythmias [OR=0.54, (0.35-0.85), P=0.007]. GDT was not associated with an increase in acute pulmonary oedema [OR=0.69, (0.43-1.10), P=0.12] or myocardial ischaemia [OR=0.70, (0.38-1.28), P=0.25]. Subgroup analysis revealed the benefit is most pronounced in patients receiving fluid and inotrope therapy to achieve a supranormal DO2I, with the use of minimally invasive cardiac output monitors. Treatment of high-risk surgical patients GDT is not associated with an increased risk of cardiac complications; GDT with fluids and inotropes to optimize DO2I during early GDT reduces postoperative CVS complications.

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.

Purpose: 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., Methods: We performed a prospective observational study in postsurgical patients. Patients were monitored with a central venous catheter, a LiDCO™plus and the Navigator™. A 250-ml intravenous fluid challenge was given over 5 min. A positive response to the fluid challenge was defined as either a stroke volume (SV) or cardiac output increase of greater than 10 %., Results: A total of 101 fluid challenges were observed in 39 patients. In 43 events (42.6 %) the SV and CO increased by more than 10 %. Pmsa increased similarly during a fluid challenge in responders and non-responders (3.1 ± 1.9 vs. 3.1 ± 1.8, p = 0.9), whereas the dVR increased in responders (1.16 ± 0.8 vs. 0.2 ± 1, p < 0.001) as among non-responders CVP increased along with Pmsa (2.9 ± 1.7 vs. 3.1 ± 1.8, p = 0.15). Resistance to venous return did not change immediately after a fluid challenge. Heart performance (Eh) decreased significantly among non-responders (0.41 ± 0.15 vs. 0.34 ± 0.13, p < 0.001) whereas among responders it did not change when compared with baseline value (0.35 ± 0.15 vs. 0.34 ± 0.12, p = 0.15)., Conclusions: The changes in Pmsa and dVR measured at the bedside during a fluid challenge are consistent with the cardiovascular model described by Guyton.

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.