Metrology part 1: definition of quality criteria.

Any measurement is always afflicted with some degree of uncertainty. A correct understanding of the different types of uncertainty, their naming, and their definition is of crucial importance for an appropriate use of measuring instruments. However, in perioperative and intensive care medicine, the metrological requirements for measuring instruments are poorly defined and often used spuriously. The correct use of metrological terms is also of crucial importance in validation studies. The European Union published a new directive on medical devices, mentioning that in the case of devices with a measuring function, the notified body is involved in all aspects relating to the conformity of the device with the metrological requirements. It is therefore the task of the scientific societies to establish the standards in their area of expertise. Adopting the same understandings and definitions among clinicians and scientists is obviously the first step. In this metrologic review (part 1), we list and explain the most important terms defined by the International Bureau of Weights and Measures regarding quantities and units, properties of measurements, devices for measurement, properties of measuring devices, and measurement standards, with specific examples from perioperative and intensive care medicine.

Metrology part 2: Procedures for the validation of major measurement quality criteria and measuring instrument properties.

A measurement is always afflicted with some degree of uncertainty. A correct understanding of the different types of uncertainty, their naming, and their definition is of crucial importance for an appropriate use of the measuring instruments. However, in perioperative and intensive care medicine, the metrological requirements for measuring instruments are poorly defined and often used spuriously. The correct use of metrological terms is also of crucial importance in validation studies. The European Union published a new directive on medical devices, mentioning that in the case of devices with a measuring function, the notified body is involved in all aspects relating to the conformity of the device with the metrological requirements. It is therefore the task of scientific societies to establish the standards in their area of expertise. After adopting the same understandings and definitions (part 1), the different procedures for the validation of major quality criteria of measuring devices must be consensually established. In this metrologic review (part 2), we review the terms and definitions of validation, some basic processes leading to the display of an indication from a physiologic signal, and procedures for the validation of measuring instrument properties, with specific focus on perioperative and intensive care medicine including appropriate examples.

Hemodynamic Effect of Different Doses of Fluids for a Fluid Challenge: A Quasi-Randomized Controlled Study.

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.

What is the impact of the fluid challenge technique on diagnosis of fluid responsiveness? A systematic review and meta-analysis.

BACKGROUND: The fluid challenge is considered the gold standard for diagnosis of fluid responsiveness. The objective of this study was to describe the fluid challenge techniques reported in fluid responsiveness studies and to assess the difference in the proportion of 'responders,' (PR) depending on the type of fluid, volume, duration of infusion and timing of assessment. METHODS: Searches of MEDLINE and Embase were performed for studies using the fluid challenge as a test of cardiac preload with a description of the technique, a reported definition of fluid responsiveness and PR. The primary outcome was the mean PR, depending on volume of fluid, type of fluids, rate of infusion and time of assessment. RESULTS: A total of 85 studies (3601 patients) were included in the analysis. The PR were 54.4% (95% CI 46.9-62.7) where <500 ml was administered, 57.2% (95% CI 52.9-61.0) where 500 ml was administered and 60.5% (95% CI 35.9-79.2) where >500 ml was administered (p = 0.71). The PR was not affected by type of fluid. The PR was similar among patients administered a fluid challenge for <15 minutes (59.2%, 95% CI 54.2-64.1) and for 15-30 minutes (57.7%, 95% CI 52.4-62.4, p = 1). Where the infusion time was ≥30 minutes, there was a lower PR of 49.9% (95% CI 45.6-54, p = 0.04). Response was assessed at the end of fluid challenge, between 1 and 10 minutes, and >10 minutes after the fluid challenge. The proportions of responders were 53.9%, 57.7% and 52.3%, respectively (p = 0.47). CONCLUSIONS: The PR decreases with a long infusion time. A standard technique for fluid challenge is desirable.

Ability and efficiency of an automatic analysis software to measure microvascular parameters.

Analysis of the microcirculation is currently performed offline, is time consuming and operator dependent. The aim of this study was to assess the ability and efficiency of the automatic analysis software CytoCamTools 1.7.12 (CC) to measure microvascular parameters in comparison with Automated Vascular Analysis (AVA) software 3.2. 22 patients admitted to the cardiothoracic intensive care unit following cardiac surgery were prospectively enrolled. Sublingual microcirculatory videos were analysed using AVA and CC software. The total vessel density (TVD) for small vessels, perfused vessel density (PVD) and proportion of perfused vessels (PPV) were calculated. Blood flow was assessed using the microvascular flow index (MFI) for AVA software and the averaged perfused speed indicator (APSI) for the CC software. The duration of the analysis was also recorded. Eighty-four videos from 22 patients were analysed. The bias between TVD-CC and TVD-AVA was 2.20 mm/mm2 (95 % CI 1.37-3.03) with limits of agreement (LOA) of -4.39 (95 % CI -5.66 to -3.16) and 8.79 (95 % CI 7.50-10.01) mm/mm2. The percentage error (PE) for TVD was ±32.2 %. TVD was positively correlated between CC and AVA (r = 0.74, p < 0.001). The bias between PVD-CC and PVD-AVA was 6.54 mm/mm2 (95 % CI 5.60-7.48) with LOA of -4.25 (95 % CI -8.48 to -0.02) and 17.34 (95 % CI 13.11-21.57) mm/mm2. The PE for PVD was ±61.2 %. PVD was positively correlated between CC and AVA (r = 0.66, p < 0.001). The median PPV-AVA was significantly higher than the median PPV-CC [97.39 % (95.25, 100 %) vs. 81.65 % (61.97, 88.99), p < 0.0001]. MFI categories cannot estimate or predict APSI values (p = 0.45). The time required for the analysis was shorter with CC than with AVA system [2'42″ (2'12″, 3'31″) vs. 16'12″ (13'38″, 17'57″), p < 0.001]. TVD is comparable between the two softwares, although faster with CC software. The values for PVD and PPV are not interchangeable given the different approach to assess microcirculatory flow.

Pharmacodynamic Analysis of a Fluid Challenge.

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.

Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191.

Transient stop-flow arm arterial-venous equilibrium pressure measurement: determination of precision of the technique.

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.

Can (and should) the venous tone be monitored at the bedside?

PURPOSE OF REVIEW: Most of our blood volume is contained in the venous compartment. The so-called 'compliant veins' are an adjustable blood reservoir, which is playing a paramount role in maintaining haemodynamic stability. The purpose of this study is to review what is known about this blood reservoir and how we can use this information to assess the cardiovascular state of critically ill patients. RECENT FINDINGS: The mean systemic filling pressure (Pmsf) is the pivot pressure of the circulation, and a quantitative index of intravascular volume. The Pmsf can be measured at the bedside by three methods described in critically ill patients. The Pmsf can be modified by the fluid therapy and vasoactive medications. SUMMARY: The Pmsf along with other haemodynamic variables can provide valuable information to correctly understand the cardiovascular status of critically ill patients and better manage the fluid therapy and cardiovascular support. Future studies using the Pmsf will show its usefulness for fluid administration.

Dynamic arterial elastance as a predictor of arterial pressure response to fluid administration: a validation study.

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.

Evaluation of cardiac function using heart-lung interactions.

Heart lung interactions can be used clinically to assist in the evaluation of cardiac function. Application of these interactions and understanding of the physiology underlying them has formed a focus of research over a number of years. The changes in preload induced by changes in intrathoracic pressure (ITP) with the respiratory cycle, have been applied to form dynamic tests of fluid responsiveness. Pulse pressure variation (PPV), stroke volume variation (SVV), end expiratory occlusion test, pleth variability index (PVI) and use of echocardiography are all clinical assessments that can be made at the bedside. However, there are limitations and pitfalls to each that restrict their use to specific situations. The haemodynamic response to treatment with continuous positive airway pressure (CPAP) in left ventricular failure is explained by the presence of heart lung interactions, and works predominately through afterload reduction. Similarly, in other disease states such as acute respiratory distress syndrome (ARDS), the effects of a change in ventilation can provide information about both the cardiac and respiratory system. This review aims to summarise how assessment of cardiac function using heart lung interactions can be performed. It introduces the underlying physiology and some of the clinical applications that are further explored in other articles within the series.

From cardiac output to blood flow auto-regulation in shock.

Shock is defined as a state in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, resulting in cellular dysoxia and organ failure. In this process, the factors that govern the circulation at a haemodynamic level and oxygen delivery at a microcirculatory level play a major role. This manuscript aims to review the blood flow regulation from macro- and micro-haemodynamic point of view and to discuss new potential therapeutic approaches for cardiovascular instability in patients in cardiovascular shock. Despite the recent advances in haemodynamics, the mechanisms that control the vascular resistance and the venous return are not fully understood in critically ill patients. The physical properties of the vascular wall, as well as the role of the mean systemic filling pressure are topics that require further research. However, the haemodynamics do not totally explain the physiopathology of cellular dysoxia, and several factors such as inflammatory changes at the microcirculatory level can modify vascular resistance and tissue perfusion. Cellular vasoactive mediators and endothelial and glucocalix damage are also involved in microcirculatory impairment. All the levels of the circulatory system must be taken into account. Evaluation of microcirculation may help one to detect under-diagnosed shock, and together with classic haemodynamics, guide one towards the appropriate therapy. Restoration of classic haemodynamic parameters is essential but not sufficient to detect and treat patients in cardiovascular shock.

Perioperative Haemodynamic Optimisation.

During the latest years, a number of studies have confirmed the benefits of perioperative haemodynamic optimisation on surgical mortality and postoperative complication rate. This process requires the use of advanced haemodynamic monitoring with the purpose of guiding therapies to reach predefined goals. This review aim to present recent evidence on perioperative goal directed therapy (GDT), with an emphasis in some aspects that may merit further investigation. In order to maximise the benefits on outcomes, GDT must be implemented as early as possible; intravascular volume optimisation should be in accordance with the response of the preload-reserve, goals should be individualised and adequacy of the intervention must be also assessed; non-invasive or minimally invasive monitoring should be used and, finally, side effects of every therapy should be taken into account in order to avoid undesired complications. New drugs and technologies, particularly those exploring the venous side of the circulation, may improve in the future the effectiveness and facilitate the implementation of this group of therapeutic interventions.

Changes in the mean systemic filling pressure during a fluid challenge in postsurgical intensive care patients.

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.