Impact of Intravenous Fluid Challenge Infusion Time on Macrocirculation and Endothelial Glycocalyx in Surgical and Critically Ill Patients.
ABSTRACT: (i) Purpose. The fluid challenge (FC) is a well-established test of preload reserve. Only limited data exist in regard to the FC efficacy based on infusion time. Slow administration may be associated with lack of effect based on fluid redistribution and external conditions changes. On the contrary, fast administration may lead to brisk fluid overload and damage to the endothelium and endothelial glycocalyx (EG). The aim of this trial was to compare the FC infusion time on its hemodynamic effects and EG. (ii) Methods. Prospective randomized single-center trial of fast (5-10 minutes) versus slow (20-30 minutes) administration of 500ml balanced crystalloid FC in spinal surgery (cohort OR) and septic shock (cohort SEP) patients. Hemodynamic response was assessed using standard monitoring and blood flow measurements; damage to EG was assessed using the perfused boundary region (PBR) via intravital microscopy monitoring in the sublingual region within relevant time points ranging up to 120 minutes. (iii) Results. Overall, 66 FCs in 50 surgical and 16 septic patients were assessed. Fluid administration was associated with increase of PBR in general (1.9 (1.8-2.1) vs. 2.0 (1.8-2.2); p= 0.008). These changes were transient in OR cohort whereas they were long-lasting in septic fluid responders. The rate of fluid responsiveness after fast versus slow administration was comparable in global population (15 (47%) vs. 17 (50%); p=0.801) as well as in both cohorts. (iv) Conclusions. Fluid challenge administration was associated with increased PBR (and presumable EG volume changes) which normalized within the next 60 minutes in surgical patients but remained impeded in septic fluid responders. The fluid responsiveness rate after fast and slow FC was comparable, but fast administration tended to induce higher, though transient, response in blood pressure.
Project description:Septic shock is a clinical emergency that occurs in more than 230,000 US patients each year. OBSERVATIONS AND ADVANCES: In the setting of suspected or documented infection, septic shock is typically defined in a clinical setting by low systolic (?90 mm Hg) or mean arterial blood pressure (?65 mm Hg) accompanied by signs of hypoperfusion (eg, oliguria, hyperlactemia, poor peripheral perfusion, or altered mental status). Focused ultrasonography is recommended for the prompt recognition of complicating physiology (eg, hypovolemia or cardiogenic shock), while invasive hemodynamic monitoring is recommended only for select patients. In septic shock, 3 randomized clinical trials demonstrate that protocolized care offers little advantage compared with management without a protocol. Hydroxyethyl starch is no longer recommended, and debate continues about the role of various crystalloid solutions and albumin.The prompt diagnosis of septic shock begins with obtainment of medical history and performance of a physical examination for signs and symptoms of infection and may require focused ultrasonography to recognize more complex physiologic manifestations of shock. Clinicians should understand the importance of prompt administration of intravenous fluids and vasoactive medications aimed at restoring adequate circulation, and the limitations of protocol-based therapy, as guided by recent evidence.
Project description:Among critically ill adults, sepsis remains both common and lethal. In addition to antibiotics and source control, fluid resuscitation is a fundamental sepsis therapy. The physiology of fluid resuscitation for sepsis, however, is complex. A landmark trial found early goal-directed sepsis resuscitation reduced mortality, but 3 recent multicenter trials did not confirm this benefit. Multiple trials in resource-limited settings have found increased mortality with early fluid bolus administration in sepsis, and the optimal approach to early sepsis resuscitation across settings remains unknown. After initial resuscitation, excessive fluid administration may contribute to edema and organ dysfunction. Using dynamic variables such as passive leg raise testing can predict a patient's hemodynamic response to fluid administration better than static variables such as central venous pressure. Whether using measures of "fluid responsiveness" to guide fluid administration improves patient outcomes, however, remains unknown. New evidence suggests improved patient outcomes with the use of balanced crystalloids compared to saline in sepsis. Albumin may be beneficial in septic shock, but other colloids such as starches, dextrans, and gelatins appear to increase the risk of death and acute kidney injury. For the clinician caring for patients with sepsis today, the initial administration of 20 mL/kg of intravenous balanced crystalloid, followed by consideration of the risks and benefits of subsequent fluid administration represents a reasonable approach. Additional research is urgently needed to define the optimal dose, rate, and composition of intravenous fluid during the management of patients with sepsis and septic shock.
Project description:BACKGROUND:Fluid challenge (FC) is one of the most common practices in Intensive Care Unit (ICU). The present study aimed to evaluate whether echocardiographic assessment of the response to FC at the end of the infusion or 20?min later could affect the results of the FC. METHODS:This is a prospective, observational, multicenter study including all ICU patients in septic shock requiring a FC of 500?mL crystalloids over 10?min. Fluid responsiveness was defined as a >?15% increase in stroke volume (SV) assessed by velocity-time integral (VTI) measurements at baseline (T0), at the end of FC (T10), then 10 (T20) and 20?min (T30) after the end of FC. RESULTS:From May 20, 2014, to January 7, 2016, a total of 143 patients were enrolled in 11 French ICUs (mean age 64?±?14?years, median IGS II 53 [43-63], median SOFA score 10 [8-12]). Among the 76/143 (53%) patient responders to FC at T10, 37 patients were transient responders (TR), i.e., became non-responders (NR) at T30 (49%, 95%CI?=?[37-60]), and 39 (51%, 95%CI?=?[38-62]) patients were persistent responders (PR), i.e., remained responders at T30. Among the 67 NR at T10, 4 became responders at T30, (6%, 95%CI?=?[1.9-15.3]). In the subgroup analysis, no statistical difference in hemodynamic and echocardiographic parameters was found between groups. CONCLUSIONS:This study shows that 51.3% of initial responders have a persistent response to fluid 30?min after the beginning of fluid infusion and only 41.3% have a transient response highlighting that fluid responsiveness is time dependent. TRIAL REGISTRATION:ClinicalTrials.gov , NCT02116413 . Registered on April 16, 2014.
Project description:Cognitive dysfunction and delirium after ICU are frequent and may partially result from brain ischemia episodes. We hypothesized that systemic inflammation (severe sepsis or septic shock) modifies the control of brain circulation and the relation between systemic and cerebral hemodynamic after a positive response to fluid challenge (FC).Three groups of patients were studied if they increased stroke volume (SV)?>?10% after 250 or 500 ml of crystalloids: control group: patients free of comorbidity anesthetized for orthopedic surgery; sepsis group: patients with severe sepsis or septic shock (classic definition); brain injury (BI) group: trauma brain jury or hemorrhagic stroke with no detectable systemic inflammation. The measurements before and after FC were mean arterial blood pressure (MAP) (radial catheter); SV and cardiac output (CO; transesophageal Doppler); bilateral middle cerebral artery (MCAv) velocity with peak systolic (PSV) and end diastolic (EDV) values (transcranial Doppler); end-tidal CO2. The role of MAP increase was investigated by an arbitrarily threshold increase of 5%, called responder in CO and MAP (RR). The remaining patients were call responders in CO and non-responders in MAP (RnR). Nonparametric tests were used for statistical analysis.Among the 86 screened patients, 66 have completed the protocol: 17 in control group; 38 in sepsis group; and 11 in BI group. All patients increased SV?>?10% after FC. Only the sepsis group increased MAP [+?12 (2-25%), p?<?0.05] with a significant increase in PSV and EDV [(17 (3-30)% and 17 (12-42)%, respectively (p?<?0.05)], which did not change in the two other groups. The septic RR or RnR had similar variations in MCAv after FC. The baseline MAP < or > baseline median MAP had similar MCAv.After a FC-induced increase in SV, MCAv (PSV and EDV) increased only in septic group, mostly independently from MAP increase and from baseline MAP level. Cerebral perfusion becomes passively dependent on systemic blood flow, suggesting a modification of the control of cerebrovascular tone in sepsis-induced systemic inflammation. This information has been considered in the clinical management of septic patients.
Project description:Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC.2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59%, CI 57-61%). In 43% (CI 41-45%) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36%, CI 34-37%). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22%, CI 20-24%). No safety variable for the FC was used in 72% (CI 70-74%) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response.The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account.
Project description:The role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the microcirculation during severe sepsis.Prospective observational study on patients admitted in a 12-beds intensive care unit of a university hospital from July 2010 to December 2011, with severe sepsis and at least two sepsis-induced organ failures occurring within 48 hours from the onset of sepsis, who received an infusion of aPC (24 mcg/kg/h for 96 hours) (aPC group). Patients with contraindications to aPC administration were also monitored (no-aPC group).At baseline (before starting aPC infusion, T0), after 24 hours (T1a), 48 hours (T1b), 72 hours (T1c) and 6 hours after the end of aPC infusion (T2), general clinical and hemodynamic parameters were collected and the sublingual microcirculation was evaluated with sidestream dark-field imaging. Total vessel density (TVD), perfused vessel density (PVD), De Backer score, microvascular flow index (MFIs), the proportion of perfused vessels (PPV) and the flow heterogeneity index (HI) were calculated for small vessels. The perfused boundary region (PBR) was measured as an index of glycocalyx damage. Variables were compared between time points and groups using non parametric or parametric statistical tests, as appropriate.In the 13 aPC patients mean arterial pressure (MAP), base excess, lactate, PaO2/FiO2 and the Sequential Organ Failure Assessment (SOFA) score significantly improved over time, while CI and ITBVI did not change. MFIs, TVD, PVD, PPV significantly increased over time and the HI decreased (p < 0.05 in all cases), while the PBR did not change. No-aPC patients (n = 9) did not show any change in the microcirculation over time. A positive correlation was found between MFIs and MAP. TVD, PVD and De Backer score negatively correlated with norepinephrine dose, and the SOFA score negatively correlated with MFIs, TVD and PVD.aPC significantly improves the microcirculation in patients with severe sepsis/septic shock.NCT01806428.
Project description:Background:The aim of this study is to examine whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration could predict fluid responsiveness in septic shock patients following fluid challenge (FC). Methods:We reviewed prospectively collected data from 79 septic shock patients who received invasive cardiac output (CO) monitoring following a 500 mL FC. Haemodynamics were recorded, and blood sampling for NT-proBNP values was performed. Patients were divided into responders and non-responders according to fluid responsiveness, which was defined as cardiac index (CI) increase ?10% induced by FC. The NT-proBNP and the CI changes were analysed using Pearson correlation. The area under the curve (AUC) for NT-proBNP was used to test its ability to distinguish responders and non-responders. Subgroup analyses were also explored. Results:Among 79 patients, there were 55 responders. High NT-proBNP values were common in the study cohort. Baseline NT-proBNP values were comparable between responders and non-responders. In general, NT-proBNP values were not significantly correlated with CI changes after FC (r=-0.104, P=0.361). Similarly, the NT-proBNP baseline values could not identify responders to FC with an AUC of 0.508 (95% confidence interval, 0.369-0.647). This result was further confirmed in the subgroup analyses. Conclusions:Baseline NT-proBNP concentration value may not serve as an indicator of fluid responsiveness in patients with septic shock and should not be an indicator to withhold fluid loading.
Project description:OBJECTIVES/HYPOTHESIS:Oxymetazoline is an ?-adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are limited data on oxymetazoline pharmacokinetics in children who undergo general anesthesia. We assessed the hemodynamic effects and systemic absorption of topically applied oxymetazoline in children undergoing various nasal procedures. STUDY DESIGN:Prospective trial. METHODS:Children ages 2 to 17 years undergoing functional endoscopic sinus surgery, turbinate resection, or adenoidectomy were enrolled. The surgeon placed oxymetazoline-soaked pledgets (1.5 mL of 0.05% solution) according to our usual clinical practice. Blood samples for oxymetazoline assay were drawn at 5, 10, 20, 45, 90, and 150 minutes, and hemodynamic data were recorded at 5-minute intervals. Data analysis included mixed-effects regression and population pharmacokinetic/pharmacodynamic modeling. RESULTS:The analysis included 27 patients, age 7 ± 4 years, who received between 2 and 12 pledgets (3-18 mL) of oxymetazoline. Relative bioavailability compared to the spray formulation was 2.3 (95% confidence interval [CI]: 1.6-3.2), with slow absorption from the mucosal surface (absorption half-life 64 minutes; 95% CI: 44-90). Mean arterial pressure did not increase with oxymetazoline instillation at the observed oxymetazoline serum concentrations (0.04-7.6 ?g/L). CONCLUSIONS:Despite concerns regarding oxymetazoline administration to mucosal membranes, we found that hemodynamic changes were clinically negligible with our usual clinical use of pledgets soaked in oxymetazoline. Compared to data on oxymetazoline in spray formulation, bioavailability was increased twofold with pledgets, but systemic absorption was very slow, contributing to low serum concentrations and limited hemodynamic effects. LEVEL OF EVIDENCE:1b. Laryngoscope, 129:2775-2781, 2019.
Project description:BACKGROUND:Improving sepsis support is one of the three pillars of a 2017 resolution according to the World Health Organization (WHO). Septic shock is indeed a burden issue in the intensive care units. Hemodynamic stabilization is a cornerstone element in the bundle of supportive treatments recommended in the Surviving Sepsis Campaign (SSC) consecutive biannual reports. MAIN BODY:The "Pandera's box" of septic shock hemodynamics is an eternal debate, however, with permanent contentious issues. Fluid resuscitation is a prerequisite intervention for sepsis rescue, but selection, modalities, dosage as well as duration are subject to discussion while too much fluid is associated with worsen outcome, vasopressors often need to be early introduced in addition, and catecholamines have long been recommended first in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has come out. Preservation of the macrocirculation through a "best" mean arterial pressure target is the actual priority but is still contentious. Microcirculation recruitment is a novel goal to be achieved but is claiming more knowledge and monitoring standardization. Protection of the cardio-renal axis, which is prevalently injured during septic shock, is also an unavoidable objective. Several promising alternative or additive drug supporting avenues are emerging, trending toward catecholamine's sparing or even "decatecholaminization." Topics to be specifically addressed in this review are: (1) mean arterial pressure targeting, (2) fluid resuscitation, and (3) hemodynamic drug support. CONCLUSION:Improving assessment and means for rescuing hemodynamics in early septic shock is still a work in progress. Indeed, the bigger the unresolved questions, the lower the quality of evidence.
Project description:BACKGROUND:The endothelial glycocalyx (eGC) covers the luminal surface of the vascular endothelium and plays an important protective role in systemic inflammatory states and particularly in sepsis. Its breakdown leads to capillary leak and organ dysfunction. Moreover, sepsis-induced alterations of sublingual microcirculation are associated with a worse clinical outcome. The present study was performed to investigate the associations between eGC dimensions and established parameters of microcirculation dysfunction in sepsis. METHODS:This observational, prospective, cross-sectional study included 40 participants, of which 30 critically ill septic patients were recruited from intensive care units of a university hospital and 10 healthy volunteers served as controls. The established microcirculation parameters were obtained sublingually and analyzed according to the current recommendations. In addition, the perfused boundary region (PBR), an inverse parameter of the eGC dimensions, was measured sublingually, using novel data acquisition and analysis software (GlycoCheck™). Moreover, we exposed living endothelial cells to 5% serum from a subgroup of study participants, and the delta eGC breakdown, measured with atomic force microscopy (AFM), was correlated with the paired PBR values. RESULTS:In septic patients, sublingual microcirculation was impaired, as indicated by a reduced microvascular flow index (MFI) and a reduced proportion of perfused vessels (PPV) compared to those in healthy controls (MFI, 2.93 vs 2.74, p?=?0.002; PPV, 98.53 vs 92.58, p?=?0.0004). PBR values were significantly higher in septic patients compared to those in healthy controls, indicating damage of the eGC (2.04 vs 2.34, p?<?0.0001). The in vitro AFM data correlated exceptionally well with paired PBR values obtained at the bedside (rs?=?-?0.94, p?=?0.02). Both PBR values and microcirculation parameters correlated well with the markers of critical illness. Interestingly, no association was observed between the PBR values and established microcirculation parameters. CONCLUSION:Our findings suggest that eGC damage can occur independently of microcirculatory impairment as measured by classical consensus parameters. Further studies in critically ill patients are needed to unravel the relationship of glycocalyx damage and microvascular impairment, as well as their prognostic and therapeutic importance in sepsis. TRIAL REGISTRATION:Retrospectively registered: Clinicaltrials.gov, NCT03960307.