Effects of Fluid Therapy on Mesenteric Microcirculation Using New Probe-Based Confocal Laser Endomicroscopy (Cellvizio®) in a Porcine Model of Endotoxic Shock.

BACKGROUND: Microcirculatory alterations have been observed at the early phase of sepsis, although macrocirculation seems preserved. The aim of this study was to analyze the effect of crystalloid fluid therapy on mesenteric microcirculation, assessed by using the confocal laser endomicroscope Cellvizio®, in an endotoxic porcine model. METHODS: It is a prospective endotoxic shock (lipopolysaccharide infusion) experimental trial. Piglets were divided into 3 groups: 6 in the sham group (no LPS injection, no fluid), 9 in the control group (LPS infusion, no fluid), and 6 in the crystalloids group (LPS infusion and fluid resuscitation with crystalloids). Fluid resuscitation consisted in a fluid bolus of 20 mL/kg 0.9% saline over 30 min followed by a 10 mL/kg/h fluid rate over 4 h. Mesenteric microcirculation was assessed using a confocal laser endomicroscope (Cellvizio®). Blood flow within capillaries was visually assessed according to the point of care microcirculation (POEM) score. RESULTS: At baseline, the 3 groups were similar regarding hemodynamic, biological, and microcirculatory parameters. At T360, the POEM score significantly decreased in the control and crystalloids groups, whereas it remained unchanged in the sham group (respectively, 1.62 ± 1.06, 1.2 ± 0.45, and 5.0 ± 0, p = 0.011). There was no significant difference in cardiac output at T360 between the sham and crystalloids groups (3.1 ± 0.8 vs. 2.3 ± 0.6, p = 0.132) or between the control and crystalloids groups (2.0 ± 0.6 vs. 2.3 ± 0.6, p = 0.90). CONCLUSION: There was no significant improvement of microcirculatory alterations after crystalloids resuscitation despite improvement in macrocirculatory parameters in early experimental sepsis.

Micafungin Population PK Analysis in Healthy and Septic Pigs: Can the Septic Porcine Model Predict the Micafungin PK in Septic Patients?

OBJECTIVES: To describe micafungin pharmacokinetic (PK) alterations of sepsis induced in piglets and to determine whether the porcine septic model is able to predict the PK of micafungin in septic patients at the plasma and peritoneal sites. METHODS: From healthy (n = 8) and septic piglet group (n = 16), total micafungin concentrations were subject to a population PK analysis using Monolix®. Data from 16 septic humans patients from others studies was used to compare micafungin PK between septic piglets and septic patients. RESULTS: Sepsis induced in piglets slightly alters the total clearance and the volume of distribution, while inter-compartment clearance is increased (from 3.88 to 5.74 L/h) as well as the penetration into peritoneal cavity (from 61 to 90%). In septic human patients, PK parameters are similar except for the Vd, which is corrected by an allometric factor based on the body weight of each species. Micafungin penetration into peritoneal cavity of humans is lower than in septic piglets (40 versus 90%). CONCLUSIONS: The sepsis induced in the porcine model alters the PK of micafungin comparable to that in humans. In addition, micafungin PK is similar between these two species at the plasma level taking into account the allometric relationship of the body weight of these species on the central volume of distribution. The porcine septic plasma model would be able to predict the micafungin PK in the septic patients. However, further studies on peritoneal penetration are necessary to characterize this inter-species difference.

Does the infusion rate of fluid affect rapidity of mean arterial pressure restoration during controlled hemorrhage.

OBJECTIVE: This study aimed to compare 2 fluid infusion rates of lactated Ringer (LR) and hydroxyethyl starch (HES) 130/0.4 on hemodynamic restoration at the early phase of controlled hemorrhagic shock. METHODS: Fifty-six anesthetized and ventilated piglets were bled until mean arterial pressure (MAP) reached 40 mm Hg. Controlled hemorrhage was maintained for 30 minutes. After this period, 4 resuscitation groups were studied (n=14 for each group): HES infused at 1 or 4mL/kg per minute or LR1 infused at 1 or 4mL/kg per minute until baseline MAP was restored. Hemodynamic assessment using PiCCO monitoring and biological data were collected. RESULTS: Time to restore baseline MAP ±10% was significantly lower in LR4 group (11±11 minutes) compared to LR1 group (41±25 minutes) (P=.0004). Time to restore baseline MAP ±10% was significantly lower in HES4 group (4±3 minutes) compared to HES1 (11±4 minutes) (P=.0003). Time to restore baseline MAP ±10% was significantly lower with HES vs LR whatever the infusion rate. No statistically significant difference was observed in cardiac output, central venous saturation, extravascular lung water, and arterial lactate between 4 and 1 mL/kg per minute groups. CONCLUSIONS: In this controlled hemorrhagic shock model, a faster infusion rate (4 vs 1mL/kg per minute) significantly decreased the time for restoring baseline MAP, regardless of the type of infused fluid. The time for MAP restoration was significantly shorter for HES as compared to LR whatever the fluid infusion rate.

Assessment of neutrophil gelatinase-associated lipocalin in the brain-dead organ donor to predict immediate graft function in kidney recipients: a prospective, multicenter study.

BACKGROUND: Delayed graft function is a major determinant of long-term renal allograft survival. Despite considerable efforts to improve donor selection and matching, incidence of delayed graft function remains close to 25%. As neutrophil gelatinase-associated lipocalin (NGAL) has been shown to predict acute renal failure, the authors tested the hypothesis that NGAL measurement in brain-dead donors predicts delayed graft function in kidney recipients. METHODS: In a prospective, multicenter, observational study, serum NGAL was measured in donors at the time of transfer to operating room. The primary endpoint was the delayed graft function, defined as the need for renal replacement therapy during the first week posttransplantation. RESULTS: Among 159 included brain-dead donors, 146 were analyzable leading to 243 renal transplantations. Of these, 56 (23%) needed renal replacement therapy. Donors' NGAL values were similar in case of both delayed and normal graft function in recipients. The area under the receiver-operating curve for NGAL to predict the need for renal replacement therapy before day 8 was 0.50 (95% CI, 0.42 to 0.59). The area under curve for NGAL to predict failure to return to a normal graft function at day 8 was 0.51 (95% CI, 0.44 to 0.59). Using multivariate analysis, NGAL was not associated to the need for renal replacement therapy (odds ratio, 0.99; 95% CI, 0.98 to1.00) or failure to return to a normal graft function at day 8 (odds ratio, 1.00; 95% CI, 0.99 to 1.00). CONCLUSION: NGAL measurement in brain-dead donors at the time of recovery failed to predict delayed or normal graft function in kidney recipients.

Respiratory variations of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious use.

INTRODUCTION: To investigate whether respiratory variation of inferior vena cava diameter (cIVC) predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure (ACF). METHODS: Forty patients with ACF and spontaneous breathing were included. Response to fluid challenge was defined as a 15% increase of subaortic velocity time index (VTI) measured by transthoracic echocardiography. Inferior vena cava diameters were recorded by a subcostal view using M Mode. The cIVC was calculated as follows: (Dmax - Dmin/Dmax) × 100 and then receiver operating characteristic (ROC) curves were generated for cIVC, baseline VTI, E wave velocity, E/A and E/Ea ratios. RESULTS: Among 40 included patients, 20 (50%) were responders (R). The causes of ACF were sepsis (n = 24), haemorrhage (n = 11), and dehydration (n = 5). The area under the ROC curve for cIVC was 0.77 (95% CI: 0.60-0.88). The best cutoff value was 40% (Se = 70%, Sp = 80%). The AUC of the ROC curves for baseline E wave velocity, VTI, E/A ratio, E/Ea ratio were 0.83 (95% CI: 0.68-0.93), 0.78 (95% CI: 0.61-0.88), 0.76 (95% CI: 0.59-0.89), 0.58 (95% CI: 0.41-0.75), respectively. The differences between AUC the ROC curves for cIVC and baseline E wave velocity, baseline VTI, baseline E/A ratio, and baseline E/Ea ratio were not statistically different (p = 0.46, p = 0.99, p = 1.00, p = 0.26, respectively). CONCLUSION: In spontaneously breathing patients with ACF, high cIVC values (>40%) are usually associated with fluid responsiveness while low values (< 40%) do not exclude fluid responsiveness.

An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study.

BACKGROUND: Predicting fluid responsiveness remains a difficult question in hemodynamically unstable patients. The author's objective was to test whether noninvasive assessment by transthoracic echocardiography of subaortic velocity time index (VTI) variation after a low volume of fluid infusion (100 ml hydroxyethyl starch) can predict fluid responsiveness. METHODS: Thirty-nine critically ill ventilated and sedated patients with acute circulatory failure were prospectively studied. Subaortic VTI was measured by transthoracic echocardiography before fluid infusion (baseline), after 100 ml hydroxyethyl starch infusion over 1 min, and after an additional infusion of 400 ml hydroxyethyl starch over 14 min. The authors measured the variation of VTI after 100 ml fluid (ΔVTI 100) for each patient. Receiver operating characteristic curves were generated for (ΔVTI 100). When available, receiver operating characteristic curves also were generated for pulse pressure variation and central venous pressure. RESULTS: After 500 ml volume expansion, VTI increased ≥ 15% in 21 patients (54%) defined as responders. ΔVTI 100 ≥ 10% predicted fluid responsiveness with a sensitivity and specificity of 95% and 78%, respectively. The area under the receiver operating characteristic curves of ΔVTI 100 was 0.92 (95% CI: 0.78-0.98). In 29 patients, pulse pressure variation and central venous pressure also were available. In this subgroup of patients, the area under the receiver operating characteristic curves for ΔVTI 100, pulse pressure variation, and central venous pressure were 0.90 (95% CI: 0.74-0.98, P < 0.05), 0.55 (95% CI: 0.35-0.73, NS), and 0.61 (95% CI: 0.41-0.79, NS), respectively. CONCLUSION: In patients with low volume mechanical ventilation and acute circulatory failure, ΔVTI 100 accurately predicts fluid responsiveness.

Disagreement between pulse contour analysis and transpulmonary thermodilution for cardiac output monitoring after routine therapeutic interventions in ICU patients with acute circulatory failure.

BACKGROUND AND OBJECTIVE: The present prospective study was aimed at assessing the reliability of the pulse contour method for measuring cardiac output (CO) after different routinely used therapeutic interventions that can influence vascular compliance and systemic vascular resistances in ICU patients (fluid challenges, changes in norepinephrine or dobutamine infusion rates and changes in ventilatory settings). METHODS: In ICU patients requiring CO monitoring, transpulmonary thermodilution CO (COTD) and pulse contour CO (COPC) were measured with a PiCCO device after therapeutic manoeuvre-free periods (≤ and >1 h) and after therapeutic interventions without recalibration. RESULTS: Three hundred fifty-two sets of CO measurement pairs in 63 ICU patients were performed. The biases (and percentage errors) between COPC and COTD for the overall paired measurement, therapeutic manoeuvre-free periods and therapeutic manoeuvres were 0.20 ± 1.09 (33%), -0.01 ± 0.93 (29%) and 0.37 ± 1.18 (34%), respectively. The percentage errors were 36 and 39% for fluid challenges and changes in norepinephrine infusion rate, respectively. CONCLUSION: In ICU patients requiring therapeutic interventions, COPC is frequently in disagreement with COTD.

Reversal of bupivacaine-induced cardiac electrophysiologic changes by two lipid emulsions in anesthetized and mechanically ventilated piglets.

BACKGROUND: Accidental IV administration of bupivacaine can compromise cardiovascular function by inducing lethal arrhythmias whose hemodynamic consequences may be alleviated by lipid emulsions. However, little is known about the electrophysiologic effects of lipid emulsions. In this study, we assessed whether 2 different lipid emulsions can reverse cardiac electrophysiologic impairment induced by the IV administration of bupivacaine in anesthetized and mechanically ventilated piglets. METHODS: Bupivacaine (4 mg . kg(-1)) was injected over a 30-second period in 26 piglets. Thirty seconds after the end of bupivacaine injection, 1.5 mL . kg(-1) saline solution for the control group, and long-chain triglyceride emulsion (LCT group) or a mixture of long-chain and medium-chain triglyceride emulsion (LCT/MCT group) were infused over 1 minute. Cardiac conduction variables and hemodynamic variables were monitored for 30 minutes after injection. RESULTS: Bupivacaine induced similar electrophysiologic and hemodynamic changes. After 3 minutes, His ventricle intervals (median and interquartiles) were 100 (85-105), 45 (35-55), and 53 (48-73) milliseconds in the control, LCT, and LCT/MCT groups, respectively (P < 0.001 between control and both lipid emulsion groups). Lipid emulsions also reversed the effects on QRS duration, atrial-His, and PQ (the onset of the P wave to the Q wave of the QRS complex) intervals. LCT/MCT emulsion restored the decrease in maximal first derivative of left ventricular pressure (P < 0.01 after 3 minutes versus control group). CONCLUSIONS: LCT and LCT/MCT emulsions reversed the lengthening of His ventricle, QRS, atrial-His, and PQ intervals induced by the IV injection of 4 mg . kg(-1) bupivacaine.

A New Echocardiographic Tool for Cardiac Output Evaluation: An Experimental Study.

BACKGROUND: The correlation between cardiac output (CO) evaluated by echocardiography and CO measured by thermodilution (COth) varies according to different studies. A new transthoracic echocardiography (TTE) tool allows automatic calculation of the subaortic velocity time index (VTIauto) and CO (COauto). The main objective was to evaluate the correlation between COth and COauto in an anesthetized, ventilated piglet hemorrhagic shock (HS) model. The secondary objectives were to evaluate the correlation between COth and CO evaluated by manual measurements of VTI, and the preload-dependency of VTIvaresp. METHODS: Eighteen piglets were bled until mean arterial pressure reached 40 mm Hg. Controlled hemorrhage was maintained for 30 min before a resuscitation phase. CO was measured by Pulse index Contour Cardiac Output thermodilution methods. At each time of the experiment, three VTI values were measured (min, med, max) and the average value was calculated. COs were calculated by TTE (COmax, COmed, COmin, COave). RESULTS: For the 204 measures attempted, the success rate was 197 (97%) manually and 122 (60%) automatically (P < 0.01). The correlation coefficients (r) between COth and, respectively, COauto, COave, COmax, COmed, and COmin were: 0.83 (95% CI [0.76; 0.88]; P < 0.01), 0.54 (95% CI [0.43; 0.63]; P < 0.01), 0.43 (95% CI [0.31; 0.54]; P < 0.01), 0.58 (95% CI [0.48; 0.67]; P < 0.01), and 0.52 (95% CI [0.41; 0.62]; P < 0.01). CONCLUSION: In an experimental model of HS, a new ultrasound tool, COauto, seems better correlated with COth than manual echocardiographic measurements.

The intrathoracic blood volume index as an indicator of fluid responsiveness in critically ill patients with acute circulatory failure: a comparison with central venous pressure.

BACKGROUND: The intrathoracic blood volume index (ITBVI) and central venous pressure (CVP) are routinely used to predict fluid responsiveness in critically ill patients with acute circulatory failure (systolic blood pressure < 90 mm Hg or vasopressor requirement). However, they have never been compared. METHODS: In this prospective interventional study, we included 35 (21 men) mechanically ventilated and sedated patients with acute cardiovascular failure requiring cardiac output measurement (transpulmonary thermodilution technique). Fluid responsiveness was defined as an increase in stroke index (cardiac output/heart rate/body surface area) > or =15%. Receiver operating characteristic curves were generated for ITBVI and CVP. RESULTS: Fluid challenge induced a stroke index increase > or =15% in 18 (51%) patients (responders). At baseline, no studied hemodynamic variables were different between responders and nonresponders. The areas under the receiver operating characteristic curves were 0.64 [95% CI: 0.46-0.80] for ITBVI and 0.68 [95% CI: 0.50-0.83] for CVP, without any statistical difference (P = 0.73). The best cut-off values for CVP and ITBVI were 9 mm Hg (sensitivity = 61%; specificity = 82%) and 928 mL . m(-2) (sensitivity = 78%; specificity = 53%). CONCLUSION: ITBVI is similar to CVP in its ability to predict fluid responsiveness in critically ill patients with acute circulatory failure.

The influence of the airway driving pressure on pulsed pressure variation as a predictor of fluid responsiveness.

OBJECTIVE: Assessing pulse pressure variation (PPV) to predict fluid responsiveness in mechanically ventilated patients with tidal volume (VT) and the impact of VT and airway driving pressure (P(plat) - PEEP) on the ability of PPV for predicting fluid responsiveness. DESIGN: Prospective interventional study. SETTING: ICU of a university hospital. PATIENTS: Fifty-seven mechanically ventilated and sedated patients with acute circulatory failure requiring cardiac output (CO) measurement. INTERVENTION: Fluid challenge was given in patients with signs of hypoperfusion (oliguria <0.5 ml kg(-1) h(-1), attempt to decrease vasopressor infusion rate). Fluid responsiveness was defined as an increase in the stroke index (SI) >or=15%. Receiver-operating characteristic (ROC) curves were generated for PPV and central venous pressure (CVP). RESULTS: The stroke index was increased >or=15% in 41 patients (71%). At baseline, CVP was lower and PPV was higher in responders. The areas under the ROC curves of PPV and CVP were 0.77 (95% CI 0.65-0.90) and 0.76 (95% CI 0.64-0.89), respectively (P = 0.93). The best cutoff values of PPV and CVP were 7% and 9 mmHg, respectively. In 30 out of 41 responders, PPV was <13%. Using a polytomic logistic regression (P(plat)--PEEP) was the sole independent factor associated with a PPV value <13% in responders. In these responders, (P(plat)--PEEP) was