A multimodal tissue perfusion measurement approach for the evaluation of the effect of pimobendan, an inodilator, in a porcine sepsis model.

Sepsis is associated with hypoperfusion and organ failure. The aims of the study were: 1) to assess the effect of pimobendan on macrocirculation and perfusion and 2) to describe a multimodal approach to the assessment of perfusion in sepsis and compare the evolution of the perfusion parameters. Eighteen anaesthetized female piglets were equipped for macrocirculation monitoring. Sepsis was induced by an infusion of Pseudomonas aeruginosa. After the occurrence of hypotension, animals were resuscitated. Nine pigs received pimobendan at the start of resuscitation maneuvers, the others received saline. Tissue perfusion was assessed using temperature gradients measured with infrared thermography (TG = core temperature - tarsus temperature), urethral perfusion index (uPI) derived from photoplethysmography and sublingual microcirculation (Sidestream dark field imaging device): De Backer score (DBs), proportion of perfused vessels (PPV), microvascular flow index (MFI) and heterogeneity index (HI). Arterial lactate and ScvO2 were also measured. Pimobendan did not improve tissue perfusion nor macrocirculation. It did not allow a reduction in the amount of noradrenaline and fluids administered. Sepsis was associated with tissue perfusion disorders: there were a significant decrease in uPI, PPV and ScvO2 and a significant rise in TG. TG could significantly predict an increase in lactate. Resuscitation was associated with a significant increase in uPI, DBs, MFI, lactate and ScvO2. There were fair correlations between the different perfusion parameters. In this model, pimobendan did not show any benefit. The multimodal approach allowed the detection of tissue perfusion alteration but only temperature gradients predicted the increase in lactatemia.

A new photoplethysmographic device for continuous assessment of urethral mucosa perfusion: evaluation in a porcine model.

This study proposes to evaluate an innovative device consisting of an indwelling urinary catheter equipped with a photoplethysmography (PPG) sensor in contact with the urethral mucosa that provides a continuous index called urethral perfusion index (uPI). The goal of this study was to determine if the uPI could bring out tissue perfusion modifications induced by hypotension and vasopressors in a porcine model. Twelve piglets were equipped for heart rate, MAP, cardiac index, stroke volume index, systemic vascular resistance index and uPI monitoring. The animals were exposed to different levels of mean arterial pressure (MAP), ranging from low to high values. Friedman tests with a posteriori multiple comparison were performed and a generalized linear mixed model (GLMM) was used to assess the relationship between uPI and MAP. Urethral Perfusion Index and other haemodynamic parameters varied significantly at the different time-points of interest. There was a positive correlation between MAP and uPI below a specific MAP value, called dissociation threshold (DT). Above this threshold, uPI and MAP were negatively correlated. This relationship, assessed with the GLMM, yielded a significant positive fixed effect coefficient (+ 0.2, P < 0.00001) below the DT and a significant negative fixed effect (- 0.14, P < 0.00001) above DT. In an experimental setting, the PPG device and its index uPI permitted the detection of urethral mucosa perfusion alterations associated with hypotension or excessive doses of vasopressors. Further studies are needed to evaluate this device in a clinical context.

Gut and sublingual microvascular effect of esmolol during septic shock in a porcine model.

INTRODUCTION: Esmolol may efficiently reduce heart rate (HR) and decrease mortality during septic shock. An improvement of microcirculation dissociated from its macrocirculatory effect may a role. The present study investigated the effect of esmolol on gut and sublingual microcirculation in a resuscitated piglet model of septic shock. METHODS: Fourteen piglets, anesthetized and mechanically ventilated, received a suspension of live Pseudomonas aeruginosa. They were randomly assigned to two groups: the esmolol (E) group received an infusion of esmolol, started at 7.5 µg⋅kg(-1)⋅min(-1), and progressively increased to achieve a HR below 90 beats⋅min(-1). The control (C) group received an infusion of Ringer's lactate solution. HR, mean arterial pressure (MAP), cardiac index (CI), stroke index (SI), systemic vascular resistance (SVR), arterio-venous blood gas and lactate were recorded. Oxygen consumption (VO2), delivery (DO2) and peripheral extraction (O2ER) were computed. Following an ileostomy, a laser Doppler probe was applied on ileal mucosa to monitor gut microcirculatory laser Doppler flow (GMLDF). Videomicroscopy was also used on ileal mucosa and sublingual areas to evaluate mean flow index (MFI), heterogeneity, ratio of perfused villi and proportion of perfused vessels. Resuscitation maneuvers were performed following a defined algorithm. RESULTS: Bacterial infusion induced a significant alteration of the gut microcirculation with an increase in HR. Esmolol produced a significant time/group effect with a decrease in HR (P <0.004) and an increase in SVR (P <0.004). Time/group effect was not significant for CI and MAP, but there was a clear trend toward a decrease in CI and MAP in the E group. Time/group effect was not significant for SI, O2ER, DO2, VO2, GMLDF and lactate. A significant time/group effect of ileal microcirculation was found with a lower ileal villi perfusion (P <0.025) in the C group, and a trend toward a better MFI in the E group. No difference between both groups was found regarding microcirculatory parameters in the sublingual area. CONCLUSIONS: Esmolol provided a maintenance of microcirculation during sepsis despite its negative effects on macrocirculation. Some parameters even showed a trend toward an improvement of the microcirculation in the gut area in the esmolol group.

A new device for continuous assessment of gut perfusion: proof of concept on a porcine model of septic shock.

INTRODUCTION: We evaluate an innovative device consisting of an enteral feeding tube equipped with a photoplethysmography (PPG) sensor in contact with the duodenal mucosa. This study aims to determine if the PPG signal, composed of a continuous (PDC) and a pulsatile part (PAC), is a reliable method to assess gut perfusion in a porcine model of septic shock. METHOD: Fourteen piglets were anesthetized and mechanically ventilated. They were randomly assigned to two groups: the nonseptic (NS) group received an infusion of Ringer's lactate solution (RL) alone, the septic (S) group received in addition a suspension of live Pseudomonas aeruginosa. Heart rate (HR), pulse oximetry (SpO2), mean arterial pressure (MAP), cardiac index (CI) and serum lactates were recorded and gut microcirculation (GM) was monitored with a laser Doppler probe applied on the duodenal serosa. PDC and PAC were given by the PPG probe inserted in the duodenum. Data was collected every 15 minutes (t0, t15…) during 150 minutes (t150). After administration of the bacteria suspension (t0), resuscitation maneuvers were performed following a defined algorithm. GM PAC, and PDC were expressed as variation from baseline (GMvar, PACvar, PDCvar). Analysis of variance (ANOVA) with repeated measures was performed to compare hemodynamic variables, with Bonferroni correction as post hoc analysis on t0, t60 and t150. RESULTS: One piglet was withdrawn from analysis due to a defective probe. S group (six piglets) received resuscitation therapy while NS group (seven piglets) did not. A significant group effect was found for the all parameters except HR. Post hoc analysis found a significant decrease for GM and PAC at t60. The correlation between PAC, PDC and microcirculatory parameters were as follows: rPACvar-GMvar = 0.496, P <0.001, rPDCvar-GMvar = 0.244; P = 0.002. In the septic group, correlations were as follows: rPAC-lactate = -0.772, P <0.001; rPDC-lactate = -0.681, P <0.01). At the onset of shock, a decrease of PAC, PDC and GM occurred before the alteration of MAP. CONCLUSIONS: PAC and PDC decreased at the onset of shock and were correlated with GM and lactate. These results confirm that PPG signal reliably reflects the early perfusion alteration of the gut. Further studies should assess the clinical use of this device.

Feasibility study and direct extraction of endogenous free metallic cations combining hemodialysis and chelating polymer.

In this article, we report the conception and the use of dialysis-based medical device for the extraction of metals. The medical device is obtained by addition in the dialysate of a functionalized chitosan that can chelate endogenous metals like iron or copper. This water-soluble functionalized chitosan is obtained after controlled reacetylation and grafting of DOTAGA. Due to the high mass of chitosan, the polymer cannot cross through the membrane and the metals are trapped in the dialysate during hemodialysis. Copper extraction has been evaluated in vitro using an hemodialysis protocol. Feasibility study has been performed on healthy sheep showing no acute toxicity througout the entire dialysis procedure and first insights of metallic extraction even on healthy animals.

Use of infrared thermography to detect early alterations of peripheral perfusion: evaluation in a porcine model.

This study aimed to evaluate the variations of infrared thermography according to rapid hemodynamic changes, by measuring the peripheral skin temperature in a porcine model. Eight healthy piglets were anesthetized and exposed to different levels of arterial pressure. Thermography was performed on the left forelimb to measure carpus and elbow skin temperature and their associated gradient with the core temperature. Changes in skin temperature in response to variations of blood pressure were observed. A negative correlation between arterial pressure and temperature gradients between peripheral and core temperature and a negative correlation between cardiac index and these temperature gradients were observed. Thermography may serve as a tool to detect early changes in peripheral perfusion.

Hematological and Hemostatic Alterations Associated With a Single Extracorporeal Renal Replacement Therapy in Dogs With Acute Kidney Injury Associated Leptospirosis: A Pilot Study.

Extracorporeal renal replacement therapy (ERRT) used in dogs with acute kidney injury (AKI) may be associated with hematological and hemostatic disorders. However, its characteristics are not fully described in dogs. The purpose of this pilot study was to characterize the impact of ERRT on hematological, hemostatic, and thromboelastometric parameters in dogs with AKI. We conducted a prospective observational single cohort study in 10 client-owned dogs with AKI associated leptospirosis undergoing ERRT. Results from the CBC, coagulation tests (prothrombin and activated partial thromboplastin times [aPTT]) and rotational thromboelastometry (TEM; intrinsic TEM [inTEM] and heparinase-based TEM [hepTEM]) were recorded before and after the first ERRT session. Blood abnormalities observed before the ERRT session included thrombocytopenia (10/10), anemia (8/10), leukocytosis (4/10), prolonged aPTT (4/10) and leukopenia (1/10). After ERRT, the platelet count decreased (-25%; P = .012) whereas leukocytes (+15%; P = .046) and aPTT (+24%; P = .006) increased. The clotting time (CT) on inTEM assay and the relative variation of CT based on inTEM and hepTEM profiles increased after the ERRT session (P = .037 and P = .048, respectively). Seven dogs, 2 dogs, and 1 dog were defined as having a normal, hypocoagulable, and hypercoagulable inTEM profile after ERRT, respectively. After ERRT, no hepTEM parameter was significantly different from before treatment. Platelet count, leukocytes, aPTT and CT were altered after the first ERRT session. Beyond the hemostatic abnormalities expected by the use of UFH, thrombocytopenia appears as the only hemostatic change after a single ERRT session in dogs with AKI.

Acute kidney injury management using intermittent low efficiency haemodiafiltration in a critical care unit: 39 dogs (2012-2015).

BACKGROUND: Veterinary studies describing acute kidney injury (AKI) management using renal replacement therapy (RRT) are limited and have primarily focused on intermittent haemodialysis in North American populations. European data are lacking, although differences in populations, pathogen and toxin exposure and RRT modalities may exist between Europe and North America. The present study reviewed RRT-managed cases from the intensive care unit (ICU) of VetAgro Sup, Lyon, France, for the period 2012-2015. The aims were to describe a 4-h RRT protocol of intermittent low efficiency haemodiafiltration, population characteristics and outcomes in canine AKI cases requiring RRT and to identify prognostic variables. We defined DeltaCreat/h as the difference between the serum creatinine level after RRT treatment N and that before treatment N + 1 divided by the time between treatments (in hours). RESULTS: Thirty-nine dogs were included, and 67% were males. The median (range) age, weight, hospitalization length and number of RRT treatments were 4.4 (0.25-15) years, 26.6 (6.7-69) kg, 8 (1-23) days and 3 (1-8) treatments, respectively. The main AKI causes were leptospirosis (74.4%) and nephrotoxins (15.4%). Age (4.0 vs 5.4 years; P = 0.04), admission urine output (0.5 mL/kg/h vs 0 mL/kg/h; P = 0.02) and hospitalization length (10 vs 4 days; P < 0.001) differed between survivors and non-survivors. Hospitalization length [odds ratio (OR) = 0.4], number of treatments (OR = 5.1), serum potassium level on day 2 (OR = 1.9), DeltaCreat/h between the first and second treatments (OR = 1.2), and UOP during hospitalization (OR = 0.2) were correlated with outcome. The main causes of death were euthanasia (44%) and haemorrhagic diatheses (33%). The overall survival rate was 54%, with 55% of survivors discharged with a median creatinine < 240 µmol/L. CONCLUSIONS: This is the first description in the veterinary literature of a 4-h protocol of intermittent low efficiency haemodiafiltration to provide RRT in a veterinary critical care unit. While this protocol appears promising, the clinical application of this protocol requires further investigation. Among parameters associated with survival, UOP and DeltaCreat/h between the first and second RRT treatments may be prognostic indicators. The applicability of these parameters to other populations is unknown, and further international, multicentre prospective studies are warranted to confirm these preliminary observations.

Effects of esmolol on systemic hemodynamics and heart rate variability measured using the Analgesia/Nociception Index in resuscitated piglets with Pseudomonas aeruginosa septic shock.

OBJECTIVE: To determine the effects of esmolol on hemodynamics and heart rate variability (HRV) in the early stage of sepsis. DESIGN: Prospective, randomized, controlled, parallel trial. SETTINGS: Veterinary research laboratory. ANIMALS: Ten anesthetized piglets. INTERVENTIONS: Septic shock was induced by infusing a suspension of live Pseudomonas aeruginosa IV in 10 anesthetized piglets. The piglets were resuscitated according to a standardized protocol using Ringer's lactate solution, norepinephrine, and milrinone. Once stabilized, the piglets were randomized to receive IV esmolol, titrated to a heart rate <90/min, or control, receiving saline. A pulmonary artery catheter and an arterial catheter were inserted for hemodynamic measurements. The Analgesia/Nociception Index (ANI) and the normalized HRV frequency domain parameters - high-frequency (HF), low frequency (LF), LF/HF ratio - were recorded using a proprietary monitor. MEASUREMENTS AND MAIN RESULTS: A significant decrease in cardiac output and heart rate, and a significant increase in systemic vascular resistance were observed over time in the esmolol group in comparison to the control group. No other differences were observed in hemodynamic parameters. No significant differences were observed in ANI variations or HRV parameters over time between groups. CONCLUSIONS: The administration of esmolol produced significant changes in hemodynamics with no change in ANI values or HRV parameters. Further study is needed to understand the effect of esmolol during sepsis.

Evaluation of haemodialysis as a protective technique for preventing high daily dose amikacin nephrotoxicity: an experimental study in an ovine model.

Changes in pharmacokinetic parameters of critically ill patients make the treatment of infections challenging, particularly when multidrug-resistant bacteria are involved. The aim of this study was to evaluate the ability of haemodialysis to reduce the exposure to high dose amikacin and prevent nephrotoxicity. Amikacin 50 mg/kg was administered intravenously to six adult sheep once-daily for four days. The sheep were divided into two groups according to the implementation (group 1) or not (group 2) of haemodialysis. In group 1, haemodialysis was performed for 4 h, initiated 2 h after starting amikacin infusion. Amikacin area under the curve (AUC) and trough concentrations (Cmin) were used as markers of amikacin-induced nephrotoxicity. The median haemodialysis amikacin clearance was 2.14 L/h (35.6 mL/min), 14% of the mean total body clearance for 24 h. Haemodialysis reduced Cmin (group 1: 0.3 µg/mL [0.3-1.1]; group 2: 1.4 µg/mL [1.1-3.9]; P = 0.0003). A trend towards reduced AUC with haemodialysis was observed (group 1: 1450 µg/mL⋅h [1311-1716]; group 2: 3126 µg/mL⋅h [2581-3171]; P = 0.10). In conclusion, haemodialysis seems interesting in reducing AUC and Cmin after the injection of high-dose of amikacin, parameters known to be involved in its induced nephrotoxicity, in an experimental ovine model.

Inhaled nitric oxide prevents NSAID-induced renal impairment in pseudo-normovolaemic piglets.

OBJECTIVE: Inhaled nitric oxide (iNO) is commonly used as a treatment of pulmonary hypertension. Its action is purported to be specific to the lung, but extrapulmonary effects have been reported. The objective of this study was to evaluate if iNO could compensate the renal impairment induced by ketoprofen, a conventional non-steroidal anti-inflammatory drug (NSAID), during general anaesthesia. METHODS: Under pseudo-normovolaemic condition, thirty piglets were randomly assigned into 5 equal groups and equipped for renal and systemic parameters measurements. A first experiment was carried out to validate methods and reproduce the renal effects of iNO (40 ppm) in comparison with a placebo (100% oxygen). In a second experiment, iNO was inhaled for 120 minutes right after NSAID treatment (ketoprofen 2 mg×kg-1 IV, and 40 ppm iNO; group KiNO) and its effects were compared to ketoprofen alone (2 mg×kg-1 IV; group K) and placebo (saline; group C). RESULTS: In this model, iNO increased significantly renal blood flow measured by ultrasonic (RBFUL: +53.2±17.2%; p = 0.008) and by PAH clearance (RBFPAH:+78.6±37.6%; p = 0.004) methods, glomerular filtration rate (GFR: +72.6±32.5%; p = 0.006) and urinary output (UO: +47.4±24.2%; p = 0.01). In the second experiment, no significant temporal variation was noted for renal parameters in groups KiNO and C, whereas a significant and constant decrease was observed in the group K for RBFUL (max -19.0±7.1%), GFR (max -26.6±10.4%) and UO (max -30.3±10.5%). CLINICAL SIGNIFICANCE: Our experiments show that iNO, released from its transport forms after its inhalation, can improve renal safety of NSAIDs. This result is promising regarding the use of NSAIDs in critical conditions, but needs to receive clinical confirmation.