Albumin Infusion Reduces Fluid Loading for Postresuscitation Syndrome in a Pig Model of Refractory Cardiac Arrest Resuscitated With Venoarterial Extra Corporeal Membrane Oxygenation.

Hemodynamic instability in postresuscitation syndrome worsens survival and neurological outcomes. Venoarterial extracorporeal membrane oxygenation (VA ECMO) for refractory cardiac arrest might improve outcomes. Hemodynamical support under VA ECMO relies on norepinephrine and crystalloids. The present work aims to assess the effects of albumin (ALB) infusion in a swine model of ischemic refractory cardiac arrest implanted by VA ECMO. Cardiac arrest was performed in 18 pigs and VA ECMO was initiated after 30 minutes cardiopulmonary resuscitation (CPR). Pigs were randomly assigned to standard care (norepinephrine + crystalloids) versus ALB group (ALB + standard care). Hemodynamical assessments were performed over 6 hours. Severe hypoalbuminemia was observed in the control group and could be reversed with ALB infusion. Total crystalloid load was significantly reduced with ALB infusion (1,000 [1,000-2,278] ml vs. 17,000 [10,000-19,000] ml, ALB versus control group, respectively, p < 0.001). There was no significant impact with regard to lactate clearance (29.16% [12.5-39.32] and 10.09% [6.78-29.36] for control versus ALB groups, respectively, p = 0.185), sublingual capillary microvascular parameters, or cerebral near-infrared spectrometer (NIRS) values. Compared to standard care, ALB infusion was highly effective in reducing fluid loading in a porcine model of postresuscitation syndrome after refractory cardiac arrest treated with VA ECMO.

Impaired Pharmacokinetics of Amiodarone under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to Bedside.

BACKGROUND: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. METHODS: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters Cmax, Tmax AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. RESULTS: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of Cmax in the VV ECMO group as compared to controls. No difference in Tmax was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. CONCLUSIONS: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

Methylene Blue Reduces Fluid Loading and Norepinephrine Requirements for Post-Resuscitation Syndrome in a Pig Model of Refractory Cardiac Arrest Resuscitated with Veno-Arterial ECMO.

BACKGROUND: Refractory cardiac arrest management relies on extracorporeal cardiopulmonary resuscitation (ECPR), requiring the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Circulatory flow recovery can be associated with an ischemia-reperfusion injury, leading to vasoplegia and vasopressor requirement. The aim of this work was to evaluate the impact on hemodynamics of a methylene blue bolus infusion in a porcine model of ischemic refractory cardiac arrest. METHODS: Ischemic refractory cardiac arrest was induced in 20 pigs. After a low flow period of 30 min, VA-ECMO was initiated and the pigs were randomly assigned to the standard care group (norepinephrine + crystalloids) or methylene blue group (IV 2 mg·kg-1 bolus of methylene blue over 30 min + norepinephrine and crystalloids). Macrocirculatory parameters and lactate clearance were measured. Sublingual microcirculation was evaluated with sidestream dark field (SDF) imaging. The severity of the ischemic digestive lesions was assessed according to the histologic Chiu/Park scale. RESULTS: Eighteen pigs were included. The total crystalloid load (5000 (6000-8000) mL vs. 17,000 (10,000-19,000) mL, p = 0.007, methylene blue vs. standard care group) and catecholamine requirements (0.31 (0.14-0.44) µg·kg-1·min-1 vs. 2.32 (1.17-5.55) µg·kg-1·min-1, methylene blue vs. standard care group, p = 0.004) were significantly reduced in the methylene blue group. There were no significant between-group differences in lactate clearance, sublingual capillary microvascular parameters assessed by SDF or histologic Chiu/Park scale. CONCLUSIONS: In our refractory cardiac arrest porcine model treated with ECPR, methylene blue markedly reduced fluid loading and norepinephrine requirements in comparison to standard care during the first 6 h of VA-ECMO.

Time-Controlled Adaptive Ventilation Does Not Induce Hemodynamic Impairment in a Swine ARDS Model.

Background: The current standard of care during severe acute respiratory distress syndrome (ARDS) is based on low tidal volume (VT) ventilation, at 6 mL/kg of predicted body weight. The time-controlled adaptive ventilation (TCAV) is an alternative strategy, based on specific settings of the airway pressure release ventilation (APRV) mode. Briefly, TCAV reduces lung injury, including: (1) an improvement in alveolar recruitment and homogeneity; (2) reduction in alveolar and alveolar duct micro-strain and stress-risers. TCAV can result in higher intra-thoracic pressures and thus impair hemodynamics resulting from heart-lung interactions. The objective of our study was to compare hemodynamics between TCAV and conventional protective ventilation in a porcine ARDS model. Methods: In 10 pigs (63-73 kg), lung injury was induced by repeated bronchial saline lavages followed by 2 h of injurious ventilation. The animals were then randomized into two groups: (1) Conventional protective ventilation with a VT of 6 mL/kg and PEEP adjusted to a plateau pressure set between 28 and 30 cmH2O; (2) TCAV group with P-high set between 27 and 29 cmH2O, P-low at 0 cmH2O, T-low adjusted to terminate at 75% of the expiratory flow peak, and T-high at 3-4 s, with I:E > 6:1. Results: Both lung elastance and PaO2:FiO2 were consistent with severe ARDS after 2 h of injurious mechanical ventilation. There was no significant difference in systemic arterial blood pressure, pulmonary blood pressure or cardiac output between Conventional protective ventilation and TCAV. Levels of total PEEP were significantly higher in the TCAV group (p < 0.05). Driving pressure and lung elastance were significantly lower in the TCAV group (p < 0.05). Conclusion: No hemodynamic adverse events were observed in the TCAV group compared as to the standard protective ventilation group in this swine ARDS model, and TCAV appeared to be beneficial to the respiratory system.

IMPACT OF DIFFERENT VENTILATION STRATEGIES ON GAS EXCHANGES AND CIRCULATION DURING PROLONGED MECHANICAL CARDIO-PULMONARY RESUSCITATION IN A PORCINE MODEL.

ABSTRACT: Background: Optimal ventilation during cardio-pulmonary resuscitation (CPR) is still controversial. Ventilation is expected to provide sufficient arterial oxygen content and adequate carbon dioxide removal, while minimizing the risk of circulatory impairment. The objective of the present study was to compare three ventilation strategies in a porcine model during mechanical continuous chest compressions (CCC) according to arterial oxygenation and hemodynamic impact. Method: Ventricular fibrillation was induced and followed by five no-flow minutes and thirty low-flow minutes resuscitation with mechanical-CCC without vasopressive drugs administration. Three groups of eight Landras pig were randomized according to the ventilation strategy: 1. Standard nonsynchronized volume-control mode (SD-group); 2. synchronized bilevel pressure-controlled ventilation (CPV-group); 3. continuous insufflation with Boussignac Cardiac-Arrest Device (BC-group). We assessed 1. arterial blood gases, 2. macro hemodynamics, 3. tissular cerebral macro and micro-circulation and 4. airway pressure, minute ventilation at baseline and every 5 minutes during the protocol. Results: Arterial PaO2 level was higher at each measurement time in SD-group (>200 mm Hg) compare to CPV-group and BC-group ( P < 0.01). In BC-group, arterial PaCO2 level was significantly higher (>90mm Hg) than in SD and CPV groups ( P < 0.01). There was no difference between groups concerning hemodynamic parameters, cerebral perfusion and microcirculation. Conclusion: Ventilation modalities in this porcine model of prolonged CPR influence oxygenation and decarboxylation without impairing circulation and cerebral perfusion. Synchronized bi-level pressure-controlled ventilation' use avoid hyperoxia and was as efficient as asynchronized volume ventilation to maintain alveolar ventilation and systemic perfusion during prolonged CPR.

Comparison of Vasopressin versus Norepinephrine in a Pig Model of Refractory Cardiogenic Shock Complicated by Cardiac Arrest and Resuscitated with Veno-arterial ECMO.

BACKGROUND: The choice of the best vasopressor after ExtraCorporeal Membrane Oxygenation (ECMO) implantation after cardiac arrest is not well defined. Circulatory flow recovery with ECMO is associated with vasoplegia and vasopressor need. The present study aimed to compare the effects of norepinephrine and vasopressin in the first 6 h after ECMO initiation. METHODS: Cardiac arrest was induced in 20 pigs by coronary surgical ligature and veno-arterial-ECMO was started after a 30-min period of cardio-pulmonary resuscitation. Pigs were randomized into two groups, arginine vasopressin (AVP) or norepinephrine (NE), with the drugs titrated to maintain a mean arterial pressure (MAP) at 65 mm Hg. Macrocirculatory and metabolic parameters were assessed by lactate clearance. Microcirculatory parameters were assessed by sublingual microcirculation with Sidestream Dark Field imaging and peripheral Near InfraRed Spectroscopy. Pulmonary edema was evaluated by measuring lung wet/dry weight ratio. RESULTS: No difference was found between groups regarding ECMO flow and MAP. Fluid resuscitation volume was higher in the NE group (14,000 [11,250-15,250] mL vs. 3,500 [1,750-4,000] mL in the AVP group, P < 0.05). Lung wet/dry weight ratio was higher in the Norepinephrine group. Lactate clearance between H0 and H6 was higher in the AVP group (47.84 [13.42-82.73]% vs. the NE group 25.66 [-7.31 to 35.34)% vs. P < 0.05). No significant difference was observed for sublingual microcirculation values. Baseline tissue oxygen saturation was comparable and higher at both H3 and H6 in the Vasopressin group comparatively to the Norepinephrine group (P < 0.05). Renal and liver function evolution also remained similar in the two groups throughout the study. CONCLUSIONS: AVP administration in refractory cardiac arrest resuscitated by veno-arterial-ECMO is associated with a faster lactate clearance, less fluid resuscitation, and less pulmonary edema when compared with NE for similar global and regional hemodynamic effects.

Low versus standard-blood-flow reperfusion strategy in a pig model of refractory cardiac arrest resuscitated with Extra Corporeal Membrane Oxygenation.

OBJECTIVE: This study was designed to assess the effect of two veno-arterial ExtraCorporeal Membrane Oxygenation (ECMO) blood-flow strategies in an experimental model of Extracorporeal Cardio-Pulmonary Resuscitation (ECPR) on macrocirculatory, metabolic and microcirculatory parameters in the first six hours of ECMO initiation. METHODS: Cardiac arrest was induced in 18 pigs by surgical ligature of the left descending coronary artery followed by a low-flow time of 40 min using internal cardiac massage. ECPR was initiated in normothermia with an ECMO blood flow of 30-35 ml.kg-1. min-1 (low-blood-flow group, LBF) or 65-70 ml.kg-1. min-1 (standard-blood-flow group, SBF), with the same mean arterial pressure target of 65 mmHg adjusted with norepinephrine. Macrocirculatory and metabolic parameters were assessed by lactate clearance and carotid blood flow. Microcirculatory parameters were assessed by sublingual microcirculation with Sidestream Dark Field (SDF) imaging and peripheral Near-InfraRed Spectrometry (NIRS). Inflammatory cytokine levels were measured with a multicomplexed ELISA-based array platform. RESULTS: There were no between-group differences at baseline and at ECMO initiation (H0). Lactate clearance at H6 was lower in LBF compared to SBF (6.67[-10.43-18.78] vs. 47.41[19.54-70.69] %, p = 0.04). Carotid blood flow was significantly lower (p<0.005) during the last four hours despite similar mean arterial pressure levels. For microvascular parameters, SDF and NIRS parameters were transitorily impaired at H3 in LBF. IL-6 cytokine level was significantly higher in LBF at the end of the experiment. CONCLUSION: In an experimental porcine model of refractory cardiac arrest treated by ECMO, a low-blood-flow strategy during the first six hours of resuscitation was associated with lower lactate clearance and lower cerebral blood flow with no benefits on ischemia-reperfusion parameters.

High Versus Low Blood-Pressure Target in Experimental Ischemic Prolonged Cardiac Arrest Treated with Extra Corporeal Life Support.

BACKGROUND: There is currently no recommendation for the mean arterial pressure target in the particular setting of Extracorporeal Cardiopulmonary Resuscitation (ECPR) in the first hours following cardiogenic shock complicated by cardiac arrest. This study aimed to assess the effects of two different levels of mean arterial pressure on macrocirculatory, microcirculatory, and metabolic functions. DESIGN: Randomized animal study. SETTING: University research laboratory. INTERVENTION: Ventricular fibrillation was induced in 14 male pigs by surgical ligature of the interventricular coronary artery. After 20 min of cardiopulmonary resuscitation, Extracorporeal Life Support (ECLS) was initiated to restore circulatory flow. Thereafter, animals were randomly allocated to a high mean arterial pressure group (High-MAP, 80-85 mm Hg) or to a standard mean arterial pressure group (Standard-MAP, 65-70 mm Hg). Assessments conducted at baseline, immediately following and 6 h after ECLS initiation were focused on lactate evolution, amount of infused fluid, and microcirculatory parameters. RESULTS: There was no significant difference between the two groups at the time of ECLS initiation and at 6 h with regard to lactate levels (High-MAP vs. Standard-MAP: 8.8 [6.7-12.9] vs. 9.6 [9.1-9.8] mmol·l, P = 0.779 and 8.9 [4.3-11.1] vs. 3.3 [2.4-11] mmol·l, P = 0.603). Infused fluid volume did not significantly differ between the two groups (4,000 [3,500-12,000] vs. 5,000 [2,500-18,000] mL, P = 0.977). There was also no significant difference between the two groups regarding renal and liver functions, and sublingual capillary microvascular flow index assessed by Sidestream Dark Field imaging. CONCLUSION: Compared with a standard mean arterial pressure regimen, targeting a high mean arterial pressure in the first hours of an experimental ECPR model did not result in any hemodynamic improvement nor in a decrease in the amount of infused fluid.

Development of an HT29 liver metastases model in nude rats.

The liver is the most frequent and fatal site of distant spreading of colorectal cancer. Most liver metastases animal models involve nude mice and an injection of tumour cells through the spleen or portal vein, or orthotopic implantation of tumour cells in the colon wall. The aim of this study was to develop a reliable rat model of liver metastases with human colorectal HT29 cells. Seventy male athymic Rowett nude rats weighing 300+/-30 g were separated into three groups. The first group (n=20) consisted of untreated rats, rats in the second group (n=20) were immunosuppressed by cyclosporin A, and those in the third group (n=30) were irradiated the day before cell grafting. Tumour cells (2 x 10(7)) were subcapsulary injected into the liver, and rats were sacrificed after 60 days. The livers were excised, and tumours were serially sectioned to determine size and volume, then fixed for histological studies. The take-rate was 55% in the first group, 35% in the second and 74% in the third group. The mean volume of tumours in the first group was 537+/-162 mm(3), 613+/-232 mm(3) in the second group and 2949+/-629 mm(3) in the third group. In conclusion, subcapsular injection of the human colonic HT29 cancer cells into the liver of preoperatively irradiated nude rats is a reliable, reproducible and easily obtained model, which should be useful for preclinical studies.

[Nifedipine in the treatment of chronic cor pulmonale]. / Apport de la nifédipine dans le traitement du coeur pulmonaire chronique.

The effects of a single dose of nifedipine (20 mg sublingual) on the haemodynamics and parameters of tissue oxygenation were assessed by right heart catheterisation and oximetry of mixed arterial and venous blood in 24 patients with pulmonary hypertension secondary to severe chronic obstructive airways disease. The haemodynamic effects of 15 days' oral therapy (30 mg/day) were studied in 10 other patients. Significant improvement in right ventricular pump function (25 p. 100 increase in cardiac index. average reduction of 3 mmHg of right ventricular end diastolic pressure), and lowering of pulmonary hypertension (mean pulmonary artery pressures reduced by an average of 10 p. 100 and total pulmonary resistance by 25 p. 100) were observed after the single dose of nifedipine. This improvement was maintained after oral therapy for 15 days. The significant improvement of tissue oxygenation was reflected by an increase in oxygen transport (+ 24 p. 100), in the coefficient of delivered oxygen (+ 19 p. 100), in the oxygen partial pressure (+ 4 p. 100) and saturation (+ 3 p. 100) in the mixed venous blood. Arterial lactate concentrations fell by about 28 p. 100. In addition, a moderate fall in ppO2 and arterial saturation was observed due to a weak shunt effect which was more than compensated by the increase in cardiac output, and especially by the increase in the coefficient of relieved oxygen. These results show that nifedipine may be a valuable addition in the treatment of cor pulmonale secondary to chronic obstructive airways disease by improving right ventricular haemodynamics and pulmonary circulation and by increasing the quantity of oxygen delivered.