Extracorporeal Albumin Dialysis in Liver Failure with MARS and SPAD: A Randomized Crossover Trial.

INTRODUCTION: Liver failure is associated with hepatic and extrahepatic organ failure leading to a high short-term mortality rate. Extracorporeal albumin dialysis (ECAD) aims to reduce albumin-bound toxins accumulated during liver failure. ECAD detoxifies blood using albumin dialysis through an artificial semipermeable membrane with recirculation (molecular adsorbent recirculating system, MARS) or without (single-pass albumin dialysis, SPAD). METHODS: We performed a randomized crossover open trial in a surgical intensive care unit. The primary outcome of the study was total bilirubin reduction during MARS and during SPAD therapies. The secondary outcomes were conjugated bilirubin and bile acid level reduction during MARS and SPAD sessions and tolerance of dialysis system devices. Inclusion criteria were adult patients presenting liver failure with factor V activity <50% associated with bilirubin ≥250 µmol/L and a complication (either hepatic encephalopathy, severe pruritus, or hepatorenal syndrome). For MARS and SPAD, the dialysis flow rate was equal to 1,000 mL/h. RESULTS: Twenty crossovers have been performed. Baseline biochemical characteristics (bilirubin, ammonia, bile acids, creatinine, and urea) were not statistically different between MARS and SPAD. Both ECAD have led to a significant reduction in total bilirubin (-83 ± 67 µmol/L after MARS; -122 ± 118 µmol/L after SPAD session), conjugated bilirubin (-82 ± 61 µmol/L after MARS; -105 ± 96 µmol/L after SPAD session), and bile acid levels (-64 ± 75 µmol/L after MARS; -56 ± 56 µmol/L after SPAD session), all nondifferent comparing MARS to SPAD. CONCLUSION: A simple-to-perform SPAD therapy with equal to MARS dialysate flow parameters provides the same efficacy in bilirubin and bile acid removal. However, clinically relevant endpoints have to be evaluated in randomized trials to compare MARS and SPAD therapies and to define the place of SPAD in the liver failure care program.

Time course of liver mitochondrial function and intrinsic changes in oxidative phosphorylation in a rat model of sepsis.

BACKGROUND: Tissue ATP depletion and oxidative stress have been associated with the severe outcomes of septic shock. One of the compensatory mechanisms to alleviate the sepsis-induced mitochondrial dysfunction could be the increase in oxidative phosphorylation efficiency (ATP/O). We propose to study liver mitochondrial function and oxidative stress and the regulatory mechanism of mitochondrial oxidative phosphorylation efficiency in an animal model of sepsis. METHODS: We induced sepsis in rats by cecal ligation and perforation (CLP). Six, 24, or 36 h following CLP, we measured liver mitochondrial respiration, cytochrome c oxidase activity, and membrane permeability. We determine oxidative phosphorylation efficiency, by measuring ATP synthesis related to oxygen consumption at various exogenous ADP concentrations. Finally, we measured radical oxygen species (ROS) generation by liver mitochondria and mRNA concentrations of UCP2, biogenesis factors, and cytokines at the same end points. RESULTS: CLP rats presented hypotension, lactic acidosis, liver cytolysis, and upregulation of proinflammatory cytokines mRNA as compared to controls. Liver mitochondria showed a decrease in ATP synthesis and oxygen consumption at 24 h following CLP. A marked uncoupling of oxidative phosphorylation appeared 36 h following CLP and was associated with a decrease in cytochrome c oxidase activity and content and ATP synthase subunit ß content (slip mechanism) and an increase in mitochondrial oligomycin-insensitive respiration, but no change in mitochondrial inner membrane permeability (no leak). Upregulation of UCP2 mRNA resulted in a decrease in mitochondrial ROS generation 24 h after the onset of CLP, whereas ROS over-generation associated with slip at cytochrome c oxidase observed at 36 h was concomitant with a decrease in UCP2 mRNA expression. CONCLUSIONS: Despite a compensatory increase in mitochondrial biogenesis factors, liver mitochondrial functions remain altered after CLP. This suggests that the functional compensatory mechanisms reported in the present study (slip at cytochrome c oxidase and biogenesis factors) were not strong enough to increase oxidative phosphorylation efficiency and failed to limit liver mitochondrial ROS over-generation. These data suggest that treatments based on cytochrome c infusion could have a role in mitochondrial dysfunction and/or ROS generation associated with sepsis.

The evolution of diastolic function during liver transplantation.

INTRODUCTION: The peroperative management of liver transplantation is still associated with many cardiocirculatory complications in which diastolic dysfunction may play a contributive role. Transoesophageal echocardiography is a monitoring device commonly used in liver transplantation allowing diastolic function assessment. METHODS: We prospectively analysed the peroperative transoesophageal echocardiography recordings of 40 patients undergoing liver transplantation in order to describe changes in diastolic function at different steps of the surgery. The diastolic function marker we used was the lateral mitral annulus motion (E' wave velocity) obtained by tissue-Doppler imaging. In addition, we also studied the left ventricular filling pressure indices and systolic function. RESULTS: As a whole, there was no global change in E' wave velocity throughout the surgery. However, 11 patients (27.5%) presented a decrease in E' wave velocity up to 15% that identified an occurrence of diastolic function alteration. In this group, other peroperative data were not different from other patients (amount of bleeding, fluid administration or vasopressive support). Conversely, this group experienced lower preoperative E' wave velocity values (9cm·s-1 versus 12cm·s-1, P=0.05) and an increased incidence of postoperative cardiorespiratory complications (OR=6 [1-56], P=0.02). Considering all patients, 18 patients had an E' wave velocity under 10cm·s-1 at unclamping, characterizing a diastolic dysfunction according to the usual criteria. This dysfunction was not associated with cardiorespiratory complications. CONCLUSION: This work investigated peroperative systematic echocardiographic evaluation of diastolic function during liver transplantation. Diastolic dysfunction occurs frequently during liver transplantation and could lead to postoperative cardiorespiratory complications.

Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria

We aimed to study the change in mitochondrial oxidative phosphorylation efficiency occurring at the early stage of septic shock in an experimental model. Thirty-six male Wistar rats were divided into two groups. In the first group, a cecal ligation and puncture (CLP) was carried out to induce septic shock for 5 h. The second group includes sham-operated rats and constitutes the control group. Blood gas analysis, alanine amino transferase, and lactic acid dosages were assayed 5 h after surgery. Liver mitochondria were isolated for in vitro functional characterization, including mitochondrial respiratory parameters, oxidative phosphorylation efficiency, oxi-radical production, membrane potential, and cytochrome c oxidase activity and content. Liver interleukin 1β (IL-1β) and tumor necrosis α mRNA levels were determined. Septic shock induced a severe hypotension occurring 180 min after CLP in association with a metabolic acidosis, an increase in plasma alanine amino transferase, liver IL-1β gene expression, and mitochondrial reactive oxygen species production. The rates of mitochondrial oxygen consumption and the activity and content of cytochrome c oxidase were significantly decreased while no alterations in the oxidative phosphorylation efficiency and inner membrane integrity were found. These results show that contrary to what was expected, liver mitochondria felt to adjust their oxidative phosphorylation efficiency in response to the decrease in the mitochondrial oxidative activity induced by CLP. This loss of mitochondrial bioenergetics plasticity might be related to mitochondrial oxidative stress and liver cytokines production

Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria.

We aimed to study the change in mitochondrial oxidative phosphorylation efficiency occurring at the early stage of septic shock in an experimental model. Thirty-six male Wistar rats were divided into two groups. In the first group, a cecal ligation and puncture (CLP) was carried out to induce septic shock for 5 h. The second group includes sham-operated rats and constitutes the control group. Blood gas analysis, alanine amino transferase, and lactic acid dosages were assayed 5 h after surgery. Liver mitochondria were isolated for in vitro functional characterization, including mitochondrial respiratory parameters, oxidative phosphorylation efficiency, oxi-radical production, membrane potential, and cytochrome c oxidase activity and content. Liver interleukin 1ß (IL-1ß) and tumor necrosis α mRNA levels were determined. Septic shock induced a severe hypotension occurring 180 min after CLP in association with a metabolic acidosis, an increase in plasma alanine amino transferase, liver IL-1ß gene expression, and mitochondrial reactive oxygen species production. The rates of mitochondrial oxygen consumption and the activity and content of cytochrome c oxidase were significantly decreased while no alterations in the oxidative phosphorylation efficiency and inner membrane integrity were found. These results show that contrary to what was expected, liver mitochondria felt to adjust their oxidative phosphorylation efficiency in response to the decrease in the mitochondrial oxidative activity induced by CLP. This loss of mitochondrial bioenergetics plasticity might be related to mitochondrial oxidative stress and liver cytokines production.

Early adverse changes in liver microvascular circulation during experimental septic shock are not linked to an absolute nitric oxide deficit.

Nitric oxide (NO) is believed to play a key role in adverse microvascular changes during sepsis. A deficit in NO has been evoked as a potential mechanism of microcirculatory deterioration in the early phase of septic shock. The aim of this study was to evaluate simultaneously and continuously both hepatic microcirculation and local NO production during early experimental sepsis. Wistar male rats were divided into two groups: a sepsis group undergoing cecal ligation and puncture (CLP) peritonitis and a control group undergoing sham surgery. Hepatic microcirculation was continuously monitored using a laser Doppler probe and local nitric oxide (NO) production by means of a specific electrode. Constitutive and inducible NO synthase production was assessed 2h after surgery, at onset of shock, and at 2 and 3h after shock. In control animals, hepatic microcirculatory perfusion and NO production remained stable throughout the experiment. In septic animals, whereas a fall in microcirculatory perfusion was noted as early as 2h after CLP, NO concentration remained stable and further increased after the onset of shock. At this time, inducible NO synthase was the only isoform significantly elevated. In this non-resuscitated experimental model of sepsis, an absolute liver deficit of NO could not explain the early adverse changes in the local microvascular system.

Comparison between respiratory variations in pulse oximetry plethysmographic waveform amplitude and arterial pulse pressure during major abdominal surgery.

BACKGROUND: To assess preload dependence, the variation of the plethysmographic waveform of pulse oximetry (ΔPOP) has been proposed as a surrogate of the pulse pressure variation (ΔPP). The aim of the study was to assess the ability of the pulse oximeter-derived plethysmographic analysis to accurately trend ΔPP in patients undergoing major abdominal surgery by using standard monitors. METHODS: A continuous recording of arterial and plethysmographic waveform was performed in 43 patients undergoing abdominal surgery. ΔPP and ΔPOP were calculated on validated respiratory cycles. RESULTS: For analysis, 92,467 respiratory cycles were kept (73.5% of cycles recorded in 40 patients). The mean of intrapatient coefficients of correlation was low (r = 0.22). The Bland and Altman analysis showed a systematic bias of 5.21; the ΔPOP being greater than the ΔPP, this bias increased with the mean value of the two indices and the limits of agreement were wide (upper 21.7% and lower -11.3%). Considering a ΔPP threshold at 12% to classify respiratory cycles as responders and nonresponders, the corresponding best cutoff value of ΔPOP was 13.6 ± 4.3%. Using these threshold values, the observed classification agreement was moderate (κ = 0.50 ± 0.09). CONCLUSIONS: The wide limits of agreement between ΔPP and ΔPOP and the weak correlation between both values cast doubt regarding the ability of ΔPOP to substitute ΔPP to follow trend in preload dependence and classify respiratory cycles as responders or nonresponders using standard monitor during anesthesia for major abdominal surgery.

Impact of intra-abdominal pressure on retrohepatic vena cava shape and flow in mechanically ventilated pigs.

Conflicting results have been found regarding correlations between right atrial pressure (RAP) and inferior vena cava (IVC) diameter in mechanically ventilated patients. This finding could be related to an increase in intra-abdominal pressure (IAP). This study was designed to clarify whether variations in IVC flow rate caused by positive pressure ventilation are associated with changes in the retrohepatic IVC cross-section (ΔIVC) during major changes in volume status and IAP. Nine pigs were anesthetized, mechanically ventilated and equipped. IAP was set at 0, 15 and 30 mmHg during two conditions, i.e. normovolemia and hypovolemia, generated by blood removal to obtain a mean arterial pressure value lower than 60 mmHg. At each IAP increment, cardiac output, IVC flow and surface area were respectively assessed by flowmeters and transesophageal echocardiography. At normal IAP, even in presence of respiratory changes in IVC flows, no ΔIVC were observed during the two conditions. At high IAP, neither ΔIVC nor modulations of IVC flow were observed whatever the volemic status. The majority of animals with an IVC area of less than 0.65 cm(2) showed evidence of IAP greater than RAP values. Negative RAP-IAP pressure gradients were found to occur with an IVC area of less than 0.65 cm(2), suggesting that IVC dimensions determined using standard ultrasound techniques may indicate the direction of the RAP-IAP gradient. The clinical relevance of the present findings is that volume status should not be estimated from retrohepatic IVC dimensions in cases of high IAP.

Pulse pressure variation and stroke volume variation during increased intra-abdominal pressure: an experimental study.

INTRODUCTION: The aim of this study was to evaluate dynamic indices of fluid responsiveness in a model of intra-abdominal hypertension. METHODS: Nine mechanically-ventilated pigs underwent increased intra-abdominal pressure (IAP) by abdominal banding up to 30 mmHg and then fluid loading (FL) at this IAP. The same protocol was carried out in the same animals made hypovolemic by blood withdrawal. In both volemic conditions, dynamic indices of preload dependence were measured at baseline IAP, at 30 mmHg of IAP, and after FL. Dynamic indices involved respiratory variations in stroke volume (SVV), pulse pressure (PPV), and systolic pressure (SPV, %SPV and Δdown). Stroke volume (SV) was measured using an ultrasound transit-time flow probe placed around the aortic root. Pigs were considered to be fluid responders if their SV increased by 15% or more with FL. Indices of fluid responsiveness were compared with a Mann-Whitney U test. Then, receiver operating characteristic (ROC) curves were generated for these parameters, allowing determination of the cut-off values by using Youden's method. RESULTS: Five animals before blood withdrawal and all animals after blood withdrawal were fluid responders. Before FL, SVV (78 ± 19 vs 42 ± 17%), PPV (64 ± 18 vs 37 ± 15%), SPV (24 ± 5 vs 18 ± 3 mmHg), %SPV (24 ± 4 vs 17 ± 3%) and Δdown (13 ± 5 vs 6 ± 4 mmHg) were higher in responders than in non-responders (P < 0.05). Areas under ROC curves were 0.93 (95% confidence interval: 0.80 to 1.06), 0.89 (0.70 to 1.07), 0.90 (0.74 to 1.05), 0.92 (0.78 to 1.06), and 0.86 (0.67 to 1.06), respectively. Threshold values discriminating responders and non-responders were 67% for SVV and 41% for PPV. CONCLUSIONS: In intra-abdominal hypertension, respiratory variations in stroke volume and arterial pressure remain indicative of fluid responsiveness, even if threshold values identifying responders and non-responders might be higher than during normal intra-abdominal pressure. Further studies are required in humans to determine these thresholds in intra-abdominal hypertension.

Effects of a continuous low-dose clonidine epidural regimen on pain, satisfaction and adverse events during labour: a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Epidural clonidine has been proposed as an adjunct for anaesthetic mixtures during labour. Administered as a bolus, clonidine may have side effects such as sedation and hypotension; its continuous infusion could be attractive in this respect. We, therefore, conducted a randomized, double-blind trial using patient-controlled epidural analgesia with a background infusion using a low dose of clonidine during labour. METHODS: A total of 128 healthy parturients in active labour received a patient-controlled epidural analgesia solution of 0.0625% levobupivacaine and sufentanil 0.25 microg ml(-1) with or without clonidine 2 microg ml(-1). Ninety-five parturients were analysed. The pain score over time was evaluated as well as drug volume utilization; supplementation bolus and side effects were recorded. The primary endpoint was maternal satisfaction [ClinicalTrials.gov Identifier (NCT00437996)]. RESULTS: Three patients in the control group failed to achieve satisfactory epidural analgesia owing to a technical issue. Although the primary endpoint was not statistically significant, analgesia was more pronounced and obtained earlier in the clonidine group. The area under the curve for the visual analogue pain score was significantly lower in the clonidine group. In this group, hourly doses of levobupivacaine and sufentanil were reduced (13.9 +/- 4.3 vs. 16.3 ml +/- 4.0; P = 0.005) as well as rescue supplementation and pruritus incidence (18 vs. 46%; P = 0.004). Maternal blood pressure was significantly lower, over time, in the clonidine group but remained within the normal range. Sedation was similar in both groups (4.3 vs. 2.0%; not significant). CONCLUSION: The addition of clonidine to epidural levobupivacaine and sufentanil for patient-controlled epidural analgesia in labour improved analgesia, reduced the supplementation rate and reduced pruritus without improvement in maternal satisfaction. Blood pressure was significantly lower in the clonidine group over time but without clinical consequence.

Factors associated with noninvasive ventilation failure in postoperative acute respiratory insufficiency: an observational study.

BACKGROUND AND OBJECTIVE: Few data are available on the efficacy of noninvasive ventilation (NIV) in postoperative patients with acute respiratory failure (ARF). METHODS: Seventy-two patients coming from the surgical wards with postoperative ARF were retrospectively evaluated. The major characteristics of patients who were intubated were compared with the characteristics of those who were not after a trial of NIV. Predictive factors for failure of NIV were analysed. RESULTS: Out of 72 patients with ARF after surgery who were treated with NIV, 42 avoided intubation (58%). On a univariate analysis, a decrease in the paO2/FiO2 ratio after 1 h of NIV (223 +/- 84 to 160 +/- 68 mmHg, P < 0.05) was associated with NIV failure and need for tracheal intubation because of nosocomial pneumonia and an increased simplified acute physiology score (SAPS) 2. In a multivariate analysis, nosocomial pneumonia [odds ratio (OR) 4.189; 95% confidence interval (CI) 1.383-12.687] and SAPS 2 higher than 35 (OR 4.969; 95% CI 1.627-15.172) were independent predictive factors of NIV failure. NIV success was associated with a reduced ICU stay (16.8 vs. 26.1 days, P < 0.001). CONCLUSION: NIV could be considered in postoperative patients who presented with ARF. Nosocomial pneumonia is predictive of NIV failure.

Prenatal nicotine alters maturation of breathing and neural circuits regulating respiratory control.

While perinatal nicotine effects on ventilation have been widely investigated, the prenatal impact of nicotine treatment during gestation on both breathing and neural circuits involved in respiratory control remains unknown. We examined the effects of nicotine, from embryonic day 5 (E5) to E20, on baseline ventilation, the two hypoxic ventilatory response components and in vivo tyrosine hydroxylase (TH) activity in carotid bodies and brainstem areas, assessed at postnatal day 7 (P7), P11 and P21. In pups prenatally exposed to nicotine, baseline ventilation and hypoxic ventilatory response were increased at P7 (+48%) and P11 (+46%), with increased tidal volume (p<0.05). Hypoxia blunted frequency response at P7 and revealed unstable ventilation at P11. In carotid bodies, TH activity increased by 20% at P7 and decreased by 48% at P11 (p<0.05). In most brainstem areas it was reduced by 20-33% until P11. Changes were resolved by P21. Prenatal nicotine led to postnatal ventilatory sequelae, partly resulting from impaired maturation of peripheral chemoreceptors and brainstem integrative sites.

Increased intra-abdominal pressure affects respiratory variations in arterial pressure in normovolaemic and hypovolaemic mechanically ventilated healthy pigs.

OBJECTIVE: To evaluate the effect of increased intra-abdominal pressure (IAP) on the systolic and pulse pressure variations induced by positive pressure ventilation in a porcine model. DESIGN AND SETTING: Experimental study in a research laboratory. SUBJECTS: Seven mechanically ventilated and instrumented pigs prone to normovolaemia and hypovolaemia by blood withdrawal. INTERVENTION: Abdominal banding gradually increased IAP in 5-mmHg steps up to 30 mmHg. MEASUREMENTS AND MAIN RESULTS: Variations in systolic pressure, pulse pressure, inferior vena cava flow, and pleural and transmural (LVEDPtm) left-ventricular end-diastolic pressure were recorded at each step. Systolic pressure variations were 6.1+/-3.1%, 8.5+/-3.6% and 16.0+/-5.0% at 0, 10, and 30 mmHg IAP in normovolaemic animals (mean+/-SD; p<0.01 for IAP effect). They were 12.7+/-4.6%, 13.4+/-6.7%, and 23.4+/-6.3% in hypovolaemic animals (p<0.01 vs normovolaemic group) for the same IAP. Fluctuations of the inferior vena cava flow disappeared as the IAP increased. Breath cycle did not induce any variations of LVEDPtm for 0 and 30 mmHg IAP. CONCLUSIONS: In this model, the systolic pressure and pulse pressure variations, and inferior vena cava flow fluctuations were dependent on IAP values which caused changes in pleural pressure swing, and this dependency was more marked during hypovolaemia. The present study suggests that dynamic indices are not exclusively related to volaemia in the presence of increased IAP. However, their fluid responsiveness predictive value could not be ascertained as no fluid challenge was performed.

Uncoupling the systemic circulation and the Ex Vivo circuit during experimental isolated liver perfusion.

Performing an ex vivo liver perfusion as a transient liver support requires perfusing the liver with a flow of 1 ml/min per kg of liver, which could reach 25% of the cardiac output when a human liver is used. This high flow could be detrimental in patients with acute liver failure. Therefore, in an ischemic-induced liver failure pig model, we developed a circuit allowing low flows going out of and into the systemic circulation, whereas the flow going through the ex vivo liver is maintained at a high value. This was obtained by uncoupling the ex vivo circuit from the systemic circulation. Ex vivo liver perfusion was performed in a closed circuit with a flow averaging 1 ml/min per kg of ex vivo liver (700 to 800 ml/min, according to the weight of the livers we used). It was linked to the systemic circulation with input and output flows equal to that used during hemodialysis (200 ml/min). Compared with previously reported direct circuits, this perfusion system was well tolerated from a circulatory point of view. After the induction of ischemic liver failure, the ex vivo liver perfusion led to an increase in urea, branched amino acids to aromatic amino acid ratio, and fractional clearance of indocyanine green and galactose and to a decrease in ammonia and lactic acid. This system allowed the ex vivo liver to keep its clearing properties despite a low extracorporeal flow. It represents an extracorporeal circuit that could be used in place of the direct extracorporeal high-flow liver perfusion.

Liver function during extracorporeal whole liver perfusion in a pig model of acute ischemic liver failure.

The shortage of livers for transplant has renewed interest in the potential of temporary liver support such as extra corporeal whole liver perfusion. In an ischemic induced liver failure model we perfused an extra corporeal liver through only a portal vein and assessed the function of this ex vivo liver by using hepatic tests to estimate elimination as well as synthesis capacities. Acute liver failure was performed in five control pigs by a hepatic devascularization associated to an end to side portocaval shunt. In a treated group, 5 to 6 h after this hepatic devascularization, animals were connected to an extra corporeal liver perfused via the portal vein with blood withdrawn from the ischemic liver animal from its portal vein. Devascularization of the liver induced an increase in liver enzymes and ammonia, a drop in the ratio of branched chain amino acids to aromatic amino acids, and a decrease in blood urea and indocyanine green and galactose clearances. In treated animals, urea, amino acid ratio, and clearances increased after the ex vivo liver perfusion. In this group, mean bile production and mean liver oxygen consumption were 13.7 +/- 3.6 ml/h and 16.1 +/- 7.7 ml/min, respectively. In an acute ischemic liver failure pig model, an extra corporeal whole liver perfusion demonstrated detoxification properties as well as synthesis capacities.