Variability of neurally-adjusted ventilatory assist (nava) compared to pressure support ventilation (psv) during the weaning phase of mechanical ventilation.

Rationale: NAVA is an assisted ventilatory mode that uses the electrical activity of the diaphragm (Edi) to trigger and cycle the ventilator, and to offer inspiratory assistance in proportion to patient effort. Since Edi varies from breath to breath, airway pressure and tidal volume also vary according to the patient's breathing pattern. Our objective was to compare the variability of NAVA with PSV in mechanically ventilated patients during the weaning phase. Methods: We analyzed the data collected for a clinical trial that compares PSV and NAVA during spontaneous breathing trials using PSV, with PS of 5 cmH2O, and NAVA, with Nava level titrated to generate a peak airway pressure equivalent to PSV of 5 cmH2O (NCT01137271). We captured flow, airway pressure and Edi at 100Hz from the ventilator using a dedicated software (Servo Tracker v2, Maquet, Sweden), and processed the cycles using a MatLab (Mathworks, USA) code. The code automatically detects the tidal volume (Vt), respiratory rate (RR), Edi and Airway pressure (Paw) on a breath-by-breath basis for each ventilatory mode. We also calculated the coefficient of variation (standard deviation, SD, divided by the mean). Results: We analyzed data from eleven patients. The mean Vt was similar on both modes (370 ±70 for Nava and 347± 77 for PSV), the RR was 26±6 for Nava and 26±7 or PSV. Paw was higher for Nava than for PSV (14±1 vs 11±0.4, p=0.0033), and Edi was similar for both modes (12±8 for Nava and 11±6 for PSV). The variability of the respiratory pattern, assessed with the coefficient of variation, was larger for Nava than for PSV for the Vt ( 23%±1% vs 15%±1%, p=0.03) and Paw (17%±1% vs 1% ±0.1%, p=0.0033), but not for RR (21% ±1% vs 16% ±8%, p=0.050) or Edi (33%±14% vs 39% ±16%,p=0.07). Conclusion: The variability of the breathing pattern is high during spontaneous breathing trials independent of the ventilatory mode. This variability results in variability of airway pressure and tidal volume, which are higher on Nava than on PSV. Our results suggest that Nava better reflects the normal variability of the breathing pattern during assisted mechanical ventilation.

Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial

Introduction: Patients undergoing mechanical ventilation (MV) are frequently administered prolonged and/or high doses of opioids which when removed can cause a withdrawal syndrome and difficulty in weaning from MV. We tested the hypothesis that the introduction of enteral methadone during weaning from sedation and analgesia in critically ill adult patients on MV would decrease the weaning time from MV. Methods: A double-blind randomized controlled trial was conducted in the adult intensive care units (ICUs) of four general hospitals in Brazil. The 75 patients, who met the criteria for weaning from MV and had been using fentanyl for more than five consecutive days, were randomized to the methadone (MG) or control group (CG). Within the first 24 hours after study enrollment, both groups received 80% of the original dose of fentanyl, the MG received enteral methadone and the CG received an enteral placebo. After the first 24 hours, the MG received an intravenous (IV) saline solution (placebo), while the CG received IV fentanyl. For both groups, the IV solution was reduced by 20% every 24 hours. The groups were compared by evaluating the MV weaning time and the duration of MV, as well as the ICU stay and the hospital stay. Results: Of the 75 patients randomized, seven were excluded and 68 were analyzed: 37 from the MG and 31 from the CG. There was a higher probability of early extubation in the MG, but the difference was not significant (hazard ratio: 1.52 (95% confidence interval (CI) 0.87 to 2.64; P = 0.11). The probability of successful weaning by the fifth day was significantly higher in the MG (hazard ratio: 2.64 (95% CI: 1.22 to 5.69; P < 0.02). Among the 54 patients who were successfully weaned (29 from the MG and 25 from the CG), the MV weaning time was significantly lower in the MG (hazard ratio: 2.06; 95% CI 1.17 to 3.63; P < 0.004). Conclusions: The introduction of enteral methadone during weaning from sedation and analgesia in mechanically ventilated patients resulted in a decrease in the weaning time from MV.

Comparison of 3 modes of automated weaning from mechanical ventilation: A bench study

Purpose: Automated weaning modes are available in some mechanical ventilators, but no studies compared them hitherto. We compared the performance of 3 automated modes under standard and challenging situations. Methods: We used a lung simulator to compare 3 automated modes, adaptive support ventilation (ASV), mandatory rate ventilation (MRV), and Smartcare, in 6 situations, weaning success, weaning failure, weaning success with extreme anxiety, weaning success with Cheyne-Stokes, weaning success with irregular breathing, and weaning failure with ineffective efforts. Results: The 3 modes correctly recognized the situations of weaning success and failure, even when anxiety or irregular breathing were present but incorrectly recognized weaning success with Cheyne-Stokes. MRV incorrectly recognized weaning failure with ineffective efforts. Time to pressure support (PS) stabilization was shorter for ASV (1-2 minutes for all situations) and MRV (1-7 minutes) than for Smartcare (8-78 minutes). ASV had higher rates of PS oscillations per 5 minutes (4-15), compared with Smartcare (0-1) and MRV (0-12), except when extreme anxiety was present. Conclusions: Smartcare, ASV, and MRV were equally able to recognize weaning success and failure, despite the presence of anxiety or irregular breathing but performed incorrectly in the presence of Cheyne-Stokes. PS behavior over the time differs among modes, with ASV showing larger and more frequent PS oscillations over the time. Clinical studies are needed to confirm our results. (C) 2012 Elsevier Inc. All rights reserved.

Low mechanical ventilation times and reintubation rates associated with a specific weaning protocol in an intensive care unit setting: a retrospective study

OBJECTIVES: A number of complications exist with invasive mechanical ventilation and with the use of and withdrawal from prolonged ventilator support. The use of protocols that enable the systematic identification of patients eligible for an interruption in mechanical ventilation can significantly reduce the number of complications. This study describes the application of a weaning protocol and its results. METHODS: Patients who required invasive mechanical ventilation for more than 24 hours were included and assessed daily to identify individuals who were ready to begin the weaning process. RESULTS: We studied 252 patients with a median mechanical ventilation time of 3.7 days (interquartile range of 1 to 23 days), a rapid shallow breathing index value of 48 (median), a maximum inspiratory pressure of 40 cmH2O, and a maximum expiratory pressure of 40 cm H2O (median). Of these 252 patients, 32 (12.7%) had to be reintubated, which represented weaning failure. Noninvasive ventilation was used postextubation in 170 (73%) patients, and 15% of these patients were reintubated, which also represented weaning failure. The mortality rate of the 252 patients studied was 8.73% (22), and there was no significant difference in the age, gender, mechanical ventilation time, and maximum inspiratory pressure between the survivors and nonsurvivors. CONCLUSIONS: The use of a specific weaning protocol resulted in a lower mechanical ventilation time and an acceptable reintubation rate. This protocol can be used as a comparative index in hospitals to improve the weaning system, its monitoring and the informative reporting of patient outcomes and may represent a future tool and source of quality markers for patient care.

Low pressure support changes the rapid shallow breathing index (RSBI) in critically ill patients on mechanical ventilation

Background: The rapid shallow breathing index (RSBI) is the most widely used index within intensive care units as a predictor of the outcome of weaning, but differences in measurement techniques have generated doubts about its predictive value. Objective: To investigate the influence of low levels of pressure support (PS) on the RSBI value of ill patients. Method: Prospective study including 30 patients on mechanical ventilation (MV) for 72 hours or more, ready for extubation. Prior to extubation, the RSBI was measured with the patient connected to the ventilator (Drager (TM) Evita XL) and receiving pressure support ventilation (PSV) and 5 cmH(2)O of positive end expiratory pressure or PEEP (RSBI_MIN) and then disconnected from the VM and connected to a Wright spirometer in which respiratory rate and exhaled tidal volume were recorded for 1 min (RSBI_ESP). Patients were divided into groups according to the outcome: successful extubation group (SG) and failed extubation group (FG). Results: Of the 30 patients, 11 (37%) failed the extubation process. In the within-group comparison (RSBI_MIN versus RSBI_ESP), the values for RSBI_MIN were lower in both groups: SG (34.79 +/- 4.67 and 60.95 +/- 24.64) and FG (38.64 +/- 12.31 and 80.09 +/- 20.71; p<0.05). In the between-group comparison, there was no difference in RSBI_MIN (34.79 +/- 14.67 and 38.64 +/- 12.31), however RSBI_ESP was higher in patients with extubation failure: SG (60.95 +/- 24.64) and FG (80.09 +/- 20.71; p<0.05). Conclusion: In critically ill patients on MV for more than 72h, low levels of PS overestimate the RSBI, and the index needs to be measured with the patient breathing spontaneously without the aid of pressure support.

Effects of intravenous furosemide on mucociliary transport and rheological properties of patients under mechanical ventilation

The use of intravenous (IV) furosemide is common practice in patients under mechanical ventilation (MV), but its effects on respiratory mucus are largely unknown. Furosemide can affect respiratory mucus either directly through inhibition of the NaK(Cl)2 co-transporter on the basolateral surface of airway epithelium or indirectly through increased diuresis and dehydration. We investigated the physical properties and transportability of respiratory mucus obtained from 26 patients under MV distributed in two groups, furosemide (n = 12) and control (n = 14). Mucus collection was done at 0, 1, 2, 3 and 4 hours. The rheological properties of mucus were studied with a microrheometer, and in vitro mucociliary transport (MCT) (frog palate), contact angle (CA) and cough clearance (CC) (simulated cough machine) were measured. After the administration of furosemide, MCT decreased by 17 ± 19%, 24 ± 11%, 18 ± 16% and 18 ± 13% at 1, 2, 3 and 4 hours respectively, P < 0.001 compared with control. In contrast, no significant changes were observed in the control group. The remaining parameters did not change significantly in either group. Our results support the hypothesis that IV furosemide might acutely impair MCT in patients under MV.

Noninvasive ventilation immediately after extubation improves weaning outcome after acute respiratory failure: a randomized controlled trial

Abstract Introduction Noninvasive ventilation (NIV), as a weaning-facilitating strategy in predominantly chronic obstructive pulmonary disease (COPD) mechanically ventilated patients, is associated with reduced ventilator-associated pneumonia, total duration of mechanical ventilation, length of intensive care unit (ICU) and hospital stay, and mortality. However, this benefit after planned extubation in patients with acute respiratory failure of various etiologies remains to be elucidated. The aim of this study was to determine the efficacy of NIV applied immediately after planned extubation in contrast to oxygen mask (OM) in patients with acute respiratory failure (ARF). Methods A randomized, prospective, controlled, unblinded clinical study in a single center of a 24-bed adult general ICU in a university hospital was carried out in a 12-month period. Included patients met extubation criteria with at least 72 hours of mechanical ventilation due to acute respiratory failure, after following the ICU weaning protocol. Patients were randomized immediately before elective extubation, being randomly allocated to one of the study groups: NIV or OM. We compared both groups regarding gas exchange 15 minutes, 2 hours, and 24 hours after extubation, reintubation rate after 48 hours, duration of mechanical ventilation, ICU length of stay, and hospital mortality. Results Forty patients were randomized to receive NIV (20 patients) or OM (20 patients) after the following extubation criteria were met: pressure support (PSV) of 7 cm H2O, positive end-expiratory pressure (PEEP) of 5 cm H2O, oxygen inspiratory fraction (FiO2) ≤ 40%, arterial oxygen saturation (SaO2) ≥ 90%, and ratio of respiratory rate and tidal volume in liters (f/TV) < 105. Comparing the 20 patients (NIV) with the 18 patients (OM) that finished the study 48 hours after extubation, the rate of reintubation in NIV group was 5% and 39% in OM group (P = 0.016). Relative risk for reintubation was 0.13 (CI = 0.017 to 0.946). Absolute risk reduction for reintubation showed a decrease of 33.9%, and analysis of the number needed to treat was three. No difference was found in the length of ICU stay (P = 0.681). Hospital mortality was zero in NIV group and 22.2% in OM group (P = 0.041). Conclusions In this study population, NIV prevented 48 hours reintubation if applied immediately after elective extubation in patients with more than 3 days of ARF when compared with the OM group. Trial Registration number ISRCTN: 41524441.

N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation

Campos R, Shimizu MH, Volpini RA, de Bragan a AC, Andrade L, Lopes FD, Olivo C, Canale D, Seguro AC. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 302: L640-L650, 2012. First published January 20, 2012; doi: 10.1152/ajplung.00097.2011.-Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the alpha-subunit of the epithelial sodium channel (alpha-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, alpha-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.

Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes and Clinical Outcomes Among Patients Without Acute Respiratory Distress Syndrome A Meta-analysis

Context Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with acute respiratory distress syndrome (ARDS). It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS. Objective To determine whether use of lower tidal volumes is associated with improved outcomes of patients receiving ventilation who do not have ARDS. Data Sources MEDLINE, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials up to August 2012. Study Selection Eligible studies evaluated use of lower vs higher tidal volumes in patients without ARDS at onset of mechanical ventilation and reported lung injury development, overall mortality, pulmonary infection, atelectasis, and biochemical alterations. Data Extraction Three reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. Data Synthesis Twenty articles (2822 participants) were included. Meta-analysis using a fixed-effects model showed a decrease in lung injury development (risk ratio [RR], 0.33; 95% CI, 0.23 to 0.47; I-2, 0%; number needed to treat [NNT], 11), and mortality (RR, 0.64; 95% CI, 0.46 to 0.89; I-2, 0%; NNT, 23) in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Meta-analysis using a random-effects model showed, in protective ventilation groups, a lower incidence of pulmonary infection (RR, 0.45; 95% CI, 0.22 to 0.92; I-2, 32%; NNT, 26), lower mean (SD) hospital length of stay (6.91 [2.36] vs 8.87 [2.93] days, respectively; standardized mean difference [SMD], 0.51; 95% CI, 0.20 to 0.82; I-2, 75%), higher mean (SD) PaCO2 levels (41.05 [3.79] vs 37.90 [4.19] mm Hg, respectively; SMD, -0.51; 95% CI, -0.70 to -0.32; I-2, 54%), and lower mean (SD) pH values (7.37 [0.03] vs 7.40 [0.04], respectively; SMD, 1.16; 95% CI, 0.31 to 2.02; I-2, 96%) but similar mean (SD) ratios of PaO2 to fraction of inspired oxygen (304.40 [65.7] vs 312.97 [68.13], respectively; SMD, 0.11; 95% CI, -0.06 to 0.27; I-2, 60%). Tidal volume gradients between the 2 groups did not influence significantly the final results. Conclusions Among patients without ARDS, protective ventilation with lower tidal volumes was associated with better clinical outcomes. Some of the limitations of the meta-analysis were the mixed setting of mechanical ventilation (intensive care unit or operating room) and the duration of mechanical ventilation. JAMA. 2012;308(16):1651-1659 www.jama.com

Endotracheal suction in intubated critically ill adult patients undergoing mechanical ventilation: a systematic review

AIM: identify and analyze in the literature the evidence of randomized controlled trials on care related to the suctioning of endotracheal secretions in intubated, critically ill adult patients undergoing mechanical ventilation. METHOD: the search was conducted in the PubMed, EMBASE, CENTRAL, CINAHL and LILACS databases. From the 631 citations found, 17 studies were selected. RESULTS: Evidence was identified for six categories of intervention related to endotracheal suctioning, which were analyzed according to outcomes related to hemodynamic and blood gas alterations, microbial colonization, nosocomial infection, and others. CONCLUSIONS: although the evidence obtained is relevant to the practice of endotracheal aspiration, the risks of bias found in the studies selected compromise the evidence's reliability.

The involvement of the spleen during chronic phase of Schistosoma mansoni infection in galectin-3(-/-) mice

Schistosoma mansoni synthesizes glycoconjugates which interact with galectin-3, eliciting an intense humoral immune response. Moreover, it was demonstrated that galectin-3 regulates B cell differentiation into plasma cells. Splenomegaly is a hallmark event characterized by polyclonal B cell activation and enhancement of antibody production. Here, we investigated whether galectin-3 interferes with spleen organization and B cell compartment during chronic schistosomiasis, using wild type (WT) and galectin-3(-/-) mice. In chronically-infected galectin-3(-/-) mice the histological architecture of the spleen, including white and red pulps, was disturbed with heterogeneous lymphoid follicles, an increased number of plasma cells (CD19(-)B220(-/low)CD138(+)) and a reduced number of macrophages (CD19(-)B220(-)Mac-1(+)CD138(-)) and B lymphocytes (CD19(+)B220(+/high)CD138(-)), compared with the WT infected mice. In the absence of galectin-3 there was an increase of annexin-V+PI- cells and a major presence of apoptotic cells in spleen compared with WT infected mice. In spleen of WT infected mice galectin-3 was largely expressed in lymphoid follicles and extrafollicular sites. Thus, we propose that galectin-3 plays a role in splenic architecture, controlling distinct events such as apoptosis, macrophage activity, B cell differentiation and plasmacytogenesis in the course of S. mansoni infection.

Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus

We compared outcomes of alveolar hemorrhage (AH) in juvenile (JSLE) and adult onset SLE (ASLE). From 263 JSLE and 1522 ASLE, the AH occurred in 13 (4.9%) and 15 (1.0%) patients, respectively (p < .001). Both groups had comparable disease duration (2.6 +/- 3.0 vs. 5.6 +/- 7.0 years, p = .151) and median SLEDAI scores [17.5 (2 to 32) vs. 17.5 (3 to 28), p = 1.000]. At AH onset, a higher frequency of JSLE were already on a high prednisone dose ( > 0.5 mg/kg/day) compared to ASLE (54% vs. 15%, p = .042). The mean drop of hemoglobin was significantly lower in JSLE (2.9 +/- 0.9 vs. 5.5 +/- 2.9 g/dL, p = .006). Although treatments with methylprednisolone, plasmapheresis, intravenous immunoglobulin and cyclophosphamide were similar in both groups (p > .050), regarding outcomes, there was a trend in high frequency of mechanical ventilation use (85% vs. 47%, p = .055) and also significant mortality (69% vs. 13%, p = .006) in JSLE compared to ASLE. The sepsis frequency was comparable in both groups (50% vs. 27%, p = .433). We have identified that AH in JSLE has a worse outcome most likely related to respiratory failure. The AH onset in JSLE already treated with high-dose steroids raises the concern of inadequate response to this treatment and reinforces the recommendation of early aggressive alternative therapies in this group of patients. Lupus (2012) 21, 872-877.

Fiber Post Cementation Strategies: Effect of Mechanical Cycling on Push-out Bond Strength and Cement Polymerization Stress

Purpose: To evaluate the effect of mechanical cycling and cementation strategies on the push-out bond strength between fiber posts and root dentin and the polymerization stresses produced using three resin cements. Materials and Methods: Eighty bovine mandibular teeth were sectioned to a length of 16 mm, prepared to 12 mm, and embedded in self-curing acrylic resin. The specimens were then distributed into 8 groups (n = 10): Gr1 - Scotchbond Multi Purpose + RelyX ARC; Gr2 - Scotchbond Multi Purpose + RelyX ARC + mechanical cycling; Gr3 - AdheSE + Multilink Automix; Gr4 - AdheSE + Multilink Automix + mechanical cycling; Gr5 - phosphoric acid + RelyX U100 (self-adhesive cement); Gr6 - phosphoric acid+ RelyX U100 + mechanical cycling; Gr7 - RelyX U100; Gr8 - RelyX U100 + mechanical cycling. The values obtained from the push-out bond strength test were submitted to two-way ANOVA and Tukey's test (p = 0.05), while the values obtained from the polymerization stress test were subjected to one-way ANOVA and Tukey's test (alpha = 0.05). Results: Mechanical cycling did not affect the bond strength values (p = 0.236), while cementation strategies affected the push-out bond strength (p < 0.001). Luting with RelyX U100 and Scotch Bond Multi Purpose + RelyX ARC yielded higher push-out bond strength values. The polymerization stress results were affected by the factor "cement" (p = 0.0104): the self-adhesive cement RelyX U100 exhibited the lowest values, RelyX ARC resulted in the highest values, while Multi link Automix presented values statistically similar to the other two cements. Conclusion: The self-adhesive cement appears to be a good alternative for luting fiber posts due to the high push-out bond strengths and lower polymerization stress values.

Celecoxib treatment does not alter recruitment and activation of osteoclasts in the initial phase of experimental tooth movement

In a previous study, we reported that the short-term treatment with celecoxib, a nonsteroidal anti-inflammatory drug (NSAID) attenuates the activation of brain structures related to nociception and does not interfere with orthodontic incisor separation in rats. The conclusion was that celecoxib could possibly be prescribed for pain in orthodontic patients. However, we did not analyze the effects of this drug in periodontium. The aim of this follow-up study was to analyze effects of celecoxib treatment on recruitment and activation of osteoclasts and alveolar bone resorption after inserting an activated orthodontic appliance between the incisors in our rat model. Twenty rats (400420 g) were pretreated through oral gavage with celecoxib (50 mg/kg) or vehicle (carboxymethylcellulose 0.4%). After 30 min, they received an activated (30 g) orthodontic appliance, set not to cause any palate disjunction. In sham animals, the appliance was immediately removed after introduction. All animals received ground food and, every 12 h, celecoxib or vehicle. After 48 h, they were anesthetized and transcardiacally perfused through the aorta with 4% formaldehyde. Subsequently, maxillae were removed, post-fixed and processed for histomorphometry or immunohistochemical analyses. As expected, incisor distalization induced an inflammatory response with certain histological changes, including an increase in the number of active osteoclasts at the compression side in group treated with vehicle (appliance: 32.2 +/- 2.49 vs sham: 4.8 +/- 1.79, P<0.05) and celecoxib (appliance: 31.0 +/- 1.45 vs sham: 4.6 +/- 1.82, P<0.05). The treatment with celecoxib did not modify substantially the histological alterations and the number of active osteoclasts after activation of orthodontic appliance. Moreover, we did not see any difference between the groups with respect to percentage of bone resorption area. Taken together with our previous results we conclude that short-term treatment with celecoxib can indeed be a therapeutic alternative for pain relieve during orthodontic procedures.

Chemopreventive effects of the dietary histone deacetylase inhibitor tributyrin alone or in combination with vitamin A during the promotion phase of rat hepatocarcinogenesis

The chemopreventive effects of tributyrin (TB) and vitamin A (VA), alone or in combination, were investigated during the promotion phase of rat hepatocarcinogenesis. Compared to diethylnitrosamine control rats. TB and TB+VA-treated rats, but not VA-treated rats, presented a lower incidence and mean number of hepatocyte nodules and a smaller size of persistent preneoplastic lesions (pPNLs). In addition, TB and TB+VA-treated rats exhibited a higher apoptotic body index in pPNL and remodeling PNL, whereas VA-treated rats presented only a higher apoptotic body index in remodeling PNL. None of the treatments inhibited cell proliferation in PNL TB and TB+VA-treated rats, but not VA-treated rats, exhibited higher levels of H3K9 acetylation and p21 protein expression. TB and VA-treated rats exhibited increased hepatic concentrations of butyric acid and retinoids, respectively. Compared to normal rats, diethylnitrosamine control animals exhibited lower retinyl palmitate hepatic concentrations. All groups had similar expression levels and exhibited similar unmethylated CRBP-I promoter region in microdissected pPNL, indicating that epigenetic silencing of this gene was not involved in alteration of retinol metabolism in early hepatocarcinogenesis. Data support the effectiveness of TB as a dietary histone deacetylase inhibitor during the promotion phase of hepatocarcinogenesis, which should be considered for chemoprevention combination strategies. (C) 2012 Elsevier Inc. All rights reserved.