Tidal volume selection in volume-controlled ventilation guided by driving pressure versus actual body weight in healthy anesthetized and mechanically ventilated dogs: A randomized crossover trial.

OBJECTIVE: To compare static compliance of the respiratory system (CstRS) and the ratio of partial pressure of end-tidal to arterial carbon dioxide (Pe'CO2/PaCO2), in healthy dogs using two approaches for tidal volume (VT) selection during volume-controlled ventilation: body mass based and driving pressure (ΔPaw) guided. STUDY DESIGN: Randomized, nonblinded, crossover, clinical trial. ANIMALS: A total of 19 client-owned dogs anesthetized for castration and ovariohysterectomy. METHODS: After a stable 10 minute baseline, each dog was mechanically ventilated with a VT selection strategy, randomized to a constant VT of 15 mL kg-1 of actual body mass (VTBW) or ΔPaw-guided VT (VTΔP) of 7-8 cmH2O. Both strategies used an inspiratory time of 1 second, 20% end-inspiratory pause, 4 cmH2O positive end-expiratory pressure and fraction of inspired oxygen of 0.4. Respiratory frequency was adjusted to maintain Pe'CO2 between 35 and 40 mmHg. Respiratory mechanics, arterial blood gases and Pe'CO2/PaCO2 were assessed. Continuous variables are presented as mean ± SD or median (interquartile range; quartiles 1-3), depending on distribution, and compared with Wilcoxon signed-rank tests. RESULTS: The VT was significantly higher in dogs ventilated with VTΔP than with VTBW strategy (17.20 ± 4.04 versus 15.03 ± 0.60 mL kg-1, p = 0.036). CstRS was significantly higher with VTΔP than with VTBW strategy [2.47 (1.86-2.86) versus 2.25 (1.79-2.58) mL cmH2O-1 kg-1, p = 0.011]. There were no differences in Pe'CO2/PaCO2 between VTΔP and VTBW strategies (0.94 ± 0.06 versus 0.92 ± 0.06, p = 0.094). No discernible difference in ΔPaw was noted between the strategies. CONCLUSIONS AND CLINICAL RELEVANCE: While no apparent difference was observed in the Pe'CO2/PaCO2 between the VT selection strategies employed, CstRS significantly increased during the VTΔP approach. A future trial should explore if VTΔP improves perioperative gas exchange and prevents lung damage.

Beneficial effects of recombinant CER-001 high-density lipoprotein infusion in sepsis: results from a bench to bedside translational research project.

BACKGROUND: Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function. METHODS: We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20 mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20 mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5 mg/kg BID, n = 5), Group C (CER-001 10 mg/kg BID, n = 5), and Group D (CER-001 20 mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers. RESULTS: CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay. CONCLUSIONS: CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage. TRIAL REGISTRATION: The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020-004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021.

Laparoscopic salpingectomy in Papio hamadryas for birth control in captivity.

OBJECTIVE: To evaluate the feasibility of laparoscopic salpingectomy in baboons (Papio hamadryas). We hypothesized that laparoscopic salpingectomy could be performed in baboon species within a reasonable amount of surgical time, with minor complications occurring at low rates. STUDY DESIGN: Case series and technique description. ANIMALS: Sixteen baboons (n = 16). METHODS: The surgical procedures were performed using the 3-port technique, with 5 mm instruments and a telescope placed at the umbilical and hypogastric regions. A salpinx dissection was performed, using a radiofrequency bipolar vessel sealing device, from the fimbriae to the uterine attachments. We evaluated the surgical duration, learning curve, and intraoperative and early postoperative complications. RESULTS: Ten adult and 6 subadult baboons with a mean weight of 9.32 kg, a range of 4-14.2 kg, and a standard deviation (SD) of 3.09 kg were included in the study. The total duration of surgery was 28.75 min (range, 16-50 min; SD, 9.60 min). The installation phase was completed in a mean time of 7.68 min (range, 3-15 min; SD, 3.43 min), and the time to complete the salpingectomy of both salpinges was 9.68 min (range, 4-20 min; SD, 3.97 min). No complications were observed in the postoperative period. CONCLUSION: Laparoscopic salpingectomy in Papio hamadryas was feasible, with an acceptable surgical time, low invasiveness, and only minor technical perioperative complications. CLINICAL SIGNIFICANCE: Laparoscopic salpingectomy could be a viable and safe therapeutic option in nonhuman primate birth-control programs.

Lung aeration and volumes following alveolar recruitment maneuvers with three airway pressures in healthy anesthetized and mechanically ventilated Beagle dogs.

OBJECTIVE: To compare the effects of three recruitment airway pressures (RPaw) on lung aeration and volumes in mechanically ventilated dogs during propofol anesthesia. STUDY DESIGN: Prospective, crossover randomized experimental study. ANIMALS: A total of eight healthy anesthetized experimental Beagle dogs in dorsal recumbency. METHODS: Dogs were mechanically ventilated with a tidal volume of 15 mL kg-1 and zero positive end-expiratory pressure and 100% oxygen. Three maneuvers consisting of a 30 second inspiration at RPaws of 15 (RPaw15), 25 (RPaw25) and 35 (RPaw35) cmH2O were performed randomly, 15 minutes apart. Changes in lung aeration and lung deformation were compared with end-expiratory baseline (before the application of each RPaw) and between-RPaws using computed tomography scans and calculations of global lung strain. Between-group comparisons were performed with one-way anova for repeated measures followed by Tukey test for multiple comparisons. A p value < 0.05 was considered significant. RESULTS: The amount of nonaeration was minimal (<1%) at baseline and not different with the application of the RPaws. The amount of hypoaeration and normoaeration during baseline decreased with all RPaws (p < 0.001). There was no difference between RPaws regarding hypoaeration (all p > 0.999), whereas normoaeration was higher at RPaw15 than RPaw25 and RPaw35 (p < 0.009). Compared with baseline, the fraction of hyperaerated alveoli increased with each RPaw (p < 0.001) and was lower during RPaw15 than RPaw25 and RPaw35 (both p ≤ 0.007). Global lung strain was lower during RPaw15 than at higher RPaw (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: A RPaw of 15 cmH2O for 30 seconds was the recommended RPaw because it was as effective at reversing hypoaeration as RPaws of 25 and 35 cmH2O but with less hyperaeration and potential for overdistension of the lungs in this particular population of dogs with negligible atelectasis.

Preliminary evaluation of the effects of a 1:1 inspiratory-to-expiratory ratio in anesthetized and ventilated horses.

OBJECTIVE: To describe some cardiorespiratory effects of an inspiratory-to-expiratory (IE) ratio of 1:1 compared with 1:3 in ventilated horses in dorsal recumbency. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A total of eight anesthetized horses, with 444 (330-485) kg body weight [median (range)]. METHODS: Horses were ventilated in dorsal recumbency with a tidal volume of 15 mL kg-1 and a respiratory rate of 8 breaths minute-1, and IE ratios of 1:1 (IE1:1) and 1:3 (IE1:3) in random order, each for 25 minutes after applying a recruitment maneuver. Spirometry, arterial blood gases and dobutamine requirements were recorded in all horses during each treatment. Electrical impedance tomography (EIT) data were recorded in four horses and used to generate functional EIT variables including regional ventilation delay index (RVD), a measure of speed of lung inflation, and end-expiratory lung impedance (EELI), an indicator of functional residual capacity (FRC). Results were assessed with linear and generalized linear mixed models. RESULTS: Compared with treatment IE1:3, horses ventilated with treatment IE1:1 had higher mean airway pressures and respiratory system compliance (p < 0.014), while peak, end-inspiratory and driving airway pressures were lower (p < 0.001). No differences in arterial oxygenation or dobutamine requirements were observed. PaCO2 was lower in treatment IE1:1 (p = 0.039). Treatment IE1:1 resulted in lower RVD (p < 0.002) and higher EELI (p = 0.023) than treatment IE1:3. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that IE1:1 improved respiratory system mechanics and alveolar ventilation compared with IE1:3, whereas oxygenation and dobutamine requirements were unchanged, although differences were small. In the four horses where EIT was evaluated, IE1:1 led to a faster inflation rate of the lung, possibly the result of increased FRC. The clinical relevance of these findings needs to be further investigated.

Absorbable fixation straps for laparoscopic gastropexy in dogs.

OBJECTIVE: To evaluate the feasibility and efficacy of laparoscopic absorbable fixation straps (AFS) for laparoscopic gastropexy in dogs. STUDY DESIGN: Cadaveric and prospective clinical study. ANIMALS: Five dog cadavers for the cadaveric study; 12 dogs for the clinical study. METHODS: The pyloric antrum was affixed to the abdominal wall laparoscopically by applying a series of straps. The cadaveric study assessed potential challenges during the procedure and stomach mucosal penetration. For the clinical study, the total duration of surgery, time to complete the gastropexy, and the number of straps used were recorded. Ultrasound evidence of adhesion, complications, and weight were monitored at 7, 30, and 90 days after surgery. Owner satisfaction was evaluated at the 6-month follow-up. RESULTS: The total duration of surgery was 25.8 minutes (range, 19-39; SD, 6.7), and the time to complete the gastropexy was 10.1 minutes (range, 7-19; SD, 3.9). The linear regression analysis revealed an inverse correlation between the time to complete the gastropexy and the order of the surgeries (r2  = 0.75, P < .05). No complications were recorded. Ultrasound examination was used to confirm gastropexy at all follow-ups. CONCLUSION: Laparoscopic gastropexy with AFS was performed in both cadavers and clinical animals with minimal complications. Persistent adhesion was demonstrated during ultrasound evaluations and in one postmortem evaluation. CLINICAL SIGNIFICANCE: This novel laparoscopic technique can be employed safely, effectively, and reasonably quickly, and the learning curve is expected to be relatively short.

Clinical efficacy of dexmedetomidine combined with lidocaine for femoral and sciatic nerve blocks in dogs undergoing stifle surgery.

OBJECTIVE: To evaluate the effects of dexmedetomidine administered perineurally or intramuscularly (IM) on sensory, motor function and postoperative analgesia produced by lidocaine for sciatic and femoral nerve blocks in dogs undergoing unilateral tibial tuberosity advancement surgery. STUDY DESIGN: Prospective, blinded, clinical study. ANIMALS: A group of 30 dogs. METHODS: Dogs were anaesthetized with acepromazine, propofol and isoflurane in oxygen/air. Electrolocation-guided femoral and sciatic nerve blocks were performed: group L, 0.15 mL kg-1 2% lidocaine (n = 10); group LDloc, lidocaine and 0.15 µg kg-1 dexmedetomidine perineurally (n = 10); group LDsys, lidocaine and 0.3 µg kg-1 dexmedetomidine IM (n = 10). After anaesthesia, sensory blockade was evaluated by response to forceps pinch on skin innervated by the saphenous/femoral, common fibular and tibial nerves. Motor blockade was evaluated by observing the ability to walk and proprioception. Analgesia was monitored with Short Form of Glasgow Composite Pain Scale for up to 4 hours after extubation. Methadone IM was administered as rescue analgesia. Data were analysed by linear mixed effect models and Kaplan-Meier test (p < 0.05). RESULTS: Median duration of the sensory blockade for all nerves was longer (p < 0.001) for group LDloc than for groups L and LDsys and was longer (p = 0.0011) for group LDsys than for group L. Proprioception returned later (p < 0.001) for group LDloc [285 (221-328) minutes] compared with group L [160 (134-179) minutes] or LDsys [195 (162-257) minutes]. Return of the ability to walk was similar among all groups. Dogs in group LDloc required postoperative rescue analgesia later (p = 0.001) than dogs in groups LDsys and L. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine administered perineurally with lidocaine prolonged sensory blockade and analgesia during the immediate postoperative period. Systemic dexmedetomidine also prolonged the sensory blockade of perineural lidocaine.

Definition and clinical evaluation of a recruiting airway pressure based on the specific lung elastance in anesthetized dogs.

OBJECTIVE: To determine the specific lung elastance (SEL) in anesthetized dogs and to evaluate the efficacy of a SEL-based recruiting airway pressure (RPaw) at improving global and regional lung aeration. STUDY DESIGN: Retrospective and prospective clinical study. ANIMALS: A total of 28 adult dogs were included in the retrospective study and six adult dogs in the prospective study. METHODS: Retrospective study: SEL and SEL-based RPaw were determined using previously published data. In mechanically ventilated dogs undergoing thoracic computed tomography (CT), SEL was calculated as ΔPL/(VT/EELV), where ΔPL is the driving transpulmonary pressure, VT is the tidal volume and EELV is the end-expiratory lung volume. The ratio of lung to respiratory system elastance (EL/Ers) was determined. SEL and EL/Ers were used to calculate the SEL-based RPaw. Prospective study: dogs underwent thoracic CT at end-expiration and at end-inspiration using the SEL-based RPaw, and global and regional aeration was determined. For analysis of regional aeration, lungs were divided into cranial, intermediate and caudal regions. Regional compliance was also calculated. A p value <0.05 was considered significant. RESULTS: The SEL and EL/Ers were 12.7 ± 3.1 cmH2O and 0.54 ± 0.07, respectively. The SEL-based RPaw was 29.1 ± 7.6 cmH2O. In the prospective study, the RPaw was 28.2 ± 1.3 cmH2O. During RPaw, hyperinflation increased (p = 0.0003) whereas poorly aerated (p < 0.0001) and nonaerated (p = 0.01) tissue decreased. Normally aerated tissue did not change (p = 0.265). Regional compliance was higher in the intermediate (p = 0.0003) and caudal (p = 0.034) regions compared with the cranial region. Aeration did not differ between regions (p > 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: An SEL-based RPaw reduces poorly and nonaerated lung tissue in anesthetized dogs. In nonsurgical anesthetized dogs, an RPaw near 30 cmH2O is effective at improving lung aeration.

Effects of topical application of tramadol with/without dexmedetomidine and proparacaine on corneal sensitivity in rats.

PURPOSE: To evaluate the corneal anesthetic effect following topical application of tramadol alone and in combination with dexmedetomidine, and compare it to proparacaine, in clinically healthy rats. METHODS: A randomized, crossover study was performed. Twenty Wistar albino rats (n = 40 eyes) were used. Corneal touch threshold (CTT) measurements (in mm) were obtained using a Cochet-Bonnet aesthesiometer. CTT measurements were obtained at baseline, 1-min following application of the topical anesthetic agent, and repeated at 5-min intervals up to 75 min. The topical protocol involved 3 treatment conditions, separated by a 2-week washout period: proparacaine, tramadol alone, and tramadol in combination with dexmedetomidine. RESULTS: CTT values were significantly decreased compared to baseline at each timepoint until completion of the 75-min evaluation in all treated eyes, regardless of the assigned treatment (p < 0.0083). With tramadol, complete corneal anesthesia (CTT = 0) was achieved within 1-5 min in 18 eyes and ranged from 5 to 25 min. Co-administration of dexmedetomidine to tramadol resulted in significantly increased CTT values from 5 to 20 min following topical application, compared to tramadol alone (p < 0.0083), and complete corneal anesthesia was achieved in only 14 out of 20 treated eyes. CONCLUSION: Tramadol might be a useful alternative to topical anesthetic agents, providing a dose-related corneal anesthetic effect. Co-administration of dexmedetomidine does not potentiate its anesthetic effect. The underlying mechanism(s) of drug antagonism between tramadol and dexmedetomidine remains to be determined.

Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides.

Endothelial dysfunction is a hallmark of LPS-induced acute kidney injury (AKI). Endothelial cells (ECs) acquired a fibroblast-like phenotype and contributed to myofibroblast generation through the endothelial-to-mesenchymal transition (EndMT) process. Of note, human adult renal stem/progenitor cells (ARPCs) enhance the tubular regenerative mechanism during AKI but little is known about their effects on ECs. Following LPS exposure, ECs proliferated, decreased EC markers CD31 and vascular endothelial cadherin, and up-regulated myofibroblast markers, collagen I, and vimentin. The coculture with ARPCs normalized the EC proliferation rate and abrogated the LPS-induced EndMT. The gene expression analysis showed that most of the genes modulated in LPS-stimulated ARPCs belong to cell activation and defense response pathways. We showed that the ARPC-specific antifibrotic effect is exerted by the secretion of CXCL6, SAA4, and BPIFA2 produced after the anaphylatoxin stimulation. Next, we investigated the molecular signaling that underlies the ARPC protective mechanism and found that renal progenitors diverge from differentiated tubular cells and ECs in myeloid differentiation primary response 88-independent pathway activation. Finally, in a swine model of LPS-induced AKI, we observed that activated ARPCs secreted CXCL6, SAA4, and BPIFA2 as a defense response. These data open new perspectives on the treatment of both sepsis- and endotoxemia-induced AKI, suggesting an underestimated role of ARPCs in preventing endothelial dysfunction and novel strategies to protect the endothelial compartment and promote kidney repair.-Sallustio, F., Stasi, A., Curci, C., Divella, C., Picerno, A., Franzin, R., De Palma, G., Rutigliano, M., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Pertosa, G. B., Castellano, G., Gallone, A., Gesualdo, L. Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides.

Continuous assessment of neuro-ventilatory drive during 12 h of pressure support ventilation in critically ill patients.

INTRODUCTION: Pressure support ventilation (PSV) should allow spontaneous breathing with a "normal" neuro-ventilatory drive. Low neuro-ventilatory drive puts the patient at risk of diaphragmatic atrophy while high neuro-ventilatory drive may causes dyspnea and patient self-inflicted lung injury. We continuously assessed for 12 h the electrical activity of the diaphragm (EAdi), a close surrogate of neuro-ventilatory drive, during PSV. Our aim was to document the EAdi trend and the occurrence of periods of "Low" and/or "High" neuro-ventilatory drive during clinical application of PSV. METHOD: In 16 critically ill patients ventilated in the PSV mode for clinical reasons, inspiratory peak EAdi peak (EAdiPEAK), pressure time product of the trans-diaphragmatic pressure per breath and per minute (PTPDI/b and PTPDI/min, respectively), breathing pattern and major asynchronies were continuously monitored for 12 h (from 8 a.m. to 8 p.m.). We identified breaths with "Normal" (EAdiPEAK 5-15 µV), "Low" (EAdiPEAK < 5 µV) and "High" (EAdiPEAK > 15 µV) neuro-ventilatory drive. RESULTS: Within all the analyzed breaths (177.117), the neuro-ventilatory drive, as expressed by the EAdiPEAK, was "Low" in 50.116 breath (28%), "Normal" in 88.419 breaths (50%) and "High" in 38.582 breaths (22%). The average times spent in "Low", "Normal" and "High" class were 1.37, 3.67 and 0.55 h, respectively (p < 0.0001), with wide variations among patients. Eleven patients remained in the "Low" neuro-ventilatory drive class for more than 1 h, median 6.1 [3.9-8.5] h and 6 in the "High" neuro-ventilatory drive class, median 3.4 [2.2-7.8] h. The asynchrony index was significantly higher in the "Low" neuro-ventilatory class, mainly because of a higher number of missed efforts. CONCLUSIONS: We observed wide variations in EAdi amplitude and unevenly distributed "Low" and "High" neuro ventilatory drive periods during 12 h of PSV in critically ill patients. Further studies are needed to assess the possible clinical implications of our physiological findings.

LPS removal reduces CD80-mediated albuminuria in critically ill patients with Gram-negative sepsis.

LPS-induced sepsis is a leading cause of acute kidney injury (AKI) in critically ill patients. LPS may induce CD80 expression in podocytes with subsequent onset of proteinuria, a risk factor for progressive chronic kidney disease (CKD) frequently observed after AKI. This study aimed to investigate the therapeutic efficacy of LPS removal in decreasing albuminuria through the reduction of podocyte CD80 expression. Between January 2015 and December 2017, 70 consecutive patients with Gram-negative sepsis-induced AKI were randomized to either have coupled plasma filtration and adsorption (CPFA) added to the standard care ( n = 35) or not ( n = 35). To elucidate the possible relationship between LPS-induced renal damage, proteinuria, and CD80 expression in Gram sepsis, a swine model of LPS-induced AKI was set up. Three hours after LPS infusion, animals were treated or not with CPFA for 6 h. Treatment with CPFA significantly reduced serum cytokines, C-reactive protein, procalcitonin, and endotoxin levels in patients with Gram-negative sepsis-induced AKI. CPFA significantly lowered also proteinuria and CD80 urinary excretion. In the swine model of LPS-induced AKI, CD80 glomerular expression, which was undetectable in control pigs, was markedly increased at the podocyte level in LPS-exposed animals. CPFA significantly reduced LPS-induced proteinuria and podocyte CD80 expression in septic pigs. Our data indicate that LPS induces albuminuria via podocyte expression of CD80 and suggest a possible role of timely LPS removal in preventing the maladaptive repair of the podocytes and the consequent increased risk of CKD in sepsis-induced AKI.

LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling.

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRß expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-ß, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRß and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-ß signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-ß and underwent PMT also upon TGF-ß receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI.

Effects of positive end-expiratory pressure alone or an open-lung approach on recruited lung volumes and respiratory mechanics of mechanically ventilated horses.

OBJECTIVE: To evaluate the effects of positive end-expiratory pressure (PEEP) alone and PEEP preceded by lung recruitment manoeuvre (LRM) on lung volumes and respiratory system mechanics in healthy horses undergoing general anaesthesia. STUDY DESIGN: Controlled, prospective clinical study. ANIMALS: A group of 15 horses undergoing arthroscopy. METHODS: Following anaesthetic induction, initial ventilatory settings were: tidal volume 15 mL kg-1, inspiratory:expiratory ratio 1:2, respiratory rate to maintain end-tidal CO2 between 5.3-6.6 kPa (40-50 mmHg). The following settings were implemented sequentially: zero PEEP (ZEEP); PEEP 10 cmH2O (PEEP); LRM (50 cmH2O for 20 seconds) followed by 10 cmH2O of PEEP (LRM + PEEP). Static compliance (Cst), driving pressure, delta end-expiratory (ΔEELV) and recruited lung volumes (RLV) were obtained 30 minutes after initiating each ventilatory strategy. Data were analyzed with paired t test or analysis of variance followed by Tukey's post hoc test. Data are shown as mean ± standard deviation; p < 0.05 was considered significant. RESULTS: PEEP induced ΔEELV of 6.68 ± 3.36 mL kg-1; ΔEELV during LRM + PEEP was 14.28 ± 5.59 mL kg-1 (p < 0.0001). The RLV was greater during the LRM + PEEP phase (12.30 ± 5.85 mL kg-1) than during PEEP (4.47 ± 3.97 mL kg-1; p < 0.0001). The Cst was unchanged from ZEEP to PEEP (0.75 ± 0.21 and 0.85 ± 0.22 mL cmH2O-1 kg-1, respectively, p = 0.36) but increased using LRM + PEEP (1.11 ± 0.25 mL cmH2O-1 kg-1, p = 0.0004). Driving pressure was lower during LRM + PEEP than during PEEP and ZEEP (16 ± 2, 19 ± 2 and 21 ± 4 cmH2O, respectively, p < 0.0001). CONCLUSIONS AND CLINICAL RELEVANCE: Unlike PEEP alone, PEEP preceded by LRM increased RLV and Cst and reduced driving pressure in horses under anaesthesia.

High-flow nasal cannula oxygen therapy decreases postextubation neuroventilatory drive and work of breathing in patients with chronic obstructive pulmonary disease.

BACKGROUND: The physiological effects of high-flow nasal cannula O2 therapy (HFNC) have been evaluated mainly in patients with hypoxemic respiratory failure. In this study, we compared the effects of HFNC and conventional low-flow O2 therapy on the neuroventilatory drive and work of breathing postextubation in patients with a background of chronic obstructive pulmonary disease (COPD) who had received mechanical ventilation for hypercapnic respiratory failure. METHODS: This was a single center, unblinded, cross-over study on 14 postextubation COPD patients who were recovering from an episode of acute hypercapnic respiratory failure of various etiologies. After extubation, each patient received two 1-h periods of HFNC (HFNC1 and HFNC2) alternated with 1 h of conventional low-flow O2 therapy via a face mask. The inspiratory fraction of oxygen was titrated to achieve an arterial O2 saturation target of 88-92%. Gas exchange, breathing pattern, neuroventilatory drive (electrical diaphragmatic activity (EAdi)) and work of breathing (inspiratory trans-diaphragmatic pressure-time product per minute (PTPDI/min)) were recorded. RESULTS: EAdi peak increased from a mean (±SD) of 15.4 ± 6.4 to 23.6 ± 10.5 µV switching from HFNC1 to conventional O2, and then returned to 15.2 ± 6.4 µV during HFNC2 (conventional O2: p < 0.05 versus HFNC1 and HFNC2). Similarly, the PTPDI/min increased from 135 ± 60 to 211 ± 70 cmH2O/s/min, and then decreased again during HFNC2 to 132 ± 56 (conventional O2: p < 0.05 versus HFNC1 and HFNC2). CONCLUSIONS: In patients with COPD, the application of HFNC postextubation significantly decreased the neuroventilatory drive and work of breathing compared with conventional O2 therapy.

A preliminary study evaluating cardiac output measurement using Pressure Recording Analytical Method (PRAM) in anaesthetized dogs.

BACKGROUND: Haemodynamic variations normally occur in anaesthetized animals, in relation to the animal status, administered drugs, sympathetic and parasympathetic tone, fluid therapy and surgical stimulus. The possibility to measure some cardiovascular parameters, such as cardiac output (CO), during anaesthesia would be beneficial for both the anaesthesia management and its outcome. New techniques for the monitoring of CO are aimed at finding methods which are non invasive, accurate and with good trending ability, which can be used in a clinical setting. The aim of this study was to compare the Pressure Recording Analytical Method (PRAM) with the pulmonary artery thermodilution (TD) for the measurement of cardiac output in 6 anaesthetized critically ill dogs. RESULTS: Fifty-four pairs of CO measurements were obtained with a median (range) of 3.33 L/min (0.81-7.21) for PRAM-CO and 3.48 L/min (1.41-6.56) for TD-CO. The Bland-Altman analysis showed a mean bias of 0.17 L/min with limits of agreement (LoA) of - 0.46 to 0.81 L/min. The percentage error resulted 18.2%. The 4-quadrant plot analysis showed an acceptable concordance (93%) between the 2 methods. The polar plot showed a good trending ability with the mean angular bias of 3.9° and radial LoA ± 12.1°. CONCLUSIONS: The PRAM resulted in good precision, acceptable concordance and good trending ability for the measure of CO in the anaesthetized dog, representing a promising alternative to thermodilution for the measurement of CO. Among all the pulse contour methods available on the market it is the only one that does not require any calibration or adjustment of the measurement. Further studies are required to verify the ability of this method to accurately measure cardiac output even during unstable hemodynamic conditions.

Perioperative analgesic effects of an ultrasound-guided transversus abdominis plane block with a mixture of bupivacaine and lidocaine in cats undergoing ovariectomy.

OBJECTIVE: To evaluate the perioperative analgesic effects of a transversus abdominis plane (TAP) block with a mixture of lidocaine and bupivacaine administered to cats undergoing ovariectomy. STUDY DESIGN: Controlled, randomized, prospective, blinded clinical study. ANIMALS: A group of 20 healthy cats. METHODS: Robenacoxib (2 mg kg-1) was administered subcutaneously 0.5 hour before intramuscular (IM) administration of ketamine (5 mg kg-1), methadone (0.1 mg kg-1) and dexmedetomidine (0.01 mg kg-1). General anesthesia was induced with intravenous (IV) propofol and maintained with isoflurane. An ultrasound-guided TAP block was performed by injecting 0.5% bupivacaine (0.2 mL kg-1) diluted in a total volume of 1.5 mL 2% lidocaine bilaterally (TAP group, n = 10) or the same volume of saline solution bilaterally in controls (CTR group, n = 10). During surgery, a 20% increase in heart rate and respiratory frequency was treated with IV fentanyl (0.001 mg kg-1). Before premedication and at 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 hours after extubation, pain was assessed with a simple descriptive pain scale, that ranged from 0 (no pain) to 4 (intense pain). For pain scores ≥3, IM methadone (0.1 mg kg-1) was administered. Data were analyzed with the Friedman or the analysis of variance (anova) test, and p < 0.05 was considered statistically significant. RESULTS: Only two cats in the CTR group were administered one dose of fentanyl during surgery. At 2, 6, 8, 12, 16, 20 and 24 hours after surgery, the pain score was higher in the CTR group. A mean dose of 0.5 ± 0.2 mg kg-1 methadone was administered to all cats in the CTR groups within 24 hours. Methadone was not administered to the TAP group (pain score < 3). CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasound-guided TAP block can be a reliable adjunctive technique, providing analgesia for up to 24 hours in cats undergoing ovariectomy.

An alveolar recruitment maneuver followed by positive end-expiratory pressure improves lung function in healthy dogs undergoing laparoscopy.

OBJECTIVE: To evaluate the effects of an alveolar recruitment maneuver (ARM) followed by 5 cmH2O positive end-expiratory pressure (PEEP) in dogs undergoing laparoscopy. STUDY DESIGN: Prospective, randomized clinical study. ANIMALS: A group of 20 dogs undergoing laparoscopic ovariectomy. METHODS: Dogs were sedated with acepromazine and methadone intramuscularly; anesthesia was induced with propofol intravenously and maintained with inhaled isoflurane. The following baseline ventilatory setting (BVS) was administered: tidal volume of 12 mL kg-1, inspiratory to expiratory ratio of 1:2, inspiratory pause 25% of inspiratory time, no PEEP and a respiratory rate to maintain end-tidal carbon dioxide tension between 5.3 and 7.3 kPa. Then, 10 minutes after the pneumoperitoneum, 10 dogs (RM) underwent a sustained inflation ARM followed by BVS plus 5 cmH2O PEEP, while 10 dogs (NO-RM) were left with BVS throughout the procedure. Gas exchange and respiratory system mechanics were evaluated before the pneumoperitoneum (PPpre), before ARM (PP10), 30 minutes later (PP30) and 20 minutes after pneumoperitoneum discontinuation (PPpost20). Data were analyzed using anova (p < 0.05). RESULTS: The Fshunt at PP30 and PPpost20 was lower (p < 0.001) in the RM (2.3 ± 2.2 and 4.7 ± 3.7%) than in the NO-RM (5.2 ± 2.1 and 11.1 ± 5.2%), and PaO2 at PP30 and PPpost20 was higher (p < 0.001) in the RM (67.3 ± 4.2 and 60.1 ± 9.4 kPa) than in the NO-RM (50.2 ± 7.4 and 45.5 ± 11.1 kPa). Static compliance of the respiratory system at PP30 and PPpost20 was greater (p < 0.001) in the RM (2.4 ± 0.2 and 2.1 ± 0.4 mL cmH2O-1 kg-1) than in the NO-RM (0.9 ± 0.4 and 1.2 ± 0.2 mL cmH2O-1 kg-1). CONCLUSIONS AND CLINICAL RELEVANCE: In dogs undergoing laparoscopy, ARM followed by 5 cmH2O PEEP improves gas exchange and respiratory system mechanics.

Impact of prolonged assisted ventilation on diaphragmatic efficiency: NAVA versus PSV.

BACKGROUND: Prolonged controlled mechanical ventilation depresses diaphragmatic efficiency. Assisted modes of ventilation should improve it. We assessed the impact of pressure support ventilation versus neurally adjusted ventilator assist on diaphragmatic efficiency. METHOD: Patients previously ventilated with controlled mechanical ventilation for 72 hours or more were randomized to be ventilated for 48 hours with pressure support ventilation (n =12) or neurally adjusted ventilatory assist (n = 13). Neuro-ventilatory efficiency (tidal volume/diaphragmatic electrical activity) and neuro-mechanical efficiency (pressure generated against the occluded airways/diaphragmatic electrical activity) were measured during three spontaneous breathing trials (0, 24 and 48 hours). Breathing pattern, diaphragmatic electrical activity and pressure time product of the diaphragm were assessed every 4 hours. RESULTS: In patients randomized to neurally adjusted ventilator assist, neuro-ventilatory efficiency increased from 27 ± 19 ml/µV at baseline to 62 ± 30 ml/µV at 48 hours (p <0.0001) and neuro-mechanical efficiency increased from 1 ± 0.6 to 2.6 ± 1.1 cmH2O/µV (p = 0.033). In patients randomized to pressure support ventilation, these did not change. Electrical activity of the diaphragm, neural inspiratory time, pressure time product of the diaphragm and variability of the breathing pattern were significantly higher in patients ventilated with neurally adjusted ventilatory assist. The asynchrony index was 9.48 [6.38- 21.73] in patients ventilated with pressure support ventilation and 5.39 [3.78- 8.36] in patients ventilated with neurally adjusted ventilatory assist (p = 0.04). CONCLUSION: After prolonged controlled mechanical ventilation, neurally adjusted ventilator assist improves diaphragm efficiency whereas pressure support ventilation does not. TRIAL REGISTRATION: ClinicalTrials.gov study registration: NCT02473172, 06/11/2015.

WHICH AIRWAY PRESSURE SHOULD BE APPLIED DURING BREATH-HOLD IN DOGS UNDERGOING THORACIC COMPUTED TOMOGRAPHY?

This randomized controlled trial study aimed to identify the optimal positive pressure (PP) level that can clear atelectasis while avoiding pulmonary hyperinflation during the breath-hold technique in dogs undergoing thoracic computed tomography (CT). Sixty dogs affected by mammary tumors undergoing thoracic CT for the screening of pulmonary metastases were randomly assigned to six groups with different levels of PP during the breath-hold technique: 0 (control), 5 (PP5), 8 (PP8), 10 (PP10), 12 (PP12), and 15 (PP15) cmH2 O. The percentage of atelectatic lung region was lower in the PP10 (3.7 ± 1.1%; P = 0.002), PP12 (3.4 ± 1.3%; P = 0.0001), and PP15 (2.8 ± 0.9%; P = 0.006) groups than in the control group (5.0 ± 2.3%), and the percentage of poorly aerated lung region was lower in the PP8 (15.1 ± 2.6%; P = 0.0009), PP10 (13.0 ± 2.0 %; P = 0.002), PP12 (13.0 ± 2.2 %; P = 0.0002), and PP15 (11.1 ± 1.9%; P = 0.0002) groups than in the control group (19.8 ± 5.0). The percentage of normally aerated lung region, however, was higher in the PP10 (79.7 ± 4.1%; P = 0.005), PP12 (79.8 ± 5.1%; P = 0.0002), and PP15 (80.2 ± 4.9%; P = 0.002) groups than in the control group (73.4 ± 6.6%). A PP of 10-12 cmH2 O during the breath-hold technique should be considered to improve lung aeration during a breath-hold technique in dogs undergoing thoracic CT.