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Background: Pulse wave transit time (PWTT) shows promise for monitoring intravascular fluid status intraoperatively. Presently, it is unknown how PWTT mirrors haemodynamic variables representing preload, inotropy, or afterload., Methods: PWTT was measured continuously in 24 adult volunteers. Stroke volume was assessed by transthoracic echocardiography. Volunteers underwent four randomly assigned manoeuvres: 'Stand-up' (decrease in preload), passive leg raise (increase in preload), a 'step-test' (adrenergic stimulation), and a 'Valsalva manoeuvre' (increase in intrathoracic pressure). Haemodynamic measurements were performed before and 1 and 5 min after completion of each manoeuvre. Correlations between PWTT and stroke volume were analysed using the Pearson correlation coefficient., Results: 'Stand-up' caused an immediate increase in PWTT (mean change +55.9 ms, P -value <0.0001, 95% confidence interval 46.0-65.7) along with an increase in mean arterial pressure and heart rate and a drop in stroke volume ( P -values <0.0001). Passive leg raise caused an immediate drop in PWTT (mean change -15.4 ms, P -value=0.0024, 95% confidence interval -25.2 to -5.5) along with a decrease in mean arterial pressure ( P -value=0.0052) and an increase in stroke volume ( P -value=0.001). After 1 min, a 'step-test' caused no significant change in PWTT measurements ( P -value=0.5716) but an increase in mean arterial pressure and heart rate ( P -values <0.0001), without changes in stroke volume ( P -value=0.1770). After 5 min, however, PWTT had increased significantly ( P -value <0.0001). Measurements after the Valsalva manoeuvre caused heterogeneous results., Conclusion: Noninvasive assessment of PWTT shows promise to register immediate preload changes in healthy adults. The clinical usefulness of PWTT may be hampered by late changes because of reasons different from fluid shifts., Clinical Trial Registration: German clinical trial register (DRKS, ID: DRKS00031978, https://www.drks.de/DRKS00031978)., (© 2024 The Authors.)

Background: Sepsis is a common disease in intensive care units worldwide, which is associated with high morbidity and mortality. This process is often associated with multiple organ failure including acute lung injury. Although massive research efforts have been made for decades, there is no specific therapy for sepsis to date. Early and best treatment is crucial. Lidocaine is a common local anesthetic and used worldwide. It blocks the fast voltage-gated sodium (Na + ) channels in the neuronal cell membrane responsible for signal propagation. Recent studies show that lidocaine administered intravenously improves pulmonary function and protects pulmonary tissue in pigs under hemorrhagic shock, sepsis and under pulmonary surgery. The aim of this study is to show that lidocaine inhalative induces equivalent effects as lidocaine intravenously in pigs in a lipopolysaccharide (LPS)-induced sepsis with acute lung injury., Methods: After approval of the local State and Institutional Animal Care Committee, to induce the septic inflammatory response a continuous infusion of lipopolysaccharide (LPS) was administered to the pigs in deep anesthesia. Following induction and stabilisation of sepsis, the study medication was randomly assigned to one of three groups: (1) lidocaine intravenously, (2) lidocaine per inhalation and (3) sham group. All animals were monitored for 8 h using advanced and extended cardiorespiratory monitoring. Postmortem assessment included pulmonary mRNA expression of mediators of early inflammatory response (IL-6 & TNF-alpha), wet-to-dry ratio and lung histology., Results: Acute respiratory distress syndrome (ARDS) was successfully induced after sepsis-induction with LPS in all three groups measured by a significant decrease in the PaO 2 /FiO 2 ratio. Further, septic hemodynamic alterations were seen in all three groups. Leucocytes and platelets dropped statistically over time due to septic alterations in all groups. The wet-to-dry ratio and the lung histology showed no differences between the groups. Additionally, the pulmonary mRNA expression of the inflammatory mediators IL-6 and TNF-alpha showed no significant changes between the groups. The proposed anti-inflammatory and lung protective effects of lidocaine in sepsis-induced acute lung injury could not be proven in this study., Competing Interests: Erik K. Hartmann is an Academic Editor for PeerJ., (© 2023 Rissel et al.)

Background: Traditional fasting rules for children prior to elective operations ("6‑4‑2 rule") often lead to prolonged fasting times with possible adverse events (discomfort, hypoglycemia, metabolic disorders, agitation/delirium). A new liberal fasting policy allowing children to drink clear fluids until being called to the operating room ("6‑4‑0") was established in our university hospital. This article describes our experiences and retrospectively examines the effects., Objective: Evaluation of real fasting times before and up to 6 months after the intervention (success and durability of changing fasting policy). Evaluation of impact on outcome parameters, such as patients' resp. parents' satisfaction as well as perioperative agitation, arterial hypotension after induction and postoperative nausea and vomiting (PONV)., Material and Methods: Retrospective evaluation of methods and interventions from 1 month before to 6 months after changing the fasting policy (June-December 2020). Statistical analysis using descriptive statistics, odds ratio and χ 2 -test., Results: Of 216 analyzed patients 44 were in the pre-change group and 172 in the post-change group. We could significantly reduce clear fluids fasting times over the 6 months after the intervention (median fasting time: from 6.1 h to 4.5 h; p = 0.034) and achieve our aim (fasting time for clear fluids less than or equal to 2h) in 47% of the patients. Fasting times became longer again reaching pre-change intervals in the 4th and 5th month, so reminder measures turned out to be necessary. By reminding the staff we could reduce fasting times again in the 6th month and restore patients' resp. parents' satisfaction. Satisfaction was improved by shorter fasting times (median school grade from 2.8 to 2.2; p = 0.004; odds ratio for better satisfaction 5.24, 2.1-13.2), and preoperative agitation was reduced (agitation modified PAED scale 1-2 in only 34.5% instead of 50%, p = 0.032). In the liberal fasting group, we observed a nonsignificant smaller incidence of hypotension after induction (7% vs. 14%, p = 0.26) while PONV was too rare in both groups for statistical purposes., Conclusion: With multiple interventions we could significantly reduce fasting times for clear fluids and improve patients' resp. parents' satisfaction as well as preoperative agitation. These interventions included regular presence in all staff meetings, a handout for both parents and staff, as well as a remark on the anesthesia protocol. Children who were operated on later in the day, benefited most from the new liberal fasting policy as they were allowed to drink until being called to the operating room. Following our experience, we consider simple and safe fasting rules for the whole staff as most important for change management. Nevertheless, we could not reduce the fasting intervals in all cases and had to remind the staff after 5 months to preserve this success. For enduring success, we suggest regular staff updates during the change process instead of one single kick-off information event., (© 2023. The Author(s).)

Purpose: Frailty is a frequent and underdiagnosed multidimensional age-related syndrome, involving decreased physiological performance reserves and marked vulnerability against major stressors. To standardize the preoperative frailty assessment and identify patients at risk of adverse surgical outcomes, commonly used global health assessment tools were evaluated. We aimed to assess three interdisciplinary preoperative screening assessments to investigate the influence of frailty status with in-hospital complications irrespective of surgical complexity and radicality in older women with ovarian cancer (OC)., Methods: Preoperative frailty status was examined by the G8 geriatric screening tool (G8 Score-geriatric screening), Eastern Cooperative Oncology Group performance status (ECOG PS-oncological screening), and American Society of Anesthesiologists Physical Status System (ASA PS-anesthesiologic screening). The main outcome measures were the relationship between perioperative laboratory results, intraoperative surgical parameters and the incidence of immediate postoperative in-hospital complications with the preoperative frailty status., Results: 116 consecutive women 60 years and older (BMI 24.8 ± 5.2 kg/m 2 ) with OC, who underwent elective oncological surgery in University Medical Center Mainz between 2008 and 2019 were preoperatively classified with the selected global health assessment tools as frail or non-frail. The rate of preoperative anemia (hemoglobin ≤ 12 g/dl) and perioperative transfusions were significantly higher in the G8-frail group (65.9% vs. 34.1%; p = 0.006 and 62.7% vs. 41.8%, p = 0.031; respectively). In addition, patients preoperatively classified as G8-frail exhibited significantly more postoperative clinical in-hospital complications (27.8% vs. 12.5%, p = 0.045) independent of chronological age and BMI. In contrast, ECOG PS and ASA PS did not predict the rates of postoperative complications (all p values > 0.05). After propensity score matching, the complication rate in the G8-frail cohort was approximately 1.7 times more common than in the G8-non-frail cohort., Conclusion: Preoperative frailty assessment with the G8 Score identified elderly women with OC recording a significantly higher rate of postoperative in-hospital complications. In G8-frail patients, preoperative anemia and perioperative transfusions were significantly more recorded, regardless of chronological age, abnormal BMI and surgical complexity. Standardized preoperative frailty assessment should be added to clinical routine care to enhance risk stratification in older cancer individuals for surgical patient-centered decision-making., (© 2022. The Author(s).)

Aims: Influencing the inflammatory response represents an important branch in ARDS research. The naturally occurring polyphenol derivative resveratrol has already been confirmed to have strong anti-inflammatory effects on the cardiac and metabolic system. In the present study, we investigated the propagated anti-inflammatory effects of intravenous resveratrol in a porcine ARDS model., Main Methods: 20 domestic pigs (30 ± 2 kg; approval G20-1-135), divided into three groups: 1. resveratrol high dose (HD; n = 8), single bolus of 20 mg/kg over 15 min. 2. resveratrol low dose (LD; n = 8), single bolus of 10 mg/kg over 15 min. 3. Vehicle (n = 4), with the carrier solution DMSO over 15 min administered after ARDS induction. ARDS induction: using BAL/oleic acid and a subsequent test period of 8 h. Measurement parameters: Hemodynamics/spirometry data were collected continuously, BGA/laboratory parameters repetitively. Post-mortem: analysis of pulmonary inflammatory markers., Statistics: Two-way analysis of variance (repeated measurement) and Student-Newman-Keuls method., Key Findings: Resveratrol HD significantly reduced the expression of TNF-alpha in lung tissue compared to the LD group (p < 0.05). A significantly increased functional residual capacity (FRC) could be demonstrated for the HD group at the end of the test (p < 0.05 for HD vs. LD/vehicle). Further, resveratrol HD reduced statistically the EVLWI compared to LD/vehicle (p < 0.05 at T4/T8)., Significance: In this study, resveratrol HD ameliorated pulmonary mechanics as reported for the FRC and EVLWI. Further, the proposed anti-inflammatory effects of resveratrol, a significant reduction in the expression of TNF-alpha was observed in the HD group., Competing Interests: Declaration of competing interest René Rissel worked as an editor for Life Sciences. The other authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The optimal ventilation strategy during cardiopulmonary resuscitation (CPR) has eluded scientists for years. This porcine study aims to validate the hypothesis that ultra-low tidal volume ventilation (tidal volume 2-3 mL kg -1 ; ULTVV) minimizes renal and hepatic end-organ damage when compared to standard intermittent positive pressure ventilation (tidal volume 8-10 mL kg -1 ; IPPV) during CPR. After induced ventricular fibrillation, the animals were ventilated using an established CPR protocol. Upon return of spontaneous circulation (ROSC), the follow-up was 20 h. After sacrifice, kidney and liver samples were harvested and analyzed histopathologically using an Endothelial, Glomerular, Tubular, and Interstitial (EGTI) scoring system for the kidney and a newly developed scoring system for the liver. Of 69 animals, 5 in the IPPV group and 6 in the ULTVV group achieved sustained ROSC and were enlisted, while 4 served as the sham group. Creatinine clearance was significantly lower in the IPPV-group than in the sham group ( p < 0.001). The total EGTI score was significantly higher for ULTVV than for the sham group ( p = 0.038). Aminotransferase levels and liver score showed no significant difference between the intervention groups. ULTVV may be advantageous when compared to standard ventilation during CPR in the short-term ROSC follow-up period.

Background: Aim of this study is to test the predictive value of Pulse Wave Transit Time (PWTT) for fluid responsiveness in comparison to the established fluid responsiveness parameters pulse pressure (ΔPP) and corrected flow time (FTc) during major abdominal surgery., Methods: Forty patients undergoing major abdominal surgery were enrolled with continuous monitoring of PWTT (LifeScope® Modell J BSM-9101 Nihon Kohden Europe GmbH, Rosbach, Germany) and stroke volume (Esophageal Doppler Monitoring CardioQ-ODM®, Deltex Medical Ltd, Chichester, UK). In case of hypovolemia (difference in pulse pressure [∆PP] ≥ 9%, corrected flow time [FTc] ≤ 350 ms) a fluid bolus of 7 ml/kg ideal body weight was administered. Receiver operating characteristics (ROC) curves and corresponding areas under the curve (AUCs) were used to compare different methods of determining PWTT. A Wilcoxon test was used to discriminate fluid responders (increase in stroke volume of ≥ 10%) from non-responders. The predictive value of PWTT for fluid responsiveness was compared by testing for differences between ROC curves of PWTT, ΔPP and FTc using the methods by DeLong., Results: AUCs (area under the ROC-curve) to predict fluid responsiveness for PWTT-parameters were 0.61 (raw c finger Q), 0.61 (raw c finger R), 0.57 (raw c ear Q), 0.53 (raw c ear R), 0.54 (raw non-c finger Q), 0.52 (raw non-c finger R), 0.50 (raw non-c ear Q), 0.55 (raw non-c ear R), 0.63 (∆ c finger Q), 0.61 (∆ c finger R), 0.64 (∆ c ear Q), 0.66 (∆ c ear R), 0.59 (∆ non-c finger Q), 0.57 (∆ non-c finger R), 0.57 (∆ non-c ear Q), 0.61 (∆ non-c ear R) [raw measurements vs. ∆ = respiratory variation; c = corrected measurements according to Bazett's formula vs. non-c = uncorrected measurements; Q vs. R = start of PWTT-measurements with Q- or R-wave in ECG; finger vs. ear = pulse oximetry probe location]. Hence, the highest AUC to predict fluid responsiveness by PWTT was achieved by calculating its respiratory variation (∆PWTT), with a pulse oximeter attached to the earlobe, using the R-wave in ECG, and correction by Bazett's formula (AUC best-PWTT 0.66, 95% CI 0.54-0.79). ∆PWTT was sufficient to discriminate fluid responders from non-responders (p = 0.029). No difference in predicting fluid responsiveness was found between best-PWTT and ∆PP (AUC 0.65, 95% CI 0.51-0.79; p = 0.88), or best-PWTT and FTc (AUC 0.62, 95% CI 0.49-0.75; p = 0.68)., Conclusion: ΔPWTT shows poor ability to predict fluid responsiveness intraoperatively. Moreover, established alternatives ΔPP and FTc did not perform better., Trial Registration: Prior to enrolement on clinicaltrials.gov (NC T03280953; date of registration 13/09/2017)., (© 2023. The Author(s).)

Purpose: The aim of this retrospective study was to evaluate the prognostic impact of global health status assessment tools in elderly patients with endometrial cancer (EC) on survival., Methods: Preoperative frailty status was assessed by the G8 geriatric screening tool (G8 Score), Lee Schonberg prognostic index, Charlson Comorbidity index and American Society of Anesthesiologists Physical Status System in women older than 60 years with EC. Univariable and multivariable Cox-regression analyses, as well as Kaplan-Meier survival analyses were performed to determine the prognostic impact. Statistical analyses were adjusted for cancer entity-specific risk factors such as conventional histopathological tumor characteristics and relevant anamnestic life style parameters., Results: 153 patients with all stages of EC who were operated at the University Medical Center Mainz between 2008 and 2019 were included. In multivariable analyses, only the G8 Score retained independent significance as a prognostic factor for disease-specific survival (DSS) (HR:4.58; 95% CI [1.35-15.51]) and overall survival (OS) (HR:2.89; 95% CI [1.31-6.39]. 92 patients (61.3%) were classified as G8-non-frail with a significantly increased DSS and OS rate compared to the 58 G8-frail patients (DSS:93.8% vs. 60.8%; p < 0.001 and OS:88.2% vs. 49.7%; p < 0.001; respectively)., Conclusions: This is the first study demonstrates the substantial clinical and prognostic impact of the G8 Score on survival in elderly women with EC. Assessing the frailty status to estimate the individual vulnerability of elderly cancer patients could be useful in preoperative decision-making to individualize treatment plans such as the surgical radicality and to improve pre- and postoperative morbidity., (© 2022. The Author(s).)

Competing Interests: Conflicts of interest: The Medumat respirator (type MEDUMAT Standard², Weinmann Emergency Medical Technology GmbH + Co. KG, Germany) and the LUCAS 2-System (Stryker, Kalamazoo, USA) were provided unconditionally by the manufacturers for animal research purposes only.

Introduction: Perioperative red blood cell (RBC) transfusions have been associated with increased morbidity and worse oncological outcome in some solid neoplasms. In order to elucidate whether RBC transfusions themselves, the preoperative anemia of cancer (AOC), or the impaired global health status might explain this impact on patients with endometrial cancer (EC) or ovarian cancer (OC), we performed a retrospective, single-institution cohort study., Materials and Methods: Women older than 60 years with EC or OC were included. The influence of RBC transfusions, AOC, and frailty status determined by the G8 geriatric screening tool (G8 score), as well as the clinical-pathological cancer characteristics on progression-free survival (PFS) and overall survival (OS), was determined by using the Kaplan-Meier method and the Cox regression analyses., Results: In total, 263 patients with EC (n = 152) and OC (n = 111) were included in the study. Patients with EC receiving RBC transfusions were faced with a significantly shorter 5-year PFS (79.8% vs. 26.0%; p < 0.001) and 5-year OS (82.6% vs. 25.7%; p < 0.001). In multivariable analyses, besides established clinical-pathological cancer characteristics, the RBC transfusions remained the only significant prognostic parameter for PFS (HR: 1.76; 95%-CI [1.01-3.07]) and OS (HR: 2.38; 95%-CI [1.50-3.78]). In OC, the G8 score stratified the cohort in terms of PFS rates (G8-non-frail 53.4% vs. G8-frail 16.7%; p = 0.010) and AOC stratified the cohort for 5-year OS estimates (non-anemic: 36.7% vs. anemic: 10.6%; p = 0.008). Multivariable Cox regression analyses determined the G8 score and FIGO stage as independent prognostic factors in terms of PFS (HR: 2.23; 95%-CI [1.16-4.32] and HR: 6.52; 95%-CI [1.51-28.07], respectively). For OS, only the TNM tumor stage retained independent significance (HR: 3.75; 95%-CI [1.87-7.53])., Discussion: The results of this trial demonstrate the negative impact of RBC transfusions on the prognosis of patients with EC. Contrastingly, the prognosis of OC is altered by the preoperative global health status rather than AOC or RBC transfusions. In summary, we suggested a cumulatively restrictive transfusion management in G8-non-frail EC patients and postulated a more moderate transfusion management based on the treatment of symptomatic anemia without survival deficits in OC patients., Competing Interests: KA reports personal fees from Eisai, Roche, MSD. MWS reports holding a patent WO 2021/176091 A1 not related to this study. SK received speaker Honoria, research funding and travek reimbursement from Vovartis Pharma GmbH Germany. MS reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Roche, and SeaGen outside the submitted work. Institutional research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre, and SeaGen. In addition, MS has a patent for EP 2390370 B1 and a patent for EP 2951317 B1issued. RS reports honoraria and expenses from Roche Pharma AG and AstraZeneca GmbH. AH reports honoraria and expenses from AstraZeneca, FBA Frauenärzte BundesAkademie GmbH, KlarigoVerlag, MedConcept, Med public GmbH, Med update GmbH, Medicultus, Pfizer, Promedicis GmbH, Pierre Fabre Pharma GmbH, Softconsult, Roche Pharma AG, Streamedup! GmbH, Tesaro Bio Germany GmbH. I am consultant to PharmaMar, Promedicis GmbH, Pierre Fabre Pharma GmbH, Roche Pharma AG and Tesaro Bio Germany GmbH. I have received funded research from Celgene. MB reports honoraria and expenses from Pharma Mar, Astra Zeneca, Tesaro, GSK, Roche, Clovis Oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Anic, Schmidt, Schmidt, Krajnak, Löwe, Linz, Schwab, Weikel, Brenner, Westphalen, Rissel, Hartmann, Conradi, Hasenburg and Battista.)

Background: Acute respiratory distress syndrome (ARDS) is a common disease in intensive care medicine. Despite intensive research, mortality rates are high, not even in COVID-19 ARDS. Thereby, pigs offer some advantages to study the characteristics of ARDS. Many different ARDS models exist. Most of the articles published focused on histopathological and microscopic lung alterations to identify the most suitable animal ARDS model. "Macroscopic" observations and descriptions are often missing. Therefore, we performed a post-hoc comparison of two common ARDS models for pigs: lipopolysaccharide (LPS) vs. a double-hit model (bronchoalveolar lavage + oleic acid infusion). We investigated hemodynamic, spirometric and laboratory changes as another main clinical part of ARDS., Results: The groups were compared by two-way analysis of variance (ANOVA) with a post-hoc Student-Newman-Keuls test. A p value lower than 0.05 was accepted as significant. All animals (n = 8 double-hit ARDS; n = 8 LPS ARDS) survived the observation period of 8 h. ARDS induction with reduced oxygen indices was successful performed in both models (76 ± 35/225 ± 54/212 ± 79 vs. 367 ± 64; T0/T4/T8 vs. BLH for double-hit; 238 ± 57/144 ± 59 vs. 509 ± 41; T4/T8 vs. BLH for LPS; p < 0.05). ARDS induced with LPS leads to more hemodynamic (mean arterial pulmonary pressure 35 ± 3/30 ± 3 vs. 28 ± 4/23 ± 4; T4/T8 LPS vs. double-hit; p < 0.05; doses of norepinephrine 1.18 ± 1.05 vs. 0.11 ± 0.16; LPS vs. double-hit for T8; p < 0.05) and inflammatory (pulmonary IL-6 expression: 2.41e-04 ± 1.08e-04 vs. 1.45e-05 ± 7.26e-06; LPS vs. double-hit; p < 0.05) alterations. ARDS induced by double-hit requires a more invasive ventilator strategy to maintain a sufficient oxygenation (PEEP at T4: 8 ± 3 vs. 6 ± 2; double-hit vs. LPS; p < 0.05)., Conclusions: Both animal ARDS models are feasible and are similar to human presentation of ARDS. If your respiratory research focus on hemodynamic/inflammation variables, the LPS-induced ARDS is a feasible model. Studying different ventilator strategies, the double-hit ARDS model offers a suitable approach., (© 2022. The Author(s).)

Epidural analgesia could influence the postoperative oncologic outcomes in patients with specific types of non-metastatic solid neoplasms. The present study aimed to investigate the impact of anesthetic technique on survival in elderly patients with ovarian cancer (OC). The records of all women with OC older than 60 years of age undergoing tumor debulking surgery at the University Medical Center of the Johannes Gutenberg University Mainz (Mainz, Germany) between January 2008 and December 2019 were obtained. The study cohort was divided into two groups based on the use of perioperative epidural anesthesia or not. First, Kaplan-Meier analysis was performed to analyze the prognostic influence of anesthetic technique on survival. Second, multivariate Cox proportional hazards model was adjusted for multiple conventional prognostic factors concerning three main categories: i) Current clinical-pathological tumor characteristics; ii) anesthesiologic parameters, including mean age, American Society of Anesthesiologists Performance Status and preexisting comorbidities summarized in the Charlson Comorbidity Index; and iii) oncological and surgical parameters such as oncological radicality and Surgical complexity Score. A total of 110 patients were included in the study and 71 (64.5%) of them received epidural analgesia. The median survival time was 26.0 months from primary debulking surgery and no significant differences in progression-free (PFS) and overall survival (OS) were noted between the 'Epidural' and 'non-Epidural' cohorts. After adjustment for the selected risk factors from the three categories, the effects of epidural analgesia on PFS and OS remained non-significant [PFS: hazard ratio (HR), 1.26; 95% CI, 0.66-2.39; and OS: HR, 0.79; 95% CI, 0.45-1.40]. The present results did not support the independent association between epidural-supplemented anesthesia and improved PFS or OS in elderly patients with standardized ovarian cancer debulking surgery., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Anic et al.)

Endotracheal intubation is often a basic requirement for translational research in porcine models for various interventions that require a secured airway or high ventilation pressures. Endotracheal intubation is a challenging skill, requiring a minimum number of successful endotracheal intubations to achieve a high success rate under optimal conditions, which is often unachievable for non-anaesthesiology researchers. Due to the specific porcine airway anatomy, a difficult airway can usually be assumed. The impossibility of establishing a secure airway can result in injury, adverse events, or death of the laboratory animal. Using a prospective, randomized, controlled evaluation approach, it has been shown that fiberoptic-assisted endotracheal intubation takes longer but has a higher first-pass success rate than conventional intubation without causing clinically relevant drops in oxygen saturation. This model presents a standardized regimen for endoscopically guided endotracheal intubation, providing a secured airway, especially for researchers who are inexperienced in the technique of endotracheal intubation via direct laryngoscopy. This procedure is expected to minimize animal suffering and unnecessary animal losses.

Background: Invasive ventilation during cardiopulmonary resuscitation (CPR) is very complex due to unique thoracic pressure conditions. Current guidelines do not provide specific recommendations for ventilation during ongoing chest compressions regarding positive end-expiratory pressure (PEEP). This trial examines the cardiopulmonary effects of PEEP application during CPR. Methods: Forty-two German landrace pigs were anaesthetised, instrumented, and randomised into six intervention groups. Three PEEP levels (0, 8, and 16 mbar) were compared in high standard and ultralow tidal volume ventilation. After the induction of ventricular fibrillation, mechanical chest compressions and ventilation were initiated and maintained for thirty minutes. Blood gases, ventilation/perfusion ratio, and electrical impedance tomography loops were taken repeatedly. Ventilation pressures and haemodynamic parameters were measured continuously. Postmortem lung tissue damage was assessed using the diffuse alveolar damage (DAD) score. Statistical analyses were performed using SPSS, and p values <0.05 were considered significant. Results: The driving pressure (Pdrive) showed significantly lower values when using PEEP 16 mbar than when using PEEP 8 mbar (p = 0.045) or PEEP 0 mbar (p < 0.001) when adjusted for the ventilation mode. Substantially increased overall lung damage was detected in the PEEP 0 mbar group (vs. PEEP 8 mbar, p = 0.038; vs. PEEP 16 mbar, p = 0.009). No significant differences in mean arterial pressure could be detected. Conclusion: The use of PEEP during CPR seems beneficial because it optimises ventilation pressures and reduces lung damage without significantly compromising blood pressure. Further studies are needed to examine long-term effects in resuscitated animals.

The calcium sensitiser levosimendan, which is used as an inodilator to treat decompensated heart failure, may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan improves cardiopulmonary function and is substantially beneficial to the inflammatory response in acute respiratory response syndrome (ARDS). Levosimendan was administered intravenously in a new experimental porcine model of ARDS. For comparison, we used milrinone, another well-known inotropic agent. Our results demonstrated that levosimendan intravenously improved hemodynamics and lung function in a porcine ARDS model. Significant beneficial alterations in the inflammatory response and lung injury were not detected.

Background: Interorgan cross-talk describes the phenomenon in which a primarily injured organ causes secondary damage to a distant organ. This cross-talk is well known between the lung and brain. One theory suggests that the release and systemic distribution of cytokines via the bloodstream from the primarily affected organ sets in motion proinflammatory cascades in distant organs. In this study, we analysed the role of the systemic distribution of cytokines via the bloodstream in a porcine ARDS model for organ cross-talk and possible inflammatory changes in the brain., Methods: After approval of the State and Institutional Animal Care Committee, acute respiratory distress syndrome (ARDS) induction with oleic acid injection was performed in seven animals. Eight hours after ARDS induction, blood (35-40 ml kg -1 ) was taken from these seven 'ARDS donor' pigs. The collected 'ARDS donor' blood was transfused into seven healthy 'ARDS-recipient' pigs. Three animals served as a control group, and blood from these animals was transfused into three healthy pigs after an appropriate ventilation period. All animals were monitored for 8 h using advanced cardiorespiratory monitoring. Postmortem assessment included cerebral (hippocampal and cortex) mediators of early inflammatory response (IL-6, TNF-alpha, iNOS, sLCN-2), wet-to-dry ratio and lung histology. TNF-alpha serum concentration was measured in all groups., Results: ARDS was successfully induced in the 'ARDS donor' group, and serum TNF-alpha levels were elevated compared with the 'ARDS-recipient' group. In the 'ARDS-recipient' group, neither significant ARDS alterations nor upregulation of inflammatory mediators in the brain tissue were detected after high-volume random allogenic 'ARDS-blood' transfusion. The role of the systemic distribution of inflammatory cytokines from one affected organ to another could not be confirmed in this study., Competing Interests: Erik Hartmann is an Academic Editor for PeerJ., (© 2022 Rissel et al.)

Background: Shedding of the endothelial glycocalyx can be observed regularly during sepsis. Moreover, sepsis may be associated with acute respiratory distress syndrome (ARDS), which requires lung protective ventilation with the two cornerstones of application of low tidal volume and positive end-expiratory pressure. This study investigated the effect of a lung protective ventilation on the integrity of the endothelial glycocalyx in comparison to a high tidal volume ventilation mode in a porcine model of sepsis-induced ARDS., Methods: After approval by the State and Institutional Animal Care Committee, 20 male pigs were anesthetized and received a continuous infusion of lipopolysaccharide to induce septic shock. The animals were randomly assigned to either low tidal volume ventilation, high tidal volume ventilation, or no-LPS-group groups and observed for 6 h. In addition to the gas exchange parameters and hematologic analyses, the serum hyaluronic acid concentrations were determined from central venous blood and from pre- and postpulmonary and pre- and postcerebral circulation. Post-mortem analysis included histopathological evaluation and determination of the pulmonary and cerebral wet-to-dry ratios., Results: Both sepsis groups developed ARDS within 6 h of the experiment and showed significantly increased serum levels of hyaluronic acid in comparison to the no-LPS-group. No significant differences in the hyaluronic acid concentrations were detected before and after pulmonary and cerebral circulation. There was also no significant difference in the serum hyaluronic acid concentrations between the two sepsis groups. Post-mortem analysis showed no significant difference between the two sepsis groups., Conclusion: In a porcine model of septic shock and ARDS, the serum hyaluronic acid levels were significantly elevated in both sepsis groups in comparison to the no-LPS-group. Intergroup comparison between lung protective ventilated and high tidal ventilated animals revealed no significant differences in the serum hyaluronic acid levels., Competing Interests: Erik K. Hartmann is an Academic Editor for PeerJ., (© 2022 Thomas et al.)

Background: We evaluated the prognostic impact of various global health assessment tools in patients older than 60 years with ovarian cancer (OC)., Methods: G-8 geriatric screening tool (G-8 score), Lee Schonberg prognostic index, Eastern Cooperative Oncology Group (ECOG) performance status, and Charlson Comorbidity Index (CCI) were determined retrospectively in a consecutive cohort of elderly patients with OC. Univariate and multivariate Cox regression analyses and Kaplan-Meier method were performed to analyze the impact of the preoperative global health status on survival., Results: 116 patients entered the study. In multivariate analysis adjusted for clinical-pathological factors, only the G-8 score retained significance as a prognostic parameter of progression-free survival (PFS) (hazard ratio [HR]: 1.970; 95% confidence interval [CI] [1.056-3.677]; p = 0.033). Fifty-six patients were classified as G-8-nonfrail with an increased PFS compared to 50 G-8-frail patients (53.4% vs. 16.7%; p = 0.010). A higher CCI was associated with decreased PFS (45.1% vs. 22.2%; p = 0.012), but it did not influence the risk of recurrences or death (p = 0.360; p = 0.111). The Lee Schonberg prognostic index, the ECOG, and age were not associated with survival., Conclusions: The G-8 score independently predicted PFS in elderly OC patients regardless of maximal surgical effort. Thus, it could be useful to assess surgical treatment based on frailty rather than age alone., (© 2021 S. Karger AG, Basel.)

Background: Many patients with acute respiratory distress syndrome (ARDS) suffer from cognitive impairment after hospital discharge. Different mechanisms have been implicated as potential causes for this impairment, inter alia cerebral inflammation. A class of drugs with antioxidant and anti-inflammatory properties are β-HMG-CoA-reductase inhibitors ("statins"). We hypothesized that treatment with rosuvastatin attenuates cerebral cytokine mRNA expression and nitro-oxidative stress in an animal model of acute lung injury., Methods: After approval of the institutional and state animal care committee, we performed this prospective randomized controlled animal study in accordance with the international guidelines for the care and use of laboratory animals. Thirty-two healthy male pigs were randomized to one of four groups: lung injury by central venous injection of oleic acid (n = 8), statin treatment before and directly after lung injury (n = 8), statin treatment after lung injury (n = 8), or ventilation-only controls (n = 8). About 18 h after lung injury and standardized treatment, the animals were euthanised, and the brains and lungs were collected for further examinations. We determined histologic lung injury and cerebral and pulmonal cytokine and 3-nitrotyrosine production., Results: We found a significant increase in hippocampal IL-6 mRNA after lung injury (p < 0.05). Treatment with rosuvastatin before and after induction of lung injury led to a significant reduction of hippocampal IL-6 mRNA (p < 0.05). Cerebral 3-nitrotyrosine was significantly higher in lung-injured animals compared with all other groups (p < 0.05 vs. animals treated with rosuvastatin after lung injury induction; p < 0.001 vs. all other groups). 3-Nitrotyrosine was also increased in the lungs of the lung-injured pigs compared to all other groups (p < 0.05 each)., Conclusions: Our findings highlight cerebral cytokine production and nitro-oxidative stress within the first day after induction of lung injury. The treatment with rosuvastatin reduced IL-6 mRNA and 3-nitrotyrosine concentration in the brains of the animals. In earlier trials, statin treatment did not reduce mortality in ARDS patients but seemed to improve quality of life in ARDS survivors. Whether this is attributable to better cognitive function because of reduced nitro-oxidative stress and inflammation remains to be elucidated., (© 2021. The Author(s).)

Objective: Extracellular histones have been identified as one molecular factor that can cause and sustain alveolar damage and were linked to high mortality rates in critically ill patients. In this pilot study, we wanted to validate the proinflammatory in vivo effects of local histone application in a prospective translational porcine model. This was combined with the evaluation of an experimental acute lung injury model using intrabronchial lipopolysaccharides, which has been published previously., Results: The targeted application of histones was successful in all animals. Animals showed decreased oxygenation after instillation, but no differences could be detected between the sham and histone treatments. The histologic analyses and inflammatory responses indicated that there were no differences in tissue damage between the groups., (© 2021. The Author(s).)

Prompt reperfusion is important to rescue ischemic tissue; however, the process itself presents a key pathomechanism that contributes to a poor outcome following cardiac arrest. Experimental data have suggested the use of levosimendan to limit ischemia-reperfusion injury by improving cerebral microcirculation. However, recent studies have questioned this effect. The present study aimed to investigate the influence on hemodynamic parameters, cerebral perfusion and oxygenation following cardiac arrest by ventricular fibrillation in juvenile male pigs. Following the return of spontaneous circulation (ROSC), animals were randomly assigned to levosimendan (12 µg/kg, followed by 0.3 µg/kg/min) or vehicle treatment for 6 h. Levosimendan-treated animals showed significantly higher brain PbtO 2 levels. This effect was not accompanied by changes in cardiac output, preload and afterload, arterial blood pressure, or cerebral microcirculation indicating a local effect. Cerebral oxygenation is key to minimizing damage, and thus, current concepts are aimed at improving impaired cardiac output or cerebral perfusion. In the present study, we showed that NIRS does not reliably detect low PbtO 2 levels and that levosimendan increases brain oxygen content. Thus, levosimendan may present a promising therapeutic approach to rescue brain tissue at risk following cardiac arrest or ischemic events such as stroke or traumatic brain injury., (© 2021. The Author(s).)

Background: Mechanical chest compression devices are accepted alternatives for cardiopulmonary resuscitation (CPR) under specific circumstances. Current devices lack prospective and comparative data on their specific cardiovascular effects and potential for severe thoracic injuries., Objectives: To compare CPR effectiveness and thoracic injuries of two mechanical chest compression devices in pigs., Study Design: Prospective randomised trial., Animals: Eighteen male German landrace pigs., Methods: Ventricular fibrillation was induced in anaesthetised and instrumented pigs and the animals were randomised into two intervention groups. Mechanical CPR was initiated by means of LUCAS™ 2 (mCCD1) or Corpuls™ cpr (mCCD2) device. Advanced life support was applied for a maximum of 10 cycles and animals achieving ROSC were monitored for 8 h. Ventilation/perfusion measurements were performed and blood gas analyses were taken. Thoracic injuries were assessed via a standardised damage score., Results: Five animals of the mCCD1 group and one animal of the mCCD2 group achieved ROSC (p = 0.048). Only the mCCD1 animals survived until the end of the monitoring period (p < 0.01). MCCD1 animals showed less pulmonary shunt (p = 0.025) and higher normal V/Q (p = 0.017) during CPR. MCCD2 animals showed significantly more severe thoracic injuries (p = 0.046)., Conclusion: The LUCAS 2 device shows superior resuscitation outcomes and less thoracic injuries compared to Corpuls cpr when used for experimental CPR in juvenile pigs. Researchers should be aware that different mCCDs for experimental studies may significantly influence the respective outcome of resuscitation studies and affect comparability of different trials. Controlled human and animal CPR studies and a standardised post-resuscitation injury evaluation could help to confirm potential hazards., Trial Registration: Trial approval number: G16-1-042-E4.

Background: The treatment of haemorrhagic shock is a challenging task. Colloids have been regarded as standard treatment, but their safety and benefit have been the subject of controversial debates. Negative effects, including renal failure and increased mortality, have resulted in restrictions on their administration. The cerebral effects of different infusion regimens are largely unknown., Objectives: The current study investigated the impact of gelatine-polysuccinate, hydroxyethyl starch (HES) and balanced electrolyte solution (BES) on cerebral integrity, focusing on cerebral inflammation, apoptosis and blood flow in pigs., Design: Randomised experimental study., Setting: University-affiliated large animal research unit., Animals: Twenty-four juvenile pigs aged 8 to 12 weeks., Intervention: Haemorrhagic shock was induced by controlled arterial blood withdrawal to achieve a combination of relevant blood loss (30 to 40 ml kg-1) and haemodynamic deterioration. After 30 min of shock, fluid resuscitation was started with either gelatine-polysuccinate, HES or BES. The animals were then monitored for 4 h., Main Outcome Measures: Cerebral perfusion and diffusion were measured via arterial-spin-labelling MRI. Peripheral tissue perfusion was evaluated via white light spectroscopy. Cortical and hippocampal samples were collected at the end of the experiment. The numbers of cerebral cell nuclei were counted and mRNA expression of markers for cerebral apoptosis [glucose transporter protein type 1 (SLC2A), lipocalin 2 (LCN-2), aquaporin-4 (AQP4)] and inflammation [IL-6, TNF-α, glial fibrillary acidic protein (GFAP)] were determined., Results: The three fluid protocols all stabilised the macrocirculation. Fluid resuscitation significantly increased the cerebral perfusion. Gelatine-polysuccinate and HES initially led to a higher cardiac output but caused haemodilution. Cerebral cell counts (as cells μm-2) were lower after colloid administration in the cortex (gelatine-polysuccinate, 1.8 ± 0.3; HES, 1.9 ± 0.4; each P < 0.05 vs. BES, 2.3 ± 0.2) and the hippocampus (gelatine-polysuccinate, 0.8 ± 0.2; HES, 0.9 ± 0.2; each P < 0.05 vs. BES, 1.1 ± 0.1). After gelatine-polysuccinate, the hippocampal SLC2A and GFAP were lower. After gelatine-polysuccinate, the cortical LCN-2 and TNF-α expression levels were increased (each P < 0.05 vs. BES)., Conclusion: In a porcine model, fluid resuscitation by colloids, particularly gelatine-polysuccinate, was associated with the occurrence of cerebral injury., Ethical Approval Number: 23 177-07/G 15-1-092; 01/2016., (Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Objective: To establish and evaluate a standardized method of targeted, intrabronchial drug delivery in pigs., Study Design: Randomized controlled trial., Animals: A total of 16 German Landrace pigs (Sus scrofa), age range 12‒16 weeks, and weighing 28‒35 kg., Methods: The animals were anaesthetized, intubated, and instrumented with extended cardiovascular monitoring. Lung injury was induced by administering via a flexible fibre-optic endoscope using 100 mL saline solution containing either 20 mg of Escherichia coli lipopolysaccharide (E. coli LPS) (n = 8) or no additive (sham, n = 8) into the two distal mainstem bronchi. The animals were monitored for 8 hours and arterial oxygenation, inspiratory pressure and arterial blood pressure were measured repeatedly. Post-mortem, lung tissue was prepared for histologic damage scoring and determination of proinflammatory cytokines Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα). Statistical analyses were performed using inter-group analysis of variance and Student's t tests. Data are presented as mean ± standard deviation. A p value <0.05 was considered significant., Results: The targeted application of LPS led to significant deterioration of oxygenation consistent with mild-to-moderate acute respiratory distress syndrome (ARDS) and hypotension (Horowitz ratio: sham 2 hour, 300 ± 39; LPS 2 hour, 193.7 ± 52; p < 0.001). Histologic analyses identified increased inflammation and oedema in the tissues of the animals in the LPS group IL-6 sham: 6.4 ± 4.4 × 10 -5 pg mL -1 ; IL-6 LPS: 2.8 ± 2.4 × 10 -4 pg mL -1 , p = 0.015., Conclusions: The targeted application of agents via flexible fibre-optic endoscopy is a valid, reliable method of causing controlled lung damage in a porcine model. The data presented suggest the feasibility and possible advantages of controlled application and could expand the array of techniques used to help understand the critical condition of ARDS. In addition, a targeted approach could help reduce animal numbers used for this purpose., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Acute respiratory distress syndrome (ARDS) is an important disease with a high incidence among patients admitted to intensive care units. Over the last decades, the survival of critically ill patients has improved; however, cognitive deficits are among the long-term sequelae. We hypothesize that acute lung injury leads to upregulation of cerebral cytokine synthesis., Methods: After approval of the institutional and animal care committee, 20 male pigs were randomized to one of three groups: (1) Lung injury by oleic acid injection (OAI), (2) ventilation only (CTR) or (3) untreated. We compared neuronal numbers, proportion of neurons with markers for apoptosis, activation state of Iba-1 stained microglia cells and cerebral mRNA levels of different cytokines between the groups 18 hours after onset of lung injury., Results: We found an increase in hippocampal TNFalpha ( p  < 0.05) and IL-6 ( p  < 0.05) messenger RNA (mRNA) in the OAI compared to untreated group as well as higher hippocampal IL-6 mRNA compared to control ( p  < 0.05). IL-8 and IL-1beta mRNA showed no differences between the groups. We found histologic markers for beginning apoptosis in OAI compared to untreated ( p  < 0.05) and more active microglia cells in OAI and CTR compared to untreated ( p  < 0.001 each)., Conclusion: Hippocampal cytokine transcription increases within 18 hours after the induction of acute lung injury with histological evidence of neuronal damage. It remains to be elucidated if increased cytokine mRNA synthesis plays a role in the cognitive decline observed in survivors of ARDS., Competing Interests: The authors declare there are no competing interests., (©2020 Kamuf et al.)

Background: Efficient airway management to facilitate tracheal intubation encompasses essential skills in anaesthesiologic and intensive care. The application of flexible fibreoptic intubation in patients with difficult airways has been identified as the recommended method in various international guidelines. However, providing the opportunity to adequately train residents can be challenging. Using large animals for practice during ongoing studies could help to improve this situation, but there is no recent data on fibreoptic intubation in swine available., Methods: Thirty male German landrace pigs were anesthetized, instrumented and randomized into two groups. The animals were either intubated conventionally using direct laryngoscopy or a single-use flexible video-endoscope. The intervention was carried out by providers with 3 months experience in conventional intubation of pigs and a brief introduction into endoscopy. Intubation attempts were supervised and aborted, when SpO2 dropped below 93%. After three failed attempts, an experienced supervisor intervened and performed the intubation. Intubation times and attempts were recorded and analysed., Results: Flexible fibreoptic intubation showed a significantly higher success rate in first attempt endotracheal tube placement (75% vs. 47%) with less attempts overall (1.3 ± 0.6 vs. 2.1 ± 1.3, P = 0.043). Conventional intubation was faster (42 s ± 6 s vs. 67 s ± 10s, P < 0.001), but showed a higher complication rate and more desaturation episodes during the trial., Conclusions: Flexible fibreoptic intubation in swine is feasible and appears to be a safer and more accessible method for inexperienced users to learn. This could not only improve resident training options in hospitals with animal research facilities but might also prevent airway complications and needless animal suffering.

The treatment of ARDS continues to pose major challenges for intensive care physicians in the 21st century with mortality rates still reaching up to 50% in severe cases. Further research efforts are needed to better understand the complex pathophysiology of this disease. There are different well-established animal models to induce acute lung injury but none has been able to adequately mimic the complex pathomechanisms of ARDS. The most crucial factor for the development of this condition is the damage to the alveolar capillary unit. The combination of two well-established lung injury models allow us to mimic in more detail the underlying pathomechanism. Bronchoalveolar lavage (BAL) leads to surfactant depletion as well as alveolar collapse. The repeated instillation of fluid volumes causes subsequent hypoxemia. Surfactant depletion is a key factor of ARDS in humans. BAL is often combined with other lung injury approaches, but not with a second hit followed by oleic acid injection (OAI) yet. Oleic acid injection leads to severely impaired gas exchange, a deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The OAI mimics most of the expected effects of ARDS consisting of extended inflammation of lung tissue with an increase of alveolar leakage and gas exchange impairment. A disadvantage of the combination of different models is the difficulty to determine the influence to the lung injury caused by BAL alone, OAI alone or both together. The model presented in this report represents the combination of BAL and OAI as a new double-hit lung injury model. This new model is easy to implement and an alternative to study different therapeutic approaches in ARDS in the future.

Background: Optimal ventilation strategies during cardiopulmonary resuscitation are still heavily debated and poorly understood. So far, no convincing evidence could be presented in favour of outcome relevance and necessity of specific ventilation patterns. In recent years, alternative models to the guideline-based intermittent positive pressure ventilation (IPPV) have been proposed. In this randomized controlled trial, we evaluated a bi-level ventilation approach in a porcine model to assess possible physiological advantages for the pulmonary system as well as resulting changes in neuroinflammation compared to standard measures., Methods: Sixteen male German landrace pigs were anesthetized and instrumented with arterial and venous catheters. Ventricular fibrillation was induced and the animals were left untreated and without ventilation for 4 minutes. After randomization, the animals were assigned to either the guideline-based group (IPPV, tidal volume 8-10 ml/kg, respiratory rate 10/min, F i O 2 1.0) or the bi-level group (inspiratory pressure levels 15-17 cmH 2 O/5cmH 2 O, respiratory rate 10/min, F i O 2 1.0). Mechanical chest compressions and interventional ventilation were initiated and after 5 minutes, blood samples, including ventilation/perfusion measurements via multiple inert gas elimination technique, were taken. After 8 minutes, advanced life support including adrenaline administration and defibrillations were started for up to 4 cycles. Animals achieving ROSC were monitored for 6 hours and lungs and brain tissue were harvested for further analyses., Results: Five of the IPPV and four of the bi-level animals achieved ROSC. While there were no significant differences in gas exchange or hemodynamic values, bi-level treated animals showed less pulmonary shunt directly after ROSC and a tendency to lower inspiratory pressures during CPR. Additionally, cytokine expression of tumour necrosis factor alpha was significantly reduced in hippocampal tissue compared to IPPV animals., Conclusion: Bi-level ventilation with a constant positive end expiratory pressure and pressure-controlled ventilation is not inferior in terms of oxygenation and decarboxylation when compared to guideline-based IPPV ventilation. Additionally, bi-level ventilation showed signs for a potentially ameliorated neurological outcome as well as less pulmonary shunt following experimental resuscitation. Given the restrictions of the animal model, these advantages should be further examined., Competing Interests: The authors declare there are no competing interests., (©2020 Ruemmler et al.)

Background: Fast and effective treatment of hemorrhagic shock is one of the most important preclinical trauma care tasks e.g., in combat casualties in avoiding severe end-organ damage or death. In scenarios without immediate availability of blood products, alternate regimens of fluid resuscitation represent the only possibility of maintaining sufficient circulation and regaining adequate end-organ oxygen supply. However, the fluid choice alone may affect the extent of the bleeding by interfering with coagulation pathways. This study investigates the impact of hydroxyethyl starch (HES), gelatine-polysuccinate (GP) and balanced electrolyte solution (BES) as commonly used agents for fluid resuscitation on coagulation using a porcine hemorrhagic shock model., Methods: Following approval by the State and Institutional Animal Care Committee, life-threatening hemorrhagic shock was induced via arterial blood withdrawal in 24 anesthetized pigs. Isovolumetric fluid resuscitation with either HES, GP or BES ( n  = 3 × 8) was performed to compensate for the blood loss. Over four hours, hemodynamics, laboratory parameters and rotational thromboelastometry-derived coagulation were analyzed. As secondary endpoint the porcine values were compared to human blood., Results: All the agents used for fluid resuscitation significantly affected coagulation. We measured a restriction of laboratory parameters, clot development and clot firmness, particularly in HES- and GP-treated animals. Hemoglobin content dropped in all groups but showed a more pronounced decline in colloid-treated pigs. This effect was not maintained over the four-hour monitoring period., Conclusion: HES, GP, and BEL sufficiently stabilized the macrocirculation, but significantly affected coagulation. These effects were most pronounced after colloid and particularly HES administration. Despite suitability for rapid hemodynamic stabilization, colloids have to be chosen with caution, because their molecular properties may affect coagulation directly and as a consequence of pronounced hemodilution. Our comparison of porcine and human coagulation showed increased coagulation activity in pig blood., Competing Interests: The authors declare there are no competing interests., (©2020 Ziebart et al.)

Cardiopulmonary resuscitation after cardiac arrest, independent of its origin, is a regularly encountered medical emergency in hospitals as well as preclinical settings. Prospective randomized trials in human subjects are difficult to design and ethically ambiguous, which results in a lack of evidence-based therapies. The model presented in this report represents one of the most common causes of cardiac arrests, ventricular fibrillation, in a standardized setting in a large animal model. This allows for reproducible observations and various therapeutic interventions under clinically accurate conditions, hence facilitating the generation of better evidence and eventually the potential for improved medical treatment.

Visual impairment and blindness are often caused by retinal ischemia-reperfusion (I/R) injury. We aimed to characterize a new model of I/R in pigs, in which the intraocular pathways were not manipulated by invasive methods on the ocular system. After 12 min of ischemia followed by 20 h of reperfusion, reactivity of retinal arterioles was measured in vitro by video microscopy. Dihydroethidium (DHE) staining, qPCR, immunohistochemistry, quantification of neurons in the retinal ganglion cell layer, and histological examination was performed. Retinal arterioles of I/R-treated pigs displayed marked attenuation in response to the endothelium-dependent vasodilator, bradykinin, compared to sham-treated pigs. DHE staining intensity and messenger RNA levels for HIF-1α , VEGF-A , NOX2 , and iNOS were elevated in retinal arterioles following I/R. Immunoreactivity to HIF-1α, VEGF-A, NOX2, and iNOS was enhanced in retinal arteriole endothelium after I/R. Moreover, I/R evoked a substantial decrease in Brn3a-positive retinal ganglion cells and noticeable retinal thickening. In conclusion, the results of the present study demonstrate that short-time ocular ischemia impairs endothelial function and integrity of retinal blood vessels and induces structural changes in the retina. HIF-1α, VEGF-A, iNOS, and NOX2-derived reactive oxygen species appear to be involved in the pathophysiology.

Background: Organ cross-talk describes interactions between a primary affected organ and a secondarily injured remote organ, particularly in lung-brain interactions. A common theory is the systemic distribution of inflammatory mediators that are released by the affected organ and transferred through the bloodstream. The present study characterises the baseline immunogenic effects of a novel experimental model of random allogeneic blood transfusion in pigs designed to analyse the role of the bloodstream in organ cross-talk., Methods: After approval of the State and Institutional Animal Care Committee, 20 anesthetized pig were randomized in a donor and an acceptor (each n  = 8): the acceptor animals each received high-volume whole blood transfusion from the donor (35-40 ml kg -1 ). Four animals received balanced electrolyte solution instead of blood transfusion (control group; n  = 4). Afterwards the animals underwent extended cardiorespiratory monitoring for eight hours. Post mortem assessment included pulmonary, cerebral and systemic mediators of early inflammatory response (IL-6, TNF-alpha, iNOS), wet to dry ratio, and lung histology., Results: No adverse events or incompatibilities occurred during the blood transfusion procedures. Systemic cytokine levels and pulmonary function were unaffected. Lung histopathology scoring did not display relevant intergroup differences. Neither within the lung nor within the brain an up-regulation of inflammatory mediators was detected. High volume random allogeneic blood transfusion in pigs neither impaired pulmonary integrity nor induced systemic, lung, or brain inflammatory response., Conclusion: This approach can represent a novel experimental model to characterize the blood-bound transmission in remote organ injury., Competing Interests: The authors declare there are no competing interests.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute lung failure in critically sick patients, which severely compromises the function of multiple organs, including the brain. Although, the optic nerve and the retina are a part of the central nervous system, the effects of ARDS on these ocular structures are completely unknown. Thus, the major goal of this study was to test the hypothesis that ARDS affects vascular function in the eye. ARDS was induced in anesthetized pigs by intratracheal injection of lipopolysaccharide (LPS). Sham-treated animals served as controls. Pigs were monitored for 8 h and then sacrificed. Subsequently, retinal arterioles and short posterior ciliary arteries were isolated and cannulated with micropipettes to measure vascular responses by videomicroscopy. Levels of reactive oxygen species (ROS) were quantified in isolated vessels using dihydroethidium (DHE). Messenger RNA expression of hypoxic, inflammatory, prooxidative, and antioxidative genes was assessed by real-time PCR. When group-dependent differences in mRNA expression levels were found for a particular gene, immunostainings were conducted. Strikingly, responses to the endothelium-dependent vasodilator, bradykinin, were markedly impaired in retinal arterioles of LPS-treated pigs, but no differences were seen between ciliary arteries of LPS- and sham-treated animals. ROS levels were increased in retinal arterioles but not in ciliary arteries of LPS-treated pigs. Messenger RNA levels for HIF-1α, VEGF-A and NOX2 were markedly increased in retinal arterioles of LPS-treated pigs, whereas ciliary arteries had only negligible mRNA level changes. Pronounced immunoreactivity for HIF-1α, VEGF-A and NOX2 was seen in the endothelium of retinal arterioles from LPS-treated pigs. Histologically, massive edema was seen especially in the retinal nerve fiber layer of pigs treated with LPS. Our study provides the first evidence that ARDS induced by intratracheal LPS application evokes endothelial dysfunction in porcine retinal arterioles together with retinal edema, indicative of vascular leakage. In contrast, ciliary arteries appear to be resistant to intratracheal LPS application., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hemorrhagic shock ranks among the main reasons for severe injury-related death. The loss of circulatory volume and oxygen carriers can lead to an insufficient oxygen supply and irreversible organ failure. The brain exerts only limited compensation capacities and is particularly at high risk of severe hypoxic damage.This article demonstrates the reproducible induction of life-threatening hemorrhagic shock in a porcine model by means of calculated blood withdrawal. We titrate shock induction guided by near-infrared spectroscopy and extended hemodynamic monitoring to display systemic circulatory failure, as well as cerebral microcirculatory oxygen depletion. In comparison to similar models that primarily focus on predefined removal volumes for shock induction, this approach highlights a titration by means of the resulting failure of macro- and microcirculation.

Background: Mechanical ventilation can lead to ventilator-induced lung injury (VILI). In addition to the well-known mechanical forces of volutrauma, barotrauma, and atelectrauma, non-mechanical mechanisms have recently been discussed as contributing to the pathogenesis of VILI. One such mechanism is oscillations in partial pressure of oxygen (PO 2 ) which originate in lung tissue in the presence of within-breath recruitment and derecruitment of alveoli. The purpose of this study was to investigate this mechanism's possible independent effects on lung tissue and inflammation in a porcine model., Methods: To separately study the impact of PO 2 oscillations on the lungs, an in vivo model was set up that allowed for generating mixed-venous PO 2 oscillations by the use of veno-venous extracorporeal membrane oxygenation (vvECMO) in a state of minimal mechanical stress. While applying the identical minimal-invasive ventilator settings, 16 healthy female piglets (weight 50 ± 4 kg) were either exposed for 6 h to a constant mixed-venous hemoglobin saturation (S mv O 2 ) of 65% (which equals a P mv O 2 of 41 Torr) (control group), or an oscillating S mv O 2 (intervention group) of 40-90% (which equals P mv O 2 oscillations of 30-68 Torr)-while systemic normoxia in both groups was maintained. The primary endpoint of histologic lung damage was assessed by ex vivo histologic lung injury scoring (LIS), the secondary endpoint of pulmonary inflammation by qRT-PCR of lung tissue. Cytokine concentration of plasma was carried out by ELISA. A bioinformatic microarray analysis of lung samples was performed to generate hypotheses about underlying pathomechanisms., Results: The LIS showed significantly more severe damage of lung tissue after exposure to PO 2 oscillations compared to controls (0.53 [0.51; 0.58] vs. 0.27 [0.23; 0.28]; P = 0.0025). Likewise, a higher expression of TNF-α (P = 0.0127), IL-1β (P = 0.0013), IL-6 (P = 0.0007), and iNOS (P = 0.0013) in lung tissue was determined after exposure to PO 2 oscillations. Cytokines in plasma showed a similar trend between the groups, however, without significant differences. Results of the microarray analysis suggest that inflammatory (IL-6) and oxidative stress (NO/ROS) signaling pathways are involved in the pathology linked to PO 2 oscillations., Conclusions: Artificial mixed-venous PO 2 oscillations induced lung damage and pulmonary inflammation in healthy animals during lung protective ventilation. These findings suggest that PO 2 oscillations represent an independent mechanism of VILI.

Background: The effects of different ventilation strategies during CPR on patient outcomes and lung physiology are still poorly understood. This study compares positive pressure ventilation (IPPV) to passive oxygenation (CPAP) and a novel ultra-low tidal volume ventilation (ULTVV) regimen in an experimental ventricular fibrillation animal model., Study Design: Prospective randomized controlled trial., Animals: 30 male German landrace pigs (16-20 weeks)., Methods: Ventricular fibrillation was induced in anesthetized and instrumented pigs and the animals were randomized into three groups. Mechanical CPR was initiated and ventilation was either provided by means of standard IPPV (RR: 10/min, V t : 8-9 ml/kg, F i O 2 : 1,0, PEEP: 5 mbar), CPAP (O 2 -Flow: 10 l/min, PEEP: 5 mbar) or ULTVV (RR: 50/min, V t : 2-3 ml/kg, F i O 2 : 1,0, PEEP: 5 mbar). Guideline-based advanced life support was applied for a maximum of 4 cycles and animals achieving ROSC were monitored for 6 h before terminating the experiment. Ventilation/perfusion ratios were performed via multiple inert gas elimination, blood gas analyses were taken hourly and extended cardiovascular measurements were collected constantly. Brain and lung tissue samples were taken and analysed for proinflammatory cytokine expression., Results: ULTVV provided sufficient oxygenation and ventilation during CPR while demanding significantly lower respiratory and intrathoracic pressures. V/Q mismatch was significantly decreased and lung injury was mitigated in surviving animals compared to IPPV and CPAP. Additionally, cerebral cytokine expression was dramatically reduced., Conclusion: Ultra-low-volume ventilation during CPR in a porcine model is feasible and may provide lung-protective benefits as well as neurological outcome improvement due to lower inflammation. Our results warrant further studies and might eventually lead to new therapeutic options in the resuscitation setting., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The acute respiratory distress syndrome is a relevant intensive care disease with an incidence ranging between 2.2% and 19% of intensive care unit patients. Despite treatment advances over the last decades, ARDS patients still suffer mortality rates between 35 and 40%. There is still a need for further research to improve the outcome of patients suffering from ARDS. One problem is that no single animal model can mimic the complex pathomechanism of the acute respiratory distress syndrome, but several models exist to study different parts of it. Oleic acid injection (OAI)-induced lung injury is a well-established model for studying ventilation strategies, lung mechanics and ventilation/perfusion distribution in animals. OAI leads to severely impaired gas exchange, deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The disadvantage of this model is the controversial mechanistic relevance of this model and the necessity for central venous access, which is challenging especially in smaller animal models. In summary, OAI-induced lung injury leads to reproducible results in small and large animals and hence represents a well-suited model for studying ARDS. Nevertheless, further research is necessary to find a model that mimics all parts of ARDS and lacks the problems associated with the different models existing today.

Introduction: The acute respiratory distress syndrome is not only associated with a high mortality, but also goes along with cognitive impairment in survivors. The cause for this cognitive impairment is still not clear. One possible mechanism could be cerebral inflammation as result of a "lung-brain-crosstalk". Even mechanical ventilation itself can induce cerebral inflammation. We hypothesized, that an acute lung injury aggravates the cerebral inflammation induced by mechanical ventilation itself and leads to neuronal damage., Methods: After approval of the institutional and state animal care committee 20 pigs were randomized to one of three groups: lung injury by central venous injection of oleic acid (n = 8), lung injury by bronchoalveolar lavage in combination with one hour of injurious ventilation (n = 8) or control (n = 6). Brain tissue of four native animals from a different study served as native group. For six hours all animals were ventilated with a tidal volume of 7 ml kg-1 and a scheme for positive end-expiratory pressure and inspired oxygen fraction, which was adapted from the ARDS network tables. Afterwards the animals were killed and the brains were harvested for histological (number of neurons and microglia) and molecular biologic (TNFalpha, IL-1beta, and IL-6) examinations., Results: There was no difference in the number of neurons or microglia cells between the groups. TNFalpha was significantly higher in all groups compared to native (p < 0.05), IL-6 was only increased in the lavage group compared to native (p < 0.05), IL-1beta showed no difference between the groups., Discussion: With our data we can confirm earlier results, that mechanical ventilation itself seems to trigger cerebral inflammation. This is not aggravated by acute lung injury, at least not within the first 6 hours after onset. Nevertheless, it seems too early to dismiss the idea of lung-injury induced cerebral inflammation, as 6 hours might be just not enough time to see any profound effect., Competing Interests: The authors have declared that no competing interests exist.

Background: Cyclic recruitment and de-recruitment of atelectasis (c-R/D) is a contributor to ventilator-induced lung injury (VILI). Bedside detection of this dynamic process could improve ventilator management. This study investigated the potential of automated lung sound analysis to detect c-R/D as compared to four-dimensional computed tomography (4DCT)., Methods: In ten piglets (25 ± 2 kg), acoustic measurements from 34 thoracic piezoelectric sensors (Meditron ASA, Norway) were performed, time synchronized to 4DCT scans, at positive end-expiratory pressures of 0, 5, 10, and 15 cmH 2 O during mechanical ventilation, before and after induction of c-R/D by surfactant washout. 4DCT was post-processed for within-breath variation in atelectatic volume (Δ atelectasis) as a measure of c-R/D. Sound waveforms were evaluated for: 1) dynamic crackle energy (dCE): filtered crackle sounds (600-700 Hz); 2) fast Fourier transform area (FFT area): spectral content above 500 Hz in frequency and above -70 dB in amplitude in proportion to the total amount of sound above -70 dB amplitude; and 3) dynamic spectral coherence (dSC): variation in acoustical homogeneity over time. Parameters were analyzed for global, nondependent, central, and dependent lung areas., Results: In healthy lungs, negligible values of Δ atelectasis, dCE, and FFT area occurred. In lavage lung injury, the novel dCE parameter showed the best correlation to Δ atelectasis in dependent lung areas (R 2 = 0.88) where c-R/D took place. dCE was superior to FFT area analysis for each lung region examined. The analysis of dSC could predict the lung regions where c-R/D originated., Conclusions: c-R/D is associated with the occurrence of fine crackle sounds as demonstrated by dCE analysis. Standardized computer-assisted analysis of dCE and dSC seems to be a promising method for depicting c-R/D.

Background: During early treatment of haemorrhagic shock maintenance of cerebral and end-organ oxygen supply by fluid resuscitation is mandatory. Gelatin-polysuccinat (GP) recently regained attention despite a still unclear risk profile and widely unknown effects on cerebral and peripheral microcirculation. This study investigates the effects of GP versus balanced electrolyte solution (BEL) with focus on cerebral regional oxygen saturation and peripheral microcirculation in a porcine haemorrhagic shock model., Methods: After Animal Care Committee approval haemorrhagic shock was induced by arterial blood withdrawal in 27 anaesthetized pigs. Consequently, the animals received rapid fluid resuscitation by either GP or BEL to replace the removed amount of blood, or remained untreated (n = 3 × 9). Over two hours cerebral regional oxygen saturation by near-infrared spectroscopy and peripheral buccal microcirculation by combined white-light spectrometry and laser-Doppler flowmetry were recorded. Secondary parameters included extended haemodynamics, spirometry, haematological and blood gas parameters., Results: Both fluid resuscitation regimes sufficiently stabilized the macro- and microcirculation in haemorrhagic shock with a more pronounced effect following GP infusion. GP administration led to a persisting, critical impairment of cerebral regional oxygen saturation through considerable haemodilution. Survival rates were 100% in both fluid resuscitation groups, but only 33% in the untreated control., Conclusion: Equal amounts of GP and BEL sufficiently stabilize systemic circulation and microcirculatory perfusion. Forced fluid resuscitation by GP should be applied with caution to prevent haemodilution-induced impairment of cerebral oxygen delivery.

Background: Oscillations of the arterial partial pressure of oxygen induced by varying shunt fractions occur during cyclic alveolar recruitment within the injured lung. Recently, these were proposed as a pathomechanism that may be relevant for remote organ injury following acute respiratory distress syndrome. This study examines the transmission of oxygen oscillations to the renal tissue and their tidal volume dependency., Methods: Lung injury was induced by repetitive bronchoalveolar lavage in eight anaesthetized pigs. Cyclic alveolar recruitment was provoked by high tidal volume ventilation. Oscillations of the arterial partial pressure of oxygen were measured in real-time in the macrocirculation by multi-frequency phase fluorimetry and in the renal microcirculation by combined white-light spectrometry and laser-Doppler flowmetry during tidal volume down-titration., Results: Significant respiratory-dependent oxygen oscillations were detected in the macrocirculation and transmitted to the renal microcirculation in a substantial extent. The amplitudes of these oscillations significantly correlate to the applied tidal volume and are minimized during down-titration., Conclusions: In a porcine model oscillations of the arterial partial pressure of oxygen are induced by cyclic alveolar recruitment and transmitted to the renal microcirculation in a tidal volume-dependent fashion. They might play a role in organ crosstalk and remote organ damage following lung injury.

Background: In acute respiratory respiratory distress syndrome (ARDS) a sustained mismatch of alveolar ventilation and perfusion (V A /Q) impairs the pulmonary gas exchange. Measurement of endexpiratory lung volume (EELV) by multiple breath-nitrogen washout/washin is a non-invasive, bedside technology to assess pulmonary function in mechanically ventilated patients. The present study examines the association between EELV changes and V A /Q distribution and the possibility to predict V A /Q normalization by means of EELV in a porcine model., Methods: After approval of the state and institutional animal care committee 12 anesthetized pigs were randomized to ARDS either by bronchoalveolar lavage (n = 6) or oleic acid injection (n = 6). EELV, V A /Q ratios by multiple inert gas elimination and ventilation distribution by electrical impedance tomography were assessed at healthy state and at five different positive endexpiratory pressure (PEEP) steps in ARDS (0, 20, 15, 10, 5 cmH 2 O; each maintained for 30 min)., Results: V A /Q, EELV and tidal volume distribution all displayed the PEEP-induced recruitment in ARDS. We found a close correlation between V A /Q < 0.1 (representing shunt and low V A /Q units) and changes in EELV (spearman correlation coefficient -0.79). Logistic regression reveals the potential to predict V A /Q normalization (V A /Q < 0.1 less than 5%) from changes in EELV with an area under the curve of 0.89 with a 95%-CI of 0.81-0.96 in the receiver operating characteristic. Different lung injury models and recruitment characteristics did not influence these findings., Conclusion: In a porcine ARDS model EELV measurement depicts PEEP-induced lung recruitment and is strongly associated with normalization of the V A /Q distribution in a model-independent fashion. Determination of EELV could be an intriguing addition in the context of lung protection strategies.

Novel devices for small-lumen ventilation may enable effective inspiration and expiratory ventilation assistance despite airway obstruction. In this study, we investigated a porcine model of complete upper airway obstruction. After ethical approval, we randomly assigned 13 anaesthetised pigs either to small-lumen ventilation following airway obstruction (n = 8) for 30 min, or to volume-controlled ventilation (sham setting, n = 5). Small-lumen ventilation enabled adequate gas exchange over 30 min. One animal died as a result of a tension pneumothorax in this setting. Redistribution of ventilation from dorsal to central compartments and significant impairment of the distribution of ventilation/perfusion occurred. Histopathology demonstrated considerable lung injury, predominantly through differences in the dorsal dependent lung regions. Small-lumen ventilation maintained adequate gas exchange in a porcine airway obstruction model. The use of this technique for 30 min by inexperienced clinicians was associated with considerable end-expiratory collapse leading to lung injury, and may also carry the risk of severe injury., (© 2015 The Association of Anaesthetists of Great Britain and Ireland.)

Objective: Cyclic recruitment and derecruitment of atelectasis can occur during mechanical ventilation, especially in injured lungs. Experimentally, cyclic recruitment and derecruitment can be quantified by respiration-dependent changes in PaO2 (ΔPaO2), reflecting the varying intrapulmonary shunt fraction within the respiratory cycle. This study investigated the effect of inspiration to expiration ratio upon ΔPaO2 and Horowitz index., Design: Prospective randomized study., Setting: Laboratory investigation., Subjects: Piglets, average weight 30 ± 2 kg., Interventions: At respiratory rate 6 breaths/min, end-inspiratory pressure (Pendinsp) 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and FIO2 1.0, measurements were performed at randomly set inspiration to expiration ratios during baseline healthy and mild surfactant depletion injury. Lung damage was titrated by repetitive surfactant washout to induce maximal cyclic recruitment and derecruitment as measured by multifrequency phase fluorimetry. Regional ventilation distribution was evaluated by electrical impedance tomography. Step changes in airway pressure from 5 to 40 cm H2O and vice versa were performed after lavage to calculate PO2-based recruitment and derecruitment time constants (TAU)., Measurements and Main Results: In baseline healthy, cyclic recruitment and derecruitment could not be provoked, whereas in model acute respiratory distress syndrome, the highest ΔPaO2 were routinely detected at an inspiration to expiration ratio of 1:4 (range, 52-277 torr [6.9-36.9 kPa]). Shorter expiration time reduced cyclic recruitment and derecruitment significantly (158 ± 85 torr [21.1 ± 11.3 kPa] [inspiration to expiration ratio, 1:4]; 25 ± 12 torr [3.3 ± 1.6 kPa] [inspiration to expiration ratio, 4:1]; p < 0.0001), whereas the PaO2/FIO2 ratio increased (267 ± 50 [inspiration to expiration ratio, 1:4]; 424 ± 53 [inspiration to expiration ratio, 4:1]; p < 0.0001). Correspondingly, regional ventilation redistributed toward dependent lung regions (p < 0.0001). Recruitment was much faster (TAU: fast 1.6 s [78%]; slow 9.2 s) than derecruitment (TAU: fast 3.1 s [87%]; slow 17.7 s) (p = 0.0078)., Conclusions: Inverse ratio ventilation minimizes cyclic recruitment and derecruitment of atelectasis in an experimental model of surfactant-depleted pigs. Time constants for recruitment and derecruitment, and regional ventilation distribution, reflect these findings and highlight the time dependency of cyclic recruitment and derecruitment.