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When deep accidental hypothermia causes circulatory failure, the best chance of survival is treatment with extracorporeal circulation (ECC) and warming of the blood. This may be difficult to achieve if the patient is first admitted to a hospital without a department of thoracic surgery. Our aim was to test a lightweight mobile system for ECC. The equipment could be transported almost anywhere, making it possible to start ECC on the spot and during transfer. The system was tested on six hypothermic pigs, two of the pigs at the institute laboratory, two of the pigs in a normal ambulance, and two of the pigs in an air force rescue helicopter. All of the pigs were transported back to the institute for warming to normal temperature. After warming, and the ECC stopped, all the pigs were in sinus rhythm and had an obviously satisfactory circulation. It is possible to bring a lightweight ECC system to the unstable patient. Treatment is possible in any hospital, ambulance or helicopter. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of clean intermittent catheterization (CIC) on prevention of urethral stricture recurrence after internal urethrotomy. Patients and methods Of 55 men who were randomly selected, 43 completed the investigation. Of these, 21 patients performed CIC weekly for 1 year following Sachse's operation for urethral stricture and 22 patients formed the control group after the same operation. All had an objective examination for urethral stricture every 2 months after surgery. Results Significantly fewer ( P < 0.01) patients developed recurrence of urethral stricture within the first postoperative year in the CIC group ( n= 4) compared with the control group ( n= 15). No CIC complications were seen, and patients who completed the CIC programme considered the method fully acceptable. Conclusion Weekly CIC is a simple method of reducing the frequency of urethral stricture recurrence after internal urethrotomy. [ABSTRACT FROM AUTHOR]

Electronic oral thermometry is performed routinely in most medical centres. From the studies available on this subject it seems difficult to find any documentation for this practice. We have conducted clinically controlled studies in which the accuracy of electronic oral thermometry (CRAFTEMP and TERUMO WCT) and that of electronic rectal thermometry (TERUMO WCT) were tested. Rectal glass mercury thermometry was used as a reference method. Two studies were designed. In study 1, 184 patients (72 women, 112 men), median age 70 (18-95) years were investigated. In study 2, 91 patients (41 women, 50 men), median age 59 (18-96) years were investigated. Electronic oral thermometry was found unacceptably inaccurate under daily routine conditions. Electronic rectal thermometry was found to be accurate. Calculations of mean temperature difference between reference measurements and test measurements (mean + or - SD) were found to be: routine oral CRAFTEMP at 0.70 + or - 0-50 degrees C, optimum oral TERUMO WCT at 0.75 + or - 0.74 degrees C, routine rectal TERUMO WCT at 0.08+ or - 0.26 degrees C optimum rectal WCT at 0.02 + or - 0.17. In the screening procedure for fever oral thermometry showed low sensitivity (routine CRAFTEMP 0.47 and optimum WCT 0.59) whereas rectal thermometry showed high sensitivity (routine TERUMO WCT 0.74 and optimum TERUMO WCT 0.91). It was concluded that rectal thermometry must be preferred to oral thermometry for daily routine measurements. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to use intracortical recording to enable the tracking of ischemic infarct development over the first few critical hours of ischemia with a high time resolution in pigs. We employed electrophysiological measurements to obtain quick feedback on neural function, which might be useful for screening, e.g., for the optimal dosage and timing of agents prior to further pre-clinical evaluation., Methods: Micro-electrode arrays containing 16 (animal 1) or 32 electrodes (animal 2-7) were implanted in the primary somatosensory cortex of seven female pigs, and continuous electrical stimulation was applied at 0.2 Hz to a cuff electrode implanted on the ulnar nerve. Ischemic stroke was induced after 30 min of baseline recording by injection of endothelin-1 onto the cortex adjacent to the micro-electrode array. Evoked responses were extracted over a moving window of 180 s and averaged across channels as a measure of cortical excitability., Results: Across the animals, the cortical excitability was significantly reduced in all seven 30 min segments following endothelin-1 injection, as compared to the 30 min preceding this intervention. This difference was not explained by changes in the anesthesia, ventilation, end-tidal CO 2 , mean blood pressure, heart rate, blood oxygenation, or core temperature, which all remained stable throughout the experiment., Conclusions: The animal model may assist in maturing neuroprotective approaches by testing them in an accessible model of resemblance to human neural and cardiovascular physiology and body size. This would constitute an intermediate step for translating positive results from rodent studies into human application, by more efficiently enabling effective optimization prior to chronic pre-clinical studies in large animals.

Introduction: Hypoxic pulmonary vasoconstriction (HPV) can be a challenging clinical problem. It is not fully elucidated where in the circulation the regulation of resistance takes place. It is often referred to as if it is in the arteries, but we hypothesized that it is in the venous side of the pulmonary circulation., Methods: In an open thorax model, pigs were treated with a veno-venous extra corporeal membrane oxygenator to either oxygenate or deoxygenate blood passing through the pulmonary vessels. At the same time the lungs were ventilated with extreme variations of inspired air from 5% to 100% oxygen, making it possible to make combinations of high and low oxygen content through the pulmonary circulation. A flow probe was inserted around the main pulmonary artery and catheters in the pulmonary artery and in the left atrium were used for pressure monitoring and blood tests. Under different combinations of oxygenation, pulmonary vascular resistance (PVR) was calculated., Results: With unchanged level of oxygen in the pulmonary artery and reduced inspired oxygen fraction lowering oxygen tension from 29 to 6.7 kPa in the pulmonary vein, PVR was doubled. With more extreme hypoxia PVR suddenly decreased. Combinations with low oxygenation in the pulmonary artery did not systematic influence PVR if there was enough oxygen in the inspired air and in the pulmonary veins., Discussion: The impact of hypoxia occurs from the alveolar level and forward with the blood flow. The experiments indicated that the regulation of PVR is mediated from the venous side., (© 2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Bevacizumab is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the management of macular edema in central retinal vein occlusion (CRVO). Studying retinal protein changes in bevacizumab intervention may provide insights into mechanisms of action. In nine Danish Landrace pigs, experimental CRVO was induced in both eyes with argon laser. The right eyes received an intravitreal injection of 0.05 mL bevacizumab (n = 9), while the left control eyes received 0.05 mL saline water (NaCl). Retinal samples were collected 15 days after induced CRVO. Label-free quantification nano-liquid chromatography-tandem mass spectrometry identified 59 proteins that were regulated following bevacizumab treatment. Following bevacizumab intervention, altered levels of bevacizumab components, including the Ig gamma-1 chain C region and the Ig kappa chain C region, were observed. Changes in other significantly regulated proteins ranged between 0.58-1.73, including for the NADH-ubiquinone oxidoreductase chain (fold change = 1.73), protein-transport protein Sec24B (fold change = 1.71), glycerol kinase (fold change = 1.61), guanine-nucleotide-binding protein G(T) subunit-gamma-T1 (fold change = 0.67), and prefoldin subunit 6 (fold change = 0.58). A high retinal concentration of bevacizumab was achieved within 15 days. Changes in the additional proteins were limited, suggesting a narrow mechanism of action.

Retinal vein occlusion (RVO) is a frequent visually disabling condition. The management of RVO continues to challenge clinicians. Macular edema secondary to RVO is often recurrent, and patients typically require intravitreal injections for several years. Understanding molecular mechanisms in RVO is a key element in improving the treatment of the condition. Studying the molecular mechanisms in RVO at the retinal level is possible using animal models of experimental RVO. Most studies of experimental RVO have been sporadic, using only a few animals per experiment. Here, we report on 10 years of experience of the use of argon laser-induced experimental RVO in 108 porcine eyes from 65 animals, including 65 eyes with experimental branch retinal vein occlusion (BRVO) and 43 eyes with experimental central retinal vein occlusion (CRVO). Reproducibility and methods for evaluating and controlling ischemia in experimental RVO are reviewed. Methods for studying protein changes in RVO are discussed in detail, including proteomic analysis, Western blotting, and immunohistochemistry. Experimental RVO has brought significant insights into molecular changes in RVO. Testing intravitreal interventions in experimental RVO may be a significant step in developing personalized therapeutic approaches for patients with RVO.

Background: The optimal pulmonary revascularisation strategy in high-risk pulmonary embolism (PE) requiring implantation of extracorporeal membrane oxygenation (ECMO) remains controversial., Methods: We conducted a systematic review and meta-analysis of evidence comparing mechanical embolectomy and other strategies, including systemic thrombolysis, catheter-directed thrombolysis or ECMO as stand-alone therapy, with regard to mortality and bleeding outcomes., Results: We identified 835 studies, 17 of which were included, comprising 327 PE patients. Overall, 32.4% were treated with mechanical pulmonary reperfusion (of whom 85.9% had surgical embolectomy), while 67.6% received other strategies. The mortality rate was 22.6% in the mechanical reperfusion group and 42.8% in the "other strategies" group. The pooled odds ratio for mortality with mechanical reperfusion was 0.439 (95% CI 0.237-0.816) (p=0.009; I 2 =35.2%) versus other reperfusion strategies and 0.368 (95% CI 0.185-0.733) (p=0.004; I 2 =32.9%) for surgical embolectomy versus thrombolysis. The rate of bleeding in patients under ECMO was 22.2% in the mechanical reperfusion group and 19.1% in the "other strategies" group (OR 1.27, 95% CI 0.54-2.96; I 2 =7.7%). The meta-regression model did not identify any relationship between the covariates "more than one pulmonary reperfusion therapy", "ECMO implantation before pulmonary reperfusion therapy", "clinical presentation of PE" or "cancer-associated PE" and the associated outcomes., Conclusions: The results of the present meta-analysis and meta-regression suggest that mechanical reperfusion, notably by surgical embolectomy, may yield favourable results regardless of the timing of ECMO implantation in the reperfusion timeline, independent of thrombolysis administration or cardiac arrest presentation., Competing Interests: Conflict of interest: G. Piazza has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Amgen and Bayer, and consulting fees from Amgen, Agile, Pfizer, and the Prairie Education and Research Cooperative. No other author has any conflict of interest to declare., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Objective: Magnetic resonance imaging (MRI)-based techniques for non-invasive assessing liver iron concentration (LIC) in patients with iron overload have a limited upper measuring range around 35 mg/g dry weight, caused by signal loss from accelerated T1-, T2-, T2* shortening with increasing LIC. Expansion of this range is necessary to allow evaluation of patients with very high LIC., Aim: To assess measuring range of a gradient-echo R2* method and a T1-weighted spin-echo (SE), signal intensity ratio (SIR)-based method (TE = 25 ms, TR = 560 ms), and to extend the upper measuring range of the SIR method by optimizing echo time (TE) and repetition time (TR) in iron-loaded minipigs., Methods: Thirteen mini pigs were followed up during dextran-iron loading with repeated percutaneous liver biopsies for chemical LIC measurement and MRIs for parallel non-invasive estimation of LIC (81 examinations) using different TEs and TRs., Results: SIR and R2* method had similar upper measuring range around 34 mg/g and similar method agreement. Using TE = 12 ms and TR = 1200 ms extended the upper measuring range to 115 mg/g and yielded good method of agreement., Discussion: The wider measuring range is likely caused by lesser sensitivity of the SE sequence to iron, due to shorter TE, leading to later signal loss at high LIC, allowing evaluation of most severe hepatic iron overload. Validation in iron-loaded patients is necessary., (© 2022. The Author(s).)

Background: In many animal experiments, it is vital to detect sudden changes in cardiac output (CO). This porcine study compared CO that was measured with a Swan-Ganz pulmonary catheter with the gold standard (which was a transit-time flow probe around the pulmonary artery) during interventions that caused hemodynamic instability., Methods: In one series, 7 pigs were exposed to sudden changes in CO. In another series, 9 pigs experienced more prolonged changes in CO. All the pigs had a Swan-Ganz catheter placed into the pulmonary artery and a flow probe around the pulmonary artery. Adrenaline infusion and controlled hemorrhage were used to increase and decrease CO, respectively. The measurements of CO before and after each intervention were compared for correlation, agreement, and the time delay that it took each method to detect at least a 30% change in CO. A Bland-Altman test was used to identify correlations and agreements between the methods., Results: In the first series, there was a delay of 5-7 min for the Swan Ganz catheter to register a 30% change in cardiac output, compared with the flow probe. However, during prolonged changes in CO in the second series, there was a good correlation between the 2 methods. Mixed venous oxygen saturation reacted faster to changes than did CO; both were measured via the Swan-Ganz catheter., Conclusions: In many animal studies, the use of Swan-Ganz catheters is suitable; however, in experiments with sudden hemodynamic instability, the flow probe is the most advantageous method for measuring CO., (© 2022 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Current diagnostic markers for pulmonary embolism (PE) are unspecific. We investigated the proteome of the exhaled breath condensate (EBC) in a porcine model of acute PE in order to identify putative diagnostic markers for PE. EBC was collected at baseline and after the induction of autologous intermediate-risk PE in 14 pigs, plus four negative control pigs. The protein profiles of the EBC were analyzed using label-free quantitative nano liquid chromatography-tandem mass spectrometry. A total of 897 proteins were identified in the EBCs from the pigs. Alterations were found in the levels of 145 different proteins after PE compared with the baseline and negative controls: albumin was among the most upregulated proteins, with 14-fold higher levels 2.5 h after PE ( p -value: 0.02). The levels of 49 other proteins were between 1.3- and 17.1-fold higher after PE. The levels of 95 proteins were lower after PE. Neutrophil gelatinase-associated lipocalin (fold change 0.3, p -value < 0.01) was among the most reduced proteins 2.5 h after PE. A prediction model based on penalized regression identified five proteins including albumin and neutrophil gelatinase-associated lipocalin. The model was capable of discriminating baseline samples from EBC samples collected 2.5 h after PE correctly in 22 out of 27 samples. In conclusion, the EBC from pigs with acute PE contained several putative diagnostic markers of PE.

Carbon monoxide (CO) is the leading cause of death by poisoning worldwide. The aim was to explore the effects of mild and severe poisoning on blood gas parameters and metabolites. Eleven pigs were exposed to CO intoxication and had blood collected before and during poisoning. Mild CO poisoning (carboxyhaemoglobin, COHb 35.2 ± 7.9%) was achieved at 32 ± 13 minutes, and severe poisoning (69.3 ± 10.2% COHb) at 64 ± 23 minutes from baseline (2.9 ± 0.5% COHb). Blood gas parameters and metabolites were measured on a blood gas analyser and nuclear magnetic resonance spectrometer, respectively. Unsupervised principal component, analysis of variance and Pearson's correlation tests were applied. A P-value ≤ .05 was considered statistically significant. Mild poisoning resulted in a 28.4% drop in oxyhaemoglobin (OHb) and 12-fold increase in COHb, while severe poisoning in a 65% drop in OHb and 24-fold increase in COHb. Among others, metabolites implicated in regulation of metabolic acidosis (lactate, P < .0001), energy balance (pyruvate, P < .0001; 3-hydroxybutyrc acid, P = .01), respiration (citrate, P = .007; succinate, P = .0003; fumarate, P < .0001), lipid metabolism (glycerol, P = .002; choline, P = .0002) and antioxidant-oxidant balance (glutathione, P = .03; hypoxanthine, P < .0001) were altered, especially during severe poisoning. Our study adds new insights into the deranged metabolism of CO poisoning and leads the way for further investigation., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Non-invasive estimation of the cardiac iron concentration (CIC) by T2* cardiovascular magnetic resonance (CMR) has been validated repeatedly and is in widespread clinical use. However, calibration data are limited, and mostly from post-mortem studies. In the present study, we performed an in vivo calibration in a dextran-iron loaded minipig model., Methods: R2* (= 1/T2*) was assessed in vivo by 1.5 T CMR in the cardiac septum. Chemical CIC was assessed by inductively coupled plasma-optical emission spectroscopy in endomyocardial catheter biopsies (EMBs) from cardiac septum taken during follow up of 11 minipigs on dextran-iron loading, and also in full-wall biopsies from cardiac septum, taken post-mortem in another 16  minipigs, after completed iron loading., Results: A strong correlation could be demonstrated between chemical CIC in 55 EMBs and parallel cardiac T2* (Spearman rank correlation coefficient 0.72, P < 0.001). Regression analysis led to [CIC] = (R2* - 17.16)/41.12 for the calibration equation with CIC in mg/g dry weight and R2* in Hz. An even stronger correlation was found, when chemical CIC was measured by full-wall biopsies from cardiac septum, taken immediately after euthanasia, in connection with the last CMR session after finished iron loading (Spearman rank correlation coefficient 0.95 (P < 0.001). Regression analysis led to the calibration equation [CIC] = (R2* - 17.2)/31.8., Conclusions: Calibration of cardiac T2* by EMBs is possible in the minipig model but is less accurate than by full-wall biopsies. Likely explanations are sampling error, variable content of non-iron containing tissue and smaller biopsies, when using catheter biopsies. The results further validate the CMR T2* technique for estimation of cardiac iron in conditions with iron overload and add to the limited calibration data published earlier.

Background: Early diagnosis of shock is a predetermining factor for a good prognosis in intensive care. An elevated central venous to arterial PCO 2 difference (∆PCO 2 ) over 0.8 kPa (6 mm Hg) is indicative of low blood flow states. Disturbances around the time of blood sampling could result in inaccurate calculations of ∆PCO 2 , thereby misrepresenting the patient status. This study aimed to determine the influences of acute changes in ventilation on ∆PCO 2 and understand its clinical implications., Methods: To investigate the isolated effects of changes in ventilation on ∆PCO 2 , eight pigs were studied in a prospective observational cohort. Arterial and central venous catheters were inserted following anaesthetisation. Baseline ventilator settings were titrated to achieve an EtCO 2 of 5±0.5 kPa (V T = 8 mL/kg, Freq = 14 ± 2/min). Blood was sampled simultaneously from both catheters at baseline and 30, 60, 90, 120, 180 and 240 s after a change in ventilation. Pigs were subjected to both hyperventilation and hypoventilation, wherein the respiratory frequency was doubled or halved from baseline. ∆PCO 2 changes from baseline were analysed using repeated measures ANOVA with post-hoc analysis using Bonferroni's correction., Results: ∆PCO 2 at baseline for all pigs was 0.76±0.29 kPa (5.7±2.2 mm Hg). Following hyperventilation, there was a rapid increase in the ∆PCO 2 , increasing maximally to 1.35±0.29 kPa (10.1±2.2 mm Hg). A corresponding decrease in the ∆PCO 2 was seen following hypoventilation, decreasing maximally to 0.23±0.31 kPa (1.7±2.3 mm Hg). These changes were statistically significant from baseline 30 s after the change in ventilation., Conclusion: Disturbances around the time of blood sampling can rapidly affect the PCO 2 , leading to inaccurate calculations of the ∆PCO 2 , resulting in misinterpretation of patient status. Care should be taken when interpreting blood gases, if there is doubt as to the presence of acute and transient changes in ventilation., Competing Interests: Competing interests: SER was a previous shareholder of OBI Medical A/S., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The search for diagnostic biomarkers for pulmonary embolism (PE) has mainly been focused on blood samples. Exhaled breath condensate (EBC) is a possible source for biomarkers specific for chronic lung diseases and cancer, yet no previous studies have investigated the potential of EBC for diagnosis of PE. The protein content in the EBC is very low, and efficient condensing of the EBC is important in order to obtain high quality samples for protein analysis. We investigated if advanced proteomic techniques in a porcine model of acute intermediate-high-risk PE was feasible using two different condensing temperatures for EBC collection. Seven pigs were anaesthetized and intubated. EBC was collected one hour after intubation. Two autologous emboli were induced through the right external jugular vein. Two hours after the emboli were administered, EBC was collected again. Condensing temperature was either -21 °C or -80 °C. Nano liquid chromatography-tandem mass spectrometry (nLC-MS/MS) was used to identify and quantify proteins of the EBC. A condensing temperature of -80 °C significantly increased the EBC volume compared with -21 °C (1.78 ± 0.25 ml vs 0.71 ± 0.12 ml) while the protein concentration in the EBC was unaltered. The mean protein concentration in the EBCs was 5.85 ± 0.93 µ g ml -1 , unaltered after PE. In total, 254 proteins were identified in the EBCs. Identified proteins included proteins of the cytoplasm, nucleus, plasma membrane and extracellular region. The protein composition did not differ according to condensing temperature. The EBC from pigs with acute intermediate-high-risk PE contained sufficient amounts of protein for analysis by nLC-MS/MS. The proteins were from relevant cellular compartments, indicating that EBC is a possible source for biomarkers for acute PE., (Creative Commons Attribution license.)

Aim: To present the results from 16 years of nationwide cooperation between the Danish Airforce Search and Rescue Service and a Tertiary Heart Centre for the classification and treatment of accidental hypothermia., Methods: A mobile extracorporeal membrane oxygenation (ECMO) retrieval team was developed and could be contacted for nationwide advice and if indicated retrieval and/or treatment of patients by means of ambulance and/or helicopter. Accidental hypothermia was classified as mild, moderate, and severe, corresponding to awake, unconscious, and lifeless. The exact temperature was not considered relevant in the primary assessment. The mild group was treated with blankets and minimal invasive with warm i.v. infusions. The moderate group was primarily treated with an ABC approach, and if circulation was unstable due to arrhythmias or bleeding, invasive warming was performed with pleural lavage under ECMO preparedness. The severe group was treated with CPR followed by ECMO. All patients were examined for underlying disorders., Results: The team was involved in 204 patients, but for 47 patients treatment was stopped as they were considered beyond therapeutic reach, leaving 157 treated patients with 108 (69%) survivors. Among 54 ECMO patients, 21 (39%) survived to hospital discharge., Conclusions: We successfully implemented a simplified classification of accidental hypothermia and initiated a nationwide cooperation for retrieval and/or treatment of accidental hypothermic patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections. Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads. It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO. Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests, and there are no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Background: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism., Methods: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat ( n =6), sildenafil ( n =6), inhaled NO ( n =6) or vehicle ( n =6). Sham animals ( n =4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis., Results: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352±29 vs . baseline: 107±6 dynes, p <0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158±35, sildenafil: -224±35, inhaled NO: -156±35 dynes, p <0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678±41 vs . vehicle 1081±93 dynes, p =0.02) and increased cardiac output (sildenafil 8.8±0.8 vs . vehicle: 5.9±0.2 L/min, p <0.001). Systemic blood pressure was unaltered in all treatment groups., Conclusion: Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.

Objectives: We investigated whether the vasopressin-analog, terlipressin induces systemic vasoconstriction and pulmonary vasodilation in a porcine model of acute pulmonary embolism., Design: Controlled, animal study., Setting: Tertiary medical center research laboratory., Subjects: Female pigs (n = 12, Cross of Land Race, Duroc, and Yorkshire ~ 60 kg)., Interventions: Acute pulmonary embolism was induced by administration of three large autologous emboli. Animals then received four increasing doses of either terlipressin (n = 6) or vehicle (n = 6)., Measurements and Main Results: Effects were evaluated in vivo at baseline, after pulmonary embolism and after each dose by invasive hemodynamic measures, transesophageal echocardiography, and blood analysis. Isolated pulmonary arteries were evaluated ex vivo in a myograph. Pulmonary embolism caused a four-fold increase in pulmonary vascular resistance (p < 0.0001) and a two-fold increase in mean pulmonary arterial pressure (p < 0.0001) compared with baseline. Terlipressin increased mean systemic blood pressure (28 ± 5 mm Hg; p < 0.0001) and systemic vascular resistance (1,320 ± 143 dynes; p < 0.0001) compared with vehicle. In the pulmonary circulation, terlipressin decreased mean pulmonary arterial pressure (-6.5 ± 1.8 mm Hg; p = 0.005) and tended to decrease pulmonary vascular resistance (-83 ± 33 dynes; p = 0.07). Terlipressin decreased cardiac output (-2.5 ± 0.5 L/min; p < 0.0001) and increased plasma lactate (2.7 ± 0.2 mmol/L; p < 0.0001), possibly indicating systemic hypoperfusion. A biomarker of cerebral ischemia, S100b, remained unchanged, suggesting preserved cerebral perfusion (0.17 ± 0.11 µg/L; p = 0.51). Ex vivo, terlipressin relaxed pulmonary and constricted mesenteric arteries., Conclusions: Terlipressin caused systemic vasoconstriction and pulmonary vasodilation in a porcine in vivo model of acute pulmonary embolism and vasorelaxation in isolated pulmonary arteries. Despite positive vascular effects, cardiac output declined and plasma lactate increased probably due to a predominantly systemic vasoconstrictor effect of terlipressin. These findings should warrant careful translation to the clinical setting and does not suggest routine use in acute pulmonary embolism.

Background: An impedance threshold device (ITD) was developed to increase venous return to the heart and therefore increase cardiac output and organ blood flow during cardiopulmonary rescue (CPR). Basic CPR aims to maintain coronary and cerebral blood flow at the minimum level necessary for survival. The present study compared the effects of an ITD on cerebral blood flow assessed as blood flow in both carotid arteries to the blood flow of a control group during prolonged CPR., Methods: Fourteen anaesthetized pigs were monitored during 60 min of CPR after induced ventricular fibrillation. The primary outcome was blood flow in both carotid arteries, and the secondary outcomes were blood pressure, acid-base parameters, plasma potassium, and plasma lactate. The pigs were randomized to mechanical compressions and ventilation with an ITD added to the ventilation or to a control group treated only with mechanical compressions and ventilation. The time course for the parameters was tested using analysis of variance., Results: The cumulative carotid blood flow in the ITD group decreased from 64 to 42 ml/min, and it decreased from 69 to 51 ml/min in the control group during 60 min of CPR. The difference was not significant. The secondary outcome measures were also not significantly different., Conclusions: This study did not show any beneficial effect of an ITD on carotid blood flow.

Background: Oxygen is a liberally dosed medicine; however, too much oxygen can be harmful. In certain situations, treatment with high oxygen concentration is necessary, e.g. after cardiopulmonary resuscitation. The amount of oxygen and duration of hyperoxia causing pulmonary damage is not fully elucidated. The aim of this study was to investigate pathophysiological and metabolite changes in lung tissue during hyperoxia while the lungs were kept open under constant low pressure., Methods: Seven pigs were exposed to 100% oxygen for five hours, using an apneic oxygenation technique with one long uninterrupted inspiration, while carbon dioxide was removed with an interventional lung assist. Arterial blood samples were collected every 30 minutes. Lung biopsies were obtained before and after hyperoxia. Microscopy and high-resolution magic angle spinning nuclear magnetic resonance spectroscopy were used to detect possible pathological and metabolite changes, respectively. Unsupervised multivariate analysis of variance and paired sample tests were performed. A two-tailed p-value ≤ 0.05 was considered significant., Results: No significant changes in arterial pH, and partial pressure of carbon dioxide, and no clear histopathological changes were observed after hyperoxia. While blood glucose and lactate levels changed to a minor degree, their levels dropped significantly in the lung after hyperoxia (p ≤ 0.04). Reduced levels of antioxidants (p ≤ 0.05), tricarboxylic acid cycle and energy (p ≤ 0.04) metabolites and increased levels of several amino acids (p ≤ 0.05) were also detected., Conclusion: Despite no histological changes, tissue metabolites were altered, indicating that exposure to hyperoxia affects lung tissue matrix on a molecular basis., (© 2019 The Authors.)

Introduction: In massive pulmonary embolism (PE) with circulatory collapse or with cardiac arrest, treatment can be difficult. Often, the diagnosis is unclear, and the time to treatment is crucial. Our institution has had an out-of-hospital team intended for the treatment of accidental hypothermia with extra corporeal membrane oxygenation (ECMO) since 2004. The team has occasionally been involved in patients suffering massive PE., Methods: We were called to 38 patients with PE, but two were assessed as untreatable. Seventeen were treated with cardiopulmonary resuscitation followed by veno-arterial ECMO. Nineteen were prepared for ECMO with sheaths in the femoral vessels and were intensively observed during diagnosis and treatment. Five of these patients later progressed to ECMO due to cardiac arrest during treatment with thrombolytic medication. Most of the patients were treated with heparin and thrombolytic medication, but if the medications were contraindicated, they were treated with either surgical thrombectomy or only with heparin awaiting spontaneous thrombolysis., Results: Of the 36 patients we intended to treat, 25 (69%) survived one month and 20 survived one year (56%). Of the 22 patients treated with ECMO, 11 survived one month (50%) and 10 survived one year (45%)., Discussion: The treatment could have been more uniform. It seems reasonable to build up a PE alert team with ECMO capability to take care of patients with massive PE., Conclusion: The treatment of thrombolytic medications in massive PE is risky, but if the patient is treated or prepared for ECMO, it can be lifesaving.

Objective: Extracorporeal membrane oxygenation (ECMO) has been widely used to stabilize patients with impairment of cardiac/respiratory function, and ECMO has been used to stabilize cardiopulmonary insufficiency caused by carbon monoxide (CO) poisoning in a porcine model. Airborne transportation in fixed wing aircraft of patients suffering from CO poisoning is challenging because as the air pressure drops, the oxygen content falls correspondingly. The aim of this study was to show the feasibility of cannulating and establishing ECMO therapy during airborne transportation after severe CO poisoning in a porcine model., Methods: An anesthetized pig was subjected to severe CO poisoning and loaded onto a Hercules aircraft. Cardiac arrest was induced at an altitude of 8,000 feet, after which cannulation and the establishment of venoarterial (VA) ECMO were performed. Vital signs were monitored, and arterial blood samples were analyzed while airborne., Results: CO poisoning was induced with carboxyhemoglobin at 58% before takeoff. We successfully cannulated the animal in-flight during cardiac arrest and initiated VA ECMO. The animal regained spontaneous circulation and was successfully weaned from ECMO. During VA ECMO, PaO 2 was maintained at high levels (420-615 mm Hg)., Conclusion: It is possible to cannulate and initiate VA ECMO treatment as airborne en route therapy for cardiac arrest and severe CO intoxication in a porcine model., (Copyright © 2019 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Introduction: Carbon monoxide (CO) poisoning is frequent worldwide but knowledge regarding the epidemiology is insufficient. The aim of this study was to clarify the extent of this intoxication, its mortality and factors associated with mortality., Materials and Methods: National databases from Statistics Denmark were used to identify individuals who suffered from CO-poisoning during 1995-2015, as well as information regarding co-morbidities, mortality and manner of death., Results: During the period from 1995 to 2015, 22,930 patients suffered from CO-poisoning in Denmark, and 21,138 of these patients (92%) were hospitalized. A total of 2,102 patients died within the first 30 days after poisoning (9.2%). Among these, 1,792 (85% of 2,102) were declared dead at the scene and 310 (15% of 2,102) died during hospitalization. Deaths due to CO-poisoning from smoke were intentional in 6.3% of cases, whereas deaths due to CO containing gases were intentional in 98.0% of cases. Among patients who survived >30 days, there was no significant difference in survival when comparing hyperbaric oxygen therapy (HBO) treatment with no HBO treatment after adjustment for age and co-morbidities such as drug abuse, psychiatric disease, stroke, alcohol abuse, arterial embolism, chronic obstructive pulmonary disease, cerebrovascular disease and atrial fibrillation. Several co-morbidities predicted poorer outcomes for patients who survived the initial 30 days., Conclusions: Poisoning from smoke and/or CO is a frequent incident in Denmark accounting for numerous contacts with hospitals and deaths. Both intoxication and mortality are highly associated with co-morbidities interfering with cognitive and physical function. Treatment with HBO was not seen to have an effect on survival., Competing Interests: The authors have declared that no competing interests exist.

Background: Severe intoxication with carbon monoxide (CO) is extremely lethal and causes numerous deaths due to cardiac or respiratory failure. Conventional intensive treatment may not be sufficient. The aim of this study was to investigate the treatment effect of extracorporeal veno-arterial extracorporeal membrane oxygenation (ECMO) following severe CO poisoning in an experimental porcine model., Methods: A total of twelve pigs were anaesthetized, routinely monitored and intoxicated by inhalation of CO until the beginning of cardiac failure and randomized to a treatment (ventilator using an FiO 2 of 100% or ECMO). In the case of cardiac arrest, advanced resuscitation using standard guidelines was performed for at least 10 min. ECMO was also initiated in the ventilation group if the return of spontaneous circulation did not occur within 10 min. Lung tissue biopsies were obtained before and after CO intoxication., Results: All animals in the ECMO group survived; however, one had to be resuscitated due to cardiac arrest. A single animal survived in the ventilator group, but five animals suffered from cardiac arrest at an average of 11.8 min after initiation of treatment. Conventional resuscitation failed in these animals, but four animals were successfully resuscitated after the establishment of ECMO. A significant decrease was noticed in PO 2 with increasing HbCO, but there was no increase in pulmonary vascular resistance. No differences in H&E-stained lung tissue biopsies were observed., Conclusions: The use of ECMO following severe CO poisoning greatly improved survival compared with conventional resuscitation in an experimental porcine model. This study forms the basis for further research among patients.

Background: Mean arterial blood pressure (MAP) and/or pump flow during normothermic cardiopulmonary bypass (CPB) are the most important factors of cerebral perfusion. The aim of this study was to explore the influence of CPB blood flow on cerebral blood flow (CBF) measured by dynamic positron emission tomography (PET) using 15 O-labelled water with no pharmacological interventions to maintain the MAP., Methods: Eight pigs (69-71 kg) were connected to normothermic CPB. After 60 minutes (min) with a CPB pump flow of 60 mL/kg/min, the pigs were changed to either 35 mL/kg/min or 47.5 mL/kg/min for 60 min and, thereafter, all the pigs returned to 60 mL/kg/min for another 60 min. The MAP was measured continuously and the CBF was measured by positron emission tomography (PET) during spontaneous circulation and at each CPB pump flow after 30 min of steady state., Results: Two pigs were excluded due to complications. CBF increased from spontaneous circulation to a CPB pump flow of 60 mL/kg/min. A reduction in CPB pump flow to 47.5 mL/kg/min (n=3) resulted in only minor changes in CBF while a reduction to 35 mL/kg/min (n=3) caused a pronounced change (correlation coefficient (R 2 ) 0.56). A return of CPB pump flow to 60 mL/kg/min was followed by an increase in CBF, except in the one pig with the lowest CBF during low flow (R 2 =0.44). CBF and MAP were not correlated (R 2 =0.20)., Conclusion: In this experimental porcine study, a relationship was observed between pump flow and CBF under normothermic low-flow CPB. The effect of low pump flow on MAP showed substantial variations, with no correlation between CBF and MAP.

Objective: Left vagus nerve (LVN) stimulation (LVNS) has been tested for lowering the blood pressure (BP) in patients with resistant hypertension (RH). Whereas, closed-loop LVNS (CL-LVNS) driven by a BP marker may be superior to open-loop LVNS, there are situations (e.g., exercising) when hypertension is normal. Therefore, an ideal anti-RH CL-LVNS system requires a variable to avoid stimulation in such conditions, for example, a respiratory marker ideally extracted from the LVN. As the LVN conducts respiratory signals, this study aimed to investigate if such signals can be recorded using implantable means and if a marker to monitor respiration could be derived from such recordings., Materials and Methods: The experiments were performed in 14 anesthetized pigs. Five pigs were subjected to changes of the respiratory frequency and nine to changes of the respiratory volume. The LVN electroneurogram (VENG) was recorded using two cuff electrodes and the respiratory cycles (RC) using a pressure transducer. To separate the afferent and efferent VENGs, vagotomy was performed between the cuffs in the first group of pigs. The VENG was squared to derive respiration-related neural profiles (RnPs) and their correlation with the RCs was investigated in regard to timing and magnitude parameters derived from the two waveforms., Results: The RnPs were morphologically similar with the RCs and the average RnPs represented accurate copies of the average RCs. Consequently, the lung inflation/deflation RC and RnP components had the same duration, the respiratory frequency changes affected in the same way both waveforms and the RnP amplitude increased linearly with the lung inflation in all tested pigs (R 2 values between 0.85 and 0.99)., Conclusions: The RnPs comprise information regarding the timing and magnitude of the respiratory parameters. As those LVN profiles were derived using implantable means, this study indicates that the RnPs could serve as respiratory markers in implantable systems., (© 2017 International Neuromodulation Society.)