Publications by authors named "Peter Herrmann"

42 Publications

Comparison of pulmonary function in isoflurane anaesthetized ventilated sheep () following administration of intravenous xylazine versus medetomidine.

Lab Anim 2021 Feb 27:23677220983366. Epub 2021 Feb 27.

School of Veterinary Medicine, Murdoch University, Australia.

Alpha receptor agonists (alpha-agonists) are useful sedative and analgesic agents in sheep, but have adverse pulmonary effects, which are reportedly similar between different alpha-agonists. This randomized crossover study compared pulmonary function after intravenous administration of an alpha-agonist, either xylazine or an equipotent dose of medetomidine in 34 female sheep anaesthetized twice. Pulmonary function was assessed using spirometry, volumetric capnography, arterial blood gas analysis 1 min prior to, and 5 and 10 min after administration of the allocated alpha 2 agonist drug. Pulmonary structural changes were subsequently assessed using computed tomography (CT). Tachypnoea or hypoxaemia prompted reversal with atipamezole and exclusion of data. Data were analysed for a fixed effect of drug using a mixed effect linear model with significance set at  < 0.05. Ten sheep administered xylazine required atipamezole while none of sheep receiving medetomidine did. Xylazine produced significantly higher respiratory frequency, airway pressures, airway resistance and arterial carbon dioxide (CO), and lower dynamic compliance, tidal volume, CO elimination and end tidal CO tension and arterial oxygen tension than medetomidine. This was associated with a significantly lower % of aerated tissue and higher % poorly and non-aerated tissue in CT images of sheep receiving xylazine versus medetomidine. In conclusion, xylazine administration produced marked decreases in pulmonary function, in ventilated isoflurane anaesthetized sheep, when compared to an equipotent dose of medetomidine when administered as an intravenous bolus supporting the use of medetomidine when alpha-agonists are required.
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http://dx.doi.org/10.1177/0023677220983366DOI Listing
February 2021

The impact of ventilation - perfusion inequality in COVID-19: a computational model.

J Appl Physiol (1985) 2021 Jan 13. Epub 2021 Jan 13.

University Medical Center of Göttingen.

COVID-19 infection may lead to an Acute Respiratory Distress Syndrome where severe gas exchange derangements may be associated, at least in the early stages, only with minor pulmonary infiltrates. This suggests that the shunt associated to the gasless lung parenchyma is not sufficient to explain CARDS hypoxemia. We designed an algorithm (VentQ), based on the same conceptual grounds described by J.B West in 1969. We set 499 ventilation-perfusion (V/Q) compartments and, after calculating their blood composition (PO, PCO and pH), we randomly chose 10 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO and PaCO were within 10% of the patient's values. We assumed that shunt fraction equaled the fraction of non-aerated lung tissue at the CT quantitative analysis. Five critically-ill patients later deceased were studied. The PaO/FiO was 91.1±18.6 mmHg and PaCO 69.0±16.1 mmHg. Cardiac output was 9.58±0.99 l/min. The fraction of non-aerated tissue was 0.33±0.06. The model showed that a large fraction of the blood flow was likely distributed in regions with very low V/Q (Q=0.06±0.02) and a smaller fraction in regions with moderately high V/Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high VA/Q inequality. Data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant V/Q inequality must be present in COVID-19. The high cardiac output and the extensive microthrombosis later found in the autopsy further support the hypothesis of a pathological perfusion of non/poorly ventilated lung tissue.
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http://dx.doi.org/10.1152/japplphysiol.00871.2020DOI Listing
January 2021

Physiological and quantitative CT-scan characterization of COVID-19 and typical ARDS: a matched cohort study.

Intensive Care Med 2020 12 21;46(12):2187-2196. Epub 2020 Oct 21.

Department of Anesthesiology, Intensive Care and Emergency Medicine, Medical University of Göttingen, Robert-Koch Straße 40, Göttingen, Germany.

Purpose: To investigate whether COVID-19-ARDS differs from all-cause ARDS.

Methods: Thirty-two consecutive, mechanically ventilated COVID-19-ARDS patients were compared to two historical ARDS sub-populations 1:1 matched for PaO/FiO or for compliance of the respiratory system. Gas exchange, hemodynamics and respiratory mechanics were recorded at 5 and 15 cmHO PEEP. CT scan variables were measured at 5 cmHO PEEP.

Results: Anthropometric characteristics were similar in COVID-19-ARDS, PaO/FiO-matched-ARDS and Compliance-matched-ARDS. The PaO/FiO-matched-ARDS and COVID-19-ARDS populations (both with PaO/FiO 106 ± 59 mmHg) had different respiratory system compliances (Crs) (39 ± 11 vs 49.9 ± 15.4 ml/cmHO, p = 0.03). The Compliance-matched-ARDS and COVID-19-ARDS had similar Crs (50.1 ± 15.7 and 49.9 ± 15.4 ml/cmHO, respectively) but significantly lower PaO/FiO for the same Crs (160 ± 62 vs 106.5 ± 59.6 mmHg, p < 0.001). The three populations had similar lung weights but COVID-19-ARDS had significantly higher lung gas volume (PaO/FiO-matched-ARDS 930 ± 644 ml, COVID-19-ARDS 1670 ± 791 ml and Compliance-matched-ARDS 1301 ± 627 ml, p < 0.05). The venous admixture was significantly related to the non-aerated tissue in PaO/FiO-matched-ARDS and Compliance-matched-ARDS (p < 0.001) but unrelated in COVID-19-ARDS (p = 0.75), suggesting that hypoxemia was not only due to the extent of non-aerated tissue. Increasing PEEP from 5 to 15 cmHO improved oxygenation in all groups. However, while lung mechanics and dead space improved in PaO/FiO-matched-ARDS, suggesting recruitment as primary mechanism, they remained unmodified or worsened in COVID-19-ARDS and Compliance-matched-ARDS, suggesting lower recruitment potential and/or blood flow redistribution.

Conclusions: COVID-19-ARDS is a subset of ARDS characterized overall by higher compliance and lung gas volume for a given PaO/FiO, at least when considered within the timeframe of our study.
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http://dx.doi.org/10.1007/s00134-020-06281-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577365PMC
December 2020

Mobilizing Carbon Dioxide Stores. An Experimental Study.

Am J Respir Crit Care Med 2021 02;203(3):318-327

Department of Anesthesiology and Intensive Care, Medical University of Göttingen, Göttingen, Germany.

Understanding the physiology of CO stores mobilization is a prerequisite for intermittent extracorporeal CO removal (ECCOR) in patients with chronic hypercapnia. To describe the dynamics of CO stores. Fifteen pigs (61.7 ± 4.3 kg) were randomized to 48 hours of hyperventilation (group "Hyper,"  = 4); 48 hours of hypoventilation (group "Hypo,"  = 4); 24 hours of hypoventilation plus 24 hours of normoventilation (group "Hypo-Baseline,"  = 4); or 24 hours of hypoventilation plus 24 hours of hypoventilation plus ECCOR (group "Hypo-ECCOR,"  = 3). Forty-eight hours after randomization, the current [Formula: see text]e was reduced by 50% in every pig. We evaluated [Formula: see text]co, [Formula: see text]o, and metabolic [Formula: see text]co ([Formula: see text]o times the metabolic respiratory quotient). Changes in the CO stores were calculated as [Formula: see text]co - metabolic V̇co. After 48 hours, the CO stores decreased by 0.77 ± 0.17 l kg in group Hyper and increased by 0.32 ± 0.27 l kg in group Hypo ( = 0.030). In group Hypo-Baseline, they increased by 0.08 ± 0.19 l kg, whereas in group Hypo-ECCOR, they decreased by 0.32 ± 0.24 l kg ( = 0.197). In the second 24-hour period, in groups Hypo-Baseline and Hypo-ECCOR, the CO2 stores decreased by 0.15 ± 0.09 l kg and 0.51 ± 0.06 l kg, respectively ( = 0.002). At the end of the experiment, the 50% reduction of [Formula: see text]e caused a Pa rise of 9.3 ± 1.1, 32.0 ± 5.0, 16.9 ± 1.2, and 11.7 ± 2.0 mm Hg h in groups Hyper, Hypo, Hypo-Baseline, and Hypo-ECCOR, respectively ( < 0.001). The Pa rise was inversely related to the previous CO stores mobilization ( < 0.001). CO from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCOR in patients with chronic hypercapnia.
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http://dx.doi.org/10.1164/rccm.202005-1687OCDOI Listing
February 2021

Does Iso-mechanical Power Lead to Iso-lung Damage?: An Experimental Study in a Porcine Model.

Anesthesiology 2020 05;132(5):1126-1137

From the Department of Anaesthesiology, Emergency and Intensive Care Medicine (F. Vassalli, I.P., F.R., E.D., D.J.A., H.G., M. Bonifazi, M. Busana, M.M.M., L.G., P.H., G.H., O.M., M.Q., L.G.) Department of Experimental Animal Medicine (V.R.), University of Göttingen, Göttingen, Germany Department of Adult Critical Care, Guy's and St. Thomas' NHS Foundation Trust, Health Centre for Human and Applied Physiological Sciences, King's College London, London, United Kingdom (F. Vasques) Department of Pathology, Lodi General Hospital, Lodi, Italy (O.L.) Regions Hospital and University of Minnesota, St. Paul, Minnesota (J.J.M.).

Background: Excessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury.

Methods: Three ventilatory strategies-high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)-were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD).

Results: At iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups.

Conclusions: Different ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.
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http://dx.doi.org/10.1097/ALN.0000000000003189DOI Listing
May 2020

Positive End-expiratory Pressure and Mechanical Power.

Anesthesiology 2019 01;130(1):119-130

From the Departments of Anesthesiology, Emergency and Intensive Care Medicine (F. Collino, F. Rapetti, F.V., G.M., T.T., F. Romitti, J.N., T.B., G.H., P.H., E.D., F. Cipulli, O.M., M.Q., L.G.) Experimental Animal Medicine (V.R.) Pathology (K.H.), University of Göttingen, Göttingen, Germany Department of Adult Critical Care, Guy's and St Thomas' National Health Service Foundation Trust, King's Health Partners, and Division of Asthma, Allergy and Lung Biology, King's College London, London, United Kingdom (L.C.) Department of Pulmonary and Critical Care Medicine, Regions Hospital and University of Minnesota, Minneapolis/St. Paul, Minnesota (J.J.M.).

Background: Positive end-expiratory pressure is usually considered protective against ventilation-induced lung injury by reducing atelectrauma and improving lung homogeneity. However, positive end-expiratory pressure, together with tidal volume, gas flow, and respiratory rate, contributes to the mechanical power required to ventilate the lung. This study aimed at investigating the effects of increasing mechanical power by selectively modifying its positive end-expiratory pressure component.

Methods: Thirty-six healthy piglets (23.3 ± 2.3 kg) were ventilated prone for 50 h at 30 breaths/min and with a tidal volume equal to functional residual capacity. Positive end-expiratory pressure levels (0, 4, 7, 11, 14, and 18 cm H2O) were applied to six groups of six animals. Respiratory, gas exchange, and hemodynamic variables were recorded every 6 h. Lung weight and wet-to-dry ratio were measured, and histologic samples were collected.

Results: Lung mechanical power was similar at 0 (8.8 ± 3.8 J/min), 4 (8.9 ± 4.4 J/min), and 7 (9.6 ± 4.3 J/min) cm H2O positive end-expiratory pressure, and it linearly increased thereafter from 15.5 ± 3.6 J/min (positive end-expiratory pressure, 11 cm H2O) to 18.7 ± 6 J/min (positive end-expiratory pressure, 14 cm H2O) and 22 ± 6.1 J/min (positive end-expiratory pressure, 18 cm H2O). Lung elastances, vascular congestion, atelectasis, inflammation, and septal rupture decreased from zero end-expiratory pressure to 4 to 7 cm H2O (P < 0.0001) and increased progressively at higher positive end-expiratory pressure. At these higher positive end-expiratory pressure levels, striking hemodynamic impairment and death manifested (mortality 0% at positive end-expiratory pressure 0 to 11 cm H2O, 33% at 14 cm H2O, and 50% at 18 cm H2O positive end-expiratory pressure). From zero end-expiratory pressure to 18 cm H2O, mean pulmonary arterial pressure (from 19.7 ± 5.3 to 32.2 ± 9.2 mmHg), fluid administration (from 537 ± 403 to 2043 ± 930 ml), and noradrenaline infusion (0.04 ± 0.09 to 0.34 ± 0.31 μg · kg(-1) · min(-1)) progressively increased (P < 0.0001). Lung weight and lung wet-to-dry ratios were not significantly different across the groups. The lung mechanical power level that best discriminated between more versus less severe damage was 13 ± 1 J/min.

Conclusions: Less than 7 cm H2O positive end-expiratory pressure reduced atelectrauma encountered at zero end-expiratory pressure. Above a defined power threshold, sustained positive end-expiratory pressure contributed to potentially lethal lung damage and hemodynamic impairment.
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http://dx.doi.org/10.1097/ALN.0000000000002458DOI Listing
January 2019

High-frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs.

Crit Care 2018 May 9;22(1):121. Epub 2018 May 9.

Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Management, University Medical Center Göttingen, Göttingen, Germany.

Background: Recent clinical studies have not shown an overall benefit of high-frequency oscillatory ventilation (HFOV), possibly due to injurious or non-individualized HFOV settings. We compared conventional HFOV (HFOV) settings with HFOV settings based on mean transpulmonary pressures (P) in an animal model of experimental acute respiratory distress syndrome (ARDS).

Methods: ARDS was induced in eight pigs by intrabronchial installation of hydrochloric acid (0.1 N, pH 1.1; 2.5 ml/kg body weight). The animals were initially ventilated in volume-controlled mode with low tidal volumes (6 ml kg) at three positive end-expiratory pressure (PEEP) levels (5, 10, 20 cmHO) followed by HFOV and then HFOV P each at PEEP 10 and 20. The continuous distending pressure (CDP) during HFOV was set at mean airway pressure plus 5 cmHO. For HFOV P it was set at mean P plus 5 cmHO. Baseline measurements were obtained before and after induction of ARDS under volume controlled ventilation with PEEP 5. The same measurements and computer tomography of the thorax were then performed under all ventilatory regimens at PEEP 10 and 20.

Results: Cardiac output, stroke volume, mean arterial pressure and intrathoracic blood volume index were significantly higher during HFOV P than during HFOV at PEEP 20. Lung density, total lung volume, and normally and poorly aerated lung areas were significantly greater during HFOV, while there was less over-aerated lung tissue in HFOV P. The groups did not differ in oxygenation or extravascular lung water index.

Conclusion: HFOV P is associated with less hemodynamic compromise and less pulmonary overdistension than HFOV. Despite the increase in non-ventilated lung areas, oxygenation improved with both regimens. An individualized approach with HFOV settings based on transpulmonary pressure could be a useful ventilatory strategy in patients with ARDS. Providing alveolar stabilization with HFOV while avoiding harmful distending pressures and pulmonary overdistension might be a key in the context of ventilator-induced lung injury.
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http://dx.doi.org/10.1186/s13054-018-2028-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943989PMC
May 2018

Reclassifying Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2018 06;197(12):1586-1595

1 Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Germany.

Rationale: The ratio of Pa to Fi (P/F) defines acute respiratory distress syndrome (ARDS) severity and suggests appropriate therapies.

Objectives: We investigated 1) whether a 150-mm-Hg P/F threshold within the range of moderate ARDS (100-200 mm Hg) would define two subgroups that were more homogeneous; and 2) which criteria led the clinicians to apply extracorporeal membrane oxygenation (ECMO) in severe ARDS.

Methods: At the 150-mm-Hg P/F threshold, moderate patients were split into mild-moderate (n = 50) and moderate-severe (n = 55) groups. Patients with severe ARDS (Fi not available in three patients) were split into higher (n = 63) and lower (n = 18) Fi groups at an 80% Fi threshold.

Measurements And Main Results: Compared with mild-moderate ARDS, patients with moderate-severe ARDS had higher peak pressures, Pa, and pH. They also had heavier lungs, greater inhomogeneity, more noninflated tissue, and greater lung recruitability. Within 84 patients with severe ARDS (P/F < 100 mm Hg), 75% belonged to the higher Fi subgroup. They differed from the patients with severe ARDS with lower Fi only in Pa and lung weight. Forty-one of 46 patients treated with ECMO belonged to the higher Fi group. Within this group, the patients receiving ECMO had higher Pa than the 22 non-ECMO patients. The inhomogeneity ratio, total lung weight, and noninflated tissue were also significantly higher.

Conclusions: Using the 150-mm-Hg P/F threshold gave a more homogeneous distribution of patients with ARDS across the severity subgroups and identified two populations that differed in their anatomical and physiological characteristics. The patients treated with ECMO belonged to the severe ARDS group, and almost 90% of them belonged to the higher Fi subgroup.
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http://dx.doi.org/10.1164/rccm.201709-1804OCDOI Listing
June 2018

Automatic quantitative computed tomography segmentation and analysis of aerated lung volumes in acute respiratory distress syndrome-A comparative diagnostic study.

J Crit Care 2017 12 8;42:184-191. Epub 2016 Nov 8.

Department of Anesthesiology, Emergency and Intensive Care Medicine, University Hospital Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany. Electronic address:

Quantitative lung computed tomographic (CT) analysis yields objective data regarding lung aeration but is currently not used in clinical routine primarily because of the labor-intensive process of manual CT segmentation. Automatic lung segmentation could help to shorten processing times significantly. In this study, we assessed bias and precision of lung CT analysis using automatic segmentation compared with manual segmentation. In this monocentric clinical study, 10 mechanically ventilated patients with mild to moderate acute respiratory distress syndrome were included who had received lung CT scans at 5- and 45-mbar airway pressure during a prior study. Lung segmentations were performed both automatically using a computerized algorithm and manually. Automatic segmentation yielded similar lung volumes compared with manual segmentation with clinically minor differences both at 5 and 45 mbar. At 5 mbar, results were as follows: overdistended lung 49.58mL (manual, SD 77.37mL) and 50.41mL (automatic, SD 77.3mL), P=.028; normally aerated lung 2142.17mL (manual, SD 1131.48mL) and 2156.68mL (automatic, SD 1134.53mL), P = .1038; and poorly aerated lung 631.68mL (manual, SD 196.76mL) and 646.32mL (automatic, SD 169.63mL), P = .3794. At 45 mbar, values were as follows: overdistended lung 612.85mL (manual, SD 449.55mL) and 615.49mL (automatic, SD 451.03mL), P=.078; normally aerated lung 3890.12mL (manual, SD 1134.14mL) and 3907.65mL (automatic, SD 1133.62mL), P = .027; and poorly aerated lung 413.35mL (manual, SD 57.66mL) and 469.58mL (automatic, SD 70.14mL), P=.007. Bland-Altman analyses revealed the following mean biases and limits of agreement at 5 mbar for automatic vs manual segmentation: overdistended lung +0.848mL (±2.062mL), normally aerated +14.51mL (±49.71mL), and poorly aerated +14.64mL (±98.16mL). At 45 mbar, results were as follows: overdistended +2.639mL (±8.231mL), normally aerated 17.53mL (±41.41mL), and poorly aerated 56.23mL (±100.67mL). Automatic single CT image and whole lung segmentation were faster than manual segmentation (0.17 vs 125.35seconds [P<.0001] and 10.46 vs 7739.45seconds [P<.0001]). Automatic lung CT segmentation allows fast analysis of aerated lung regions. A reduction of processing times by more than 99% allows the use of quantitative CT at the bedside.
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http://dx.doi.org/10.1016/j.jcrc.2016.11.001DOI Listing
December 2017

Impact of Non-Invasive Ventilation on Sympathetic Nerve Activity in Chronic Obstructive Pulmonary Disease.

Lung 2017 02 16;195(1):69-75. Epub 2016 Nov 16.

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37099, Göttingen, Germany.

Purpose: Chronic obstructive pulmonary disease (COPD) is associated with elevated sympathetic nerve activity, which is probably linked to an increased cardiovascular risk, and may contribute to muscle dysfunction by heightened muscle vasoconstrictor drive. We hypothesized that resistive unloading of respiratory muscles by intermittent non-invasive ventilation (NIV) reduces sympathetic tone at rest and during subsequent handgrip exercise in patients with COPD.

Methods: Muscle sympathetic nerve activity (MSNA) in the peroneal nerve, heart rate, blood pressure, CO, and SpO were continuously recorded in 5 COPD patients with intermittent NIV and 11 control COPD patients without NIV. Static and dynamic handgrip exercises were performed before and after NIV.

Results: At baseline, heart rate-adjusted MSNA (bursts/100 heart beats) did not differ between groups. NIV did not significantly affect MSNA levels at rest. However, during handgrip exercises directly following NIV, MSNA was lower than before, which was significant for dynamic handgrip (67.00 ± 3.70 vs. 62.13 ± 4.50 bursts/100 heart beats; p = 0.035 in paired t test). In contrast, MSNA (non-significantly) increased in the control group during repeated dynamic or static handgrip. During dynamic handgrip, tCO was lower after NIV than before (change by -5.04 ± 0.68 mmHg vs. -0.53 ± 0.64 in the control group; p = 0.021), while systolic and diastolic blood pressure did not change significantly.

Conclusions: NIV reduces sympathetic activation during subsequent dynamic handgrip exercise and thereby may elicit positive effects on the cardiovascular system as well as on muscle function in patients with COPD.
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http://dx.doi.org/10.1007/s00408-016-9965-1DOI Listing
February 2017

Lung hyperaeration assessment by computed tomography: correction of reconstruction-induced bias.

BMC Anesthesiol 2016 08 24;16(1):67. Epub 2016 Aug 24.

Department of Surgical Sciences and Integrated Diagnostics, IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy.

Background: Computed tomography (CT) reconstruction parameters, such as slice thickness and convolution kernel, significantly affect the quantification of hyperaerated parenchyma (VHYPER%). The aim of this study was to investigate the mathematical relation between VHYPER% calculated at different reconstruction settings, in mechanically ventilated and spontaneously breathing patients with different lung pathology.

Methods: In this retrospective observational study, CT scans of patients of the intensive care unit and emergency department were collected from two CT scanners and analysed with different kernel-thickness combinations (reconstructions): 1.25 mm soft kernel, 5 mm soft kernel, 5 mm sharp kernel in the first scanner; 2.5 mm slice thickness with a smooth (B41s) and a sharp (B70s) kernel on the second scanner. A quantitative analysis was performed with Maluna® to assess lung aeration compartments as percent of total lung volume. CT variables calculated with different reconstructions were compared in pairs, and their mathematical relationship was analysed by using quadratic and power functions.

Results: 43 subjects were included in the present analysis. Image reconstruction parameters influenced all the quantitative CT-derived variables. The most relevant changes occurred in the hyperaerated and normally aerated volume compartments. The application of a power correction formula led to a significant reduction in the bias between VHYPER% estimations (p < 0.001 in all cases). The bias in VHYPER% assessment did not differ between lung pathology nor ventilation mode groups (p > 0.15 in all cases).

Conclusions: Hyperaerated percent volume at different reconstruction settings can be described by a fixed mathematical relationship, independent of lung pathology, ventilation mode, and type of CT scanner.
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http://dx.doi.org/10.1186/s12871-016-0232-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995787PMC
August 2016

Effects of varenicline on sympatho-vagal balance and cue reactivity during smoking withdrawal: a randomised placebo-controlled trial.

Tob Induc Dis 2016 8;14:26. Epub 2016 Aug 8.

Department of Cardiology and Pneumology, University Medical Centre Göttingen, D-37099 Göttingen, Germany.

Background: Varenicline is an effective smoking cessation medication. Some concern has been raised that its use may precipitate adverse cardiovascular events although no patho-physiological mechanism potentially underlying such an effect has been reported. The aim of this study was to test the hypothesis that varenicline impacts on sympatho-vagal balance during smoking withdrawal.

Methods: In this randomised, placebo-controlled trial, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), heart rate, and blood pressure were assessed in 17 smokers four weeks before a quit attempt (baseline) and again on the third day of that quit attempt (acute smoking withdrawal).

Results: Regarding the primary endpoint of our study, we did not find a significant effect of varenicline compared to placebo on changes in MSNA burst incidence between baseline and acute smoking withdrawal (-3.0 ± 3.3 vs.-3.9 ± 5.0 bursts/100 heart beats; p = 0.308). However, heart rate and systolic blood pressure significantly decreased in the placebo group only, while no significant changes in these parameters were observed in the varenicline group. Exposure to smoking cues during acute withdrawal lead to a significant increase of heart rate in the placebo group, while heart rate decreased in the varenicline group, and the difference in these changes was significant between groups (+2.7 ± 1.0 vs.-1.8 ± 0.5 1/min; p = 0.002). In all 17 participants combined, a significant increase in heart rate during smoking cue exposure was detected in subjects who relapsed in the course of six weeks after the quit date compared to those who stayed abstinent (+2.5 ± 1.2 vs.-1.1 ± 0.7; p = 0.018). Six-week abstinence rates were higher in the varenicline group compared to placebo (88 vs. 22 % p = 0.015).

Conclusion: We did not find evidence of adverse effects of varenicline on sympatho-vagal balance. Varenicline probably blunts the heart rate response to smoking cues, which may be linked to improved cessation outcome.
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http://dx.doi.org/10.1186/s12971-016-0091-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977756PMC
August 2016

Sympathetic Activation is Associated with Exercise Limitation in COPD.

COPD 2016 10 1;13(5):589-94. Epub 2016 Feb 1.

a Clinic for Cardiology and Pneumology , University Medical Center Göttingen , Göttingen , Germany.

Exercise intolerance, skeletal muscle dysfunction, and reduced daily activity are central in COPD patients and closely related to quality of life and prognosis. Studies assessing muscle exercise have revealed an increase in sympathetic outflow as a link to muscle hypoperfusion and exercise limitation. Our primary hypothesis was that muscle sympathetic nerve activity (MSNA) correlates with exercise limitation in COPD. MSNA was evaluated at rest and during dynamic or static handgrip exercise. Additionally, we assessed heart rate, blood pressure, CO2 tension, oxygen saturation (SpO2), and breathing frequency. Ergospirometry was performed to evaluate exercise capacity. We assessed MSNA of 14 COPD patients and 8 controls. In patients, MSNA was negatively correlated with peak oxygen uptake (VO2% pred) (r = -0.597; p = 0.040). During dynamic or static handgrip exercise, patients exhibited a significant increase in MSNA, which was not observed in the control group. The increase in MSNA during dynamic handgrip was highly negatively correlated with peak exercise capacity in Watts (w) and peak oxygen uptake (VO2/kg) (r = -0.853; p = 0.002 and r = -0.881; p = 0.002, respectively). Our study reveals an association between increased MSNA and limited exercise capacity in patients with COPD. Furthermore, we found an increased sympathetic response to moderate physical exercise (handgrip), which may contribute to exercise intolerance in COPD.
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http://dx.doi.org/10.3109/15412555.2015.1136272DOI Listing
October 2016

Adjusting ventilator off-cycling in invasively ventilated COPD patients needs comprehensive adjustments.

Minerva Anestesiol 2016 07 1;82(7):743-50. Epub 2015 Dec 1.

Department of Anesthesiology, University of Goettingen Medical School, Goettingen, Germany -

Background: Patient-ventilator asynchrony that prolongs weaning and increases morbidity and mortality is common during invasive ventilation of patients with chronic obstructive pulmonary disease (COPD). In this context, the inspiratory cycling criteria (iCC) of the ventilator during assisted pressure support (PS) ventilation is a poorly acknowledged key factor. We investigated the changes of flow and pressure parameters that resulted from varying the iCC in a simulated COPD lung model.

Methods: A lung simulator was connected to an ICU ventilator through an endotracheal tube. We studied iCC settings from 10% to 70% at different respiratory rates (RR) (15 and 30 bpm) and pressure support (PS) (5 and 15 cmH2O) settings and registered asynchrony-index, double-triggering, expiratory trigger latency (TLEXP), intrinsic PEEP (PEEPi), expiratory pressure time product (PTPEXP) and tidal volume.

Results: At iCC≤20%, asynchrony occurred in 50% of all recordings in high RR/high PS. At a low RR, double triggering occurred at high iCC settings. It appeared at 50% iCC with low PS and at 60% iCC with high PS. TLEXP was positive at iCC 10% to 30% but decreased with increasing iCC (P<0.001). At low RR/high PS settings, PEEPi decreased at iCC≤40% but increased at iCC≥50%. High RR/low PS constantly reduced PTPEXP up to 60% iCC. Changes in iCC strongly influenced the resulting tidal volume.

Conclusions: Non-adapted ventilator iCC can cause patient-ventilator asynchrony. The success of assisted invasive ventilation and weaning relies on meticulous adjustments.
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July 2016

Patient-Ventilator Interaction During Noninvasive Ventilation in Simulated COPD.

Respir Care 2016 Jan 10;61(1):15-22. Epub 2015 Nov 10.

Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Germany.

Background: During noninvasive ventilation (NIV) of COPD patients, delayed off-cycling of pressure support can cause patient ventilator mismatch and NIV failure. This systematic experimental study analyzes the effects of varying cycling criteria on patient-ventilator interaction.

Methods: A lung simulator with COPD settings was connected to an ICU ventilator via helmet or face mask. Cycling was varied between 10 and 70% of peak inspiratory flow at different breathing frequencies (15 and 30 breaths/min) and pressure support levels (5 and 15 cm H2O) using the ventilator's invasive and NIV mode with and without an applied leakage.

Results: Low cycling criteria led to severe expiratory cycle latency. Augmenting off-cycling reduced expiratory cycle latency (P < .001), decreased intrinsic PEEP, and avoided non-supported breaths. Setting cycling to 50% of peak inspiratory flow achieved best synchronization. Overall, using the helmet interface increased expiratory cycle latency in almost all settings (P < .001). Augmenting cycling from 10 to 40% progressively decreased expiratory pressure load (P < .001). NIV mode decreased expiratory cycle latency compared with the invasive mode (P < .001).

Conclusion: Augmenting the cycling criterion above the default setting (20-30% peak inspiratory flow) improved patient ventilator synchrony in a simulated COPD model. This suggests that an individual approach to cycling should be considered, since interface, level of pressure support, breathing frequency, and leakage influence patient-ventilator interaction and thus need to be considered.
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http://dx.doi.org/10.4187/respcare.04141DOI Listing
January 2016

Low respiratory rate plus minimally invasive extracorporeal Co2 removal decreases systemic and pulmonary inflammatory mediators in experimental Acute Respiratory Distress Syndrome.

Crit Care Med 2014 Jun;42(6):e451-60

1Dipartimento dell'Emergenza e Trapianti d'Organo, Sezione di Anestesiologia e Rianimazione, Università degli Studi Aldo Moro, Bari, Italy. 2Intensive Care, Ospedale Di venere, Bari, Italy. 3Dipartimento dell'Emergenza e Trapianti d'Organo, Sezione di Chirurgia Veterinaria, Università degli Studi Aldo Moro, Bari, Italy. 4Dottorato in Scienze Chirurgiche Sperimentali e Terapie Cellulari, Università degli Studi Aldo Moro, Bari, Italy. 5Center for Anesthesiology, Emergency and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany. 6Dipartimento di Scienze Biomediche ed Oncologia Umana, Cattedra di Statistica Medica, Università degli Studi Aldo Moro, Bari, Italy.

Objective: The Acute Respiratory Distress Syndrome Network protocol recommends limiting tidal volume and plateau pressure; it also recommends increasing respiratory rate to prevent hypercapnia. We tested a strategy that combines the low tidal volume with lower respiratory rates and minimally invasive CO2 removal.

Subjects: Ten lung-damaged pigs (instilled hydrochloride).

Interventions: Two conditions randomly applied in a crossover fashion: the Acute Respiratory Distress Syndrome Network protocol and the Acute Respiratory Distress Syndrome Network protocol plus lower respiratory rate plus minimally invasive Co2 removal. A similar arterial Co2 partial pressure was targeted in the two conditions.

Measurements And Main Results: Physiological parameters, computed tomography scans, plasma and bronchoalveolar lavage concentrations of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-α. During the lower respiratory rate condition, respiratory rate was reduced from 30.5 ± 3.8 to 14.2 ± 3.5 (p < 0.01) breaths/min and minute ventilation from 10.4 ± 1.6 to 4.9 ± 1.7 L/min (p < 0.01). The extracorporeal device removed 38.9% ± 6.1% (79.9 ± 18.4 mL/min) of CO2 production. During the lower respiratory rate condition, interleukin-6, interleukin-8, and tumor necrosis factor-α concentrations were significantly lower in plasma; interleukin-6 and tumor necrosis factor-α concentrations were lower in bronchoalveolar lavage, whereas the concentrations of the other cytokines remained unchanged.

Conclusion: The strategy of lower respiratory rate plus minimally invasive extracorporeal CO2 removal was feasible and safe and, as compared with the Acute Respiratory Distress Syndrome Network protocol, reduced the concentrations of some, but not all, of the tested cytokines without affecting respiratory mechanics, gas exchange, and hemodynamics.
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http://dx.doi.org/10.1097/CCM.0000000000000312DOI Listing
June 2014

Posttraumatic and postoperative osteomyelitis: surgical revision strategy with persisting fistula.

Arch Orthop Trauma Surg 2014 Feb 14;134(2):159-65. Epub 2013 Dec 14.

Berufsgenossenschaftliche Unfallklinik Ludwigshafen, Abteilung für Unfallchirurgie und Orthopädie, Ludwig Guttmann Strasse 13, 67071, Ludwigshafen am Rhein, Germany,

Introduction: Posttraumatic and postoperative osteomyelitis (PPO) with bacteria colonisation during trauma and associated surgery is an increasing clinical problem. This study investigated the treatment of PPO by surgical revision including irrigation, debridement, and temporary hardware maintenance. In addition, a drainage was inserted as persisting fistula to control osteomyelitis until fracture healing was achieved. Trauma- and osteomyelitis-related factors that influenced the study outcome were determined.

Patients And Methods: 67 consecutive patients with PPO were included. At onset of PPO, patients had incomplete fracture healing. Patients were subdivided by time of PPO occurrence (acute, subacute or chronic), initial soft tissue trauma, anatomical location, and initial fracture type (AO classification). The study outcome measures included radiographic and clinical follow-up.

Results: 59 patients could be followed for an average of 23 months after revision surgery. A bone healing was achieved by 89% of patients after 14.7 ± 13.4 weeks. Fractures of the lower extremity, open fractures and comminuted C-type fractures took significantly longer to achieve bone healing (p < 0.05 each). Time of PPO occurrence did not influence bone healing. After fracture consolidation, no re-infection was found.

Conclusions: This study showed high rates of bone healing, indicating that this strategy with persisting fistula should be considered as alternative treatment option in patients with PPO.
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http://dx.doi.org/10.1007/s00402-013-1907-2DOI Listing
February 2014

Can we predict addiction to opioid analgesics? A possible tool to estimate the risk of opioid addiction in patients with pain.

Pain Physician 2013 Nov-Dec;16(6):593-601

Medical University of Vienna, Vienna, Austria.

Background: The use of opioid analgesics in the treatment of chronic pain conditions has long been controversial. They have been reported to be relatively safe when prescribed with caution, but a brief and valid instrument to estimate a person's risk of addiction is still missing.

Objective: The aim of this study was to investigate a self-rating questionnaire allowing an estimation of a person's risk of addiction to opioid analgesics.

Study Design: Retrospective review.

Setting: Four Austrian hospitals.

Methods: Seven hundred forty-one patients were interviewed. Of these, 634 patients were affected with chronic pain while 107 patients had a history of opioid addiction. Patients were interviewed about alcohol and nicotine consumption and family history of psychiatric disorders. Attitudes towards medication and the origin of pain were examined. We asked patients with an opioid addiction and patients suffering from chronic pain to complete a short questionnaire intended to help screen for addiction potential.

Results: Compared to the patients suffering from chronic pain, patients with an opioid addiction significantly more often had alcohol- and nicotine-related pathologies and psychiatric comorbidity. A family history of mental illness and developmental problems were significantly more frequent in this group. Compared to those not addicted, those with an opioid addiction had significantly higher expectations concerning the potential of medication to change one's mental state; they thought that psychological  factors might contribute to the pain they feel.

Limitations: The main limitation of this study is the use of a self-rating instrument which reduces objectivity and introduces the possibility of misreporting. Also, the 2 groups differ in number and are not homogenous.

Conclusion: We found differences in questionnaire responses between patients with an opioid addiction and patients suffering from chronic pain to be dependent upon the prevalence of current or former addiction, psychiatric history, attitudes towards medication, and ideas about the origin of pain. We believe these factors have predictive value in estimating a patient with pain's risk of addiction.
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August 2014

Effects of acute intracranial hypertension on extracerebral organs: a randomized experimental study in pigs.

J Neurol Surg A Cent Eur Neurosurg 2012 Sep 16;73(5):289-95. Epub 2012 Aug 16.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University Hospital Göttingen, Göttingen, Germany.

Background: The study was conducted to determine the effects of isolated acute intracranial hypertension (AICH) on extracerebral organs.

Design: A total of 14 mechanically ventilated pigs were randomized to two groups of seven each: (1) control and (2) AICH.

Methods: AICH was induced by inflating an intracranial balloon catheter. The inflation volume was adjusted to keep intracranial pressure between 30 and 40 cm H2O. Hemodynamics, gas-exchange, and global oxygen delivery parameters were observed over a 4-hour period. At the end of the 4-hour period, tissue samples of heart, lungs, liver, and kidneys were collected and histologically graded for inflammation, edema, and cell damage (necrosis) using semiquantitative scores.

Results: Animals with AICH had increased heart rate and cardiac output, and higher scores for inflammation, edema, and necrosis in heart, lung, kidney, and liver tissues (all p < 0.05). Peripheral and mixed-venous oxygen saturations were unaffected.

Conclusions: Isolated AICH induces injury to multiple extracerebral organs, even in the absence of hypoperfusion or hypoxemia.
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http://dx.doi.org/10.1055/s-0032-1304813DOI Listing
September 2012

Effects of pulmonary acid aspiration on the lungs and extra-pulmonary organs: a randomized study in pigs.

Crit Care 2012 Dec 12;16(2):R35. Epub 2012 Dec 12.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Göttingen Medical Center, Robert-Koch-Straße 40, 37075 Göttingen, Germany.

Introduction: There is mounting evidence that injury to one organ causes indirect damage to other organ systems with increased morbidity and mortality. The aim of this study was to determine the effects of acid aspiration pneumonitis (AAP) on extrapulmonary organs and to test the hypothesis that these could be due to circulatory depression or hypoxemia.

Methods: Mechanically ventilated anesthetized pigs were randomized to receive intrabronchial instillation of hydrochloric acid (n = 7) or no treatment (n = 7). Hydrochloric acid (0.1 N, pH 1.1, 2.5 ml/kg BW) was instilled into the lungs during the inspiratory phase of ventilation. Hemodynamics, respiratory function and computer tomography (CT) scans of lung and brain were followed over a four-hour period. Tissue samples of lung, heart, liver, kidney and hippocampus were collected at the end of the experiment.

Results: Acid instillation caused pulmonary edema, measured as increased extravascular lung water index (ELWI), impaired gas exchange and increased mean pulmonary artery pressure. Gas exchange tended to improve during the course of the study, despite increasing ELWI. In AAP animals compared to controls we found: a) cardiac leukocyte infiltration and necrosis in the conduction system and myocardium; b) lymphocyte infiltration in the liver, spreading from the periportal zone with prominent areas of necrosis; c) renal inflammation with lymphocyte infiltration, edema and necrosis in the proximal and distal tubules; and d) a tendency towards more severe hippocampal damage (P > 0.05).

Conclusions: Acid aspiration pneumonitis induces extrapulmonary organ injury. Circulatory depression and hypoxemia are unlikely causative factors. ELWI is a sensitive bedside parameter of early lung damage.
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http://dx.doi.org/10.1186/cc11214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681347PMC
December 2012

Validation of a new non-invasive blood pressure measurement method on mice via pulse wave propagation time measurement on a cuff.

Biomed Tech (Berl) 2011 Jun;56(3):153-8

Mannheim Biomedical Engineering Laboratories (MABEL), University Hospital Mannheim, Heidelberg University, Germany.

In the present article, we describe the validation of a new non-invasive method for measuring blood pressure (BP) which also enables to determine the three BP values: systolic, diastolic and mean value. Our method is based on the pulse transit time (PTT) measurement along an artery directly at the BP cuff. The accuracy of this method was evaluated by comparison with the direct simultaneous measurement of blood pressure from 40 anesthetized female mice. Close correlation between the gained data from these two methods was observed.
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http://dx.doi.org/10.1515/BMT.2011.013DOI Listing
June 2011

Effects of high-frequency oscillatory ventilation on systemic and cerebral hemodynamics and tissue oxygenation: an experimental study in pigs.

Neurocrit Care 2012 Oct;17(2):281-92

Department of Anaesthesiology, Emergency-and Intensive Care Medicine, University of Göttingen Medical School, Göttingen, Germany.

Background: In this study, we compare the effects of high frequency oscillatory ventilation (HFOV) with those of lung-protective volume-controlled ventilation (VCV) on cerebral perfusion, tissue oxygenation, and cardiac function with and without acute intracranial hypertension (AICH).

Methods: Eight pigs with healthy lungs were studied during VCV with low tidal volume (V(T): 6 ml kg(-1)) at four PEEP levels (5, 10, 15, 20 cm H(2)O) followed by HFOV at corresponding transpulmonary pressures, first with normal ICP and then with AICH. Systemic and pulmonary hemodynamics, cardiac function, cerebral perfusion pressure (CPP), cerebral blood flow (CBF), cerebral tissue oxygenation, and blood gases were measured after 10 min at each level. Transpulmonary pressures (TPP) were calculated at each PEEP level. The measurements were repeated with HFOV using continuous distending pressures (CDP) set at TPP plus 5 cm H(2)O for the corresponding PEEP level. Both measurement series were repeated after intracranial pressure (ICP) had been raised to 30-40 cm H(2)O with an intracranial balloon catheter.

Results: Cardiac output, stroke volume, MAP, CPP, and CBF were significantly higher during HFOV at normal ICP. Systemic and cerebral hemodynamics was significantly altered by AICH, but there were no differences attributable to the ventilatory mode.

Conclusion: HFOV is associated with less hemodynamic compromise than VCV, even when using small tidal volumes and low mean airway pressures. It does not impair cerebral perfusion or tissue oxygenation in animals with AICH, and could, therefore, be a useful ventilatory strategy to prevent lung failure in patients with traumatic brain injury.
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http://dx.doi.org/10.1007/s12028-011-9566-zDOI Listing
October 2012

Cardiopulmonary function and oxygen delivery during total liquid ventilation.

Pediatr Pulmonol 2011 Oct 2;46(10):964-75. Epub 2011 May 2.

Department of Anaesthesiology and Intensive Care Medicine, University Medical Center Mannheim, Mannheim, Germany.

Introduction: Total liquid ventilation (TLV) with perfluorocarbons has shown to improve cardiopulmonary function in the injured and immature lung; however there remains controversy over the normal lung. Hemodynamic effects of TLV in the normal lung currently remain undetermined. This study compared changes in cardiopulmonary and circulatory function caused by either liquid or gas tidal volume ventilation.

Methods: In a prospective, controlled study, 12 non-injured anesthetized, adult New Zealand rabbits were primarily conventionally gas-ventilated (CGV). After instrumentation for continuous recording of arterial (AP), central venous (CVP), left artrial (LAP), pulmonary arterial pressures (PAP), and cardiac output (CO) animals were randomized into (1) CGV group and (2) TLV group. In the TLV group partial liquid ventilation was initiated with instillation of perfluoroctylbromide (12 ml/kg). After 15 min, TLV was established for 3 hr applying a volume-controlled, pressure-limited, time-cycled ventilation mode using a double-piston configured TLV. Controls (CGV) remained gas-ventilated throughout the experiment.

Results: During TLV, heart rate, CO, PAP, MAP, CVP, and LAP as well as derived hemodynamic variables, arterial and mixed venous blood gases, oxygen delivery, PVR, and SVR did not differ significantly compared to CGV.

Conclusions: Liquid tidal volumes suitable for long-term TLV in non-injured rabbits do not significantly impair CO, blood pressure, and oxygen dynamics when compared to CGV.
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http://dx.doi.org/10.1002/ppul.21461DOI Listing
October 2011

Inspiratory resistive loading does not increase sympathetic tone in COPD.

Respir Med 2010 Jan 19;104(1):107-13. Epub 2009 Jul 19.

Department of Cardiology and Pneumology, University Hospital Goettingen, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany.

Objectives: Neurohumoral activation has been shown to be present in patients with chronic obstructive pulmonary disease (COPD). The increase in respiratory muscle work might be responsible for the observed elevation of sympathetic tone via a respiratory muscle ergoreflex in these patients. The aim of this study is to investigate whether moderately increasing inspiratory resistive loading will impact on sympathetic activity in healthy subjects and COPD patients.

Methods: Efferent muscle sympathetic nerve activity, blood pressure, heart rate and respiratory movements were continuously measured in 15 patients and 15 healthy control subjects. In order to increase work of breathing as evaluated by the tension-time index, inspiratory resistive loading was performed while patients were breathing through a spirometer.

Results: At baseline, sympathetic nerve activity was significantly elevated in patients. Resistive loading increased work of breathing (tension-time index) by roughly 110% (COPD) and 130% (controls) but did not significantly alter blood gases or sympathetic activity in either group.

Conclusions: Doubling the work of breathing does not affect sympathetic activation in COPD patients or healthy control subjects. Thus in COPD the respiratory muscle ergoreflex does not seem to play a major role in sympathoexcitation.
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http://dx.doi.org/10.1016/j.rmed.2009.06.011DOI Listing
January 2010

High flow biphasic positive airway pressure by helmet--effects on pressurization, tidal volume, carbon dioxide accumulation and noise exposure.

Crit Care 2009 5;13(3):R85. Epub 2009 Jun 5.

Department of Anaesthesiology, Emergency and Critical Care Medicine, University of Göttingen, 37075 Göttingen, Germany.

Introduction: Non-invasive ventilation (NIV) with a helmet device is often associated with poor patient-ventilator synchrony and impaired carbon dioxide (CO2) removal, which might lead to failure. A possible solution is to use a high free flow system in combination with a time-cycled pressure valve placed into the expiratory circuit (HF-BiPAP). This system would be independent from triggering while providing a high flow to eliminate CO2.

Methods: Conventional pressure support ventilation (PSV) and time-cycled biphasic pressure controlled ventilation (BiVent) delivered by an Intensive Care Unit ventilator were compared to HF-BiPAP in an in vitro lung model study. Variables included delta pressures of 5 and 15 cmH2O, respiratory rates of 15 and 30 breaths/min, inspiratory efforts (respiratory drive) of 2.5 and 10 cmH2O) and different lung characteristics. Additionally, CO2 removal and noise exposure were measured.

Results: Pressurization during inspiration was more effective with pressure controlled modes compared to PSV (P < 0.001) at similar tidal volumes. During the expiratory phase, BiVent and HF-BiPAP led to an increase in pressure burden compared to PSV. This was especially true at higher upper pressures (P < 0.001). At high level of asynchrony both HF-BiPAP and BiVent were less effective. Only HF-BiPAP ventilation effectively removed CO2 (P < 0.001) during all settings. Noise exposure was higher during HF-BiPAP (P < 0.001).

Conclusions: This study demonstrates that in a lung model, the efficiency of NIV by helmet can be improved by using HF-BiPAP. However, it imposes a higher pressure during the expiratory phase. CO2 was almost completely removed with HF-BiPAP during all settings.
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http://dx.doi.org/10.1186/cc7907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717454PMC
October 2009

The impact of the severity of sepsis on the risk of hypoglycaemia and glycaemic variability.

Crit Care 2008 21;12(5):R129. Epub 2008 Oct 21.

Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Goettingen, Robert-Koch-Strasse 40, Goettingen, 37075, Germany.

Introduction: The purpose of this study was to assess the relation between glycaemic control and the severity of sepsis in a cohort of patients treated with intensive insulin therapy (IIT).

Methods: In a prospective, observational study, all patients in the intensive care unit (ICU) (n = 191) with sepsis, severe sepsis or septic shock were treated with IIT (target blood glucose (BG) level 80 to 140 mg/dl instead of strict normoglycaemia). BG values were analysed by calculating mean values, rate of BG values within different ranges, rate of patients experiencing BG values within different levels and standard deviation (SD) of BG values as an index of glycaemic variability.

Results: The number of patients with hypoglycaemia and hyperglycaemia was highly dependent on the severity of sepsis (critical hypoglycaemia < or = 40 mg/dl: sepsis: 2.1%, severe sepsis: 6.0%, septic shock: 11.5%, p = 0.1497; hyperglycaemia: >140 mg/dl: sepsis: 76.6%, severe sepsis: 88.0%, septic shock: 100%, p = 0.0006; >179 mg/dl: sepsis: 55.3%, severe sepsis: 73.5%, septic shock: 88.5%, p = 0.0005; >240 mg/dl: sepsis: 17.0%, severe sepsis: 48.2%, septic shock: 45.9%, p = 0.0011). Multivariate analyses showed a significant association of SD levels with critical hypoglycaemia especially for patients in septic shock (p = 0.0197). In addition, SD levels above 20 mg/dl were associated with a significantly higher mortality rate relative to those with SD levels below 20 mg/dl (24% versus 2.5%, p = 0.0195).

Conclusions: Patients with severe sepsis and septic shock who were given IIT had a high risk of hypoglycaemia and hyperglycaemia. Among these patients even with a higher target BG level, IIT mandates an increased awareness of the occurrence of critical hypoglycaemia, which is related to the severity of the septic episode.
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http://dx.doi.org/10.1186/cc7097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592768PMC
August 2009

Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome.

Am J Respir Crit Care Med 2007 Jan 12;175(2):160-6. Epub 2006 Oct 12.

Università di Torino, Dipartimento di Anestesiologia e Rianimazione, Ospedale S. Giovanni Battista-Molinette, Corso Dogliotti 14, 10126 Turin, Italy.

Rationale: Tidal volume and plateau pressure limitation decreases mortality in acute respiratory distress syndrome. Computed tomography demonstrated a small, normally aerated compartment on the top of poorly aerated and nonaerated compartments that may be hyperinflated by tidal inflation.

Objectives: We hypothesized that despite tidal volume and plateau pressure limitation, patients with a larger nonaerated compartment are exposed to tidal hyperinflation of the normally aerated compartment.

Measurements And Main Results: Pulmonary computed tomography at end-expiration and end-inspiration was obtained in 30 patients ventilated with a low tidal volume (6 ml/kg predicted body weight). Cluster analysis identified 20 patients in whom tidal inflation occurred largely in the normally aerated compartment (69.9 +/- 6.9%; "more protected"), and 10 patients in whom tidal inflation occurred largely within the hyperinflated compartments (63.0 +/- 12.7%; "less protected"). The nonaerated compartment was smaller and the normally aerated compartment was larger in the more protected patients than in the less protected patients (p = 0.01). Pulmonary cytokines were lower in the more protected patients than in the less protected patients (p < 0.05). Ventilator-free days were 7 +/- 8 and 1 +/- 2 d in the more protected and less protected patients, respectively (p = 0.01). Plateau pressure ranged between 25 and 26 cm H(2)O in the more protected patients and between 28 and 30 cm H(2)O in the less protected patients (p = 0.006).

Conclusions: Limiting tidal volume to 6 ml/kg predicted body weight and plateau pressure to 30 cm H(2)O may not be sufficient in patients characterized by a larger nonaerated compartment.
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http://dx.doi.org/10.1164/rccm.200607-915OCDOI Listing
January 2007

Oleic acid vs saline solution lung lavage-induced acute lung injury: effects on lung morphology, pressure-volume relationships, and response to positive end-expiratory pressure.

Chest 2006 Aug;130(2):392-401

Department of Anesthesiology and Critical Care Medicine, University Hospital of Mannheim, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer Ufer, Germany.

Objective: To compare two lung injury models (oleic acid [OA] and saline solution washout [SW]) regarding lung morphology, regional inflation, and recruitment during static pressure-volume (PV) curves, and the effects of positive end-expiratory pressure (PEEP) below and above the lower inflection point (Pflex).

Methods: Fourteen adult pigs underwent OA or SW lung injury. Lung volumes were measured using CT. PV curves were obtained with simultaneous CT scanning at lung apex and base. Fractional inflation and recruitment were compared to data on PEEP above and below Pflex.

Results: Severity of lung injury was comparable. At zero PEEP, SW showed an increased amount of edema and poorly aerated lung volume, recruitment during inspiration, and a better oxygenation response with PEEP. Whole-lung PV curves were similar in both models, reflecting changes in alveolar inflation or deflation. On the inspiratory PV limb, recruitment and inflation were on the same line, while there was a substantial difference between deflation and derecruitment on the expiratory limb. PEEP-induced recruitment at lung apex and base was at or above the derecruitment line on the expiratory limb and showed no relationship to the whole-lung expiratory PV curve.

Conclusions: The following conclusions were made: (1) OA and SW models are comparable in mechanics but not in lung injury characteristics; (2) neither inspiratory nor expiratory whole-lung PV curves are useful to select PEEP in order to optimize recruitment; and (3) after recruitment, there is no difference in derecruitment between the models at high PEEP, while more collapse occurs at lower PEEP in the basal sections of SW lungs.
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http://dx.doi.org/10.1378/chest.130.2.392DOI Listing
August 2006

Risk management strategies in the postmarketing period : safety experience with the US and European bosentan surveillance programmes.

Drug Saf 2005 ;28(11):971-80

Department of Global Drug Safety, Drug Regulatory Affairs and Biometry, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.

In view of the shortcomings of the current system for postmarketing drug surveillance that is based on voluntary spontaneous adverse drug reaction (ADR) reporting, new approaches are needed. We describe an approach involving a combination of limited distribution, patient and physician education, as well as a novel pharmaco-vigilance system that is capable of promoting the safe and adequate use of a new drug. Importantly, it provides the possibility of calculating true ADR occurrence rates, as the exposed population (denominator) and the number of patients with events (numerator) are known. These measures were taken for the oral dual endothelin ET(A)/ET(B) antagonist bosentan (Tracleer). In recent guidelines issued by the European Society of Cardiology, American College of Chest Physicians and the WHO, this drug is considered as first-line oral treatment for the treatment of pulmonary arterial hypertension, a devastating orphan disease associated with a poor prognosis. Bosentan was approved in 2001/2 on the basis of two pivotal studies that showed improved exercise capacity and haemodynamic parameters while delaying time to clinical worsening. Elevations in serum liver aminotransferase levels of >3 times the upper limit of normal were noted in 10.2% of patients (placebo-subtracted incidence). Therefore, liver function tests have to be performed on a regular basis. In addition, bosentan has potential as a teratogen. In the US, a controlled distribution network for bosentan (Tracleer) Access Program [T.A.P.]) and the development of a patient database to follow patients was set up. Accompanied by comprehensive physician and patient education programmes, T.A.P. was developed to provide a mechanism to assist with the primary risk management goals for bosentan therapy, namely pregnancy prevention and liver enzyme monitoring and prevention of hepatic injury. In Europe, the Tracleer) Excellence (TRAX PMS) database is a novel European non-interventional, prospective, internet-based surveillance system initiated by the manufacturer in cooperation with the European Medicines Agency. It collected potential safety signals associated with bosentan use including adverse events, elevations of liver aminotransferase levels, other abnormal laboratory values, death and hospitalisation. TRAX PMS has accrued 79% of all known patients in the EU and the data provide supportive 'real-life' evidence on the long-term safety of bosentan. The two different systems had similar goals and outcomes. The data received concerning thousands of patient-years of use have confirmed the clinical trial results regarding product safety and the favourable benefit/risk ratio of bosentan, especially with regard to known type A adverse events. The clinical monitoring algorithm has also been confirmed. In addition, no rare type B events were uncovered despite the increased reporting rate. These systems might serve as templates for future pharmaco-vigilance efforts regarding drugs that require particular safety attention.
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http://dx.doi.org/10.2165/00002018-200528110-00001DOI Listing
January 2006

Uneven distribution of ventilation in acute respiratory distress syndrome.

Crit Care 2005 Apr 21;9(2):R165-71. Epub 2005 Feb 21.

Department of Anaesthesiology and Intensive Care, Sahlgrenska University Hospital, Göteborg, Sweden.

Introduction: The aim of this study was to assess the volume of gas being poorly ventilated or non-ventilated within the lungs of patients treated with mechanical ventilation and suffering from acute respiratory distress syndrome (ARDS).

Methods: A prospective, descriptive study was performed of 25 sedated and paralysed ARDS patients, mechanically ventilated with a positive end-expiratory pressure (PEEP) of 5 cmH2O in a multidisciplinary intensive care unit of a tertiary university hospital. The volume of poorly ventilated or non-ventilated gas was assumed to correspond to a difference between the ventilated gas volume, determined as the end-expiratory lung volume by rebreathing of sulphur hexafluoride (EELVSF6), and the total gas volume, calculated from computed tomography images in the end-expiratory position (EELVCT). The methods used were validated by similar measurements in 20 healthy subjects in whom no poorly ventilated or non-ventilated gas is expected to be found.

Results: EELVSF6 was 66% of EELVCT, corresponding to a mean difference of 0.71 litre. EELVSF6 and EELVCT were significantly correlated (r2 = 0.72; P < 0.001). In the healthy subjects, the two methods yielded almost identical results.

Conclusion: About one-third of the total pulmonary gas volume seems poorly ventilated or non-ventilated in sedated and paralysed ARDS patients when mechanically ventilated with a PEEP of 5 cmH2O. Uneven distribution of ventilation due to airway closure and/or obstruction is likely to be involved.
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http://dx.doi.org/10.1186/cc3058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1175934PMC
April 2005