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Inhaled Anesthetics Exert Different Protective Properties in a Mouse Model of Ventilator-Induced Lung Injury

Strosing, Karl Michael MD, DESA; Faller, Simone PhD; Gyllenram, Veronica; Engelstaedter, Helen MD; Buerkle, Hartmut MD; Spassov, Sashko PhD; Hoetzel, Alexander MD, MA

doi: 10.1213/ANE.0000000000001296
Critical Care and Resuscitation: Research Report

BACKGROUND: Mechanical ventilation is an important perioperative tool in anesthesia and a lifesaving treatment for respiratory failure, but it can lead to ventilator-associated lung injury. Inhaled anesthetics have demonstrated protective properties in various models of organ damage. We compared the lung-protective potential of inhaled sevoflurane, isoflurane, and desflurane in a mouse model of ventilator-induced lung injury (VILI).

METHODS: C57BL/6N mice were randomized into 5 groups (n = 8/group). One group served as a control and 4 groups were subjected to mechanical ventilation with air (12 mL/kg tidal volume) for 6 hours. Ventilated animals were anesthetized with either ketamine and acepromazine, or 1 of 3 inhaled anesthetics: isoflurane, sevoflurane, or desflurane. Lung injury was assessed by lung histology, neutrophil counts, and interleukin-1β concentrations in bronchoalveolar lavage fluid. Antioxidant effects were explored by evaluation of production of reactive oxygen species (ROS) and glutathione content in lung tissue by immunofluorescence staining and confocal laser scanning microscopy. Changes in intercellular adhesion molecule-1 and src-protein-tyrosine-kinase levels were determined by real-time polymerase chain reaction and Western blot.

RESULTS: Compared with nonventilated controls, ventilated mice anesthetized with ketamine had thickened alveolar walls, elevated VILI scores, higher polymorph neutrophil counts, and increased ROS production. Mice anesthetized with isoflurane and sevoflurane showed thinner alveolar septa, lower VILI scores, lower polymorph neutrophil counts, and lower interleukin-1β concentrations than ketamine mice. The expression of intercellular adhesion molecule-1/src-protein-tyrosine-kinase was neither affected by mechanical ventilation nor affected by administration of inhaled anesthetics. Mice anesthetized with isoflurane and sevoflurane showed less ROS production and higher glutathione contents compared with ketamine mice. Unexpectedly, desflurane-ventilated mice showed similar signs of lung injury compared with mice ventilated with air alone and receiving ketamine anesthesia. Desflurane failed to inhibit inflammatory responses and ROS production in lung tissue and developed no antioxidant potential.

CONCLUSIONS: Although isoflurane and sevoflurane prevent ventilator-associated lung injury, desflurane does not. As an underlying mechanism, both inhaled anesthetics exert major anti-inflammatory and antioxidative effects.

Supplemental Digital Content is available in the text.Published ahead of print March 28, 2016

From the Department of Anaesthesiology and Critical Care Medicine, Freiburg University Medical Center, Freiburg, Germany.

Accepted for publication February 3, 2016.

Published ahead of print March 28, 2016

Funding: This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Bonn, Germany) to Alexander Hoetzel (DFG HO 2464/3-1).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Karl Michael Strosing, MD, DESA, Department of Anaesthesiology and Critical Care Medicine, Freiburg University Medical Center, Hugstetter Str. 55, D-79106, Freiburg, Germany. Address e-mail to karl.strosing@uniklinik-freiburg.de.

Mechanical ventilation is a lifesaving treatment for respiratory failure but can lead to ventilator-associated lung injury. Even in the absence of an adult respiratory distress syndrome, high tidal volume ventilation can injure the lungs,1 and recent data suggest that high intraoperative tidal volumes also can be associated with injury.2 Moreover, because lung damage is inhomogeneously distributed, even low tidal volume ventilation can result in overinflation in recruited regions or cause significant shear stress from alveolar recruitment and derecruitment.3 Complementary therapeutic options are thus needed urgently to reduce ventilator-associated lung injury. Inhaled anesthetics may have therapeutic potential in this context. First, they have shown organ-protective properties in various insult models.4–6 Second, they have been safely used over decades in daily anesthesia practice. Finally, recent research has demonstrated the feasibility of inhaled anesthetics, that is, isoflurane and sevoflurane, for sedation in intensive care medicine.7 To clarify the effect of inhaled anesthetics, we compared the effects of isoflurane, sevoflurane, and desflurane in a mouse model of ventilator-induced lung injury (VILI).

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METHODS

Experimental Protocols

All experimental procedures were performed with male C57BL/6N mice (22–26 g; Charles River, Sulzfeld, Germany) in accordance with the guidelines of, and permission from, the local ethics committee (University Medical Center Freiburg, permission no. G-07/25). Mice initially were anesthetized with either ketamine (90 mg/kg, intraperitoneal [IP]) and acepromazine (0.9 mg/kg, IP) or inhaled anesthetic (isoflurane 2.2 ± 0.5 %Vol, MAC 1.7; sevoflurane 3.3 ± 0.5 %Vol, MAC 1.0; desflurane 8.8 ± 1.1 %Vol, MAC 1.2).8 To maintain deep sedation during animal preparation, the dose of each inhaled anesthetic was titrated individually to no-response to tail clamp stimulation. After induction of anesthesia, an arterial catheter was placed into the left carotid artery, followed by a tracheotomy and tracheal catheterization. As soon as mechanical ventilation was initiated, muscular relaxation (pancuronium 2 mg/kg, IP) was applied. Ventilation was maintained for 6 hours after via the use of a rodent ventilator (Voltek Enterprises, Toronto, Ontario, Canada) in a volume-controlled mode. The ventilator was set to a tidal volume of 12 mL/kg, f = 80 to 90/min, and positive end-expiratory pressure = 2 cm H2O. Every 60 minutes, an alveolar recruitment maneuver was performed (5 seconds of inspiratory pressure hold at 30 cm H2O). Maintenance of anesthesia was achieved by continuous administration of IP ketamine and acepromazine or by inhalation of isoflurane (1.3 ± 0.2 %Vol, MAC 1.0), sevoflurane (2.9 ± 0.5 %Vol, MAC 1.0), or desflurane (7.6 ± 0.5 %Vol, MAC 1.0).8 In all experiments, mean arterial pressure, rectal temperature, anesthetic dose, volume replacement, static compliance, peak pressure, plateau pressure, and ventilation frequency were recorded every 30 minutes. After 30 minutes and at the end of the experiments, arterial blood gas analyses were performed. After the experiments, mice were euthanized by exsanguination. Nonventilated controls were subjected to induction of anesthesia and identical instrumentation but were killed immediately thereafter.

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Experimental Groups

Forty mice were randomized into 5 groups (n = 8/group): nonventilated controls (C) or ventilated for 6 hours receiving IP anesthesia with ketamine, or inhaled anesthesia with isoflurane, sevoflurane, or desflurane.

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Analysis

A bronchoalveolar lavage (BAL) was performed via the tracheal catheter in the right lung lobes, and the fraction of polymorph neutrophils was determined by direct microscopic count after Diff-Quik® staining (Siemens Healthcare Diagnostics, Eschborn, Germany). After shock-frosting tissue samples were taken from the right upper lung, the left lung was perfused with paraformaldehyde under a constant pressure of 20 cm H2O, embedded into optimal cutting temperature compound, and frozen on liquid nitrogen. All samples were stored at −80°C. Alveolar wall diameters were measured digitally (AxioVision@ 4.8 software; Carl Zeiss, Jena, Germany), and the degree of lung damage was assessed by a modified score of VILI score as formerly described9 by a blinded investigator.

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Immunoblotting

Lung tissue samples were homogenized and subjected to Western blot as previously described.10 After protein transfer, the membranes were incubated with antibodies against intercellular adhesion molecule-1 (ICAM-1; sc-1511; Santa Cruz Biotechnology, Heidelberg, Germany), src-protein (2108; Cell Signaling; New England Biolabs, Frankfurt, Germany), and phospho-src-protein (2101; Cell Signaling). After stripping, membranes were reblotted with glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) for equal loading control. Bands were detected (ECL™ Western Blotting Analysis System, GE Healthcare, Buckinghamshire, United Kingdom), exposed to radiographic films (GE Healthcare), and digitally analyzed by densitometry (ImageJ 1.43u software, Bethesda, MD).

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Enzyme-Linked Immunosorbent Assay

BAL aliquots were analyzed using commercial interleukin-1β and sICAM-1 enzyme-linked immunosorbent assay kits (R&D Systems GmbH, Wiesbaden, Germany) according to the manufacturer’s instructions.

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Immunofluorescence Staining and Analysis

Lung sections were fixed with acetone (10 minutes, −20°C), rehydrated with phosphate-buffered saline (PBS, 20 minutes), and blocked with 2% bovine serum albumin in PBS for 20 minutes. After several washing steps with PBS, the primary antibody against ICAM-1 (1:50, sc-1511; Santa Cruz Biotechnology, Inc.) was incubated for 3 hours followed by further washing steps. The secondary antibody (1:1000, Alexa Fluor® 488 Dye A11034; Life Technologies, Darmstadt, Germany) was incubated for 1 hour in darkness. The slides were covered after washing with fluorescence mounting medium (S3023; Dako GmbH, Hamburg, Germany), dried, and stored at −20°C. Fluorescent images were acquired from a Zeiss microscope using a Plan-Neofluar 20× lens. Six whole images (magnification ×200) of each lung were analyzed. A semiquantitative analysis of the mean intensity of fluorescence was performed (ZEN® 2010 software; Carl Zeiss) and expressed on a 16-bit grayscale.

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RNA Extraction and cDNA Synthesis

Total RNA was extracted from lung homogenates using RNeasy® Plus Mini Kit (QIAGEN GmbH, Hilden, Germany) in conformance with the manufacturer’s guidelines. Concentration and purity of total RNA were determined by spectrophotometry. The cDNA was synthesized from 500 ng of RNA with a TaqMan® Reverse Transcription Reagents kit (Life Technologies, total reaction volume of 50 μL). The reaction components were incubated at 25°C for 10 minutes and then at 48°C for 30 minutes. Finally, the mixture was heated at 95°C for 5 minutes.

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Semiquantitative Polymerase Chain Reaction

Quantitative real-time polymerase chain reaction was performed in 96-well plates in duplicate using TaqMan Universal PCR Master Mix (Life Technologies) and an ABI Prism 7000 Sequence Detection System (Life Technologies) according to the manufacturer’s instructions. The primer/probe set for ICAM-1 was Mm00516023_m1; TaqMan Rodent GAPDH Control Reagent (Life Technologies) was used for the control. Gene expression profiles were analyzed by the 2−ΔΔCT method11 and normalized with the corresponding CT values of GAPDH control. CT values were calculated by ABI Prism 700 SDS software (Life Technologies).

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Detection of Reactive Oxygen Species

Dihydroethidium (Life Technologies) was used to detect reactive oxygen species (ROS) in lung tissue as described previoulsy.12 In brief, unfixed frozen lung tissue samples were cryosectioned (6 μm) and stained with 2 μM dihydroethidium. Lung sections were covered and incubated in a humidified chamber at 37°C for 30 minutes protected from light. Fluorescence of red was measured with a confocal laser scanning microscope (LSM 510 META NLO; Carl Zeiss). Densitometry analyses were performed with ImageJ (1.43u) software.

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Detection of Glutathione

ThiolTracker™ Violet (Life Technologies) was used to detect glutathione in lung tissue. Tissue sections were prepared as described previously before measurement of red fluorescence (excitation at 405 nm, long pass filter at 450 nm) with a confocal laser scanning microscope (objective lens 20×, image 420.84 × 420.84 μm; LSM 510; Carl Zeiss). Densitometry analyses were performed with ZEN 2011 software (Carl Zeiss).

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Statistical Analysis

Experiments were performed with n = 8 mice per group after power calculations before the study to define group sizes. Power calculations were based on the assumed differences in neutrophil counts in the BAL that represents the most potent sign of lung injury in our model.4–7 End points for the power calculations were differences in means 15, SD 8, number of groups 5, power 0.8, and α 0.05. Because of technical problems in preparation and sampling, we had to exclude some data points. Thus, outcome parameters resulted in group sizes of n = 5 to 8.

Data were analyzed for normal variation and accordingly tested with 1-way analysis of variance (ANOVA) or Kruskal-Wallis test. For normal distributed data, post hoc analyses were initially performed using the Student-Newman-Keuls post hoc test. However, the actual P values of the Tukey post hoc test that was applied after ANOVA testing are depicted to correct for familywise error rates. Comparison of both statistical methods and P values of Student-Newman-Keuls testing to control for false discovery rate is provided as Supplementary Figures 4, 5, 10, and 11 (Supplemental Digital Content, http://links.lww.com/AA/B413).13 All ANOVA and Tukey calculations were performed with SigmaPlot 11.0 statistical software (Systat Software Inc., Erkrath, Germany). In the case of a failed test for normal distribution or equal variance, nonparametric testing was applied, and the Kruskal-Wallis test followed by the Dunn multiple comparisons test was used (GraphPad Prism 6; GraphPad Software, Inc., La Jolla, CA). All statistical methods and results, corresponding to all tables and figures, are shown in detail as Supplementary Figures 1 to 11 (Supplemental Digital Content, http://links.lww.com/AA/B413). P values <0.05 were considered significant. P values >0.15 were considered as no difference. Graphs represent means ± SEM or median values with interquartile range depending on the distribution of data.

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RESULTS

Effects of Inhaled Anesthetics on Physiological Parameters During Mechanical Ventilation

Table 1

Table 1

With respect to lung function, static lung compliance, and gas exchange, we found no difference between mice exposed to mechanical ventilation and ketamine anesthesia and mechanical ventilation in the presence of inhaled anesthetics (Table 1; Supplemental Digital Content, Supplementary Figures 1–3, http://links.lww.com/AA/B413). The pH during mechanical ventilation was lower in the isoflurane group than that in the ketamine group. Mean arterial blood pressure readings were decreased in the ventilated groups treated with inhaled anesthetics compared with the ketamine group, reaching statistical significance in the isoflurane group. However, we observed no differences in blood pressure between mice ventilated with different inhaled anesthetics (Table 1; Supplemental Digital Content, Supplementary Figures 1–3, http://links.lww.com/AA/B413).

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Effects of Inhaled Anesthetics on VILI

Figure 1

Figure 1

Compared with nonventilated controls, ketamine animals developed more edema. In marked contrast, mice ventilated with isoflurane or sevoflurane had levels of histologic lung injury comparable with nonventilated control animals. However, mice ventilated with desflurane demonstrated more lung injury (Fig. 1A). Quantitative analysis of alveolar wall diameters confirmed that mechanical ventilation during ketamine anesthesia increased wall thickness by 57% compared with nonventilated animals. Although isoflurane or sevoflurane led to significantly decreased alveolar wall thickness compared with the ketamine group, desflurane showed no effect (Fig. 1B; Supplemental Digital Content, Supplementary Figure 4, http://links.lww.com/AA/B413). Quantitative analysis of the VILI scores also showed a higher degree of lung injury in the ketamine group compared with nonventilated controls. Both isoflurane and sevoflurane reduced the VILI score almost to the control level, and again, inhalation of desflurane displayed no protective effect compared with mechanical ventilation under ketamine anesthesia (Fig. 1C; Supplemental Digital Content, Supplementary Figure 5, http://links.lww.com/AA/B413).

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Effect of Inhaled Anesthetics on Lung Inflammation

Figure 2

Figure 2

Compared with nonventilated controls, mechanical ventilation in ketamine-anesthetized mice increased the fraction of polymorph neutrophils in BAL fluid. Mice ventilated with isoflurane or sevoflurane showed a reduction in neutrophil infiltration compared with the ketamine group that was not different from nonventilated controls. In contrast, neutrophil infiltration in mice given desflurane did not differ from that in ventilated mice receiving ketamine (Fig. 2A; Supplemental Digital Content, Supplementary Figure 6, http://links.lww.com/AA/B413). Likewise, the proinflammatory cytokine interleukin (IL)-1β was slightly increased in the BAL fluid of ketamine animals compared with controls. The use of isoflurane and sevoflurane prevented the increase in IL-1β, whereas IL-1β levels were even more elevated in mice given desflurane (Fig. 2B; Supplemental Digital Content, Supplementary Figure 7, http://links.lww.com/AA/B413).

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Effect of Mechanical Ventilation and Inhaled Anesthetics on the ICAM-1 Signal Transduction Pathway

Table 2

Table 2

Neither mechanical ventilation nor administration of inhaled anesthetics affected the expression of ICAM-1 mRNA or protein in lung tissue (Table 2; Supplemental Digital Content, Supplementary Figures 8 and 9, http://links.lww.com/AA/B413). We further examined lung cryosections after immunofluorescence staining against ICAM-1 protein to enhance sensitivity and found no differences in optical density between any groups. To explore the possibility that mechanical ventilation and inhaled anesthetics might affect downstream signaling of ICAM-1 without altering its expression, the src pathway was investigated. In this respect, the induction of phospho-src-protein (Tyr416) in lung tissue was slightly elevated in all ventilated mice but not different between groups (Table 2; Supplemental Digital Content, Supplementary Figure 9, http://links.lww.com/AA/B413). In addition, we found no differences between groups in the expression of total src-protein and the inactivating form of phospho-src-protein (Tyr527) in lung tissue (data not shown).

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Effect of Mechanical Ventilation and Inhaled Anesthetics on ROS Production in Lung Tissue

Figure 3

Figure 3

Compared with nonventilated controls, mechanical ventilation induced lung ROS production in mice anesthetized with ketamine that was prevented by administration of isoflurane or sevoflurane (Fig. 3A). In contrast, desflurane inhalation did not affect ROS production compared with mechanical ventilation alone (Fig. 3A). Densitometry data analysis of all animals showed an increase in ROS production through mechanical ventilation that was prevented by isoflurane or sevoflurane but not by desflurane (Fig. 3B; Supplemental Digital Content, Supplementary Figure 10, http://links.lww.com/AA/B413).

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Effect of Mechanical Ventilation and Inhaled Anesthetics on Glutathione Content in Lung Tissue

Figure 4

Figure 4

In contrast to nonventilated controls and ventilated animals receiving ketamine, inhalation of isoflurane or sevoflurane markedly increased the antioxidant glutathione content in the lung (Fig. 4A). However, the glutathione content in the lungs of desflurane-ventilated animals was lower compared with isoflurane or sevoflurane animals and similar to ketamine-treated mice (Fig. 4A). Likewise, densitometric analysis of all experiments revealed a clear increase in glutathione levels in the lungs of isoflurane- or sevoflurane-treated mice compared with controls, ketamine-anesthetized, or desflurane-ventilated groups (Fig. 4B; Supplemental Digital Content, Supplementary Figure 11, http://links.lww.com/AA/B413).

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DISCUSSION

The results of the present animal study indicate that (1) ventilation with a tidal volume of 12 mL/kg led to histologic and biomarker evidence of lung injury and pulmonary inflammation in mice. (2) Application of isoflurane or sevoflurane mitigated both the histological and inflammatory marker evidence of VILI and the proinflammatory response to mechanical ventilation. (3) The ICAM-1/src pathway does not appear to play a major mechanistic role in the effect we observed. However, our data suggest that inhaled anesthetic-mediated inhibition of ROS production and the induction of the antioxidative protein, glutathione, could explain the lung-protective effects of isoflurane and sevoflurane during the mechanical ventilation we observed. (4) In sharp contrast to isoflurane and sevoflurane, desflurane failed to exert a similar lung-protective, anti-inflammatory, or antioxidative effect.

In this study, our intention was to examine any protective effects of currently used inhaled anesthetics in VILI. Hence, we chose a well-established animal model that produces moderate lung injury using clinically relevant tidal volumes.14,15 Our results show clear infiltration of polymorph neutrophils, increased diameter of alveolar walls, and elevated VILI scores without impaired oxygenation or static compliance. As we have previously shown, administration of isoflurane prevented lung injury in response to mechanical ventilation.9 In this study, identical protective effects were observed with sevoflurane. Organ protection mediated through inhaled anesthetics has been reported by our group and others. Isoflurane, as well as sevoflurane, inhalation prevents organ damage in response to various insults.4–6,8,9,16–19 The prevention of IL-1β release, as well as the low number of recruited neutrophil cells in our study, suggests an anti-inflammatory action of sevoflurane and isoflurane as a key mechanism in the lung-protective effect we observed. Isoflurane and sevoflurane have shown anti-inflammatory and antioxidative effects in ischemia-reperfusion–induced lung injury and endotoxin-induced in vitro cellular injury in alveolar macrophages and neutrophils.17,18 Other reports further support this argument by demonstrating that IL-1 receptor blockade prevents failure of the alveolar barrier and neutrophil recruitment into the lung in experimental VILI.20

Our results extend these observations in 2 ways: first, we analyzed lung ICAM-1 expression and its downstream pathway because early pulmonary sequestration of neutrophils is an important step in ventilator-induced immune response and may be ICAM-1 dependent.21,22 In addition, isoflurane and sevoflurane can interact with the binding of neutrophils to endothelial ICAM-1 and decrease its expression in sepsis-induced lung injury.16,23,24 We found that application of inhaled anesthetics did not influence ICAM-1 expression in VILI. Our results are contrary to those of Zhao et al.,25 who found that sevoflurane abolished mRNA and protein expression levels of ICAM-1 in lipopolysaccharide-induced acute lung injury. Current data are conflicting with respect to ICAM-1 in lung injury, with recent publications demonstrating both the presence22 and the absence26 of mechanical-ventilation–induced endothelial activation in the absence of ICAM-1 regulation. Because of the conflicting data in the literature, we evaluated downstream activation of src-tyrosine-kinases but found no differences among the interventional groups. This lack of effect of injurious ventilation and/or inhaled anesthetics on ICAM-1 expression and the downstream src pathway suggests an ICAM-1–independent mechanism of lung protection in VILI by isoflurane and sevoflurane.

Second, we investigated ROS and the regulation of the antioxidant glutathione in lung tissue. The cyclic mechanical strain by mechanical ventilation can trigger ROS production and may be an initial step in the development of VILI.27 Antioxidative interventions, such as intracellular free-radical scavengers or N-acetylcysteine, have been shown to reduce VILI in mice.28,29 Isoflurane and sevoflurane have also prevented oxidative stress, ROS overexpression, and inflammatory response in sepsis-induced lung injury.16,30 Our study adds to this knowledge by showing that isoflurane and sevoflurane amplify the antioxidant capacity in the lung.

The most unexpected finding in this study was that, in contrast to sevoflurane and isoflurane, desflurane failed to prevent VILI despite a previously described protective effect against ischemia-reperfusion injury in the heart, the kidney, and the brain.8,31,32 Although in vitro data suggest that the anti-inflammatory effects of inhaled anesthetics are because of trifluorinated carbon groups,33 the absence of a desflurane effect we observed indicates that the trifluorinated carbon group theory does not completely explain the anti-inflammatory properties of inhaled anesthetics. Our results suggest that the lack of anti-inflammatory properties and failed lung protection are consequences of the lack of antioxidant effects of desflurane. These results are supported by a report showing that desflurane generates more oxidative stress in ventilated swine than sevoflurane,34 and human data finding increased oxidative stress with desflurane in the first hour after elective surgery.35 Compared with the effect in sevoflurane-anesthetized patients, the administration of desflurane also caused higher concentrations of IL-1β, IL-6, and tumor necrosis factor-α in plasma and BAL of lung in healthy patients undergoing elective tympanoplasty.36

Our study directly compares 3 inhaled anesthetics with respect to VILI in an in vivo model. We showed lung-protective and anti-inflammatory properties of isoflurane and sevoflurane in preventing VILI. Furthermore, our results suggest that the positive effects of isoflurane and sevoflurane are caused by their antioxidative action. Unexpectedly, desflurane was neither lung-protective nor antioxidative in our setting of isolated VILI. Our study may motivate further research concerning the choice of inhaled anesthetics as immunomodulative agents in ventilated patients.

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DISCLOSURES

Name: Karl Michael Strosing, MD, DESA.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Karl Michael Strosing has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Simone Faller, PhD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Simone Faller approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Veronica Gyllenram.

Contribution: This author helped conduct the study.

Attestation: Veronica Gyllenram approved the final manuscript.

Name: Helen Engelstaedter, MD.

Contribution: This author helped prepare the manuscript.

Attestation: Helen Engelstaedter has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Hartmut Buerkle, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Hartmut Buerkle has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Sashko Spassov, PhD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Sashko Spassov approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Alexander Hoetzel, MD, MA.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Alexander Hoetzel has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Avery Tung, MD.

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