Detlef Obal, MD, PhD, DESA is an Assistant Professor in the Department of Anesthesiology, Perioperative, and Pain Medicine. He is also a Member of the Stanford Cardiovascular Institute. Dr. Obal completed his medical training at the Universities of Manchester (UK), Pretoria (South Africa) and Düsseldorf (Germany).

Dr. Obal earned his MD/PhD degree from the Heinrich-Heine University of Düsseldorf, Germany and his PhD degree from the University of Louisville, KY. His previous work focuses on multiple aspects of cardiac regeneration under the influence of different anesthetics and cardioprotective strategies (i.e. pre- and postconditioning) using different transgenic mouse models. He completed his postdoctoral training at the Stanford Cardiovascular Institute (Laboratory of Joseph Wu) at which he studied the effects of opioids on the cardiovascular system, using inducible pluripotent stem cells (iPSC) derived cardiomyocytes and endothelial cells.

His laboratory focuses on improving anesthesia care by focusing on individuals’ phenotypical and genetic background. The major areas of interest of his laboratory are understanding the basic mechanism of G-protein coupled receptor signaling on iPSC-derived cardiac and endothelial cells (in collaboration with the Brian Kobilka and Steven Chu labs) and describing the effect of anesthetics on early cardiovascular development.

Dr. Obal received multiple awards including the best poster price of the European Society of Anaesthesiology, Stanford Cardiovascular Institute Seed Grant, and the Stanford Maternal & Child Health Research Institute’s (MCHRI) TIP grant.

Dr. Obal is a Board-Certified Anesthesiologist and a Diplomate of the European Society of Anaesthesiology (DESA) with a clinical commitment of 20% of his time.

Administrative Appointments

  • Assistant Editor, Anesthesia & Analgesia (2019 - Present)

Honors & Awards

  • Dean's Citation Award, University of Louisville (2014)
  • Diplomate of the European Society of Anesthesiology (DESA), European Society of Anesthesiology (2005)
  • Euroanesthesia 2003 Best Abstract Prize, European Society of Anesthesiology (2003)
  • Doctoral Thesis, "Doctor of Medicine", University of Duesseldorf, Germany (1999)

Professional Education

  • PhD, University of Louisville, Physiology and Biophysics (2014)
  • Board Certification, German Board of Anesthesiology and Intensive Care Medicine, Anesthesiology and Perioperative Care (2004)

Current Research and Scholarly Interests

I am primarily working at the Cardiovascular Institute (Director Joseph Wu, MD, PhD), studying the effect of different anesthetics on human induced pluripotent stem cells (hiPSC). Considering the current opioid epidemic, I am currently focusing on the effect of chronic opioid exposure on endothelial and cardiac function.

Clinical Trials

  • EcoAnaesthesia Facemask Versus Standard Facemask During Anesthesia Induction Not Recruiting

    This study will evaluate the efficiency of the EcoAnesthesia mask and its advantages over the standard facemask used in our practice. The satisfaction by the anesthesia provider and its ease of use may change the standard practice in airway management. In addition to these additional effects on patient safety, the facemask is affordable and may reduce the environmental burden of anesthesia waste.

    Stanford is currently not accepting patients for this trial.

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  • The ENIGMA II Trial:Nitrous Oxide Anaesthesia and Cardiac Morbidity After Major Surgery: a Randomised Controlled Trial Not Recruiting

    To investigate the safety of nitrous oxide (N2O) anaesthesia in patients with risk factors for coronary artery disease undergoing major surgery.

    Stanford is currently not accepting patients for this trial.

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  • Use of New Supraglottic Airway Devices in Severely Obese Patients: A Feasibility Study Not Recruiting

    The purpose of this study is to determine whether two new airway devices used during anesthesia called iGEL™ and KING-LTS-DTM work well and are safe in obese patients. They both work well in thin patients, but have not been tested in obese patients.

    Stanford is currently not accepting patients for this trial.

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Stanford Advisees

Professional Interests

As a translational scientist, I am interested in combining clinical data with patient specific characteristics to optimize anesthesia care. With the advantages in human genetics and tools like human inducible stem cells, I am trying to understand patients' specific needs and reactions to anesthetics, so that we will be able to provide individualized anesthesia care in the future.

Work Experience

  • Assistant Professor, Department of Anesthesiology and Perioperative Medicine, University of Louisville (2/1/2006 - 8/15/2018)


    Louisville, KY, USA

  • Staff Anesthesiologist, Department of Anesthesiology, Heinrich-Heine University Duesseldorf (5/1/2004 - 2/1/2006)


    Moorenstr. 5, Duesseldorf, Germany

All Publications

  • Generation of two induced pluripotent stem cell lines from patients suffering from pulmonary hypertension. Stem cell research Chen, G., Orozco, L., Parmisano, S., Jahng, J. W., Vera, C. D., Zhuge, Y., Wu, J. C., Obal, D. 2023; 72: 103218


    Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease, with an estimated 500-1000 new cases diagnosed every year. A portion of these cases may be caused by mutations in the BMPR2 gene, suggesting a possible genetic component in the development of the disease. Here, we report two human induced pluripotent stem cell (iPSC) lines generated from IPAH patients. Both cell lines provide valuable insight into the molecular and cellular mechanisms of IPAH and can be used to further understand the disease.

    View details for DOI 10.1016/j.scr.2023.103218

    View details for PubMedID 37804546

  • Detecting and measuring of GPCR signaling - comparison of human induced pluripotent stem cells and immortal cell lines. Frontiers in endocrinology Chen, G., Obal, D. 2023; 14: 1179600


    G protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that play a major role in many physiological processes, and thus GPCR-targeted drug development has been widely promoted. Although research findings generated in immortal cell lines have contributed to the advancement of the GPCR field, the homogenous genetic backgrounds, and the overexpression of GPCRs in these cell lines make it difficult to correlate the results with clinical patients. Human induced pluripotent stem cells (hiPSCs) have the potential to overcome these limitations, because they contain patient specific genetic information and can differentiate into numerous cell types. To detect GPCRs in hiPSCs, highly selective labeling and sensitive imaging techniques are required. This review summarizes existing resonance energy transfer and protein complementation assay technologies, as well as existing and new labeling methods. The difficulties of extending existing detection methods to hiPSCs are discussed, as well as the potential of hiPSCs to expand GPCR research towards personalized medicine.

    View details for DOI 10.3389/fendo.2023.1179600

    View details for PubMedID 37293485

    View details for PubMedCentralID PMC10244570

  • Nasopharyngeal Ventilation Compared to Facemask Ventilation: A Prospective, Randomized, Crossover Trial in Two Different Elective Cohorts. Cureus Lenhardt, R., Akca, O., Obal, D., Businger, J., Cooke, E. 2023; 15 (5): e39049


    BACKGROUND: Facemask ventilation is routinely used to preoxygenate patients before endotracheal intubation during anesthesia induction or to secure ventilation in patients with respiratory insufficiency. Occasionally, facemask ventilation cannot be performed adequately. The placement of a regular endotracheal tube through the nose into the hypopharynx may be a valid alternative to improve ventilation and oxygenation before endotracheal intubation (nasopharyngeal ventilation). We tested the hypothesis that nasopharyngeal ventilation is superior in its efficacy compared to traditional facemask ventilation.METHODS: In this prospective, randomized, crossover trial, we enrolled surgical patients requiring either nasal intubation (cohort #1, n = 20) or patients who met "difficult to mask ventilate" criteria (cohort #2, n = 20). Patients in each cohort were randomly assigned to receive pressure-controlled facemask ventilation followed by nasopharyngeal ventilation or vice versa. The ventilation settings were kept constant. The primary outcome was tidal volume. The secondary outcome was the difficulty of ventilation, measured using the Warters grading scale.RESULTS: Tidal volume was significantly increased by nasopharyngeal ventilation in cohort #1 (597 ± 156 ml vs.462 ± 220 ml, p = 0.019) and cohort #2 (525 ± 157 ml vs.259 ± 151 ml, p < 0.01). Warters grading scale for mask ventilation was 0.6 ± 1.4 in cohort #1, and 2.6 ± 1.5 in cohort #2.CONCLUSION: Patients at risk for difficult facemask ventilation may benefit from nasopharyngeal ventilation to maintain adequate ventilation and oxygenation before endotracheal intubation. This ventilation mode may offer another option for ventilation at induction of anesthesia and during the management of respiratory insufficiency, especially in the setting of "unexpected" ventilation difficulty.

    View details for DOI 10.7759/cureus.39049

    View details for PubMedID 37323341

  • Elucidating effects of environmental exposure using human-induced pluripotent stem cell disease modeling. EMBO molecular medicine Chandy, M., Obal, D., Wu, J. C. 2022: e202013260


    Induced pluripotent stem cells (iPSCs) are a powerful modeling system for medical discovery and translational research. To date, most studies have focused on the potential for iPSCs for regenerative medicine, drug discovery, and disease modeling. However, iPSCs are also a powerful modeling system to investigate the effects of environmental exposure on the cardiovascular system. With the emergence of e-cigarettes, air pollution, marijuana use, opioids, and microplastics as novel cardiovascular risk factors, iPSCs have the potential for elucidating the effects of these toxins on the body using conventional two-dimensional (2D) arrays and more advanced tissue engineering approaches with organoid and other three-dimensional (3D) models. The effects of these environmental factors may be enhanced by genetic polymorphisms that make some individuals more susceptible to the effects of toxins. iPSC disease modeling may reveal important gene-environment interactions that exacerbate cardiovascular disease and predispose some individuals to adverse outcomes. Thus, iPSCs and gene-editing techniques could play a pivotal role in elucidating the mechanisms of gene-environment interactions and understanding individual variability in susceptibility to environmental effects.

    View details for DOI 10.15252/emmm.202013260

    View details for PubMedID 36285490

  • Integrated Multilayer Omics Reveals the Genomic, Proteomic, and Metabolic Influences of Histidyl Dipeptides on theHeart. Journal of the American Heart Association Yan, K., Mei, Z., Zhao, J., Prodhan, M. A., Obal, D., Katragadda, K., Doelling, B., Hoetker, D., Posa, D. K., He, L., Yin, X., Shah, J., Pan, J., Rai, S., Lorkiewicz, P. K., Zhang, X., Liu, S., Bhatnagar, A., Baba, S. P. 2022: e023868


    Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, beta-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of beta-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that beta-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.

    View details for DOI 10.1161/JAHA.121.023868

    View details for PubMedID 35730646

  • Triomic Approach Reveals the Metabolic, Genomic and Proteomic Influences of the Endogenous Histidyl Dipeptides on Heart Yan, K., Mei, Z., Zhao, J., Obal, D., Katragadda, K., Hoetker, D., Posa, D., Shah, J., Lorkiewicz, P., Bhatnagar, A., Baba, S. P. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • A Guide to Understanding "State-of-the-Art" Basic Research Techniques in Anesthesiology. Anesthesia and analgesia Obal, D., Wu, S., McKinstry-Wu, A., Tawfik, V. L. 2020


    Perioperative medicine is changing from a "protocol-based" approach to a progressively personalized care model. New molecular techniques and comprehensive perioperative medical records allow for detection of patient-specific phenotypes that may better explain, or even predict, a patient's response to perioperative stress and anesthetic care. Basic science technology has significantly evolved in recent years with the advent of powerful approaches that have translational relevance. It is incumbent on us as a primarily clinical specialty to have an in-depth understanding of rapidly evolving underlying basic science techniques to incorporate such approaches into our own research, critically interpret the literature, and improve future anesthesia patient care. This review focuses on 3 important and most likely practice-changing basic science techniques: next-generation sequencing (NGS), clustered regularly interspaced short palindromic repeat (CRISPR) modulations, and inducible pluripotent stem cells (iPSCs). Each technique will be described, potential advantages and limitations discussed, open questions and challenges addressed, and future developments outlined. We hope to provide insight for practicing physicians when confronted with basic science articles and encourage investigators to apply "state-of-the-art" technology to their future experiments.

    View details for DOI 10.1213/ANE.0000000000004801

    View details for PubMedID 32371742

  • The obesity paradox: does it exist in the perioperative period? International anesthesiology clinics Obal, D., Wadhwa, A. 2020

    View details for DOI 10.1097/AIA.0000000000000278

    View details for PubMedID 32250998

  • Perioperative analgesic administration during the 2018 parenteral opioid shortage in the United States - A retrospective analysis. Journal of clinical anesthesia Kim, R. K., Gao, Z. n., Hastie, T. n., Obal, D. n. 2020; 66: 109892

    View details for DOI 10.1016/j.jclinane.2020.109892

    View details for PubMedID 32502773

  • Is Fresh Frozen Plasma Still Necessary for Management of Acute Traumatic Coagulopathy? Current Anesthesiology Reports Giles, N. R., Obal, D. 2020
  • Induced Pluripotent Stem Cells as a Platform to Understand Patient-Specific Responses to Opioids and Anaesthetics. British journal of pharmacology Obal, D. n., Wu, J. C. 2020


    Recent advances in human induced pluripotent stem cell (iPSC) technology may provide unprecedented opportunities to study patient-specific responses to anaesthetics and opioids. In this review, we will 1) examine the advantages and limitations of iPSC technology, 2) summarize studies using iPSCs that have contributed to our current understanding of anaesthetics and opioid action on the cardiovascular and central nervous system, and 3) describe how iPSC technology can be used to further develop personalized analgesic and sedative pharmacotherapies with reduced or minimal detrimental cardiovascular effects.

    View details for DOI 10.1111/bph.15228

    View details for PubMedID 32767563

  • Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury. Journal of the American Heart Association Zhao, J. n., Conklin, D. J., Guo, Y. n., Zhang, X. n., Obal, D. n., Guo, L. n., Jagatheesan, G. n., Katragadda, K. n., He, L. n., Yin, X. n., Prodhan, M. A., Shah, J. n., Hoetker, D. n., Kumar, A. n., Kumar, V. n., Wempe, M. F., Bhatnagar, A. n., Baba, S. P. 2020: e015222


    BACKGROUND Myocardial ischemia reperfusion (I/R) injury is associated with complex pathophysiological changes characterized by pH imbalance, the accumulation of lipid peroxidation products acrolein and 4-hydroxy trans-2-nonenal, and the depletion of ATP levels. Cardioprotective interventions, designed to address individual mediators of I/R injury, have shown limited efficacy. The recently identified enzyme ATPGD1 (Carnosine Synthase), which synthesizes histidyl dipeptides such as carnosine, has the potential to counteract multiple effectors of I/R injury by buffering intracellular pH and quenching lipid peroxidation products and may protect against I/R injury. METHODS AND RESULTS We report here that β-alanine and carnosine feeding enhanced myocardial carnosine levels and protected the heart against I/R injury. Cardiospecific overexpression of ATPGD1 increased myocardial histidyl dipeptides levels and protected the heart from I/R injury. Isolated cardiac myocytes from ATPGD1-transgenic hearts were protected against hypoxia reoxygenation injury. The overexpression of ATPGD1 prevented the accumulation of acrolein and 4-hydroxy trans-2-nonenal-protein adducts in ischemic hearts and delayed acrolein or 4-hydroxy trans-2-nonenal-induced hypercontracture in isolated cardiac myocytes. Changes in the levels of ATP, high-energy phosphates, intracellular pH, and glycolysis during low-flow ischemia in the wild-type mice hearts were attenuated in the ATPGD1-transgenic hearts. Two natural dipeptide analogs (anserine and balenine) that can either quench aldehydes or buffer intracellular pH, but not both, failed to protect against I/R injury. CONCLUSIONS Either exogenous administration or enhanced endogenous formation of histidyl dipeptides prevents I/R injury by attenuating changes in intracellular pH and preventing the accumulation of lipid peroxidation derived aldehydes.

    View details for DOI 10.1161/JAHA.119.015222

    View details for PubMedID 32515247

  • Role of Transient Receptor Potential Ankyrin-1 in Isoflurane-Induced Myocardial Depression in Mice Obal, D., Katragadda, K., Jagatheesan, G., Dassanayaka, S., Brittian, K., Riggs, D., Conklin, D. J. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Transient Receptor Potential Ankyrin-1 (TRPA1) Channel Contributes to Myocardial Ischemia-Reperfusion Injury. American journal of physiology. Heart and circulatory physiology Conklin, D. J., Guo, Y., Jagatheesan, G., Nystoriak, M. A., Obal, D., Kilfoil, P., Guo, L., Hoetker, J. D., Bolli, R., Bhatnagar, A. 2019


    Myocardial ischemia-reperfusion (I/R) results in generation of free radicals, accumulation of lipid peroxidation-derived unsaturated aldehydes, variable angina (pain) and infarction. Transient receptor potential ankyrin-1 (TRPA1) mediates pain signaling and is activated by unsaturated aldehydes, including acrolein and 4-hydroxynonenal. The contribution of TRPA1 (a calcium permeable channel) to I/R-induced myocardial injury is unknown. We tested the hypothesis that cardiac TRPA1 confers myocyte sensitivity to aldehyde accumulation and promotes I/R injury. Although TRPA1-null mice had similar basal cardiovascular function as WT mice, TRPA1-null mice had significantly smaller infarct size than WT mice (WT, 34.1±9.3% of risk region; TRPA1-null, 14.3±9.9%, n=8,7, respectively, p<0.05) despite similar I/R-induced area at risk (AAR: WT, 40.3±8.4%; TRPA1-null, 42.2±11.3%) following myocardial I/R (30 min I, 24h R) in situ. Positive TRPA1 immunofluorescence was present in mouse and human hearts, and was co-localized with Connexin 43 at intercalated discs in isolated murine cardiomyocytes. Cardiomyocyte TRPA1 was confirmed by qRT-PCR, DNA sequencing, Western blotting and electrophysiology. A role of TRPA1 in cardiomyocyte toxicity was demonstrated in isolated cardiomyocytes exposed to acrolein, an I/R-associated toxin, that induced calcium accumulation and hypercontraction -- effects significantly blunted by HC-030031, a TRPA1 antagonist. HC-030031-induced protection was quantitatively equivalent to that of SN-6, a Na+/Ca2+ exchange inhibitor, further supporting a role of calcium overload in acrolein-induced cardiomyocyte toxicity. These data indicate that cardiac TRPA1 activation likely contributes to I/R injury, and thus, TRPA1 may be a novel therapeutic target for decreasing myocardial I/R injury.

    View details for DOI 10.1152/ajpheart.00106.2018

    View details for PubMedID 30735434

  • Histidyl Dipeptide Carnosine Imparts Cardiac Protection During Ischemia Reperfusion Injury by Sequestering Lipid Peroxidation Products and Buffering Intracellular pH Zhao, J., Guo, Y., Conklin, D., Guo, L., Obal, D., Posa, D., Hoetker, D., Prodhan, A., Zhang, X., Bhatnagar, A., Baba, S. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial. Anesthesia and analgesia Beattie, W. S., Wijeysundera, D. N., Chan, M. T., Peyton, P. J., Leslie, K. n., Paech, M. J., Sessler, D. I., Wallace, S. n., Myles, P. S., Galagher, W. n., Farrington, C. n., Ditoro, A. n., Baulch, S. n., Sidiropoulos, S. n., Bulach, R. n., Bryant, D. n., O'Loughlin, E. n., Mitteregger, V. n., Bolsin, S. n., Osborne, C. n., McRae, R. n., Backstrom, M. n., Cotter, R. n., March, S. n., Silbert, B. n., Said, S. n., Halliwell, R. n., Cope, J. n., Fahlbusch, D. n., Crump, D. n., Thompson, G. n., Jefferies, A. n., Reeves, M. n., Buckley, N. n., Tidy, T. n., Schricker, T. n., Lattermann, R. n., Iannuzzi, D. n., Carroll, J. n., Jacka, M. n., Bryden, C. n., Badner, N. n., Tsang, M. W., Cheng, B. C., Fong, A. C., Chu, L. C., Koo, E. G., Mohd, N. n., Ming, L. E., Campbell, D. n., McAllister, D. n., Walker, S. n., Olliff, S. n., Kennedy, R. n., Eldawlatly, A. n., Alzahrani, T. n., Chua, N. n., Sneyd, R. n., McMillan, H. n., Parkinson, I. n., Brennan, A. n., Balaji, P. n., Nightingale, J. n., Kunst, G. n., Dickinson, M. n., Subramaniam, B. n., Banner-Godspeed, V. n., Liu, J. n., Kurz, A. n., Hesler, B. n., Fu, A. Y., Egan, C. n., Fiffick, A. N., Hutcherson, M. T., Turan, A. n., Naylor, A. n., Obal, D. n., Cooke, E. n. 2018


    Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery.We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs).MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival.MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

    View details for DOI 10.1213/ANE.0000000000003310

    View details for PubMedID 29533264

  • Transient Receptor Potential Ankyrin-1 Deficiency in Mice Protected Against Myocardial Ischemia-Reperfusion Injury Conklin, D. J., Guo, Y., Jagatheesan, G., Kilfoil, P., Nystoriak, M., Obal, D., Bolli, R., Bhatnagar, A. LIPPINCOTT WILLIAMS & WILKINS. 2017
  • Exercise-Induced Changes in Glucose Metabolism Promote Physiologic Cardiac Growth. Circulation Gibb, A. A., Epstein, P. N., Uchida, S., Zheng, Y., McNally, L. A., Obal, D., Katragadda, K., Trainor, P. J., Conklin, D. J., Brittian, K. R., Tseng, M. T., Wang, J., Jones, S. P., Bhatnagar, A., Hill, B. G. 2017


    Background -Exercise promotes metabolic remodeling in the heart, which is associated with physiologic cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiologic cardiac growth. Methods -We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. Results -Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, upon exercise adaptation and recovery there was an increase in myocardial phosphofructokinase activity and glycolysis. Cardiac-specific expression of a kinase-deficient PFK2 transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient PFK2 in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiologic cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions -Exercise-induced decreases in glycolytic activity stimulate physiologic cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

    View details for DOI 10.1161/CIRCULATIONAHA.117.028274

    View details for PubMedID 28860122

  • Red Cell Storage Duration Does Not Affect Outcome after Massive Blood Transfusion in Trauma and Nontrauma Patients: A Retrospective Analysis of 305 Patients BIOMED RESEARCH INTERNATIONAL Bautista, A., Wright, T. B., Meany, J., Kandadai, S. K., Brown, B., Khalafalla, K., Hashem, S., Smith, J. W., Ayyoubi, T. M., Dalton, J. E., Wadhwa, A., Sessler, D. I., Obal, D. 2017: 3718615


    Prolonged storage of packed red blood cells (PRBCs) may increase morbidity and mortality, and patients having massive transfusion might be especially susceptible. We therefore tested the hypothesis that prolonged storage increases mortality in patients receiving massive transfusion after trauma or nontrauma surgery. Secondarily, we considered the extent to which storage effects differ for trauma and nontrauma surgery.We considered surgical patients given more than 10 units of PRBC within 24 hours and evaluated the relationship between mean PRBC storage duration and in-hospital mortality using multivariable logistic regression. Potential nonlinearities in the relationship were assessed via restricted cubic splines. The secondary hypothesis was evaluated by considering whether there was an interaction between the type of surgery (trauma versus nontrauma) and the effect of storage duration on outcomes.305 patients were given a total of 8,046 units of PRBCs, with duration ranging from 8 to 36 days (mean ± SD: 22 ± 6 days). The odds ratio [95% confidence interval (CI)] for in-hospital mortality corresponding to a one-day in mean PRBC storage duration was 0.99 (0.95, 1.03, P = 0.77). The relationship did not differ for trauma and nontrauma patients (P = 0.75). Results were similar after adjusting for multiple potential confounders.Mortality after massive blood transfusion was no worse in patients transfused with PRBC stored for long periods. Trauma and nontrauma patients did not differ in their susceptibility to prolonged PRBC storage.

    View details for DOI 10.1155/2017/3718615

    View details for Web of Science ID 000402291200001

    View details for PubMedID 28589139

    View details for PubMedCentralID PMC5446873

  • Intraoperative dexamethasone does not increase the risk of postoperative wound infection: a propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX). British journal of anaesthesia Corcoran, T. n., Kasza, J. n., Short, T. G., O'Loughlin, E. n., Chan, M. T., Leslie, K. n., Forbes, A. n., Paech, M. n., Myles, P. n. 2017; 118 (2): 190–99


    In a post hoc analysis of the ENIGMA-II trial, we sought to determine whether intraoperative dexamethasone was associated with adverse safety outcomes.Inverse probability weighting with estimated propensity scores was used to determine the association of dexamethasone administration with postoperative infection, quality of recovery, and adverse safety outcomes for 5499 of the 7112 non-cardiac surgery subjects enrolled in ENIGMA-II.Dexamethasone was administered to 2178 (40%) of the 5499 subjects included in this analysis and was not associated with wound infection [189 (8.7%) vs 275 (8.3%); propensity score-adjusted relative risk (RR) 1.10; 95% confidence interval (CI) 0.89-1.34; P=0.38], severe postoperative nausea and vomiting on day 1 [242 (7.3%) vs 189 (8.7%); propensity score-adjusted RR 1.06; 95% CI 0.86-1.30; P=0.59], quality of recovery score [median 14, interquartile range (IQR) 12-15, vs median 14, IQR 12-16, P=0.10), length of stay in the postanaesthesia care unit [propensity score-adjusted median (IQR) 2.0 (1.3, 2.9) vs 1.9 (1.3, 3.1), P=0.60], or the primary outcome of the main trial. Dexamethasone administration was associated with a decrease in fever on days 1-3 [182 (8.4%) vs 488 (14.7%); RR 0.61; 95% CI 0.5-0.74; P<0.001] and shorter lengths of stay in hospital [propensity score-adjusted median (IQR) 5.0 (2.9, 8.2) vs 5.3 (3.1, 9.1), P<0.001]. Neither diabetes mellitus nor surgical wound contamination status altered these outcomes.Dexamethasone administration to high-risk non-cardiac surgical patients did not increase the risk of postoperative wound infection or other adverse events up to day 30, and appears to be safe in patients either with or without diabetes mellitus.NCT00430989.

    View details for DOI 10.1093/bja/aew446

    View details for PubMedID 28100522

  • Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial BRITISH JOURNAL OF ANAESTHESIA Chan, M. V., Peyton, P. J., Myles, P. S., Leslie, K., Buckley, N., Kasza, J., Paech, M. J., Beattie, W. S., Sessler, D. I., Forbes, A., Wallace, S., Chen, Y., Tian, Y., Wu, W. K., Australian New Zealand Coll 2016; 117 (6): 801-811


    Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia.We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong.At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50-0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain.Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene.NCT00430989.

    View details for DOI 10.1093/bja/aew338

    View details for Web of Science ID 000389640900016

    View details for PubMedID 27956679

  • Casein Kinase 1 alpha Gene Therapy Facilitates Cardiac Regeneration After Myocardial Infarction in Mice Obal, D., Katragadda, K., Tomlin, A., Book, M., Bhatnagar, A., Guo, Y., Bolli, R., Rokosh, G. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury CIRCULATION RESEARCH Conklin, D. J., Guo, Y., Jagatheesan, G., Kilfoil, P. J., Haberzettl, P., Hill, B. G., Baba, S. P., Guo, L., Wetzelberger, K., Obal, D., Rokosh, D., Prough, R. A., Prabhu, S. D., Velayutham, M., Zweier, J. L., Hoetker, J., Riggs, D. W., Srivastava, S., Bolli, R., Bhatnagar, A. 2015; 117 (5): 437–49


    Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed.We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury.In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism of 4-hydroxy-trans-2-nonenal or trans-2-hexanal; on ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than wild-type hearts. GSTP deficiency did not affect I/R-induced free radical generation, c-Jun N-terminal kinase activation, or depletion of reduced glutathione. Acrolein exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na(+)/Ca(++) exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than wild-type myocytes to acrolein-induced protein crosslinking and cell death.GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes, such as acrolein.

    View details for DOI 10.1161/CIRCRESAHA.114.305518

    View details for Web of Science ID 000359658700008

    View details for PubMedID 26169370

    View details for PubMedCentralID PMC4854443

  • Cardiomyocyte Specific Conditional Overexpression Of Stromal Cell Derived Factor 1 Facilitates Cardiac Regeneration After Permanent Coronary Artery Ligation In Mice Obal, D., Brittian, K., Book, M., Bhatnagar, A., Guo Yiru, Bolli, R., Rokosh, G. LIPPINCOTT WILLIAMS & WILKINS. 2014
  • Perioperative Doses of Ondansetron or Dolasetron Do Not Lengthen the QT Interval MAYO CLINIC PROCEEDINGS Obal, D., Yang, D., Sessler, D. I. 2014; 89 (1): 69–80


    To test the primary hypothesis that ondansetron or dolasetron extends the rate-corrected QT electrocardiographic interval (QTc) greater than 60 milliseconds or increases the fraction of patients with QTc greater than 500 milliseconds in patients having noncardiac surgery, and the secondary hypothesis that QTc prolongation is worse in diabetic patients.We extracted data from the Cleveland Clinic's Perioperative Health Documentation System between March 25, 2006, and September 30, 2010, and additional perioperative medications from Cleveland Clinic pharmacy's Epic Cost of Goods Sold (COGS) system. We searched for patients who had a preoperative electrocardiogram within 1 month of surgery and postoperatively within 2 hours. We excluded patients given an antiemetic drug other than ondansetron or dolasetron perioperatively, and those given amiodarone.A total of 1429 patients given serotonin-3 receptor (5HT3R) antagonists and 1022 controls met the enrollment criteria. Seventeen percent of patients given 5HT3R antagonists (n=242) and 22% of controls (n=220) had postoperative QTc exceeding 500 milliseconds. Mean ± SD presurgical and postsurgical QTc, respectively, were 438±37 milliseconds and 464±41 milliseconds for 5HT3R antagonist patients and 443±40 milliseconds and 469±47 milliseconds for control patients. Univariable mean ± SD perioperative increases in QTc were 26±39 and 26±48 milliseconds in the 2 groups. After adjusting for confounding variables, there were no differences in the mean increase in QTc in patients who were and were not given 5HT3R antagonists: -0.1 milliseconds (97.5% CI, -5.2 to 5.0 milliseconds; multivariable P=.97). The QTc was prolonged, but not significantly, in diabetic patients given 5HT3R antagonists (P=.16).The average QTc prolongation from baseline was only 6%. Perioperative use of ondansetron or dolasetron was not associated with extended QT prolongation, and these results did not vary by diabetic status. Perioperative use of 5HT3R antagonists does not produce potentially dangerous perioperative electrocardiographic changes and does not seem to warrant a drug safety warning from the Food and Drug Administration.

    View details for DOI 10.1016/j.mayocp.2013.10.008

    View details for Web of Science ID 000329163600014

    View details for PubMedID 24388024

  • The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet (London, England) Myles, P. S., Leslie, K. n., Chan, M. T., Forbes, A. n., Peyton, P. J., Paech, M. J., Beattie, W. S., Sessler, D. I., Devereaux, P. J., Silbert, B. n., Schricker, T. n., Wallace, S. n. 2014; 384 (9952): 1446–54


    Nitrous oxide is commonly used in general anaesthesia but concerns exist that it might increase perioperative cardiovascular risk. We aimed to gather evidence to establish whether nitrous oxide affects perioperative cardiovascular risk.We did an international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned via automated telephone service, stratified by site, to receive a general anaesthetic with or without nitrous oxide. Attending anaesthetists were aware of patients' group assignments, but patients and assessors were not. The primary outcome measure was a composite of death and cardiovascular complications (non-fatal myocardial infarction, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Our modified intention-to-treat population included all patients randomly assigned to groups and undergoing induction of general anaesthesia for surgery. This trial is registered at, number NCT00430989.Of 10,102 eligible patients, we enrolled 7112 patients between May 30, 2008, and Sept 28, 2013. 3543 were assigned to receive nitrous oxide and 3569 were assigned not to receive nitrous oxide. 3483 patients receiving nitrous oxide and 3509 not receiving nitrous oxide were assessed for the primary outcome. The primary outcome occurred in 283 (8%) patients receiving nitrous oxide and in 296 (8%) patients not receiving nitrous oxide (relative risk 0·96, 95% CI 0·83–1·12; p=0·64). Surgical site infection occurred in 321 (9%) patients assigned to nitrous oxide, and in 311 (9%) patients in the no-nitrous oxide group (p=0·61), and severe nausea and vomiting occurred in 506 patients (15%) assigned to nitrous oxide and 378 patients (11%) not assigned to nitrous oxide (p<0·0001).Our findings support the safety profile of nitrous oxide use in major non-cardiac surgery. Nitrous oxide did not increase the risk of death and cardiovascular complications or surgical-site infection, the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis, and a desired effect of reduced volatile agent use was shown.Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China.

    View details for DOI 10.1016/S0140-6736(14)60893-X

    View details for PubMedID 25142708

  • Cardiac myocyte-specific transgenic ecSOD targets mitochondria to protect against Ca2+ induced permeability transition FRONTIERS IN PHYSIOLOGY Luo, J., Obal, D., Dimova, N., Tang, X., Rokosh, G. 2013; 4: 295


    ecSOD function has prototypically been associated with the extracellular space due to its secretion and localization to the extracellular matrix. A myocyte-specific ecSOD transgenic mouse has shown that it can also be localized to the myocyte intracellular compartment and is capable of attenuating Reactive oxygen species (ROS) formation and increasing NO bioavailability after ischemia reperfusion. Here, the subcellular localization of transgenic ecSOD was further defined by subcellular fractionation, immunofluorescent confocal microscopy, and Western analysis. Its impact on mitochondrial function was assessed by mitochondrial permeability transition (MPT). ecSOD was found to exist in cytosolic and nuclear fractions in addition to membrane. Colocalization of ecSOD with myocardial mitochondria was further demonstrated by confocal microscopy and subcellular fractionation of mitochondria and Western analysis. Isolated ventricular myocytes from cardiac-specific transgenic ecSOD mice were protected from hypoxia reoxygenation injury. Increased ecSOD colocalization to myocardial mitochondria in ecSOD Tg hearts limited MPT in response to Ca(2+) challenge. These results demonstrate that ecSOD is not restricted to the extracellular space and can alter MPT response to Ca(2+) suggesting mitochondrial localization of ecSOD can affect key mitochondrial functions such as MPT which are integral to cell survival.

    View details for DOI 10.3389/fphys.2013.00295

    View details for Web of Science ID 000346774000292

    View details for PubMedID 24194719

    View details for PubMedCentralID PMC3810602

  • Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion BASIC RESEARCH IN CARDIOLOGY Obal, D., Dai, S., Keith, R., Dimova, N., Kingery, J., Zheng, Y., Zweier, J., Velayutham, M., Prabhu, S. D., Li, Q., Conklin, D., Yang, D., Bhatnagar, A., Bolli, R., Rokosh, G. 2012; 107 (6): 305


    Increased levels of extracellular superoxide dismutase (ecSOD) induced by preconditioning or gene therapy protect the heart from ischemia/reperfusion injury. To elucidate the mechanism responsible for this action, we studied the effects of increased superoxide scavenging on nitric oxide (NO) bioavailability in a cardiac myocyte-specific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocyte-specific ecSOD activity 27.5-fold. Transgenic ecSOD was localized to the sarcolemma and, notably, the cytoplasm of cardiac myocytes. Ischemia/reperfusion injury was attenuated in ecSOD Tg hearts, in which infarct size was decreased and LV functional recovery was improved. Using the ROS spin trap, DMPO, electron paramagnetic resonance (EPR) spectroscopy demonstrated a significant decrease in ROS in Tg hearts during the first 20 min of reperfusion. This decrease in ROS was accompanied by an increase in NO production determined by EPR using the NO spin trap, Fe-MGD. Attenuated ROS in ecSOD Tg myocytes was also supported by decreased production of peroxynitrite (ONOO(-)). Increased NO bioavailability was confirmed by attenuated guanylate cyclase-dependent (p-VASP) signaling. In conclusion, attenuation of ROS levels by cardiac-specific ecSOD overexpression increases NO bioavailability in response to ischemia/reperfusion and protects against reperfusion injury. These findings are the first to demonstrate increased NO bioavailability with attenuation of ROS by direct measurement of these reactive species (EPR, reactive fluorescent dyes) with cardiac-specific ecSOD expression. This is also the first indication that the predominantly extracellular SOD isoform is capable of cytosolic localization that affects myocardial intracellular signal transduction and function.

    View details for DOI 10.1007/s00395-012-0305-1

    View details for Web of Science ID 000312073200010

    View details for PubMedID 23099819

    View details for PubMedCentralID PMC3505528

  • Ultrasound Guidance for Deep Peripheral Nerve Blocks: A Brief Review ANESTHESIOLOGY RESEARCH AND PRACTICE Wadhwa, A., Kandadai, S., Tongpresert, S., Obal, D., Gebhard, R. 2011: 262070


    Nerve stimulation and ultrasound have been introduced to the practice of regional anesthesia mostly in the last two decades. Ultrasound did not gain as much popularity as the nerve stimulation until a decade ago because of the simplicity, accuracy and portability of the nerve stimulator. Ultrasound is now available in most academic centers practicing regional anesthesia and is a popular tool amongst trainees for performance of nerve blocks. This review article specifically discusses the role of ultrasonography for deeply situated nerves or plexuses such as the infraclavicular block for the upper extremity and lumbar plexus and sciatic nerve blocks for the lower extremity. Transitioning from nerve stimulation to ultrasound-guided blocks alone or in combination is beneficial in certain scenarios. However, not every patient undergoing regional anesthesia technique benefits from the use of ultrasound, especially when circumstances resulting in difficult visualization such as deep nerve blocks and/or block performed by inexperienced ultrasonographers. The use of ultrasound does not replace experience and knowledge of relevant anatomy, especially for visualization of deep structures. In certain scenarios, ultrasound may not offer additional value and substantial amount of time may be spent trying to find relevant structures or even provide a false sense of security, especially to an inexperienced operator. We look at available literature on the role of ultrasound for the performance of deep peripheral nerve blocks and its benefits.

    View details for DOI 10.1155/2011/262070

    View details for Web of Science ID 000215200900006

    View details for PubMedID 21808644

    View details for PubMedCentralID PMC3145343

  • The Effect of Aminophylline on Loss of Consciousness, Bispectral Index, Propofol Requirement, and Minimum Alveolar Concentration of Desflurane in Volunteers ANESTHESIA AND ANALGESIA Turan, A., Kasuya, Y., Govinda, R., Obal, D., Rauch, S., Dalton, J. E., Akca, O., Sessler, D. I. 2010; 110 (2): 449–54


    Adenosine is a soporific neuromodulator; aminophylline, which is clinically used as a bronchodilator, antagonizes the action of adenosine in the central nervous system. Thus, we tested the hypothesis that aminophylline delays loss of consciousness (LOC) and speeds recovery of consciousness (ROC) with propofol anesthesia, and that aminophylline increases the minimum alveolar concentration (MAC) of desflurane.In this double-blind crossover study, volunteers were randomized to either aminophylline or saline on different days. Aminophylline 6 mg/kg was given IV, followed by 1.5 mg x kg(-1) x h(-1) throughout the study day. After 1 h of aminophylline or saline administration, propofol 200 mg was given at a rate of 20 mg/min. The bispectral index was continuously monitored, as were times to LOC and ROC. After recovery from propofol, general anesthesia was induced with sevoflurane and subsequently maintained with desflurane. The Dixon "up-and-down" method was used to determine MAC in each volunteer after repeated tetanic electrical stimulation.Eight volunteers completed both study days. Time to LOC was prolonged by aminophylline compared with saline (mean +/- SD) (7.7 +/- 2.03 min vs 5.1 +/- 0.75 s, respectively, P = 0.011). The total propofol dose at LOC was larger with aminophylline (2.2 +/- 0.9 vs 1.4 +/- 0.4 mg/kg, P = 0.01), and the time to ROC was shorter (6.18 +/- 3.96 vs 12.2 +/- 4.73 min, P = 0.035). The minimum bispectral index was greater with aminophylline (51 +/- 15 vs 38 +/- 9, P = 0.034). There was no difference in MAC.Aminophylline decreases the sedative effects of propofol but does not affect MAC of desflurane as determined by tetanic electrical stimulation.

    View details for DOI 10.1213/ANE.0b013e3181c6be7e

    View details for Web of Science ID 000273922100033

    View details for PubMedID 19955506

  • Cardiac Myocyte-Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition CIRCULATION West, M. B., Rokosh, G., Obal, D., Velayutham, M., Xuan, Y., Hill, B. G., Keith, R. J., Schrader, J., Guo, Y., Conklin, D. J., Prabhu, S. D., Zweier, J. L., Bolli, R., Bhatnagar, A. 2008; 118 (19): 1970–78


    Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning, but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia/reperfusion injury.Constitutive overexpression of iNOS in transgenic mice (alpha-myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but it profoundly decreased infarct size in mice subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion. In comparison with wild-type hearts, isolated iNOS-transgenic hearts subjected to ischemia for 30 minutes followed by 40 minutes of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[(3)H]-glucose. Reperfusion-induced loss of NAD(+) and mitochondrial release of cytochrome c were attenuated in iNOS-transgenic hearts, indicating reduced mitochondrial permeability transition. The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and mitochondrial permeability transition-induced NAD(+) loss was decreased in wild-type but not iNOS-null mice treated with the NO donor diethylene triamine/NO 24 hours before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-transgenic hearts and was increased in wild-type hearts treated with the mitochondrial permeability transition inhibitor cyclosporin A.Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This cardioprotection is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.

    View details for DOI 10.1161/CIRCULATIONAHA.108.791533

    View details for Web of Science ID 000260602500009

    View details for PubMedID 18936326

    View details for PubMedCentralID PMC2763350

  • Effect of sevoflurane preconditioning on ischaemia/reperfusion injury in the rat kidney in vivo. European journal of anaesthesiology Obal, D. n., Dettwiler, S. n., Favoccia, C. n., Rascher, K. n., Preckel, B. n., Schlack, W. n. 2006; 23 (4): 319–26


    Whereas the protective effect of anaesthetic and ischaemic preconditioning has been described for several organs, it is uncertain whether this mechanism is also effective in the kidney. We compared the effect of preconditioning with sevoflurane and preconditioning with short episodes of ischaemia on renal ischaemia/reperfusion injury in the rat in vivo.Fourteen days after right-sided nephrectomy, anaesthetized male Wistar rats were randomly assigned to a sham-operated group (no arterial occlusion, n = 5) or underwent 45 min of left renal artery occlusion (control group, n = 9) followed by 3 days of reperfusion. Two further experimental groups of animals were preconditioned prior to ischaemia either by administering 1 MAC sevoflurane for 15 min followed by 10 min of washout (sevoflurane group, n = 10) or by subjecting the animals to three short episodes of renal ischaemia (ischaemia-preconditioned group, n = 8). Blood creatinine was measured during reperfusion and morphological damage was assessed by histological examination.Baseline creatinine values were similar in all four groups (0.7 +/- 0.2 mg dL-1; mean +/- SD) and remained unchanged in the sham-operated animals after 3 days (0.8 +/- 0.2 mg dL-1). Creatinine levels increased in the ischaemic preconditioning group (3.3 +/- 1.2 mg dL-1) and sevoflurane preconditioning group (4.0 +/- 1.1 mg dL-1) compared to the control group (1.6 +/- 0.6 mg dL-1). Morphological damage was less severe in the control group, i.e. in animals without preconditioning, than in both preconditioning groups.Neither sevoflurane nor ischaemic preconditioning preserves renal function or attenuates cell damage in the rat in vivo.

    View details for DOI 10.1017/S0265021505002000

    View details for PubMedID 16469207

  • Post-conditioning by a short administration of desflurane reduced renal reperfusion injury after differing of ischaemia times in rats. British journal of anaesthesia Obal, D. n., Rascher, K. n., Favoccia, C. n., Dettwiler, S. n., Schlack, W. n. 2006; 97 (6): 783–91


    'Anaesthetic post-conditioning', that is administration of anaesthetics during early reperfusion, is known to have positive effects on several organs. For the kidney, however, the effects of post-conditioning by volatile anaesthetics are not well researched. We examined renal function and morphology after post-conditioning by desflurane.Anaesthetized rats were subjected to 30 or 45 min of renal ischaemia 14 days after contralateral nephrectomy. Post-conditioning was achieved by administration of 1 MAC desflurane (6.7 vol%) for 15 min during early reperfusion (all groups n=8). Cystatin C (CyC), creatinine clearance (Cl(Cr)) and fractional sodium excretion (FE(Na)) were measured in the awake rats over 3 days. Cell damage was graded from 1 to 4 in histological sections. Functional variables [mean (SD)] were compared statistically by a one-way anova followed by Bonferroni's multiple comparison test and histological scores (median and range) by Kruskal-Wallis test followed by Dunn's multiple comparison test.Pre-ischaemia function did not differ between the groups, but was markedly reduced after ischaemia. After 30 min ischaemia, the area under the curve (AUC) for Cl(Cr) was smaller in the desflurane than in the control group [21.5 (5.0) vs 31.6 (5.1) ml min(-1) h, P<0.05]. After 45 min desflurane reduced the AUC compared with the control group for both CyC [15 (4) vs 21 (3) mg litre(-1) h] and FE(Na) [1054 (221) vs 1570 (572)% h, both P<0.05). Morphological differences were greater between the 30 min groups [control: 2.75 (2.0-3.5) vs desflurane: 1.5 (1.0-2.5); P<0.05] than between the 45 min groups [control: 3.5 (3.0-4.0) vs desflurane: 3.0 (1.5-4.0)].Desflurane post-conditioning protects renal function and tissue. This protection was greater after the short episode than after the long episode of ischaemia.

    View details for DOI 10.1093/bja/ael245

    View details for PubMedID 16997839

  • Effects of halothane, sevoflurane and desflurane on the force-frequency relation in the dog heart in vivo. Canadian journal of anaesthesia = Journal canadien d'anesthesie Preckel, B. n., Obal, D. n., Möllenheim, J. n., Hennes, J. n., Heiderhoff, M. n., Thämer, V. n., Schlack, W. n. 2006; 53 (11): 1118


    Frequency potentiation is the increase in force of contraction induced by an increased heart rate (HR). This positive staircase phenomenon has been attributed to changes in Ca2+ entry and loading of intracellular Ca2+ stores. Volatile anesthetics interfere with Ca2+ homeostasis of cardiomyocytes. We hypothesized that frequency potentiation is altered by volatile anesthetics and investigated the influence of halothane (H), sevoflurane (S) and desflurane (D) on the positive staircase phenomenon in dogsin vivo.Dogs were chronically instrumented for measurement of left ventricular (LV) pressure and cardiac output. Heart rate was increased by atrial pacing from 120 to 220 beats·min-1 and the LV maximal rate of pressure increase (dP/ dtmax) was determined as an index of myocardial performance. Measurements were performed in conscious dogs and during anesthesia with 1.0 minimal alveolar concentrations of each of the three inhaled anesthetics.Increasing HR from 120 to 220 beats·min-1 increased dP/dtmax from 3394 ± 786 (mean ± SD) to 3798 ± 810 mmHg sec-1 in conscious dogs. All anesthetics reduced dP/dtmax during baseline (at 120 beatss·min-1: H, 1745 ± 340 mmHgs·sec-1; S, 1882 ± 418; D, 1928 ± 454, allP < 0.05vs awake) but did not influence the frequency potentiation of dP/dtmax (at 220 beatss·min-1: H, 1981 ± 587 mmHgs·sec-1; S, 2187 ± 787; D, 2307 ± 691). The slope of the regression line correlating dP/dtmax and HR was not different between awake and anesetized dogs. Increasing HR did not influence cardiac output in awake or anesthetized dogs.These results indicate that volatile anesthetics do not alter the force-frequency relation in dogs in vivo.

    View details for DOI 10.1007/BF03022881

    View details for PubMedID 27771912

  • Peri-operative myocardial ischaemia - Reply ANAESTHESIA Obal, D., Kindgen-Milles, D., Schoebel, F., Schlack, W. 2005; 60 (7): 715-716
  • Peri-operative myocardial ischaemia ANAESTHESIA Ackroyd, C. R., Milner, Q. J. 2005; 60 (7): 714-715
  • The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-epsilon and p38 MAPK. British journal of pharmacology Weber, N. C., Toma, O. n., Wolter, J. I., Obal, D. n., Müllenheim, J. n., Preckel, B. n., Schlack, W. n. 2005; 144 (1): 123–32


    Xenon is an anesthetic with minimal hemodynamic side effects, making it an ideal agent for cardiocompromised patients. We investigated if xenon induces pharmacological preconditioning (PC) of the rat heart and elucidated the underlying molecular mechanisms. For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received either the anesthetic gas xenon, the volatile anesthetic isoflurane or as positive control ischemic preconditioning (IPC) during three 5-min periods before 25-min ischemia. Control animals remained untreated for 45 min. To investigate the involvement of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), rats were pretreated with the PKC inhibitor calphostin C (0.1 mg kg(-1)) or the p38 MAPK inhibitor SB203580 (1 mg kg(-1)). Additional hearts were excised for Western blot and immunohistochemistry. Infarct size was reduced from 50.9+/-16.7% in controls to 28.1+/-10.3% in xenon, 28.6+/-9.9% in isoflurane and to 28.5+/-5.4% in IPC hearts. Both, calphostin C and SB203580, abolished the observed cardioprotection after xenon and isoflurane administration but not after IPC. Immunofluorescence staining and Western blot assay revealed an increased phosphorylation and translocation of PKC-epsilon in xenon treated hearts. This effect could be blocked by calphostin C but not by SB203580. Moreover, the phosphorylation of p38 MAPK was induced by xenon and this effect was blocked by calphostin C. In summary, we demonstrate that xenon induces cardioprotection by PC and that activation of PKC-epsilon and its downstream target p38 MAPK are central molecular mechanisms involved. Thus, the results of the present study may contribute to elucidate the beneficial cardioprotective effects of this anesthetic gas.

    View details for DOI 10.1038/sj.bjp.0706063

    View details for PubMedID 15644876

    View details for PubMedCentralID PMC1575984

  • Opioide receptors are mediator of late cardioprotection - involvement of the nuclear transcription factor kappa B Frassdorf, J., Weber, N. C., Toma, O., Obal, D., Kojda, G., Preckel, B., Schlack, W., Schober, O., Schrader, J. VERLAG FERDINAND SCHONINGH. 2005: 149-151
  • The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesthesia and analgesia Obal, D. n., Dettwiler, S. n., Favoccia, C. n., Scharbatke, H. n., Preckel, B. n., Schlack, W. n. 2005; 101 (5): 1252–60


    Volatile anesthetics induce myocardial preconditioning and can also protect the heart when given at the onset of reperfusion-a practice recently termed "postconditioning." We investigated the role of mitochondrial KATP (mKATP)-channels in sevoflurane-induced cardioprotection for both preconditioning and postconditioning alone and whether there is a synergistic effect of both. Rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Infarct size was determined by triphenyltetrazolium staining. The following protocols were used: 1) preconditioning (S-Pre, n = 10, achieved by 2 periods of 5 min sevoflurane administration (1 MAC) followed by 10 min of washout); 2) sevoflurane postconditioning (1 MAC of sevoflurane given for 2 min at the beginning of reperfusion; S-Post, n = 10); 3) administration before and after ischemia (S-Pre + S-Post, n = 10). Protocols 1-3 were repeated in the presence of 5-hydroxydecanoate (5HD), a specific mKATP-channel-blocker (S-Pre + S-Post + 5HD, S-Pre + 5HD: n = 10; S-Post + 5HD: n = 9). Nine rats served as untreated controls (CON) or received 5HD alone (5HD, n = 10). Both S-Pre (23% +/- 13% of the area at risk, mean +/- sd) and S-Post (18% +/- 5%) reduced infarct size compared with CON (49% +/- 11%, both P < 0.05). S-Pre + S-Post resulted in a larger reduction of infarct size (12% +/- 5%, P = 0.054 versus S-Pre) compared with administration before or after ischemia alone. 5HD diminished the protection in all three sevoflurane treated groups (S-Pre + 5HD, 35% +/- 12%; S-Post + 5HD, 44% +/- 12%; S-Pre + S-Post + 5HD, 46% +/- 14%;) but given alone had no effect on infarct size (41% +/- 13%). Sevoflurane preconditioning and postconditioning protects against myocardial ischemia-reperfusion injury. The combination of preconditioning and postconditioning provides additive cardioprotection and is mediated, at least in part, by mKATP-channels.

    View details for DOI 10.1213/01.ANE.0000181336.96511.32

    View details for PubMedID 16243977

  • Morphine induces late cardioprotection in rat hearts in vivo: the involvement of opioid receptors and nuclear transcription factor kappaB. Anesthesia and analgesia Frässdorf, J. n., Weber, N. C., Obal, D. n., Toma, O. n., Müllenheim, J. n., Kojda, G. n., Preckel, B. n., Schlack, W. n. 2005; 101 (4): 934–41, table of contents


    Delta1-opioid receptor agonists can induce cardioprotection by early and late preconditioning (LPC). Morphine (MO) is commonly used for pain treatment during acute coronary syndromes. We investigated whether MO can induce myocardial protection by LPC and whether a nuclear transcription factor kappaB (NF-kappaB)-dependent intracellular signaling pathway is involved. Rats were subjected to 25 min of regional ischemia and 2 h of reperfusion 24 h after treatment with saline (NaCl; 0.9% 5 mL), lipopolysaccharide of Escherichia coli (LPS; 1 mg/kg), or MO (3 mg/kg). LPS is a trigger of LPC and served as positive control. Naloxone (NAL) was used to investigate the role of opioid receptors in LPC and was given before NaCl, LPS, or MO application (trigger phase) or before ischemia-reperfusion (mediator phase). Infarct size (percentage area at risk) was 59% +/- 9%, 51% +/- 6%, or 53% +/- 10% in the NaCl, NAL-NaCl, and NaCl-NAL groups, respectively. Pretreatment with MO reduced infarct size to 20% +/- 6% after 24 h (MO-24h), and this effect was abolished by NAL in the trigger (NAL-MO, 53% +/- 14%) and in the mediator (MO-NAL, 60% +/- 8%) phases. Pretreatment with LPS reduced infarct size to 23% +/- 8%. NAL administration in the trigger phase had no effect on infarct size (NAL-LPS 30% +/- 16%), whereas NAL during the mediator phase of LPC abolished the LPS-induced cardioprotection (LPS-NAL 54% +/- 8%). The role of NF-kappaB in morphine-induced LPC was investigated by Western blot and electrophoretic mobility shift assay. Morphine and LPS treatment increased phosphorylation of the inhibitory protein kappaB, leading to an increased activity of NF-kappaB. Thus, MO induces LPC similarly to LPS and it is likely that this cardioprotection is mediated at least in part by activation of NF-kappaB. Opioid receptors are involved as mediators in both MO- and LPS-induced LPC but as triggers only in MO-induced LPC.Like lipopolysaccharide, morphine induces late preconditioning and activation of nuclear transcription factor-kappaB. Opioid receptors are involved as mediators in both morphine- and lipopolysaccharide-induced late preconditioning but as triggers only in morphine-induced late preconditioning.

    View details for DOI 10.1213/01.ane.0000172130.70274.84

    View details for PubMedID 16192499

  • Partial liquid ventilation in acute salt water-induced lung injury. European journal of anaesthesiology Schober, P. n., Seidel, D. n., Kalb, R. n., Obal, D. n., Pakulla, M. A., Loer, S. A. 2005; 22 (7): 536–40


    Salt-water aspiration results in pulmonary oedema and hypoxia. We tested the hypothesis that partial liquid ventilation has beneficial effects on gas exchange and rate of survival in acute and extended salt water-induced lung injury.Anaesthetized, ventilated rats (tidal volume 6 mL kg(-1), PEEP 5 cmH2O) received a tracheal salt-water instillation (3%, 8 mL kg(-1) body weight) and were randomly assigned to three groups (n = 10 per group). While lungs of Group 1 were gas-ventilated, lungs of Group 2 received a single perfluorocarbon instillation (30 min after the injury, 5 mL kg(-1) perfluorocarbon) and lungs of Group 3 received an additional continuous perfluorocarbon application into the treachea (5 mL kg(-1) h(-1)) Arterial blood gases were measured with an intravascular blood gas sensor.Salt-water instillation resulted in a marked decrease in PaO2 values within 30 min (from 432 +/- 65 to 83 +/- 40 mmHg, FiO2 = 1.0, P < 0.01). Arterial oxygenation improved in all three groups irrespective of treatment. We observed no significant differences between groups in peak PaO2 and PaCO2 values.Our results suggest that partial liquid ventilation has no additional beneficial effects on gas exchange after life-threatening salt water-induced lung injury when compared to conventional gas ventilation with positive end-expiratory pressure.

    View details for PubMedID 16045144

  • Coronary artery angioplasty for treatment of peri-operative myocardial ischaemia. Anaesthesia Obal, D. n., Kindgen-Milles, D. n., Schoebel, F. n., Schlack, W. n. 2005; 60 (2): 194–97


    Increasing numbers of elderly patients with severe co-existing medical diseases undergo major surgery. With these patients there is also an accompanying risk of age-related cardiovascular complications such as life-threatening myocardial ischaemia. We present a patient who suffered a myocardial infarction after a hemicolectomy and suffered a cardiac arrest in the recovery room. The therapeutic options available (e.g. coronary artery bypass grafting, acute percutaneous coronary angioplasty and peri-operative thrombolysis) are discussed and the successful management of the case by coronary angioplasty and stent implantation is described.

    View details for DOI 10.1111/j.1365-2044.2004.04031.x

    View details for PubMedID 15644020

  • Role of protein kinase C-epsilon (PKCepsilon) in isoflurane-induced cardioprotection. British journal of anaesthesia Obal, D. n., Weber, N. C., Zacharowski, K. n., Toma, O. n., Dettwiler, S. n., Wolter, J. I., Kratz, M. n., Müllenheim, J. n., Preckel, B. n., Schlack, W. n. 2005; 94 (2): 166–73


    Volatile anaesthetics precondition the heart against infarction, an effect partly mediated by activation of the epsilon isoform of protein kinase C (PKCepsilon). We investigated whether cardioprotection by activation of PKCepsilon depends on the isoflurane concentration.Anaesthetized rats underwent 25 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups (n=10 in each group): isoflurane preconditioning induced by 15 min administration of 0.4 minimal alveolar concentration (MAC) (0.4MAC), 1 MAC (1MAC) or 1.75 MAC (1.75MAC) followed by 10 min washout before ischaemia. Each protocol was repeated in the presence of the PKC inhibitor staurosporine (10 microg kg(-1)): 0.4MAC+S, 1MAC+S and 1.75MAC+S. Controls were untreated (CON) and additional hearts received staurosporine without isoflurane (S). In a second set of experiments (n=6 in each group) hearts were excised before the infarct inducing ischaemia, and phosphorylation and translocation of PKCepsilon were determined by western blot analysis.Isoflurane reduced infarct size from a mean of 61(SEM 2)% of the area at risk in controls to 20(1)% (0.4MAC), 26(3)% (1MAC) and 30(1)% (1.75MAC) (all P<0.01 vs CON or S). This protection was partially reversed by administration of staurosporine in the 0.4MAC+S group (30[2]%; P<0.05 vs 0.4MAC) group, but not after administration of 1 MAC or 1.75 MAC isoflurane (26[2]% and 31[2]%, respectively). Thus 0.4MAC increased PKCepsilon phosphorylation, and this effect was blocked by staurosporine. Higher concentrations of isoflurane did not change PKCepsilon phosphorylation. PKCepsilon was translocated to the membrane fraction after administration of 0.4 MAC isoflurane, but not after 1.0 or 1.75 MAC.Although isoflurane preconditioning resulted in a reduction in infarct size at all concentrations used, the protection was mediated by phosphorylation and translocation of PKCepsilon only at 0.4 MAC.

    View details for DOI 10.1093/bja/aei022

    View details for PubMedID 15542537

  • Sevoflurane-induced preconditioning did not improve renal function after ischaemia/reperfusion Obal, D., Dettwiler, S., Ley, S., Preckel, B., Schlack, W. LIPPINCOTT WILLIAMS & WILKINS. 2004: 51
  • Continuous intra-arterial blood gas monitoring in rats. Laboratory animals Pakulla, M. A., Obal, D. n., Loer, S. A. 2004; 38 (2): 133–37


    Studies on lung injury and its treatment options are often performed on small animals like rats. Because conventional blood gas analyses may not detect rapid changes in gas exchange during respiratory distress syndrome and intermittent blood withdrawal can result in hypo-volaemia and anaemia, we tested the applicability and accuracy of a continuous intravascular blood gas monitor (Paratrend 7+). Anaesthetized and ventilated rats with a body weight of 398 +/-45 g (n =22) had a 20-gauge cannula inserted in both carotid arteries. A photochemical blood gas sensor for continuous measurement (Paratrend 7+) was advanced into the aorta via the left carotid artery. Blood was sampled for intermittent blood gas analysis by means of the right carotid artery. Arterial pO(2) was varied by applying different inspiratory oxygen concentrations, and arterial pCO(2) by applying different respiratory rates. Paired blood gas measurements (n =136) were analysed over a wide range of pO(2) values (5.3-76.8 kPa). We found an acceptable correlation for pO(2) (r(2)=0.98), pCO(2) (r(2)=0.96) and pH (r(2)=0.92). The calculated bias and imprecision for pO(2) was -1.0 +/- 3.3 kPa, for pCO(2) 0.04 +/- 0.28 kPa and for hydrogen ion concentration -0.05 +/-2.2 nmol/l. We conclude that in rats, continuous blood gas monitoring with a photochemical blood gas sensor provides pO(2), pCO(2) and pH measurements with acceptable accuracy.

    View details for DOI 10.1258/002367704322968803

    View details for PubMedID 15070452

  • Desflurane preconditioning induces time-dependent activation of protein kinase C epsilon and extracellular signal-regulated kinase 1 and 2 in the rat heart in vivo. Anesthesiology Toma, O. n., Weber, N. C., Wolter, J. I., Obal, D. n., Preckel, B. n., Schlack, W. n. 2004; 101 (6): 1372–80


    Activation of protein kinase C epsilon (PKC-epsilon) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) are important for cardioprotection by preconditioning. The present study investigated the time dependency of PKC-epsilon and ERK1/2 activation during desflurane-induced preconditioning in the rat heart.Anesthetized rats were subjected to regional myocardial ischemia and reperfusion, and infarct size was measured by triphenyltetrazoliumchloride staining (percentage of area at risk). In three groups, desflurane-induced preconditioning was induced by two 5-min periods of desflurane inhalation (1 minimal alveolar concentration), interspersed with two 10-min periods of washout. Three groups did not undergo desflurane-induced preconditioning. The rats received 0.9% saline, the PKC blocker calphostin C, or the ERK1/2 inhibitor PD98059 with or without desflurane preconditioning (each group, n = 7). Additional hearts were excised at four different time points with or without PKC or ERK1/2 blockade: without further treatment, after the first or the second period of desflurane-induced preconditioning, or at the end of the last washout phase (each time point, n = 4). Phosphorylated cytosolic PKC-epsilon and ERK1/2, and membrane translocation of PKC-epsilon were determined by Western blot analysis (average light intensity).Desflurane significantly reduced infarct size from 57.2 +/- 4.7% in controls to 35.2 +/- 16.7% (desflurane-induced preconditioning, mean +/- SD, P < 0.05). Both calphostin C and PD98059 abolished this effect (58.8 +/- 13.2% and 64.2 +/- 15.4% respectively, both P < 0.05 versus desflurane-induced preconditioning). Cytosolic phosphorylated PKC-epsilon reached its maximum after the second desflurane-induced preconditioning and returned to baseline after the last washout period. Both calphostin C and PD98059 inhibited PKC-epsilon activation. ERK1/2 phosphorylation reached its maximum after the first desflurane-induced preconditioning and returned to baseline after the last washout period. Calphostin C had no effect on ERK1/2 phosphorylation.Both, PKC and ERK1/2 mediate desflurane-induced preconditioning. PKC-epsilon and ERK1/2 are both activated in a time dependent manner during desflurane-induced preconditioning, but ERK1/2 activation during desflurane-induced preconditioning is not PKC dependent. Moreover, ERK1/2 blockade abolished PKC-epsilon activation, suggesting ERK-dependent activation of PKC-epsilon during desflurane-induced preconditioning.

    View details for PubMedID 15564945

  • Effect of lidocaine on ischaemic preconditioning in isolated rat heart. British journal of anaesthesia Barthel, H. n., Ebel, D. n., Müllenheim, J. n., Obal, D. n., Preckel, B. n., Schlack, W. n. 2004; 93 (5): 698–704


    Lidocaine is frequently used as an agent to treat ventricular arrhythmias associated with acute myocardial ischaemia. Lidocaine is a potent blocker not only of sodium channels, but also of ATP-sensitive potassium channels. The opening of these channels is a key mechanism of ischaemic preconditioning. We investigated the hypothesis that lidocaine blocks the cardioprotection induced by ischaemic preconditioning.Isolated rat hearts (n=60) were subjected to 30 min of no-flow ischaemia and 60 min of reperfusion. Control hearts (CON) underwent no further intervention. Preconditioned hearts (PC) received two 5-min periods of ischaemia separated by 10 min of reflow before the 30 min ischaemia. In three groups, lidocaine was infused at concentrations of 2, 10 or 20 microg ml(-1) for 5 min before the preconditioning ischaemia. Left ventricular developed pressure (LVDP) and infarct size (IS) (triphenyltetrazolium choride staining) were measured as variables of ventricular function and cellular injury, respectively.PC reduced IS from 24.8 (sem 4.1) % to 4.0 (0.7) % of the area at risk (P<0.05). Adding 2 or 10 microg ml(-1) lidocaine had no effect on IS compared with PC alone (3.7 (0.7) %, 6.9 (1.8) %). Adding 20 microg ml(-1) lidocaine increased IS to 14.1 (2.5) % compared with PC (P<0.05). Baseline LVDP was similar in all groups (111.4 (2.1) mm Hg). Compared with CON, PC improved functional recovery (after 60 min of reperfusion; 52.3 (5.9) mm Hg vs 16.0 (4.0) mm Hg, P<0.01). The improved ventricular function was not influenced by addition of 2 or 10 microg ml(-1) lidocaine (47.3 (5.7) mm Hg, not significant; 45.3 (7.3) mm Hg, not significant), but was blocked by the infusion of 20 microg ml(-1) lidocaine (22.5 (8.0) mm Hg, P<0.01 vs PC).Lidocaine blocks the cardioprotection induced by ischaemic preconditioning only at supratherapeutic concentrations.

    View details for DOI 10.1093/bja/aeh262

    View details for PubMedID 15347610

  • Hydrochloric acid-induced lung injury: effects of early partial liquid ventilation on survival rate, gas exchange, and pulmonary neutrophil accumulation. Intensive care medicine Pakulla, M. A., Seidel, D. n., Obal, D. n., Loer, S. A. 2004; 30 (11): 2110–19


    Partial liquid ventilation can improve respiratory functions in acid-induced lung injury. We studied the effects of the interval between induction of injury and initiation of partial liquid ventilation on survival, gas exchange, and pulmonary neutrophil accumulation.Anesthetized rats were randomly assigned to one of five groups ( n = 6 per group). Group 1 served as the control group, in the other groups an extended lung injury was induced by intratracheal instillation of hydrochloric acid. Whereas lungs of group 2 were gas-ventilated, group 3 received an early partial liquid ventilation (5 min after acid instillation) and group 4 a delayed partial liquid ventilation (30 min after acid instillation, 5 ml/kg perfluorocarbon). Group 5 received an additional continuous perfluorocarbon application of 5 ml x kg(-1) x h(-1) (30 min after acid instillation). Blood gases were measured with an intravascular blood gas sensor.Acid instillation resulted in a marked decrease in PO(2)-values within 30 min (from 481+/-37 mmHg to 128+/-71 mmHg, FiO(2) 1.0). Survival rate of the study period (12 h) was higher with early partial liquid ventilation. We observed no differences between groups in peak PO(2)-values during treatment. Histopathological examination, however, showed less pulmonary neutrophil accumulation in lungs of the early partial liquid ventilation group when compared to the delayed partial liquid ventilation group.Our results suggest that early partial liquid ventilation increases survival after extended acid-induced lung injury. While effects on arterial oxygenation appear not to predict acute survival we observed less intrapulmonary neutrophil accumulation with early partial liquid ventilation.

    View details for DOI 10.1007/s00134-004-2419-x

    View details for PubMedID 15448887

  • Haemodynamic changes during halothane, sevoflurane and desflurane anaesthesia in dogs before and after the induction of severe heart failure. European journal of anaesthesiology Preckel, B. n., Müllenheim, J. n., Hoff, J. n., Obal, D. n., Heiderhoff, M. n., Thämer, V. n., Schlack, W. n. 2004; 21 (10): 797–806


    The effects of desflurane and sevoflurane on the failing myocardium are still uncertain. We investigated the effects of different concentrations of sevoflurane, desflurane and halothane in dogs with pacing induced chronic heart failure.Global (left ventricular pressure, left ventricular dP/dt, Konigsbergtransducer) and regional myocardial function (systolic segment length shortening, ultrasonic crystals) were measured in chronically instrumented dogs with tachycardia induced severe congestive heart failure. Measurements were performed in healthy dogs and after induction of heart failure in the awake state and during anaesthesia with 0.75, 1.0, 1.25 and 1.75 minimum alveolar concentration (MAC) of halothane, sevoflurane or desflurane.The anaesthetics reduced dP/dtmax in a dose-dependent manner in healthy dogs (dP/dtmax decreased to 43-53% of awake values at 1.75 MAC). Chronic rapid left ventricular pacing increased heart rate and left ventricular end-diastolic pressure and decreased mean arterial pressure, left ventricular systolic pressure and dP/dtmax. The reduction in contractility was similar in the failing myocardium (to 41-50% of awake values at 1.75 MAC). Segmental shortening was reduced during anaesthesia by 50-62% after pacing compared with 22-44% in normal hearts. While there were similar effects of the different anaesthetics on diastolic function in healthy dogs, after induction of heart failure a more pronounced increase of the time constant of isovolumic relaxation and a greater decrease of dP/dtmin was observed with sevoflurane than with desflurane, indicating a stronger depression of diastolic function.While the negative inotropic effects of sevoflurane and desflurane were similar in normal and in the failing myocardium in vivo, desflurane led to a better preservation of diastolic function in the failing myocardium.

    View details for PubMedID 15678735

  • Partial liquid ventilation in acid-induced lung injury - Effects of immediate and delayed initiation Pakulla, M. A., Obal, D., Seidel, D., Loer, S. A. SPRINGER. 2003: S147
  • Cardioprotection against reperfusion injury is maximal with only two minutes of sevoflurane administration in rats. Canadian journal of anaesthesia = Journal canadien d'anesthesie Obal, D. n., Scharbatke, H. n., Barthel, H. n., Preckel, B. n., Müllenheim, J. n., Schlack, W. n. 2003; 50 (9): 940–45


    Volatile anesthetics can protect the heart against reperfusion injury. When sevoflurane is given for the first 15 min of reperfusion, a concentration corresponding to one minimum alveolar concentration (MAC) provides a maximum protective effect. The present study addresses the question of how long sevoflurane has to be administered to achieve the best cardioprotection.Chloralose anesthetized rats were subjected to a 25-min occlusion of a major coronary artery, followed by 90 min of reperfusion. During the initial phase of reperfusion, an end-tidal concentration of 2.4 vol.% of sevoflurane (1 MAC) was given for two (n = 8), five (n = 8) or ten minutes (n = 7). Seven rats served as untreated controls. We measured left ventricular (LV) pressure, mean aortic pressure and infarct size (triphenyltetrazolium staining).Administration of sevoflurane for two minutes resulted in the greatest reduction of infarct size to 15% (8-22 [mean (95% confidence interval)] of the area at risk compared with controls [51 (47-55) %, P < 0.001]. Five or ten minutes of sevoflurane administration reduced infarct size to 26 (18-34) and 26 (18-35) % [P < 0.05], respectively. The cardiodepressant effect of sevoflurane varied with the duration of its administration: LV dP/dt was reduced from 6332 mmHg x sec(-1) (5771-6894) during baseline to 4211 mmHg x sec(-1) (3031-5391), 3811 mmHg x sec(-1) (2081-5540) and 3612 mmHg x sec(-1) (2864-4359) after two, five and ten minutes of reperfusion, respectively.Administration of 1 MAC sevoflurane for the first two minutes of reperfusion effectively protects the heart against reperfusion injury in rats in vivo. A longer administration time had lesser cardioprotective effects in this experimental model.

    View details for DOI 10.1007/BF03018744

    View details for PubMedID 14617594

  • One MAC of sevoflurane provides protection against reperfusion injury in the rat heart in vivo. British journal of anaesthesia Obal, D. n., Preckel, B. n., Scharbatke, H. n., Müllenheim, J. n., Höterkes, F. n., Thämer, V. n., Schlack, W. n. 2001; 87 (6): 905–11


    Volatile anaesthetics protect the heart against reperfusion injury. We investigated whether the cardioprotection induced by sevoflurane against myocardial reperfusion injury was concentration-dependent. Fifty-eight alpha-chloralose anaesthetized rats were subjected to 25 min of coronary artery occlusion followed by 90 min of reperfusion. Sevoflurane was administered for the first 15 min of reperfusion at concentrations corresponding to 0.75 (n=11), 1.0 (n=11), 1.5 (n=13), or 2.0 MAC (n=12). Eleven rats served as untreated controls. Left ventricular peak systolic pressure (LVPSP, tipmanometer) and cardiac output (CO, flowprobe) was measured. Infarct size (IS, triphenyltetrazolium staining) was determined as percentage of the area at risk. Baseline LVPSP was 131 (126-135) mm Hg (mean (95% confidence interval)) and CO 33 (31-36) ml min(-1), similar in all groups. During early reperfusion, sevoflurane reduced LVPSP in a concentration-dependent manner to 78 (67-89)% of baseline at 0.75 MAC (not significant vs controls 99 (86-112)%), 71 (62-80)% at 1 MAC (P<0.05), 66 (49-83)% at 1.5 MAC (P<0.05) and 56 (47-65)% at 2 MAC (P<0.05). CO remained constant. While 0.75 MAC of sevoflurane had no effect on IS (34 (27-41)% of the area at risk) compared with controls (38 (31-45)%, P=0.83), 1.0 MAC reduced IS markedly to 23 (17-30)% (P<0.05). Increasing the concentration to 1.5 MAC (23 (17-30)%) and 2 MAC (23 (13-32)%, both P<0.05 vs controls) had no additional protective effect. One MAC sevoflurane protected against myocardial reperfusion injury. Increasing the sevoflurane concentration above 1 MAC resulted in no further protection.

    View details for PubMedID 11878695

  • Influence of the angiotensin II AT1 receptor antagonist irbesartan on ischemia/reperfusion injury in the dog heart. Basic research in cardiology Preckel, B. n., Schlack, W. n., Gonzàlez, M. n., Obal, D. n., Barthel, H. n., Thämer, V. n. 2000; 95 (5): 404–12


    The aim of the present study was to investigate whether the non-peptide angiotensin II type 1 (AT1) receptor antagonist irbesartan (SR 47436, BMS 186295, 2-n-butyl-3 [2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro [4,4]non-1-en-4-one) has myocardial protective effects during regional myocardial ischemia/reperfusion in vivo. Eighteen anesthetized open-chest dogs were instrumented for measurement of left ventricular and aortic pressure (tip manometer and pressure transducer, respectively), and coronary flow (ultrasonic flowprobes). Regional myocardial function was assessed by Doppler displacement transducers as systolic wall thickening (sWT) in the antero-apical and the postero-basal wall. The animals underwent 1 h of left anterior descending coronary artery (LAD) occlusion and subsequent reperfusion for 3 hours. Irbesartan (10 mg kg(-1), n = 9) or the vehicle (KOH, control, n = 9) was injected intravenously 30 min before LAD occlusion. Regional myocardial blood flow (RMBF) was measured after irbesartan injection and at 30 min LAD occlusion using colored microspheres. Infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. There was no recovery of sWT in the LAD perfused area in both groups at the end of the experiments (systolic bulging, -15.1+/-6.1% of baseline (irbesartan) vs. -12.3+/-3.0% (control), mean+/-SEM). Irbesartan led to an increase in RMBF in normal myocardium (2.47+/-0.40 vs. 1.35+/-0.28 ml min(-1) g(-1), p<0.05), and also to an increase in collateral blood flow to the ischemic area (0.27+/-0.04 vs. 0.17+/-0.02 ml min(-1) g(-1), P = <0.05). Infarct size (percent of area at risk) was 24.8+/-3.2 % in the treatment group compared with 26.9+/-4.8% in the control group (P = 0.72). These results indicate that a blockade of angiotensin II AT1 receptors with irbesartan before coronary artery occlusion led to an increase in RMBF, but did not result in a significant reduction of myocardial infarct size.

    View details for PubMedID 11099168

  • Left stellate ganglion block has only small effects on left ventricular function in awake dogs before and after induction of heart failure. Anesthesia and analgesia Müllenheim, J. n., Preckel, B. n., Obal, D. n., Heiderhoff, M. n., Hoff, J. n., Thämer, V. n., Schlack, W. n. 2000; 91 (4): 787–92


    Left stellate ganglion block (LSGB) results in acute sympathetic denervation of the left ventricular (LV) posterobasal wall. We investigated the effects of LSGB in chronically instrumented awake dogs before and after the induction of pacing-induced congestive heart failure. Twelve dogs were instrumented for measurement of global hemodynamics [LV pressure (LVP)], its first derivative (dP/dt), cardiac output (CO), and regional myocardial function (systolic posterobasal segment length shortening, mean velocity [SLmv]). Before the induction of heart failure (n = 12), LSGB did not affect CO [3.2+/-1.4 (control, mean +/- SD) vs. 3.3+/-1.6 L/min (LSGB, P = 0.45)] and SLmv (11.1+/-4.0 vs. 10.8+/-4.0 mm/s, P = 0.16), but slightly reduced LVP (130+/-12 vs. 125+/-14 mm Hg, P = 0.04), dP/dt(max) (3614+/-755 vs. 3259+/-644 mm Hg/s, P = 0.003) and dP/dt(min) (-3153+/-663 vs. -2970+/-725 mm Hg/s, P = 0.03). During heart failure (n = 8), global hemodynamics [CO (2.8+/-1.2 vs. 2.7+/-1.2 L/min, P = 0.04), LVP (119+/-6 vs. 112+/-9 mm Hg, P = 0.01), dP/dt(max) (1945+/-520 vs. 1824+/-554 mm Hg/s, P = 0.03) and dP/dt(min) (-2402+/-678 vs. -2243+/-683 mm Hg/s, P = 0.04)], as well as regional myocardial function, were significantly different after LSGB [SLmv] (8.0+/-3.8 vs. 6.9+/-3.4 mm/s, P = 0.02)]. In conclusion, even during heart failure, the hemodynamic changes after LSGB are small, confirming its broad margin of safety.

    View details for PubMedID 11004027

  • Effect of volatile anaesthetics on frequency-dependency of myocardial contractility in chronically instrumented dogs Obal, D., Heideroff, M., Preckel, B., Thamer, Schlack, W. PROF SCI PUBL. 1999: 57-58
  • Effect of a left stellate ganglion block on left ventricular function in chronically instrumented dogs Heiderhoff, M., Obal, D., Preckel, B., Thamer, Schlack, W. PROF SCI PUBL. 1999: 62
  • Effect of acidotic blood reperfusion on reperfusion injury after coronary artery occlusion in the dog heart. Journal of cardiovascular pharmacology Preckel, B. n., Schlack, W. n., Obal, D. n., Barthel, H. n., Ebel, D. n., Grunert, S. n., Thämer, V. n. 1998; 31 (2): 179–86


    A prolongation of the intracellular acidosis after myocardial ischemia can protect the myocardium against reperfusion injury. In isolated hearts, this was achieved by prolongation of the extracellular acidosis. The aim of this study was to investigate whether regional reperfusion with acidotic blood after coronary artery occlusion can reduce infarct size and improve myocardial function in vivo. Anesthetized open-chest dogs were instrumented for measurement of regional myocardial function, assessed by sonomicrometry as systolic wall thickening (sWT). Infarct size was determined by triphenyltetrazolium staining after 3 h of reperfusion. The left anterior descending coronary artery (LAD) was perfused through a bypass from the left carotid artery. The animals underwent 1 h of LAD occlusion and subsequent bypass-reperfusion with normal blood (control, n = 6) or blood equilibrated to pH = 6.8 by using 0.1 mM HCl during the first 30 min of reperfusion (HCl, n = 5). Regional collateral blood flow (RCBF) at 30-min occlusion was measured by using colored microspheres. There was no difference in recovery of sWT in the LAD-perfused area between the two groups at the end of the experiments [-2.8+/-1.2% (HCl) vs. -4.4+/-2.5% (control); mean +/- SEM; p = NS]. RCBF was comparable in both groups. Infarct size (percentage of area at risk) was reduced in the treatment group (12.8+/-2.8%) compared with the control group (26.2+/-4.8%; p < 0.05). These results indicate that reperfusion injury after coronary artery occlusion can be reduced by a prolonged local extracellular acidosis in vivo.

    View details for PubMedID 9475258

  • Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo. British journal of anaesthesia Preckel, B. n., Schlack, W. n., Comfère, T. n., Obal, D. n., Barthel, H. n., Thämer, V. n. 1998; 81 (6): 905–12


    It is known that volatile anaesthetics protect myocardial tissue against ischaemic and reperfusion injury in vitro. In this investigation, we have determined the effects of the inhalation anaesthetics, enflurane, isoflurane, sevoflurane and desflurane, administered only during early reperfusion, on myocardial reperfusion injury in vivo. Fifty chloralose-anaesthetized rabbits were subjected to 30 min of occlusion of a major coronary artery followed by 120 min of reperfusion. Left ventricular pressure (LVP, tip-manometer), cardiac output (CO, ultrasonic flow probe) and infarct size (triphenyltetrazolium staining) were determined. During the first 15 min of reperfusion, five groups of 10 rabbits each received 1 MAC of enflurane (enflurane group), isoflurane (isoflurane group), sevoflurane (sevoflurane group) or desflurane (desflurane group), and 10 rabbits served as untreated controls (control group). Haemodynamic baseline values were similar between groups (mean LVP 106 (SEM 2) mm Hg; CO 281(7) ml min-1). During coronary occlusion, LVP and CO were reduced to the same extent in all groups (LVP 89% of baseline; CO 89%). Administration of inhalation anaesthetics during early reperfusion further reduced both variables, but they recovered after discontinuation of the anaesthetics to values not different from control animals. Infarct size was reduced from 49 (5)% of the area at risk in the control group to 32 (3)% in the desflurane group (P = 0.021), and to 36 (2)% in the sevoflurane group (P = 0.097). In the enflurane group, infarct size was 39 (5)% (P = 0.272). Isoflurane had no effect on infarct size (48 (5)%, P = 1.000). The results show that desflurane and sevoflurane markedly reduced infarct size and therefore can protect myocardium against reperfusion injury in vivo. Enflurane had only a marginal effect and isoflurane offered no protection against reperfusion injury in vivo. These different effects suggest different protective mechanisms at the cellular level.

    View details for PubMedID 10211018

  • Halothane reduces reperfusion injury after regional ischaemia in the rabbit heart in vivo. British journal of anaesthesia Schlack, W. n., Preckel, B. n., Barthel, H. n., Obal, D. n., Thämer, V. n. 1997; 79 (1): 88–96


    In addition to having anti-ischaemic effects, halothane can protect isolated rat hearts and isolated cardiomyocytes against reperfusion injury of the "oxygen paradox" type. The aim of this study was to investigate if halothane can also protect against myocardial reperfusion injury in vivo. Twenty-two rabbits anaesthetized with alpha-chloralose underwent 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Seven animals received 1 MAC of halothane for the first 15 min of reperfusion (halothane group), and eight animals served as untreated controls (controls group). In seven additional animals, the haemodynamic effects of halothane were antagonized by an i.v. infusion of noradrenaline (halothane-noradrenaline group). We measured cardiac output (CO) by an ultrasonic flow probe around the ascending aorta, left ventricular pressure (LVP) by a tip manometer and infarct size by triphenyltetrazolium staining. Baseline LVP was mean 92 (SEM 4) mm Hg and CO was 289 (16) ml min-1. During coronary occlusion, LVP was reduced to 86 (4)% of baseline and CO to 84 (4)% (similar in all groups). During halothane administration at reperfusion, LVP declined further to 55 (6)% of baseline and CO to 66 (9)% (P < 0.05 halothane group vs control group). Noradrenaline prevented the reduction in LVP (halothane-noradrenaline group 87 (5)% of baseline, control group 84 (6)% and reduction in CO (halothane-noradrenaline group 89 (5)%, control group 83 (6)%. Infarct size was 49 (6)% of the area at risk in controls and was reduced markedly by administration of halothane to 32 (3)% in the halothane group (P < 0.05) and to 30 (3)% in the halothane-noradrenaline group (P < 0.05). Treatment with halothane during the early reperfusion period after myocardial ischaemia protected the myocardium against infarction in vivo, independent of the haemodynamic effect of halothane.

    View details for PubMedID 9301395

  • Inotropic effects of different NO-donors in the dog heart in vivo. Preckel, B., Kojda, G., Schlack, W., Barthel, H., Ebel, D., Obal, D., Grunert, S., Kottenberg, G., Noack, E., Thamer SPRINGER VERLAG. 1997: O37