Prof. MD PhD M.W. Hollmann

Position

Full Professor

Main activities

Education, Patient care, Research

Specialisation

Anesthesiology, Intensive Care, Emergency Medicine, Pain Therapy and Palliative Care

Focus of research

Mission statement and ambition

Research in the Department of Anesthesiology will serve our patients by improving the safety and quality of perioperative care and (chronic) pain management. We will provide a stimulating and attractive academic environment for translational anaesthesia research of the highest quality, by providing a unique combination of top facilities for both clinical research and basic laboratory research. Continual motivation and inspiration of young researchers is the key driver in achieving our goals.

Research in the Department of Anesthesiology will focus on five main research lines, which are cardioprotection, anesthetics & signal transduction, (chronic) pain management, hemodynamic optimization and cerebral air embolism.

Cardioprotection is aligned with AMC’s main focus on cardiovascular diseases, and within our research, we set up several translational studies aiming to verify the in vitro and in vivo observed cardioprotective actions of pre- and postconditioning in humans by different pharmacological interventions and also remote ischemic conditioning.

Anesthetics and signal transduction belongs to AMC’s emphasis on inflammation and immunology. Within this area, we will further study basic mechanisms of (local) anesthetics, in particular the effects of (local) anesthetics on tumor biology.

Research related to (chronic) pain management addresses effects of regional anesthesia in diabetes pre-clinically as well as clinically. In addition, within the area of chronic pain management we focus on neuromodulation for neuropathic pain management. Research in neuromodulation will focus on two research lines; New stimulation modes and strategies for Dorsal Column Stimulation (DCS) and Neurostimulation for peripheral neuropathic pain (related to painful polyneuropathies or postsurgical pain).

Perioperative and hemodynamic optimization aims at improving the patients conditions perioperatively in close collaboration with the different surgical, nursing and paramedical specialties with a special focus on fluid- and hemodynamic management in all phases.

Within the area of cerebral air embolism research we set out to determine pathophysiological mechanisms, prophylactic and therapeutic treatments of patients suffering from cerebral air embolism.

Experimental Anesthesiology

Experimental Anesthesiology is imbedded in the common L.E.I.C.A. laboratory (Laboratory of Experimental Intensive Care & Anesthesiology). Worth mentioning, uniting the basic research efforts of the two sister disciplines in one lab, L.E.I.C.A is the first laboratory of its kind in the Netherlands and almost unique in Europe. Main research lines and good examples for translational science are cardioprotection and molecular mechanisms of anesthetics. Innovative growing ventures relate to the patho-physiology and therapy of cerebral air embolism, the quantification of mitochondrial oxygen in situ and the effects of anesthetics on tumor biology.

Research topic: Cardiovascular

L.E.I.C.A.’s cardioprotection group consists of several leading experts (Prof. Hollmann, Prof. Schlack, Prof. Preckel, Dr. Hauck-Weber and Dr. Zuurbier) in the field of Ischemia/Reperfusion (I/R) injury, pre- and postconditioning of the heart. Our research group within the LEICA laboratory focusses primarily on protection of heart, blood vessels and other organs against temporary periods of no oxygen. No oxygen conditions occur frequently in several clinical conditions (surgery, cardiac by-pass operations, shock, stroke, transplantation) and during an acute heart attack. This research therefore has a high clinical and society relevance: it can lead to improvements in clinical care and in the fight against cardiovascular diseases (still number one diseases in humans). 

We use cell culture models, isolated organs and in vivo models together with a large arsenal of different biochemical analysis methods (eg Western blotting, Real time PCR, immunohistochemistry, Elisa, FACS). Parts of the research are also performed in the clinical setting on the OR depending on the translational approach of the study. Main research focus is on 1) improving our understanding of the working mechanisms of protection, and 2) development of clinical relevant applications of protective strategies (i.e. translational research). 

1)         Unravelling the molecular machinery resulting in protection against cell death.

Our current focus is on mitochondrial function, caveolin signalling, mitochondria-hexokinase interactions and inflammatory mediators, because our research strongly indicates that these entities are the important nodal regulatory points of protective signalling

2)         Development of clinically-relevant protective strategies

Many basic laboratory derived protective strategies have ultimately failed clinically. An important reason for this failing has been that the basic researcher does not take fully into account the clinical conditions of the patients. Our laboratory is ideally suited to resolve these problems, because it constitutes the close collaboration between basic researchers and clinicians. In the protective strategies that we are developing and studying special care is therefore given to these clinical conditions, such as health status of the organisms, anaesthetics used, the presence of medical drugs. At this moment the focus is on remote ischemic preconditioning, special anaesthetic agents and helium breathing as clinically-applicable interventions to protect the organ/tissue against period of no oxygen.

Pathophysiology and therapy of cerebral air embolism

In a collaboration project with the Dutch Ministry of Defence, cerebral arterial gas embolism (a complication occurring in diving, but also as a complication of invasive medical procedures) is simulated in an experimental animal model and the pathophysiology, prevention and treatment is investigated.

 

Research topic: Molecular Mechanisms of anesthetics

GPCRs and Signaltransduction

Prof. Hollmann is a well renowned expert for the effects of anesthetics, in particular local anesthetics (LA), on signal transduction of G-protein coupled receptors (GPCRs). His findings on LA interactions with specific G protein subunits and G protein signalling transduction pathways have led to a revival of the systemic use of LA in the perioperative setting for indications others than pain management (e.g, modulation of inflammation and coagulation). Future research projects will try to identify the active parts within the LA structure, responsible for their protective effects as well as the corresponding target sites, allowing the development of new drugs: specifically indicated for modulation of coagulation and immune function, but lacking the typical “side effects” of LA, namely the sodium channel blockade. Dr. Stevens complements this research line with his experimental studies on neurotoxicity of anesthetics (mainly local anesthetics).

The basic research of Dr. Philipp Lirk is carried out in close collaboration with Departments of Neuroanatomy, Neurology, Cardiology and Clinical Neurophysiology. On the level of Basic science, we seek to explore the pharmacology and toxicology of local anesthetics. In past years, this research has focused on mechanisms and prevention of local anesthetic-induced neurotoxicity, while recently we have investigated epigenetic consequences of administration of local anesthetics and opioids. On the translational level, we are interested how diabetic neuropathy affects performance and safety of regional anesthesia, in particular peripheral nerve blockade. We have established a comprehensive model of regional anesthesia in diabetic neuropathy, including genetically altered rats (ZDF), neurophysiology to assess severity of neuropathy, percutaneous nerve blocks, behavioral testing, neurohistopathology and patch clamp electrophysiology.

 

Anesthetics & Tumorbiology

Shifting the focus of anesthesia research from the primarily perioperative outcome to long-term outcome, we set up a new, innovative research line investigating the effect of different anesthetic regimes on cell biology of tumor cells. Cancer surgery is usually performed under general anaesthesia with postoperative analgesia provided by opioids. The stress of surgery, general anesthetics, and opioid analgesics might be each immunosuppressive and specifically inhibit cell-mediated immunity that is critical for control of minimal residual disease. Opioids and stress also might increase angiogenesis, which promotes growth of cancer cells. Regional anaesthesia and analgesia may reduce the risk of cancer recurrence because it blocks the neuroendocrine stress response, decreases or eliminates the need for general anesthetics, and obviates the need for postoperative opioids

Clinical Research

Clinical research in the Department of Anesthesiology is rather diverse reflecting the diversity of the speciality. However, one of the main research lines pertains to cardioprotection. Since this is also in the spotlight of our experimental research, translation from the bench to the bedside is a strength of our research group.

Research topic: Cardiovascular

Cardioprotection: Anesthetics and Noble Gases

Combining the expertise of Prof Hollmann, Prof. Preckel, Prof. Schlack, Dr. Hauck, and Dr. Zuurbier makes for one of the world’s leading research groups in this field. Cardioprotective effects of various anesthetic strategies, tested on the cellular level and in animal experiments in L.E.I.C.A, were and will be tested in the clinical setting. In collaboration with the Department of Neurology from the AMC and the Tergooi-Ziekenhuis Blaricum we start to evaluate the application of helium in patients with acute stroke. Whether helium might also be used after cardiac arrest has been evaluated in collaboration with the Department of Intensive Care of the AMC. In addition, the department of Anesthesiology of the AMC is the leading center for an international multicenter study on the effects of ischemic remote pre- and postconditioning on outcome after coronary artery surgery. In this patient population, molecular mechanisms of remote preconditioning will be determined, allowing translation of basic findings from animal experiments (which are performed in close collaboration with the Department of Anesthesiology, University of Düsseldorf, Germany) to the clinical situation. We also intent to investigate (in collaboration with the Department of Surgery and the Department of Medical Medicine) the phenomenon of remote postconditioning in patients subjected to kidney transplantation.

Cerebral Perfusion

The main aim of this research line is to unravel the effect of oxygen on brain blood flow regulation. The results have important implications for amongst others the understanding and treatment of acute mountain sickness. For the treatment of patients with compromised cerebral autoregulation (CA) and oxygenation of the brain our studies evaluate(d) the importance of arterial hypertension and/or oxygen administration. Employing Near Infra-Red Spectroscopy (NIRS) to monitor cerebral tissue oxygenation, the role of oxygen in CA during changes in blood pressure or different levels of arterial blood oxygenation will be determined. Using new self-developed analyzing techniques, we are able to quantify the ability of the cerebral vasculature to counter-regulate sudden changes in blood pressure, which occur frequently in the perioperative setting. Vasoactive medication, intravenous and volatile anesthetics influence autonomic nervous system activity and thereby result in considerable changes in blood pressure and alteration of the systemic cardiovascular regulation. Cerebral vessels are richly innervated by sympathetic nerves, but there is controversy about the role of sympathetic nerves in regulation of cerebral blood flow (CBF). Leaving all other regulatory mechanisms of CA unaffected we will create a cerebral sympathetic activity “knock out” model by blocking the superior stellate ganglion (SGB) unilaterally to quantify sympathetic contribution to the regulation of cerebral blood flow (CBF). If  the regulation of the cerebral blood flow deteriorates during sympathetic blockade, the brain could be extra vulnerable to a decrease in blood pressure during the use of anesthetics.    

In addition, we will investigate the influence of changes in cerebral perfusion pressure and cerebral blood flow on CA in patients undergoing cardiac surgery with extracorporeal bypass, with and without pre-existing diseases (such as diabetes, stroke etc.).

Hemodynamic Optimization

Perioperative fluid and cardiovascular management is a core competence of the anaesthetists domain. Haemodynamic control has been linked to anaesthetic benchmarks, like nausea and vomiting, pain, tissue oxygenation, cardiopulmonary disorders, need of revision surgery, duration of hospital stay, and bowel recovery time. However, perioperative fluid handling comprises the type of fluids in general, their exact composition and the respective amounts. There is, for example, increasing evidence that an exclusive use of crystalloids might overload the interstitial space, leading to tissue edema, anastomotic leakage and thereby hampering patient outcome. Recent studies indicate perioperative fluid “restriction” during major surgical interventions to be beneficial to the patient. In different patient populations undergoing major abdominal surgery, we seek to determine optimal perioperative fluid management to reduce morbidity and improve gastrointestinal function, thereby reducing hospital stay and health care costs throughout the perioperative process. For this topic we work together with international experts and more than ten national partner anaesthesia departments

Decision Support

Clinical guidelines are a commonly used means to translate scientific evidence to good clinical care. They serve many purposes, but are generally agreed on to get the right (state of art) treatment for the right patient, reduce uncontrolled variation and improve clinical care. However, in practice, the implementation of guidelines may be limited by poor adherence. The aim of this project is to investigate which factors that influence non adherence to guidelines can be addressed by using decision support as an integrated system within the Patient Data Management System.  This system constantly monitors the data in the patient record and provides assistance in recognizing or even predicting potential complications and impending non-adherence and provide decision assistance with as little disruption of clinical care as possible. We proved that these systems can improve guideline adherence and can improve quality of care for a specific guideline and now aim to expand the system and optimize it to be more robust and applicable to other guidelines and situations. Moreover, we will look in to unintended consequences of decision support and reasons for residual non-adherence.

Optimizing perioperative metabolism as a cardiovascular risk factor

The incidence of diabetes mellitus in the general population is increasing into epidemic proportions and this is reflected in the surgical population. Patients with diabetes mellitus are at risk of postoperative complications; however the evidence for treatment of perioperative diabetes is surprisingly scarce. In this clinical research line we aim to identify risk factors for postoperative complications in patients with diabetes, improve detection of hyperglycaemia with novel monitoring techniques and study perioperative treatment in randomized clinical trials. Another focus is perioperative hyperglycaemia without a pre-existing diagnosis of diabetes mellitus and the diagnosis and impact of diabetes mellitus on perioperative cerebral and cardiac autonomic failure.

Research topic: other clinical research

Long-term effects of Regional anesthesia:

This research line has two objectives: The first is to define the impact of regional anesthesia (in particular ultrasound-guided peripheral nerve blockade) on functional outcome in orthopaedic surgery and development of chronic pain in a mixed surgical population. Secondly, to determine the effects of an opioid-sparing anesthetic regimen on tumor recurrence in patients undergoing breast cancer surgery. This project will be done in close collaboration with the German (Prof. H. Walczak) and Dutch (Dr. J. Jonkers) Cancer Center and translates our basic science findings on anesthetics and tumor biology to the clinical environment.

Other research efforts (Dr. P. Lirk) include the relevance of peripheral nerve block in the Emergency room focusing on hip fractures in the elderly (DEPTHIP study), the role of regional anesthesia in the prevention of phantom limb pain (PLATA study series), and safety aspects of Epidural anesthesia, a project carried out on behalf of the Dutch Society of Anesthesia.

 Big data and Patient Monitoring using Novel techniques

The future of science lies in the collaboration between research groups and departments. The Department of Anesthesiology at the AMC is one of only two non-US divisions to join the Multicenter Perioperative Outcomes Group (MPOG) project (Dr. P. Lirk, Drs. F. Kooij), and we have uploaded our first data the „Anesthesia Quality Institute (AQI)“ of the American Society of Anesthesiology (ASA). We are actively contributing towards MPOG research projects, and have submitted our first Research Proposal to the MPOG Research Committee.

In addition, we are exploring the potential clinical benefits of wireless monitoring of surgical (high-risk) patients using a new RFID technology (Sensium^®), and have recently been awarded an Innovative Patient Care project grant to investigate how this monitoring might influence the “failure to detect” of the surgical patient, and thereby improve patient outcome.

 

Perioperative optimization

Enhanced Recovery After Surgery (ERAS) has proven to reduce surgical complication rates. We perform (implementation) research in close cooperation with GI surgeons, cardiothoracic surgeons, cardiologists, ICU physicians, dieticians, physiotherapists, nurses and ICT experts to improve current care practices (eating, drinking, mobilization and pain management), improve compliance and empower the perioperative patient (eHealth solutions). We also work together with machine and deep learning experts to develop real-time and continuous warning systems to signal and treat complications early.

Neuromodulation for chronic neuropathic pain treatment

The research line “New stimulation modes and strategies for Dorsal Column Stimulation” addresses the dose-response relationship between the amount of energy applied to the spinal cord and clinical outcome. This in relation to other variables, such as the anatomical target of stimulation and electrode configuration. Examples are the multi-center High And LOw energyfrequency RCT (HALO study) and the multicenter PAResthesia Vs Anatomical guided stimulation RCT (PARVA study).  The research line “Neurostimulation for peripheral neuropathic pain” is dedicated to gathering evidence for specific neuropathic pain diagnosis and to optimize clinical outcome in neurostimulation for this condition. Examples of investigator-initiated studies are Dorsal Root Ganglion (DRG) stimulation for neuropathic arm pain (AMS-01 study) and for phantom limb pain (AMS-02 study). In addition, we participate in several multi-center sponsored post-market studies An , for example: RCT foot pain (12-SMI-2014), RCT groin pain (24-SMI-2014), low back pain (18-SMI-2013) and post-surgical pain (20-SMI-2013).

Sedation - Safety &  Effectivity

 

In cooperation of the Departments of Anesthesiology and the Departments of Gastroenterology & Hepatology of the Academic Medical Center, Amsterdam and the University Medical Center Utrecht, this research line focusses on the differences in patient safety and satisfaction, effectivity and experiences by the gastroenterologists when sedation is given by a sedation anesthesia nurse (SAN), experienced in airway management, or a gastroenterologist, who is doing the gastroenterological procedure at the same time.

Prehospital Advanced Life Support – Airway management and ventilation during out-of-hospital resuscitation

In cooperation with the AmsteRdam REsuscitation STudies (ARREST) group of dr. Ruud Koster (AMC), this research focusses on airway management, ventilation and wave-form capnography during prehospital resuscitation. Main questions are: is endotracheal intubation or a supraglottic airway device the best airway management technique during Advanced Life Support? What ventilation frequency is optimal? What does the level of end-tidal CO2 tell us about the cause of the arrest? 

Research Networks & Large Clinical Trials

The Department of Anesthesiology is not only involved but also quite frequently main coordinating center for numerous national and international large-scale multi-center trials. The Department is/was frequently funded by the European Society of Anesthesiologists (ESA) Clinical Network (ESA-CTN, e.g. EUSOS, POPULAR (Steering committee), PROVHILO (Main center), LAS VEGAS (Main center), PROBESE (National coordinator), PROTHOR (National coordinator), PLATA (Main center), NECTARINE). Prof. Hollmann and Dr. Hemmes are part of the Protective Ventilation Network (PROVENET). Prof. Hollmann and Dr. Lirk together with Dr. Ridderikhof (Emergency Department AMC) are the leading investigators for the ZONMW supported PANAMA and DEPTHHip trial. Prof. Hollmann, Prof. Boer (VuMC) and Prof. Buhre (MUMC) are the Principal Investigators for the ZonMW funded national TRACE trial. Together with Prof. Boermeester (Department of Surgery, AMC) Prof. Hollmann is the lead investigator for the ZonMw supported EPOCH study. In addition, Prof. Hollmann is part of the NIMIT consortium (STW funded) and national coordinator for the EU COST project on anesthesia & cancer.

Collaborations – research environment

Nationally

The Anesthesiology Research Department has extensive and varying national collaborations within the AMC, but also with other Dutch academic centers. Among others the most intensive and prominent are:

Within the AMC we have established collaborations with the Dept. of Intensive Care (Prof. Vroom & Prof. M. Schultz), Dept. of Experimental Surgery (Prof. T.M. v Gulik), Dept. of Surgery (Prof. W.A. Bemelman & Dr. M. Idu & Dr. M.A. Boermeester), Dept. of Experimental Internal Medicine (Prof. T van de Poll), Dept. of Endocrinology (Prof. E. Fliers), Dept. of Gatroenterology & Hepatology (Prof. G.E.E. Boeckxstaens), Dept. of traumatology (Dr. C. Goslings), Dept. of Neurology (Dr. Y. Roos), Dept. of Cardiology (Dr. R. Koster – ARREST group)  and Dept. of Epidemiology (Dr. J.C. Korevaar)

Externally with the:

-          Department of Anesthesiology, Erasmus MC Rotterdam for research on Xenon & cardioprotection (Dr. J. Hofland)

-          Department of Anesthesiology, LUMC for research on preoperative assessment, pain and GPCR signal transduction (Prof. A. Dahan & Dr. A de Roode & Dr. F . Boer)

-          Department of Anesthesiology, UMCU for research on Sedation for Non-Anesthesiologists (Prof. C.J. Kalkman & Prof. H. Knape)

-          Department of Anesthesiology, OLVG for Decision Support research (Dr. J.E. Kal & Drs T. Klok)

-          Department of Anesthesiology, Diakonessen Hospital Utrecht for research on Neuromodulation (Dr. X. Zuidema)

-          Department of Neurology, Tergooi-Ziekenhuis Blaricum for Helium in stroke patients (dr. J. de Kruijk)

-          Department of Anesthesiology, AVL Amsterdam for research on pain therapy (Dr. M. Sramek)

-          Division of Molecular Biology, Netherlands Cancer Institute for research on anesthetics and tumor biology (Dr. J. Jonkers)

-          Ministry of Defense, Royal Netherlands Navy, and specifically the Diving Medical Center, Den Helder for research on cerebral arterial gas embolism.

-          ‘Dutch GDT & Benchmark network’; Departments of Anesthesiology of Westfriesgasthuis, Onze Lieve Vrouwe Gasthuis, VUmc, LUMC, Albert Schweitzer Ziekenhuis, Reinier de Graaf ziekenhuis, UMCG, Anthoni van Leeuwenhoek, Medisch Centrum Alkmaar

-          Prof. dr. J. Hans DeVries, Department of Endocrinology, AMC

-          Dr. J. Hermanides, Department of Anesthesiology, Pain and Palliative Care, RadboudUMC, Nijmegen

-          Department of Anesthesiology, Rijnstate Hospital Arnhem for research on Neuromodulation (dr. J.W. Kallewaard)

-          Department of Anesthesiology, Alrijne Hospital Leiderdorp for research on Neuromodulation (dr. K. Burger)

-          Department of Anesthesiology, Noordwest Hospital Group Alkmaar for research on Neuromodulation (dr. S. de Graaf and dr. H. Pelleboer)

 

Internationally

-          Department of Anesthesiology, Univ. of Heidelberg, Germany for research on local anesthetics, ultrasound-guided regional anesthesia and lung physiology (Dr. S. Herroeder & Dr. J Kessler)

-          Department of Anesthesiology, Univ. of Duesseldorf, Germany, Basic mechanisms of remote pre- and post-conditioning (Prof. Dr. I. Bauer, Prof. dr. B. Pannen)

-          Department of Anesthesiology, Univ. of Virginia, US for research on local anesthetics & GPCRs (Prof. M.E. Durieux)

-          Department of Anesthesiology, Perioperative and Critical Care Medicine, Parcelsus Medical University, Austria, for research on local anesthetics & pain therapy (Prof. Dr. P. Gerner)

-          Department of Anatomy, Innsbruck Medical University, Austria, for research on neurotoxicity of local anesthetics (Prof. Dr. Lars Klimaschewski)

-          Department of Gynecology, Laboratory of Clinical Biochemistry, Innsbruck Medical University, Austria, for research on epigenetic effects of local anesthetics

-          Department of Anesthesiology, Hospital for Joint Diseases, New York University, NY, for research on clinical application of peripheral nerve blocks (Prof. Dr. Arthur Atchabahian)

-          Department of Anesthesiology, University of Vienna, Austria for research on regional anesthesia & Outcome (Prof. P. Marhofer & Dr. E. Fleischmann)

-          Department of Anesthesiology, University of California, San Diego,VA San Diego Healthcare System, VS (Professor Hemal H. Patel, PhD Professor & Vice-Chair for Research,Director, UCSD Cardiac/Neuro Protection Laboratories

-          Klinik für Anästhesiologie und Operative Intensivmedizin Campus Kiel, Germany, (Prof. Dr. Martin Albrecht)

-          Department of Anesthesiology & Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Germany (Priv.-Doz. Dr. med. Christian Stoppe)

-     Universitätsklinik für Anästhesiologie und Schmerztherapie, Inselspital, 3010 Bern, Switzerland (Priv.-Doz. Dr. med. Jürgen Knapp, DESA EDIC)

-          Department of Critical Care, University of Pittsburgh for research on mean systemic filling pressure (Prof. M. Pinsky)

-          Department of Anesthesiology, Critical Care and Physiology, McGill University, Montreal, Canada (Prof. S. Magder)

-          Department of Anesthesiology and Critical Care, Hôspital Universitaire de Genève, Geneva, Switzerland (Dr K. Bendjelid & Dr B. Bollen)

-          Department of Anesthesiology, Rutgers University, New Jersey, USA (Prof. G. Atlas)

-          Department of Anesthesiology, Critical Care and Pain Medicine, "Sapienza" University of Rome, Rome, Italy, (Dr. F. Bilotta)

  

Funding
The work is funded by the German Research Society (DFG), NWO, Society of Cardiovascular Anesthesia (SCA), European Society of Anesthesiologists (ESA), Dutch Ministry of Defense, Medical Faculty of the University of Heidelberg, Germany, Medical Faculty of the Academic Medical Center (AMC), Amsterdam, The Netherlands and Institutional grants.