Perioperative organ protection

 

Head of research: Beatrice Beck Schimmer, MD

Current projects:

1. Desflurane and its effect on postoperative morbidity and mortality in patients undergoing thoracic surgery: A multicentre randomized trial
SNSF grant 320030_141216; Swiss Society of Anaesthesiology and Reanimation SGAR; Lung Zurich

Volatile anaesthetics i.e. sevoflurane, desflurane and isoflurane have shown their protective effects in heart-, brain-, liver- and lung tissue in the context of ischemia-reperfusion injury. However, large studies with convincing results regarding improved clinical outcome such as less complications and/or reduced mortality are missing.

In this randomized controlled multicentre trial we enrolled 460 patients undergoing lung surgery with one-lung-ventilation, a setting which is necessary to immobilise the lung in order to assist the surgeon for the operative procedure. At the same time, however, this manoeuvre implies hypoxia-reoxygenation and triggers a subsequent inflammatory reaction similar to ischemia-reperfusion.

The trial was conducted in cooperation with four Swiss hospitals: Kantonsspital St. Gallen, Kantonsspital Münsterlingen, University Hospital Bern and University Hospital Basel. Patients enrolled in the study were randomly assigned either to the intravenous anaesthetic propofol (control group) or the volatile anaesthetic desflurane (intervention group). Major postoperative complications – re-surgery with or without anaesthesia, one or multiple organ dysfunction and mortality – were defined as primary endpoints and were consecutively measured up to 6 months in the postoperative phase.

The results of this study will be very important for the choice of the best anaesthesia regimen in thoracic surgery with one-lung ventilation.

Open to see more Projects about organ protection:

2.1 Does anaesthesia technique affect the presence of circulating tumour cells in primary  
      breast carcinoma?

SNSF grant 316030_150803.

The mechanism of metastasis is a complex process in which the immune system plays a major role. Perioperative stress together with the immunosuppressive effect of anaesthetics might impair tumour cell 'fight' by attenuating naturally occurring mechanisms. As a consequence tumour spread may be favoured.

So far, no stable surrogate marker reflecting the influence of anaesthesia on tumour spread is available. The main hypothesis of this study is based on the fact that detection of circulating tumour cells (CTC) in breast cancer surgery can be used for this purpose.

In this prospective randomized controlled study, the influence of a volatile (sevoflurane) versus an intravenous (propofol) anaesthesia will be examined with a calculated sample size of 230. Primary endpoint is the number of CTC in the immediate postoperative phase (up to day 4). Other possibly important key players in the metastatic cascade such as the number and activity of immune cells are considered as secondary endpoints.

2.2 Which general anaesthetic is the best for patients undergoing pancreatic cancer surgery
     to avoid local and systemic metastasis? A randomized controlled trial.

Similar to the breast cancer study, we hypothesize that the type of general anaesthetics (volatile versus intravenous) may determine the level of circulating tumour cells (CTC) in the postoperative phase in patients with pancreatic adenocarcinoma undergoing pancreatic resection and thereby would influence tumour recurrence.

This trial aims at assessing the effects of the general anaesthetic desflurane on peak CTC levels in the postoperative phase compared to propofol. Patients will be randomised to anaesthesia with either desflurane or propofol. CTC after curative surgery in patients with adenocarcinoma of the pancreas are defined as the primary endpoint. To further compare effects of desflurane and propofol CTC kinetics during follow-up, local and systemic tumour recurrence as well as  overall survival in the study patients will be determined (secondary endpoints).

3. Impact of sevoflurane on the blood brain barrier function.

Zurich Center for Integrative Human Physiology (ZIHP): funded cooperative project 
Responsible reseacher: Martin Schläpfer, MD, MSC

The blood brain barrier consisting of endothelial cells, astrocytes and pericytes, is vital for brain homeostasis. It effectively protects the brain from infections as well as from large toxic molecules. The blood brain barrier may be impaired by various mechanisms such as cerebral haemorrhage due to a ruptured aneurysm, ischemia, trauma or severe infection.

Within this project we investigate the impact of sevoflurane on the blood brain barrier in an in vivo model of subarachnoid haemorrhage. We hypothesise that sevoflurane may have a protective effect on the structure and function of the blood brain barrier. So far, the use of volatile anaesthetics in patients with acute brain injury such as ischemia, bleeding or trauma has been avoided as these agents may increase intracerebral pressure. This could have detrimental effects on the already injured brain tissue. Therefore a special focus will be set on this safety aspect.

4. Protective effects of volatile anaesthetics during long-term sedation.

In certain centres, volatile anaesthetics are routinely used for long-term sedation in patients in intensive care units. It is known from clinical studies that these anaesthetics attenuate inflammatory processes in the lung when used in a short-term approach during surgery. If these positive findings can be translated into the scenario of long-term application, and additionally sedation, is not yet known. We established an in vitro as well as in vivo model of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) to assess the effect of volatile anaesthetics on pulmonary cells/tissue after a 24-hour exposure. In the in vitro experiments we aim at elucidating mechanisms, which are then translated into an in vivo setup of ALI/ARDS. Pulmonary inflammatory mediators as well as cellular changes and clinical relevant parameters such as oxygenation will be determined. Findings of these studies will help design and establish future clinical trials. 

5. Possible organ protective effects of hexafluoroisopropanol (HFIP)

5.1. Possible organ protective effects of hexafluoroisopropanol (HFIP) in a model of
       myocardial infarction

Coronary heart disease is one of the major causes of death in the western civilization. To reduce the ischemic injury due to atherosclerotic plaque formation of the infarcted heart, the treatment of choice is the timely reperfusion of the infarcted, non-perfused area. However, reperfusion of the infarcted myocardial tissue itself leads to a subsequent ischemia-reperfusion injury.  An option to reduce the ischemia-reperfusion-induced inflammatory response would be the use of volatile anaesthetics upon reperfusion. While this is possible during the invasive procedure of coronary artery bypass graft surgery as the patients are under anaesthesia, interventions such as placement of intracoronary stents do not allow application of volatile anaesthetics as there is no need for a general anaesthesia.

Our research group has recently shown the immunomodulatory potential of hexafluoroisopropanol (HFIP) in severe systemic inflammation. HFIP is a water-soluble metabolite of sevoflurane, consisting of trifluorinated carbon groups. In this current study we will evaluate the effect of HFIP application on inflammation and remodelling processes in a model of myocardial ischemia-reperfusion injury.

5.2. Hexafluoroisopropanol (HFIP): bringing a drug from preclinical to clinical testing
        
Unitectra, Technology Transfer, University of Zurich

As previously shown hexafluoroisopropanol (HFIP) attenuates severe inflammatory processes such as sepsis both in vitro and in vivo. This metabolite of the volatile anesthetic sevoflurane is water-soluble, which would allow an intravenous infusion. Moreover when using HFIP an anaesthetic effect is missing. Therefore the application would not be restricted to controlled environments such as operating theaters or intensive care units.

In an acute as well as in a chronic phase of sepsis this water-soluble sevoflurane metabolite decreased systemic inflammation, but also positively impacted on the inflammatory orchestration in various organs such as liver, lung and kidney. Moreover, HFIP improved survival rate in a sepsis model from 20% to 80%. As a further consequence in the development of this drug further in vivo studies will be performed, which should finally allow drafting a first phase I trial.