Anesthesia, General Clinical Trial
Official title:
Metabolic and Physiological Changes During Minor Orthopaedic Surgery in Otherwise Healthy Patients
The air we breathe contains 21% of oxygen. Oxygen is vital for the cells ability to produce
energy and without it we could not survive. Oxygen normally exists as a molecule consisting
of two atoms, O2. It has two unpaired electrons and thus is unstable and willing to accept
electrons to become stable. During the formation of ATP a transportation of electrons happens
over the inner membrane of the mitochondria's. Oxygen can accept these and is thereby reduced
to water. Normally about 4% is not fully reduced and instead produces superoxide. Superoxide
is transformed to hydrogen peroxide by superoxide dismutase (SOD) and then into oxygen and
water by catalase and glutathione peroxidase. It is also possible for hydrogen peroxide to be
converted to hydroxyl radicals by Fenton reactions. All these radicals are called reactive
oxygen species (ROS) and they are highly reactive and capable to induce damage to cellular
components as proteins, DNA and lipids. Under normal conditions SOD, catalase and glutathione
peroxidase work as anti-oxidative compounds to prevent oxidative stress and damage. However,
under hyperoxic conditions these defences can be overwhelmed, resulting in the formation of
excess ROS and thus oxidative damage.
During general anaesthesia the use of supplemental oxygen to avoid life-threatening
hypoxaemia has been common practice for many years and a fixed fraction of inspired oxygen
(FiO2) ranging from 0.3 to 1.0 is often used. This lead to supranormal levels of oxygen in
the lungs and most of the patients also have supranormal levels of partial pressure of
arterial oxygen in their blood.
This study will examine otherwise healthy ambulant patients undergoing minor orthopaedic
surgery during general anaesthesia to elucidate metabolic and physiological changes caused by
ventilation with FiO2 0.50 for at least 45 minutes using standard respiratory settings.
Exhaled breath condensate (EBC) and arterial blood will be collected prior to and after
surgery. The two EBCs and two blood samples will be stored at -80°C for analysis after all
patients have been included. The metabolic changes will be measured with NMR technique and
multivariate statistical analysis comparing baseline values with values obtained after oxygen
exposure.
Collapse of the small airways induced by anaesthesia and FiO2 will be evaluated by measuring
resistance and reactance with airway oscillometry after surgery compared to a baseline
measurement before surgery.
Oxygen supplement during general anaesthesia During general anaesthesia the use of
supplemental oxygen to avoid life-threatening hypoxaemia has been common practice for many
years. This lead to supranormal levels of oxygen in the lungs (hyperoxia) and most patients
also have supranormal levels of partial pressure of arterial oxygen (PaO2) in their blood
(hyperoxaemia). The same iatrogen hyperoxia is also common in mechanically ventilated
patients in the intensive care unit. Is seems to be forgotten that supplemental oxygen is a
medicine and like all medication it should not be administered in excess.
During general anaesthesia a fixed fraction of inspired oxygen ranging from 0.3 to 1.0 is
often used. Patients are monitored with continuously measurement of peripheral oxygen
saturation and if this is low or an arterial gas shows low PaO2 then FiO2 is further
increased. However, a decrease beyond the prefixed FiO2 is seldom done even if oxygen
saturation is 100% or the arterial gas shows a high PaO2.
More and more evidence question the safety of this liberal use of hyperoxia as high oxygen
supplement and the formation of ROS can lead to cell dysfunction and thereby contribute to
pulmonary dysfunction postoperatively.
Adverse effects of oxygen FiO2 exceeding the atmospheric content of 0.21 can have direct
toxic effects on lung tissue especially for FiO2 exceeding 0.60. Studies from the 1970's
showed that when breathing FiO2 1.0 for more than four hours people experienced mild symptoms
like tracheobronchitis and pleuritic. This is a mild irritation behind the sternum, in the
airways or in the lungs. This discomfort is aggravated by deep inspiration and can cause
cough. They also showed that a high FiO2 of 0.95-1.0 given for several days lead to pulmonary
edema and eventually lung fibrosis. High FiO2 also induce collapse of lung areas leading to
pulmonary shunt because of reabsorption atelectasis and induce pulmonary vasodilatation but
otherwise induce vasoconstriction in all others vascular beds (except in uterus) and thereby
reduce cardiac output and end organ perfusion.
The precise mechanism of the direct cellular damage and vasoconstriction is unknown but is
believed to be due to increased production of ROS5.
In the clinical setting with critical ill patients hyperoxia and hyperoxaemia has been
associated with increased mortality specifically in subgroups of patients with stroke,
traumatic brain injury and those resuscitated from cardiac arrest and it is also shown to
increased infarct size and mortality after cerebral and myocardial infarction. Perioperative
treatment with high FiO2 has also been associated with increased mortality and major
respiratory complications.
Metabonomics Lately there has been a lot of attention on the formation of ROS during
hyperoxic conditions. Besides induction oxidative stress ROS also affects a number of
signal-transduction-pathways that leads to cellular changes. These changes can be detected
using metabonomics.
Metabonomics is the analysis of all small molecules or metabolites present in a given sample
using nuclear magnetic resonance (NMR) or mass spectrometry (MS). Metabonomics gives a
"snapshot" of all metabolites in a given sample and thus has great potential to find several
new biomarkers by analysis of the continuous changes in the metabolic profile in response to
a given exposure.
Oscillometry Anaesthesia and high FiO2 lead to collapse of the small airways. A new airway
oscillometry system (TremoFlo C-100) enables a simple and non-invasive measurement of changes
in the small airways. The system measure resistance and reactance non-invasively during
normal breathing.
The trial We will examine otherwise healthy ambulant patients undergoing minor orthopaedic
surgery during general anaesthesia to elucidate metabolic and physiological changes caused by
ventilation with FiO2 0.50 for 45 minutes following standard settings. Exhaled breath
condensate (EBC) and arterial blood will be collected prior to the surgery and repeated
during surgery after 45 minutes of mechanical ventilation with a FiO2 0.50. The two EBCs and
two blood samples will be stored at -80°C for analysis after all patients have been included.
The metabolic changes will be measured with NMR technique and multivariate statistical
analysis comparing baseline values with values obtained after 45 minutes of oxygen exposure.
All specimens will be destroyed after the NMR analyses. Collapse of the small airways induced
by anaesthesia and FiO2 will be evaluated by measuring resistance and reactance after surgery
compared to a baseline measurement before surgery.
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