Critically ill patients often require admission to the intensive care unit (ICU). When patients develop organ failures and end up on a ventilator, there are changes in the body's cell function that can increase the risk of poor outcomes. All cells, in order to function normally, have mitochondria, which help them generate energy and transfer vital messages between cells. However, during critical illness, the mitochondria in the cells can function less effectively and die prematurely, or their new synthesis and regeneration can be severely affected. This can result in continuous multi-organ failure with a lack of recovery and muscle wasting, causing severe weakness and an inability to function normally.
In this study, the investigators aim to assess mitochondrial capacity using three methods with varying levels of invasiveness. The investigators are planning to recruit 20 patients in the ICU who are on a ventilator for breathing support. The investigators plan to measure mitochondrial capacity from a breath test, blood cells, and muscle cells.
The investigators will collect breath samples after consuming an amino acid, which is a component of protein in our body and is commonly found in food. This amino acid is only broken down by the mitochondria. This safe test allows us to measure how much mitochondrial capacity remains in the body after the modified amino acid is broken down by the mitochondria. In comparison, the investigators will use standard methods which includes blood tests and muscle biopsy to examine the mitochondrial function of platelets (blood cells) and muscle cells. The investigators will also use non-invasive techniques (ultrasound and 'MyotonPRO') to assess muscle.
This study will help us determine the best way to assess mitochondrial function and capacity in critically ill patients and to understand strengths and weaknesses of different approaches.
When patients' mitochondrial function or capacity is impaired, the investigators can provide them with particular nutrition to improve mitochondrial activity. Because evaluating this at the bedside is challenging, it is impossible to tell which patients may benefit from specific therapies that improve mitochondrial function. If this breath test provides an assessment similar to the standard, sophisticated mitochondrial testing, the investigators could use it at the bedside in the future, which may improve patient outcomes and help design large clinical trials.
Adults ≥ 18 years
Mechanically ventilated at time of recruitment
Defined as critically ill by the responsible clinician
Recruited within 48-hours of intubation
Patients < 18 years
Patient is being treated on an end-of-life pathway or active treatment is likely to be withdrawn within 24-hours
Patient has significant liver dysfunction (Child-Pugh ≥ class 3)
Patient is not absorbing enterally (defined as 2 x NG aspirates of > 500ml)
Critically ill adult (\>18 years) patients who have been mechanically ventilated will be recruited from the Intensive Care Unit at University Hospital Southampton.
Cohort
Prospective
Not listed
Feasibility of assessing mitochondrial capacity by three different methods
Feasibility of assessing mitochondrial capacity in critically ill patients from different biological samples \[skeletal muscle, platelets and breath\] by three different methods, assessing the proportion of successful participants recruited, samples taken, and samples processed. The physiologic parameter used to assess each of these methods is detailed further below.
To evaluate mitochondrial capacity using 13C-ketoisocaproate breath test.
To evaluate the mitochondrial capacity in critically ill patients using the 13C-ketoisocaproate breath test. Data collection is in the form of breath samples taken from the ventilator circuit. Exhaled ratio of 13CO2 following the oral administration of 13C-KICA should reflect mitochondrial metabolism and is used to assess the outcome measure.
To evaluate mitochondrial capacity using mitochondrial respiration in skeletal muscle
To evaluate global mitochondrial capacity in critically ill patients using mitochondrial respiration in skeletal muscle. Muscle samples will be assessed using high resolution respirometry to assess their mitochondrial capacity and function.
To evaluate mitochondrial capacity using the mitochondrial respiration of platelets
To evaluate mitochondrial capacity by measuring the mitochondrial respiration of platelets in critically ill patients. Mitochondrial capacity and function of platelets will be assessed using high resolution respirometry, to allow assessment of this outcome measure.
Longitudinal assessment of mitochondrial capacity in critical illness
Longitudinal assessment of mitochondrial capacity in critical ill patients during their admission to critical care. The physiological parameters described in the other objectives of this study will be assessed over 120 hours to assess how mitochondrial function may change over this period.
Exploratory outcome 1: To assess targeted and untargeted metabolomics in critically ill patients using analysis of the metabolites in biological samples collected.
To assess targeted and untargeted metabolomics in critically ill patients. This outcome measure will be assessed using analysis of the samples collected (blood and muscle).
Exploratory outcome 2: To assess mitochondrial specific metabolic markers in critically ill patients
The outcome will be assessed using redox analysis of the samples collected.
Exploratory outcome 3: To assess oxidative stress in critically ill patients
The outcome will be assessed using redox analysis of the samples collected.
Exploratory outcome 4: To assess redox variations in critically ill patients
The outcome will be assessed using redox analysis of the samples collected.
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