The assessment of long-term in vivo muscle protein synthesis rates in ICU patients using deuterated water methodology

Muscle wasting occurs rapidly in critically ill patients and impacts both short
and long term outcomes. Altered protein metabolism drives muscle loss in ICU
patients, with muscle protein breakdown exceeding muscle protein synthesis.
Interventions aimed at attenuating muscle loss by stimulating muscle protein
synthesis rates are hampered by a lack of knowledge on altered muscle protein
turnover rates during critical illness. Only a few studies have specifically
assessed muscle protein synthesis by using contemporary intravenous stable
isotope infusions, which allows the assessment of muscle protein synthesis over
a short (<9 hours) period of time. Results from such acute studies can be
difficult to extend or translate into long-term clinical practice and outcomes.
Oral deuterated water (2H2O) dosing provides an alternative method that can be
utilized to extend the measurement of muscle protein synthesis over a period of
several days or weeks. It could therefore provide a valuable tool to study
muscle protein synthesis during ICU admission and the impact of different
anabolic interventions. Although multiple studies using the deuterated water
methodology have been performed in both healthy volunteers and patients, it has
not yet been performed in critically ill patients.

The present study aims to assess the feasibility of deuterated water dosing in
critically ill patients to assess long-term in vivo skeletal muscle protein
synthesis rates.

The study design consists of an observational study (with invasive
measurements) to determine changes in muscle protein synthesis in critically
ill patients during 5 consecutive days of ICU admission.

A 5 day deuterated water dosing protocol will be conducted during ICU admission
to measure diurnal rates of muscle protein synthesis. Patients will receive
400ml of 70 mol% enriched deuterated water on day 1, followed by a daily
maintenance dose of 50 ml for four consecutive days. Blood samples (60 ml
total) will be collected during the study to measure plasma free 2H-alanine
enrichments. On day 2 and 5, a skeletal muscle biopsy will be taken from the m.
vastus lateralis to measure muscle protein-bound 2H-alanine enrichment levels.
This protocol has been previously approved in young and older volunteers in MEC
15-3-008, 15-3-003, 15-3-035, 15-30-55, and 15-30-38.

The burden and risks associated with participation are minimal. Blood sampling
is minimal (60 ml divided over 5 days) and will be conducted through indwelling
arterial catheters already in place for routine clinical care, thus avoiding
the need for puncture and associated hematoma risks. Muscle biopsies will be
taken under local anaesthesia by an experienced physician, but carries a small
risk of a small local hematoma and may cause some minor discomfort up to 24 h
after completion. The discomfort is comparable to muscle soreness or the pain
one has after bumping into a table. The majority of subjects are expected to be
sedated during muscle biopsy, further limiting any discomfort experienced.
Repeated leg ultrasounds will be performed (4 times), which do not pose any
harm to the individual subjects. For the duration of the study protocol, 50 ml
of 70% deuterated water will be administered daily via a nasogastric feeding
tube placed for routine care to enrich the body water pool to approximately
~0.7 APE (Atom Percent Excess). Deuterated water dosing to achieve a body water
enrichment of ~0.7 APE is completely safe as it is far below the threshold for
biological toxicity in humans (approximately 20 APE) and will be returned to
baseline enrichments within 30 days. There is no direct benefit for the
participants except for their contribution to the scientific knowledge of
skeletal muscle wasting, in particular muscle protein synthesis rates during
critical illness, which will be obtained from this study and used in the
future.