The Effect of Crystalloids and Colloids on Visceral Blood Flow
Condition: Fluid Overload; Water Electrolyte Imbalance; Acid Base Imbalance
MeSH terms: Water-Electrolyte Imbalance; Acid-Base Imbalance
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Patients often require fluid replacement during and after an operation. This is usually given
      through veins in the arm using an intravenous cannula and doctors have traditionally used
      fluid containing sodium chloride (saline). However accumulating evidence suggests that large
      infusions of saline are associated with adverse physiological effects including acidification
      of the blood and a rise in potassium and chloride levels. Studies in animals have shown that
      high levels of chloride in the blood and excess saline can cause blood vessels in the kidney
      to constrict leading possibly to a decrease in kidney function. Improvement in acid-base
      balance and kidney function may be observed with balanced solutions containing constituents
      that are more closely matched to the body's own fluid composition. However, little is known
      about the physiological effects of these solutions as they have only recently been developed.

      Magnetic resonance imaging (MRI) is a radiological modality which can now assess blood flow
      and supply of the kidney noninvasively without the need for the injection of radiological
      dyes known as contrast agents. This is now of major importance due to the possible adverse
      effects of MRI contrast agents leading to Nephrogenic Systemic Fibrosis (NSF), a progressive
      disease which has been observed in some kidney patients after receiving 'gadolinium based'
      contrast agents. This has therefore led to increased interest and demand for noncontrast
      based imaging methods. In this study we aim to compare the effects of balanced versus
      unbalanced fluid infusions in healthy human volunteers:

      We will aim to measure:

        1. Blood biochemical composition and acidity

        2. Kidney function and supply as measured by dynamic MRI
    

Detailed description: 
      Type of Study: Two phase double blind, randomised crossover study. In phase A (crystalloid),
      we will compare the effects of Plasmalyte 148 with 0.9% saline and in phase B (colloid) we
      will compare the effects of PVR with Voluven.

      Participants will either be involved in phase A or phase B not both. In each phase
      participants will receive a randomly assigned fluid and then the comparator fluid 1 week
      later.

      Subject selection: 24 healthy, male volunteers, (12 for each phase) between the age of 18 and
      40, and weighing between 65 and 80 kg will be recruited for of the study. Informed consent
      will be obtained before entering volunteers into the study.

      Study Protocol: Volunteers will report for the study at 09.00 hours after a fast from
      midnight and having abstained from alcohol, nicotine, tea and coffee for at least 24 hours.
      After voiding of the bladder, height will recorded to the nearest 0.01 m, weight measured to
      the nearest 0.1 kg using Avery 3306ABV scales (Avery Berkel, Royston, UK), and body mass
      index calculated.

      Any urine passed over a 24 hour period from the start of the infusion will be collected for
      measurement of creatinine clearance, osmolality and electrolytes. Two venous cannulae will be
      inserted, one in each forearm and blood will be sampled for full blood count, haemoglobin,
      electrolytes, creatinine, albumin and osmolality. A venous blood gas sample will also be
      obtained to calculate base excess. Serum and urinary osmolality will be measured on a Fiske
      2400 Osmometer (Vitech Scientific Ltd., Partridge Green, West Sussex, UK) using a freezing
      point depression method which has a coefficient of variance (CV) of 1.2%. A Vitros 950
      analyser (Ortho Clinical Diagnostics, Amersham, UK) will be used to measure serum sodium (CV
      0.6%), potassium (CV 1.0%), magnesium, chloride (CV 1.1%), bicarbonate, (CV 4.0%), urea (CV
      2.0%) and albumin (CV 1.6%). Strong ion difference will be calculated by subtracting the
      serum chloride concentration from the sum of the serum concentrations of sodium and
      potassium.28 Urinary sodium (CV 1.5%) and potassium (CV 1.5%) will be assayed on a Vitros 250
      analyser (Ortho Clinical Diagnostics, Amersham, UK). Haematological parameters will be
      measured on a Sysmex SE 9500 Analyser (Sysmex UK Ltd., Milton Keynes, UK) using direct
      current hydrodynamic focusing and cumulative pulse height detection. The CV for haemoglobin
      and packed cell volume estimation is 11.5%.

      In Phase A, 12 subjects will receive 2 litres of 0.9% saline BP (Baxter Health Care,
      Thetford, UK) or Plasmalyte® (Baxter Health Care, Thetford, UK). The assignment of the
      initial infused solution will be random followed by the alternate solution at crossover. The
      crystalloid solution will be infused in the supine position over 60 minutes.

      In Phase B, 12 subjects will receive 1 litre of PlasmaVolume® (Baxter Health Care, Thetford,
      UK) or Voluven® (Fresenius Kabi, Bad Homburg, Germany). The initial infused solution will be
      randomly assigned and the subject will receive the alternate solution at the crossover
      timepoint. The starch solution will be infused in the supine position over 30 minutes. A
      nurse who will not be involved in the study will mask all labels and administration sets on
      the infusion bags with opaque tape and also perform the randomisation. Randomisation will
      performed using sequentially numbered paired sealed opaque envelopes. The aforementioned
      blood tests will be repeated at 30/60 minute intervals for 4 hours. Subjects will be
      encouraged to void urine as the need arises, and on completion of the study. In addition to
      laboratory data, time to first void and void volume will be recorded. Postinfusion urine will
      be pooled and analysed for osmolality, pH and concentrations of electrolytes and NGAL. The
      crossover experiment will be repeated with the alternate infusion not used in the first
      study, 7-10 days later. Participation in the crossover phase will be postponed one week if
      the baseline laboratory work shows continued effect of hemodilution or phlebotomy with a
      hematocrit decrease of 3% or greater from the first infusion baseline.

      Monitoring of volunteers: Pulse oximetry will be performed continuously during the infusion.
      Blood pressure will be measured every 15 min for the first two hours and then every 30 min
      until the end of the study. Infusions will be stopped if there is any evidence of
      hypersensitivity or anaphylactic reactions or for the following:

      The pulse rate rises above 110/minute or falls below 50/minute. The SaO2 falls below 92% The
      blood pressure rises above 140 mm Hg systolic or 95 mm Hg diastolic The blood pressure falls
      below 90 mm Hg systolic or 55 mm Hg diastolic The volunteer expresses the desire to have the
      infusion stopped.
    

Intervention name(s): Crystalloid; Colloid
Intervention type(s): Drug; Drug
Intervention description(s): 2 litres intravenous infusion in 60 minutes; 1 litre intravenous infusion over 30 minutes
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Fluid Therapy; Water Electrolyte Imbalance; Acid Base Imbalance; Renal Circulation; Magnetic Resonance Imaging