CArdio PulmOnary Exercise Testing and IntRAvenous Iron- 'CAPOEIRA-I STUDY'
Condition: Anemia; Anemia, Iron Deficiency
MeSH terms: Anemia; Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Observational

Summary: 
      Red blood cells contain a chemical called haemoglobin which carries oxygen from the lungs
      around the body. When the amount of haemoglobin is reduced, a patient is 'anaemic'. Anaemia
      can have many causes, but affects about a third of patients having major surgery in hospital.
      After their operation these anaemic patients are more likely to suffer serious complications.
      This may be because the body needs extra oxygen - and so enough haemoglobin - to heal and
      recover successfully from the trauma of surgery.

      For a similar reason, patients' overall fitness before surgery is very important. Less fit
      patients are much more likely to get complications after surgery. To help us assess the risk
      of complications, the investigators measure patients' fitness before surgery using a cycling
      exercise test. The investigators monitor a number of things that show us how well the heart,
      the lungs and the muscles respond when they are under stress. People who are very anaemic
      tend to perform less well on this cycling test.

      Anaemia is often due to a lack of iron, which helps make haemoglobin. Usually people get iron
      from foods such as red meat and spinach. Some conditions mean that patients lose iron, such
      as a tumour bleeding. Other illnesses make it difficult for the body to absorb iron from the
      gut in the first place. Both lead to a state of low iron in the body and eventually this
      leads to anaemia. One way to treat anaemia quickly before surgery is to give iron into the
      bloodstream (intra-venous). It is thought that this might reduce the risk of complications
      after surgery, but it is not known whether this is because it improves overall fitness, or
      for other reasons.

      The investigators plan to carry out a study called CAPOEIRA-I (CArdio PulmOnary Exercise
      testing and IntRAvenous Iron) to find out whether giving patients intravenous iron improves
      their fitness. The investigators will measure this by doing a cycle exercise test before and
      then at least 10 days after the iron is given. The investigators will also measure how much
      the total amount of haemoglobin chnages with iron treatment. Intravenous iron is already
      routinely used for these patients, so the only additional activity for the study is the extra
      exercise test, some extra blood tests and the measurement of haemoglobin after the iron has
      taken effect.
    

Detailed description: 
      Anaemia is common in the elective surgical population, a prevalence of around 30% being
      consistently reported in large cohorts.

      Cardiopulmonary exercise testing (CPET), which provides an objective assessment of aerobic
      fitness by measuring oxygen consumption (O2) and carbon dioxide production is widely
      considered the gold standard assessment of functional capacity as it dynamically tests the
      pulmonary, cardiovascular and musculoskeletal system and their interplay in a single test.
      CPET parameters are affected by a number of patient factors including effort, ability to turn
      the pedals on an exercise bike, pulmonary function, and crucially oxygen delivery to the
      respiring tissues, which is dependent on blood oxygen content and flow to the tissues via
      cardiac output.

      The oxygen carrying capacity of arterial blood is largely influenced by the haemoglobin
      content (or total haemoglobin mass (tHb-mass)). tHb-mass affects CPET performance to a
      greater degree than haemoglobin concentration ([Hb]). [Hb] is dependent on plasma volume (PV)
      and shows a greater fluctuation day to day than tHb-mass.

      Studies in athletes show the detrimental affect of blood volume loss (i.e. deliberate
      venesection) and haemoglobin content loss on CPET performance. The corollary of this is
      illegal blood manipulation, which improves CPET performance. The same is seen post altitude
      training camps with increased tHb-mass leading to improved maximal exercise performance.

      Aerobic capacity is defined as the maximum amount of oxygen that can be consumed by the body
      per unit time and is the gold standard measure of physical fitness. VO2max is classically
      defined as 'a plateau in oxygen uptake attained during maximal exercise despite further
      increases in exercise workload, thereby defining the limits of the cardiorespiratory system'.
      However, many individuals do not reach a plateau in oxygen uptake despite maximum exertion,
      and the term VO2peak is used instead. This is the highest measured oxygen consumption during
      exercise and is typically averaged over a 30 second period. O2 at anaerobic threshold (VO2AT)
      is defined as: 'the highest sustained intensity of exercise for which the measurement of
      oxygen uptake can account for the entire energy requirement.' An alternative definition is
      'the exercise intensity at which lactate starts to accumulate in the blood stream above
      rest'. These oxygen uptake variables are in part dependent on the oxygen carrying capacity of
      the blood, which is in turn dependent on blood haemoglobin levels.

      Major surgery places an increased metabolic demand on the body. Perhaps for this reason, both
      lower preoperative VO2peak and VO2AT values are associated with increased morbidity and
      mortality after major surgery. Much of the literature in this area is derived from studies
      reporting CPET variables. Given that the oxygen uptake variables VO2peak and VO2AT are
      positively correlated with tHb-mass, it may be that some of the physical fitness-outcome
      relationship is mediated through haemoglobin-related effects rather than cardiorespiratory
      function, providing a mechanistic basis to poor CPET performance in many patients with
      anaemia.

      Few studies have examined the impact of blood manipulation - either transfusion or iron
      therapy - on CPET variables in patients. A study by Wright et al examined 20 patients with
      chronic anaemia due to 'stable haematological conditions' requiring blood transfusions. A
      CPET was performed before the blood transfusion and repeated 2-6 days after the transfusion
      of 1-4 units of blood (median 3). A mean rise in [Hb] from 8.3-11.2 g dl-1 was associated
      with a mean (SD) rise in O2AT from 10.4 (2.4) to 11.6 (2.5) mlkg-1min -1, (p= 0.018). (10).
      When corrected for the change in Hb concentration, the anaerobic threshold increased by a
      mean (SD) of 0.39 (0.74) ml kg-1 min-1 per g dl-1 Hb.

      The results were consistent with a study in patients with beta thalassaemia major that
      compared exercise performance before, and 2 hours after haemotransfusion. Exercise duration
      increased from 7.3 (+/- 2.8) to 10.3 (+/- 2.3) minutes (p<0.05), and O2 peak increased from
      28.5 (+/- 5.0) to 36.2 (+/- 7.1) ml kg-1min-1; (p<0.05).

      Measuring haemoglobin concentration vs. total haemoglobin mass

      Traditionally, the concentration of circulating haemoglobin [Hb] has been used as a clinical
      measure of the blood's oxygen carrying capacity. However, a low [Hb] may be due to a reduced
      amount of haemoglobin (absolute mass of circulating haemoglobin; tHb-mass) or an increased
      volume of dilution (plasma volume). Thus, [Hb] may be stable and tHb-mass low in the context
      of acute bleeding, [Hb] normal or elevated but tHb-mass low in the context of dehydration, or
      [Hb] low but tHb-mass normal or high in the context of excess plasma volume (fluid).
      Therefore, the use of [Hb] to define blood oxygen carrying capacity may be misleading under
      some circumstances.

      tHb-mass represents the absolute mass of circulating haemoglobin in the body, the measured
      [Hb] being dependent upon tHb-mass and blood volume (BV) (sum of plasma volume (PV) and total
      red cell volume]). The proportion of oxygen carried in solution in plasma is trivial (0.3 ml
      per 100 ml of plasma) under normal physiological conditions, whereas each gram of Hb binds up
      to 1.39 mL of oxygen. Thus, tHb-mass is the principal determinant of total blood O2-carrying
      capacity and may provide additional information regarding the clinical status of patients
      than that provided by [Hb] alone.

      Alternatively, a recently developed blood test capable of estimating absolute vascular
      volumes may be applied as a direct test to correct for any plasma volume fluctuations
      influencing a [Hb] value. As the model requires only a simple blood sample it may be a
      suitable alternative to estimate vascular volumes (and tHb-mass) if the patient is unable to
      perform the oCOR technique.

      Classification of anaemia

      The terminology around the classification of anaemia can be complex. There is no single
      laboratory parameter comprehensively reflecting the overall iron status of an individual. The
      POAS pathway used at UHS simplifies this (Appendix 1). In the perioperative period there are
      a number of possible causes of iron-related anaemia:

        -  Iron deficiency: Ferritin <30 g,l-1

        -  Iron deficiency and functional iron deficiency (FID) (ferritin 30-100g.l-1 with TSAT
           <20% and a CRP >5.

        -  Iron restriction/deplete Ferritin 30-100 with TSAT >20% or CRP raised/normal.

        -  If Ferritin is >100g,l-1 cause of anaemia could be non iron deficient anaemia or FID

        -  Functional iron deficiency: insufficient iron incorporation into erythroid precursors
           despite apparently adequate body iron stores. Recognised by the presence of stainable
           iron in the bone marrow, with a normal serum ferritin value,

        -  Anaemia of chronic inflammation: functional iron deficiency caused by chronic
           inflammation.

        -  A blood film is useful to detect iron deficiency alongside FID to determine which
           patients may benefit from iron therapy.

      The investigators have defined how anaemia is classified and who would be eligible for
      intravenous iron therapy based on international consensus and local hospital guidelines.
      Patients who do not fall into the clear groups of iron deficiency, iron repletion or
      functional iron deficiency as per the POAS guidance are not suitable for intravenous iron and
      will not be eligible for this study.

      Research statement

      Preoperative anaemia is common, and is associated with poorer outcomes after major surgery.
      Impaired physical performance, as assessed by CPET, is likewise associated with impaired
      outcomes, and may be partly due to pre-operative anaemia.

      The investigators wish to test the feasibility of performing a CPET test then administering
      intravenous iron and repeating a CPET prior to surgery in patients being considered for
      elective surgery. The investigators want to find out if treating anaemic patients who are
      suitable for intravenous iron therapy affects their CPET variables. This will help to inform
      further work to see if intravenous iron therapy combined with CPET adjusted risk
      stratification improves morbidity and/or mortality for anaemic patients undergoing major
      elective surgery.
    

Intervention name(s): MonoFer
Intervention type(s): Drug
Intervention description(s): Anaemic patients undergoing major surgery who would routinely be receiving intravenous iron 'MonoFer' will get this as part of routine care. They will then have a CPET repeated at least 10 days afterwards.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        This cohort is composed of patients attending University Hospital Southampton NHS
        Foundation trust for major surgery who are found to be anaemic as part of routine clinical
        screening and are deemed suitable for intravenous iron therapy by the clinical team.
      
Biospecimen description: 
      Plasma stored in freezers at University Hospital Southampton
    
Keywords: Cardiopulmonary exercise testing; Intravenous iron; Total haemoglobin mass