WO2015150827A1

WO2015150827A1 - Systems and methods for medical data processing and analysis

Info

Publication number: WO2015150827A1
Application number: PCT/GB2015/051044
Authority: WO
Inventors: Andrew Mark Shaw
Original assignee: Attomarker Limited
Priority date: 2014-04-04
Filing date: 2015-04-02
Publication date: 2015-10-08
Also published as: GB201406126D0

Abstract

We describe a method of estimating an effective volume of body fluid, the effective volume comprising a circulating blood volume (CBV) or circulating plasma volume (CPV), the method comprising: inputting first data defining a first measured concentration (Co), of a blood or plasma component in a patient; inputting second data defining a second measured concentration (C²) of a blood or plasma component in the patient, wherein said second measured concentration is a concentration measured after administration of a known fluid volume (V_f); determining estimate data representing an estimate of an effective volume (V_e) of said CBV or CPV from said first and second measured data and said known fluid volume(V_f); and storing and/or outputting said estimate data.

Description

Systems and Methods for Medical Data Processing and Analysis

FIELD OF THE INVENTION This invention relates to systems, methods and computer program code for processing human (or animal) medical data to estimate circulating blood and/or plasma volume. In embodiments we will describe methods for determining effective fluid compartment partition volumes. BACKGROUND TO THE INVENTION

Fluid resuscitation and goal-directed fluid management in the peri-operative period and acute care scenarios are currently informed by haemodynamic monitoring techniques, based upon the interpretation of pressure waves deduced from arterial monitoring. These have been shown to produce improved outcome but the 'wet' and 'dry' debate and the composition of the fluid, crystalloids vs colloids remain contentious. Administration of peri-operative fluids results in the dilution of all components of the blood serum. However, the onset of the surgical stress responseand the acute phase response to inflammation changes the permeability of the vasculature allowing plasma components to explore volumes of distribution other than the circulating blood volume (CBV) of the red blood cells: the interstitial and intracellular compartments. This fluid shifting and compartmentalisation leads to the now discredited concept of "third space" and whether the fluid shift is attributable to surgical stress response or the perioperative fluid regimen.

Fluid shifts between different compartments are, in part, responsible for interstitial and cellular oedema leading to typical post-operative weight gains of 3-6 kg, which has been linked with poor prognosis. The effects of oedema on the patient recovery and the physiological effects of excessive fluid administration have been considered in detail and include; the increased demands on cardiac output, increased fluid accumulation in the lungs, decreased oxygen tension around healing wounds, increased renal demand, anastomatic instability and inhibition of gastrointestinal mobility with resulting ileus. Despite well-established complications, there appears to be no proven optimal peri- or post-operative fluid regimen, in part associated with the difficulties in measuring the CBV and CPV. CBV measurements are comparatively difficult usually involving the use of a radioactive tracer such as ¹²⁵l, ³⁵S0₄ ^2" and ⁸²Br^~, and monitoring the dilution of the tracer. There are other non-radiation-based techniques based on platelet density, carbon monoxide labelling of haemoglobin, continuous haematocrit monitoring and double-dye labelling to establish compartmentalisation or fluid shifting peri-operatively. However none of these measurements are performed routinely in clinical practice. Further, the CPV and CBV peri-operatively will evolve over time with the anaesthetic, the surgical stress response, the type and extent of the surgery and the acute phase response (APR). The renal clearance rate of infused fluid during surgery is reduced by 10-20% of that compared with conscious volunteers and these factors contribute to the observed oedema. A routine measure of CBV and CPV that could be performed quickly and routinely would realise the potential for goal-directed fluid management regimens.

SUMMARY OF THE INVENTION

Broadly speaking we will describe a method by which the effective volume in different body compartments may be determined. We will also describe a method by which the fluid equilibrium partitioning may be determined.

We will further describe a method by which the rate of partitioning and time to equilibrium may be determined.

In embodiments the method employs a quantitative assay for each blood component:

which in one embodiment can be the standard laboratory tests which in another embodiment can be a point-of-care test. In embodiments the method can be used to optimise the fluid regimen for patient management differentiating between the efficacy of, for example but not exclusively, crystalloid, saline or colloid.

In embodiments the method allows the changes in the volume to be determined in response to constriction or dilation drugs.

In embodiments the method allows changes in surgical stress response to be profiled. The effective volume method allows the dose of any drug or equivalent to be assessed and optimised for maximum efficacy. In embodiments the method allows for dosing regimens such as bolas dosing to be optimised for maximum efficacy.

In embodiments the method allows for personalised dosing and monitoring to be performed, for example:

Highly toxic drugs such as chemotherapy

Optimising antibiotic dose

In embodiments the method allows mass loss to be determined from fluid compartments for different blood components indicating activation or performance of body physiology systems. For example:

Blood components have different functions such as white blood cells which are indicative of infection or inflammation;

The mass loss for platelets for example reports on clotting processes; Immunoglobin mass loss reports to antibody complex formation;

Complement protein mass changes points to Complement activation and consumption indicating triggers of the cascade.

In embodiments differential effective volume measurements pre-operatively can be used to stratify or personalise patient care.

In embodiments the differential effective volume measurements can be used to identify patient co-morbidities both alone and when combined with clearance measurements, for example one or more of

Vasculature diseases

Lymphatic efficiencies

Oedema monitoring care

Kidney function and dialysis management

Liver function efficacy The differential effective volume correlations allows drug partition and drug clearance volumes to be compared and optimised, leading to drug localisation estimates. Thus in embodiments we describe a method to derive an effective volume for blood component concentrations to estimate CBV and CPV. The method is derived from a pilot study on patients undergoing elective abdominal surgery measuring blood component concentrations over a time course from admission, pre-operatively and 2-4 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs 48 hrs and daily to discharge. From these time course measurements we derive an effective volume for each of the components to estimate CBV and CPV. The effective volume for the components of the blood participating in the APR and surgical response is interpreted in the context of recruitment to inflammation processes and the fluid compartment volumes.

According to a further aspect of the invention there is therefore provided a method of estimating an effective volume of body fluid, the effective volume comprising a circulating blood volume (CBV) or circulating plasma volume (CPV), the method comprising: inputting first data defining a first measured concentration (C°), of a blood or plasma component in a patient; inputting second data defining a second measured concentration (C²) of a blood or plasma component in the patient, wherein said second measured concentration is a concentration measured after administration of a known fluid volume (V_f); determining estimate data representing an estimate of an effective volume (V_e) of said CBV or CPV from said first and second measured data and said known fluid volume(V_f); and storing and/or outputting said estimate data.

The measured concentration may be concentration of one or more of a biomarker, a concentration of a blood component, and a concentration of a drug. For example one or both of a concentration of haemoglobin and red blood cells (RBCs) may be employed to estimate circulating blood volume. Additionally or alternatively one or more acute phase response (APR) proteins, in particular C3, C4 and CRP, may be employed to estimate circulating plasma volume (CPV); further additionally or alternatively a platelet concentration may be employed to estimate CPV. Where an APR protein is used to estimate the volume optionally the method may include compensating for a rate of APR regulation in the body, for example compensating for an estimated response during surgery. Additionally or alternatively a protein such as immunoglobulin (not a reported acute phase protein) may be employed to estimate CPV. Optionally one or more estimates derive from different concentration measures may be combined to produce a combined estimate of CBV or CPV.

Still further optionally, compensation may be applied, in particular to the second measured concentration, for a renal clearance rate of the patient, optionally selecting a rate dependent on whether or not the patient is undergoing surgery. When compensating for a clearance or other rate the second measured concentration may be a concentration determined at a known or measured time interval after the first concentration measurement. The known fluid volume administered to the patient may be administered intravenously and may, for example, be either a colloid or crystalloid infusion. In some preferred approaches the volume of fluid administered is less than 2 litres, one litre, or preferably less than 0.5 litres. The time interval between the first and second measurements is preferably less than five hours, four hours, three hours, two hours or one hour.

In embodiments the effective volume is estimated dependent upon a ratio of the first and second measured concentrations, taking into account the fluid volume administered. More particularly in embodiments a formula of the form described later may be employed, although it is not necessary to use this precise formula. For example, depending upon whether a compensation for a rate of change of a measured substance and/or renal clearance rate is applied the precise form of the formula to determine effective volume may differ from that given later.

The invention further provides processor control code (computer program code) to implement the above-described systems and methods, for example on a general purpose computer system or on a digital signal processor (DSP). The code is provided on a carrier such as a disk, CD- or DVD-ROM, programmed memory such as nonvolatile memory (e.g. Flash) or read-only memory (Firmware). Code (and/or data) to implement embodiments of the invention may comprise source, object or executable code in a conventional programming language (interpreted or compiled) such as C, or assembly code. As the skilled person will appreciate such code and/or data may be distributed between a plurality of coupled components in communication with one another. In a related aspect the invention provides a medical data estimation system, the system comprising: working memory; program memory; a processor coupled to said working memory and to said program memory; an input to receive first data defining a first measured concentration (C°), of a blood or plasma component in a patient, and second data defining a second measured concentration (C²) of a blood or plasma component in the patient, wherein said second measured concentration is a concentration measured after administration of a known fluid volume (V_f); and wherein said program memory stores processor control code to: determine estimate data representing an estimate of an effective volume (V_e) of said CBV or CPV from said first and second measured data and said known fluid volume(V_f); and store and/or output said estimate data.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects of the invention will now be further described, by way of example only, with reference to the accompanying figures in which:

Figure 1 shows a Consort Plot for the pilot trial;

Figure 2 shows dilution profiles: (a) platelets, Hb and IgG; and (b) IgG, C3 and C4;

Figure 3 shows effective volume estimates for Hb, Red Blood Cells, White Blood Cells, Neutrophils, Lymphocytes, Platelets, IgG, C3, C4 and CRP; and

Figure 4 shows a table of effective volume measurements for each plasma component and fluid compartment volume estimates.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

We present data from a pilot study on patients undergoing elective abdominal surgery measuring blood component concentrations over a time course from admission, preoperative^ and 2-4 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs 48 hrs and daily to discharge. From these time course measurements we derive an effective volume for each of the components to estimate CBV and CPV. The effective volume for the components of the blood participating in the APR and surgical response is interpreted in the context of recruitment to inflammation processes and the fluid compartment volumes.

Analytical Methods

The pilot study recruited a cohort of 45 patients undergoing major elective abdominal/pelvic surgery at The Royal Devon & Exeter Hospital. Routine blood samples were taken from the patients for a blood analysis of Hb, red blood cells, white blood cells, lymphocytes, neutrophils, and platelets. Additional trial samples were collected over the time course of their hospital stay for the measurement of the biomarkers C3, C4, CRP and IgG performed with the standard assays available in the Clinical Chemistry laboratory. The schedule of tests is summarised in the Consort Plot, Figure 1 . Samples were collected as EDTA-stabilised plasma then divided into 5 aliquots automatically and frozen at -80°C. Patient exclusion criteria were deliberately low to recruit a full spectrum of procedures, however, the following exclusions were imposed: unable/unwilling to provide informed consent, pregnant women, patients less than 18 years of age, diabetes, inflammatory bowel disorders, immune-suppressed, immune-suppression or steroid treatment within the last 12 months. The patient data, assay results and clinical observations were anonym ised by the clinicians and recorded with encryption and password protection. The proposal received ethical LREC approval from the South West Committee A, UK, REC being assigned the reference number 10/H0107/66a.

Complement Component and Biomarker Assays

Blood assays and the assays for C3, C4, CRP and IgG were performed locally in the Clinical Chemistry Laboratory and Immunology laboratories. All assays were performed by Cobas® Immonoturbidimetric assays on Roche/Hitachi analysis platforms with the following accuracy and detection limits shown in brackets (percentage accuracy, detection limit): C3 (4.0%, 0.04 g/L), C4 (7.1 %, 0.015 g/L), CRP (4.1 %,0.3 mg/L) and IgG (3.7%, 0.3 g/L).

Statistical Analysis

All data are presented as a Boxplot. On each box, the central mark is the median, the upper and lower edges of the box are the 25th and 75th percentiles, the whiskers extend to the most extreme data points not considered outliers, and outliers are plotted individually. The Kolmogorov-Smirnov test for normality was used for the parameter distributions and the Mann-Witney U-Test (Wilcoxen Rank Test) was used to assess significance in median differences. The statistical analysis was performed using MatLab(29).

Mathematical Analysis

The dilution of each blood component by a known volume of fluid challenge was interpreted as a component mass distributed in an effective volume calibrated by the known fluid volume. Given a measured concentration of plasma components on admission, C_B°_i0 , the mass or cell number, M °. , and the effective component volume V_eff are related by the Equation 1 : M

V,

Equation 1

The volume may be calibrated by the injection of a known volume of pre-operative fluids, V_fiui_tj, typically 1 L. The concentration of each plasma component at 2 hours into the procedure C_B ² _i0 , is also given by Equation 1 ,and on the assumption that the masses of each component remain constant, M _i0 = M _i0, the effective volume, V_eff, for each component may be derived, Equation 2:

V

. V.

c²

Equation 2 The interpretation of the effective volume parameter, its accuracy and the validity of the assumptions in its derivation are discussed below.

Note that this does not rely on an assumption of no blood loss. If there were blood loss the effective volume would decrease. Thus repeat measurements of Hb showing a fall in Hb concentration would be indicative of decreasing effective volume and potentially blood loss or internal bleeding.

Results

The design is summarised in the Consort plot, Figure 1 . The time course profiles for some of the serum components are shown in Figure 2, normalised to their admission levels. Each component shows a change in concentration associated with the induction fluids: Hb, platelets and IgG show a permanent dilution in the serum, Figure 2(a). Similar measurements were made for C3 and C4, the synthesis of which is triggered in the liver by the APR, returning to the admission levels, Figure 2(b). The effective volumes for each of the blood component derived from the early-time dilution are derived according to Equation 2 and are summarised as a boxplot in Figure 3 and Figure 4 shows a table of effective volume measurements for each plasma component and fluid compartment volume estimates. The effective volumes are not normally distributed in the cohort failing the Kolmogorov-Smirnov test. The effective volumes derived from the red blood cell volume and Hb volumes estimates are highly correlated (R² = 0.953); both estimates are of the same volume derived from different assays. The median CBV estimate may be associated with the V(Hb) and V(RBC) and for a 1 L bolus dilution is determined as 4.8 L a volume that includes the volume of the cell and the serum. The median CPV may be determined from the effective volume derived from IgG as 2.7 L as concentration of this species does not change over the time course. The effective volume estimates for the other blood components, cellular or protein, are all measures of the APR activity and vary significantly from the CBV ( P values shown in Figure 4). Discussion

The study assesses the validity of using bolus dilution of the blood to determine the effective circulating volume of different components of blood using the assumptions inherent in Equation 1 and 2. The concentration of any blood component is determined by the mass of each component distributed within an effective (circulating) volume. The component concentration is estimated from a number of different assay technologies routinely available in the clinical chemistry laboratory and quality assured. Injection of a known volume of fluid dilutes all components with a characteristic effective volume and equilibration occurs within one hour. The Hb and red blood cell assays and effective volumes are identified as the CBV including the volume within the cells themselves to produce estimates of 4.8 L. The underlying assumption is that the original number of blood cells is conserved: there is no blood loss to the CBV. Blood loss within the procedure is typically less than 500 imL introducing an error of -10% in the CBV (may be much higher and packed cells are replacing whole blood). Changes in the CBV during recovery may indicate internal bleeding.

The limitations in the accuracy of the effective volume estimates may be considered in the context of the surgical and the APR. The volume of fluid delivered from pre-packed bags is well determined with a filling error of 1% and similar delivery error (the bag may not be completely empty). The second measurement error is that of the assay which are typically 5% and are known for each assay, checked weekly. There are also errors associated with dynamic changes to the effective volumes in the body and losses of fluid. The renal clearance rate of patients undergoing major abdominal surgery is estimated to be 5 - 30 imL/min, eliminating only 5-15% of the fluid regimen during the period of the surgery lasting 2 hrs. The clearance rate of healthy individuals would suggest 40 - 50% of the pre-operative load would be cleared in a 2 hr period, corresponding to a typical clearance rate of 60-1 10 ml/min. There are additional insensible or transpiration losses, which are estimated from the open abdomen to be 1 ml_/hr/kg,(28) which for a procedure lasting 2 hrs, and for 100 kg patient amounts to 200 imL The administration of 1 L of crystalloid increases the CBV by 1 L depending on the elasticity and permeability of the vasculature and is coupled with a rise in pressure. It is this rise that is indirectly measured by surrogate markers, i.e. blood pressure and the blood flow-wave formation. The effective volume determination therefore depends on the volume of the bolus administered and is expected to vary non-linearly, probably reaching an elastic limit. A 1 L bolus will increase the plasma volume by approximately 30%.

Given the contributions to the accuracy of the effective volume measurements detailed above a recommend protocol may be derived. The effective volume of any blood components can be determined by the administration of 250 imL bolus of fluid followed by the measurement of the component concentration 1 hr post administration. The volume increase to the plasma (determined by the effective volume for IgG) will be less than 9% and comparable to the accuracy of the assays and the clearance rate of the anaesthetised patient. The estimated total accuracy of the estimate is 15%. Different components report different effective volumes. The CBV(Hb) = 4.7 L is significantly larger than the CPV(lgG) = 2.8L. The Hb and RBC and other cellular assays includes the volumes of the cell in the effective cell volume, whereas the proteins effective volumes estimate the CPV. These figures may be compared with the conventional estimates of blood volume for men 77.6 imL/kg and women of 65.2 imL/kg (mean values) giving typical blood volumes of 5.5 L and 4.4 L. (The data are not separated by sex in this trial). Similarly, clearance volumes for some drugs range from aspirin, 9.9 L (male) to ethanol, 46 L (male) and beyond.

An APR protein may be defined as one that changes its concentration either up or down by 25%(9), usually regulated by the liver. Hence, the effective volume of a plasma component will depend on the rate of regulation (up or down) changing the mass term in Equation 1 ; an increasing mass production gives a larger effective volume with the converse being true. IgG is not a reported acute phase protein(9) and is thus a reasonable measure of the CPV. CRP, C3 and C4 are however synthesised as part of the acute phase response and show volumes smaller than CPV(lgG). Similarly, the cellular components of the blood are all recruited to the inflammatory site and show a small volume than the CBV(Hb). The platelets in particular have a very small volume associated with their recruitment from the blood in coagulation and their larger rate of production from Megakaryocyte. The effective volume estimates may be compared with other volume measures and re- derived from data presented in other studies. The circulating volume derived in a trial using ¹²⁵l-labelled albumin was determined to be 3.35 L for hypovolaemic patients and 4.08 L for non-hypovolaemic, which may be compared with the CPV volume derived in this study. Similarly in a study to compare the accuracy of CO-Hb and ⁵³Cr methods (33) CPVs were measured in the range of 2.5L - 6L consistent with the range derived from our V(lgG) estimates of CPV. In a study looking at the effects of fluid regimen on outcome from abdominal aortic aneurysm trial (34) the measured Hb effective volume re-derived from their data produces a CBV of 7.25 L following a median pre-operative fluid load of 2 L and a CBV of 8.75 L for patients receiving a media 3.5 L pre-operative fluid load in acute normovolumaic heamodilution (ANH). Both figures are consistent with our effective volumes and demonstrate the bolus-volume dependence of the effective volume determination. Similarly, bioimpediance measurements, haematocrit and albumin concentrations determinations reported following major abdominal surgery indicate V(Ab) = 14.5 L and V(Hb) = 12.1 L for a 2.5 L mean fluid intake on the day of operation.

The differential compartment filling effect of colloids and crystalloid infusion has been studied and the concentration of albumin was reported following infusion of 500 imL of hydroxyethyl starch (130/0.4) over 15 minutes; a V(Ab) estimate may be derived from their data of 4.2 L (similarly for their total protein assay). The starch infusion suggests an effective volume between the CBV and CPV derived here consistent with the mixed composition of the blood. These data suggest that starches persist in the intravascular volume.

Thus the simple effective volume measurement derived in this study is consistent with CPV and CBV derived in other studies under varying conditions of patient surgical stress and acute phase response. The effective volume derived on admission and then from subsequent normal blood analysis, allowing sufficient time for equilibration, may provide a direct measure of hyper- and hypo-volaemia and additional information in acute normovolaemic haemodilution fluid regimens producing better informed goal- directed fluid regimens. Further, all components of the plasma are diluted with fluid administration including biomarker concentrations, blood components and drug concentrations. Knowing the CPV and CBV of a patient on admission may better target the dose of drugs and the fluid regimen for the resuscitation of un-well patients in complex disease states. No doubt many other effective alternatives will occur to the skilled person. It will be understood that the invention is not limited to the described embodiments and encompasses modifications apparent to those skilled in the art lying within the spirit and scope of the claims appended hereto.

Claims

1. A method of estimating an effective volume of body fluid, the effective volume comprising a circulating blood volume (CBV) or circulating plasma volume (CPV), the method comprising:

inputting first data defining a first measured concentration (C°), of a blood or plasma component in a patient;

inputting second data defining a second measured concentration (C²) of a blood or plasma component in the patient, wherein said second measured concentration is a concentration measured after administration of a known fluid volume (V_f);

determining estimate data representing an estimate of an effective volume (V_e) said CBV or CPV from said first and second measured data and said known fluid volume(V_f); and

storing and/or outputting said estimate data.

2. A method as claimed in claim 1 wherein said determining said estimating data comprises evaluating

.

3. A method as claimed in claim 1 or 2 wherein said determining of said estimate data further comprises compensating for a renal clearance rate.

4. A method as claimed in claim 1 , 2 or 3 wherein said first and second measured concentrations comprise concentrations of haemoglobin and/or red blood cells, and wherein said effective volume comprises an effective CBV.

5. A method as claimed in any preceding claim wherein said first and second measured concentrations comprise concentrations of one or more acute phase response proteins, in particular C3, C4 and/or CRP, and wherein said effective volume comprises an effective CPV.

6. A method as claimed in claim 5 further comprises compensating for a rate of acute phase response regulation.

7. A method as claimed in any preceding claim wherein said first and second measured concentrations comprise concentrations of immunoglobulin (IgG); and wherein said effective volume comprises an effective CPV.

8. A method as claimed in any preceding claim further comprising identifying a group to which the patient belongs from amongst a plurality of patient groups, wherein said identifying is dependent on said estimate data; and outputting patient group data identifying said group.

9. A carrier carrying processor control code to implement the method of any preceding claim.

10. A medical data estimation system, the system comprising:

working memory;

program memory;

a processor coupled to said working memory and to said program memory; an input to receive first data defining a first measured concentration (C°), of a blood or plasma component in a patient, and second data defining a second measured concentration (C²) of a blood or plasma component in the patient, wherein said second measured concentration is a concentration measured after administration of a known fluid volume (V_f); and

wherein said program memory stores processor control code to:

determine estimate data representing an estimate of an effective volume (V_e) of said CBV or CPV from said first and second measured data and said known fluid volume(V_f); and

store and/or output said estimate data.

11 . A method in which the effective volume in different body compartments is determined.

12. A method in which a measure of fluid equilibrium partitioning is determined.

13. A method in which a rate of fluid equilibrium partitioning and time to equilibrium is determined.

14. A method as claimed in any one of claims 11 to 13 wherein said method employs a quantitative assay for each blood component, preferably determined by one or more standard laboratory tests.

15. A method as claimed in any one of claims 11 to 13 wherein said method employs a quantitative assay for each blood component, preferably determined by a point-of-care test.

16. A method as claimed in any one of claims 1 1 to 15 wherein said method is used to optimise a fluid regimen for patient management by differentiating between the efficacy of substances in particular crystalloid, saline or colloid.

17. A method as claimed in any one of claims 1 1 to 16 wherein said method allows a change in said effective volume to be determined in response to constriction or dilation drugs.

18. A method as claimed in any one of claims 1 1 to 17 wherein said method allows changes in surgical stress response to be profiled.

19. A method as claimed in claim 1 1 wherein said method allows the dose of a drug or equivalent to be assessed and optimised for maximum efficacy.

20. A method as claimed in any one of claims 1 1 to 19 wherein said method allows a dosing regimen such as bolas dosing to be optimised for maximum efficacy.

21. A method as claimed in any one of claims 1 1 to 20 wherein said method allows for personalised dosing and monitoring to be performed for highly toxic drugs such as chemotherapy drugs and/or for optimising an antibiotic dose.

22. A method as claimed in any one of claims 1 1 to 21 wherein said method allows mass loss to be determined from fluid compartments for different blood components indicating activation or performance of body physiology systems, wherein said different blood components comprise one or more of:

white blood cells which are indicative of infection or inflammation; platelets, where a mass loss for said platelets is indicative of clotting processes;

immunoglobin, where a mass loss for said immunoglobulin is indicative of antibody complex formation; and

complement protein mass, where a change in said protein mass is indicative of complement activation and consumption indicating triggers of a cascade.

23. A method in which differential effective volume measurements of different body compartments are used pre-operatively to stratify or personalise patient care.

24. A method in which differential effective volume measurements of different body compartments are used to identify patient co-morbidities alone or when combined with clearance measurements, in particular for one or more of:

Vasculature diseases;

Lymphatic efficiencies;

Oedema monitoring care;

Kidney function and dialysis management; and

Liver function efficacy.

25. A method in which differential effective volume correlations for different body compartments are used to allow drug partition and/or drug clearance volumes to be compared and optimised, leading to a drug localisation estimate.