The simplest indicator dilution method is to add an indicator substance at a known concentration and constant rate into the blood flow and to measure its concentration downstream.
Providing that perfect mixing has occurred, the dilution factor gives the ratio of the two flows in the steady state. Stewart (1897), who was the first to use this principle for measuring cardiac output, infused sodium chloride over 10-15 seconds and measured the change in electrical resistance of the blood. When this had fallen to a steady level during the constant infusion he withdrew a blood sample and derived the dilution factor.
A more practical method is to add the indicator as an injection and to measure the concentration time profile of the passage of this bolus at a point downstream of the injection. Typically the concentration rises to a rounded peak and falls away more slowly as the remaining indicator is washed out. Such a curve may be considered as a large number of elements of sufficiently short time duration that for each element the flow and concentration are effectively constant.
The concentration of the marker multiplied by the flow and the time duration of each element gives the quantity of marker passed by that element. The sum of these quantities should therefore equal the total quantity of indicator added as the bolus. If the flow is constant for the duration of the curve, i.e. is the same for each of the elements, it may be calculated simply as the quantity of indicator injected divided by the total area under the dilution curve. The shape of the curve is unimportant providing that the total area can be found.
The bolus injection method of measuring cardiac output was first described by Henriques (1913), who injected sodium thiocyanate and then withdrew arterial blood samples at 1second intervals for a subsequent in vitro colorimetric analysis. He identified the problem of the indicator starting to recirculate before the first pass was complete. White (1947) derived cardiac output from continuously recorded dilution curves and the method was further developed by Hamilton et al., (1932) and others for use in man.
Many different indicators have been tried but the first successful was a dye indocyanine green, whose concentration curve can be measured in blood by light absorption. Like the Fick method (Fick, 1870), it is accurate but difficult to carry out. The densitometer, which measures indocyanine green concentration, had to be calibrated with samples of the individual patient’s blood containing known concentrations of the green dye. This technique was time consuming. A newer variant of this method was that of pulse dye densitometry where an optical sensor is used to record the arterial indocyanine green curve.
Clinically, by the 1980’s and into the early 1990’s pulmonary artery thermodilution, in which cold fluid (or sometimes pulses of heat) is injected, became the most commonly used invasive method of determining cardiac output (Fegler, 1954, Branthwaite & Bradley, 1968; Yelderman, 1992). More recently transpulmonary thermodilution was introduced into clinical practice. This is a technique that was originally described by Hamilton in 1928, where the concentration time curve of a cold marker substance was measured by a sensor in the femoral artery.
Invasive thermodilution techniques suffer from a number of disadvantages including the risk of significant patient morbidity, the requirement for central venous or pulmonary artery catheterization or, in the case of transpulmonary thermodilution – central artery, usually femoral, catheterization. Thermodilution techniques also only provided intermittent cardiac output values or at best highly averaged/damped “continuous” data. Collectively, these limitations restricted haemodynamc monitoring to cardiac surgical and limited numbers of severely ill intensive care patients. Monitoring was also largely undertaken without the benefit of a proven clinical protocol to guide subsequent interventions to hemodynamic end points. By the start of the 21st Century there was a clear requirement for the development of less invasive methods for the continuous monitoring of cardiac output and the in tandem development of more effective protocols for the hemodynamic management of high risk patients.
References – Indicator Dilution Method History
Branthwaite MA, Bradley RD. Measurement of cardiac output by thermal dilution in man. Journal of Applied Physiology 1968; 24: 434-438.
Fegler G. Measurement of cardiac output in anesthetized animals by athermodilution method. Quarterly Journal of Experimental Physiology 1954;39: 153-164.
Fick A. Ueber die Messung des Blutquantums in den Herzventrikeln. Sitzungsberichteder Physiologisch-Medizinosche Gesellschaft zu Wurzburg 1870; 2: 16.
Ganz W, Donoso R, Marcus HS, Forrester JS, Swan HJC. A new technique for measurement of cardiac output by thermodilution in man. American Journal of Cardiology 1971; 27: 392-396.
Henriques V. Uber die Verteilung des Blutes vom linken Herzen zwischendem Herzen und dem übrigen Organismus. Biochemische Zeitschrift 1913;56: 230-248
Hamilton WF, Moore JW, Kinsman JM. Simultaneous determination of the pulmonary and systemic circulation times in man and of a figure related to cardiac output. Am J Physiol 1928; 84: 338 – 44
Hamilton WF, Remington JW. The measurement of the stroke volume from the pressure pulse. American Journal of Physiology 1947; 148: 14-24
Stewart GN. Researches on the circulation time and on the influences which affect it. Journal of Physiology 1897; 22: 159-183
Yelderman ML, Ramsay MA, Quinn MD, Paulsen AW, McKown RC, Gillman PH. Continuous thermodilution cardiac output measurement in intensive care unit patients. Journal of Cardiothoracic and Vascular Anesthesia 1992; 6: 270-274.
White HL. Measurement of cardiac output by a continuously recording conductivity method. American Journal of Physiology 1947; 151: 45-57
The use of lithium as an alternative indicator for the estimation of cardiac output was first described by Linton, Band, and Haire (1993) and has been independently validated by other researchers (Garcia-Rodriguez et al., 2002; Kurita et al., 1997) among others.
In brief, isotonic lithium chloride (150 mM) is injected as a bolus (0.002–0.004 mmol/kg) via the central, or peripheral, venous route and a concentration–time curve generated by an ex vivo ion-selective electrode attached to the peripheral arterial pressure line. The cardiac output is calculated from the lithium dose and the area under the concentration–time curve prior to recirculation using the equation:
Where ‘Area’ is the integral of the primary lithium dilution curve, and ‘PCV’ is the packed red cell volume. A correction for PCV is necessary to transform plasma flow into total blood flow—because lithium is distributed only in the plasma (fluid) component of the blood.
The voltage response of the lithium ion sensitive electrode is proportional to the percentage change of ion concentration. As lithium is not normally present in the plasma, extremely small doses can be used to achieve a high signal to noise ratio. These lithium doses are too small to exert pharmacological effects. Multiple dosing with lithium has been investigated extensively and the pharmacokinetics of intravenous lithium chloride in man and in animals has been described (Hatfield, McDonell, Lemke, & Black, 2001; Jonas et al.,2001). The safety profile is now well established, with the recommended maximum total dose having to be exceeded many times before toxic levels are reached. The technical innovation of the LiDCO System is both in the method of using the lithium ion as an intra vascular marker substance and the design and application of the ion-selective electrode, which comprises a lithium sensitive electrode situated in a flow through cell.
The LiDCO System is at least as accurate a measurement of cardiac output as the older and more invasive catheter based approaches, but with the advantages of being simple and quick to set-up by a nurse or doctor, with no complications associated with its use.
• Very accurate and precise measurement of cardiac output and derived parameters such as oxygen delivery
• Minimally invasive – measurement can be made with peripheral vein access – without the need for central venous or pulmonary artery catheters
• Allows intermittent calibration of continuous blood pressure based (PulseCO) cardiac output measurements
• Applications: In challenging clinical situations eg sepsis and oxygen debt situations where highly precise measurements of blood flow and
oxygen delivery are required for resuscitation.
General Supporting References
1. Linton RAF, Band DM & Haire KM. (1993) A new method of measuring cardiac output in man using lithium dilution. British Journal of Anaesthesia; 71: 262-266
2. Band D, Linton R. (1994) A New way of Measuring Cardiac Output. The Physiological Society Magazine 17:21
3. Linton RAF, Band DM, O’Brien TK, Linton NWF & Jonas MM. (1998) Lithium dilution cardiac output measurement – a brief review. In: State-of-the-Art Technology in Anesthesia and Intensive Care, pp 61-66. Edited by: Ikeda K, Doi M & Kazama T; pub. Elsevier Science B.V., Amsterdam
4. Jonas, Linton, O’Brien, Band, Linton, Kelly, Burden, Chevalier, Thompson, Birch and Powell. (2001) The pharmacokinetics of intravenous lithium chloride in patients and normal volunteers. Journal of Trace and Microprobe Techniques. 19: 313-320
5. Mason D, O’Grady M, Woods P, McDonell W. (2002) Effect of background serum lithium concentrations on the accuracy of lithium dilution cardiac output determination in dogs. American Journal of Veterinary Research; 63: 1048 – 1052
6. Kurita T, Morita K, Kawasaki H, Fujii K, Kazama T, Sato S. (2002) Lithium Dilution Cardiac Output Measurement in Oleic Acid-Induced Pulmonary Edema. Journal of Cardiothoracic and Vascular Anesthesia, Vol 16, No 3 (June): pp 334-337
Lithium dilution – comparison against electromagnetic flow probe & Fick
7. Kemps H, Thijssen E, Schep G, Sleutjes B,De Vries W, Hoogeveen A, Wijn P, Doevendans P. (2008) Evaluation of two methods for continuous cardiac output assessment during exercise in chronic heart failure patients. J Appl Physiol 105: 1822-1829
8. Kurita T, Morita K, Kato S, Kikura M, Horie M, Ikeda K. (1997) Comparison of the accuracy of the lithium dilution technique with the thermodilution technique for measurement of cardiac output. British Journal of Anaesthesia; 79: 770-775
Lithium dilution – comparison against pulmonary artery thermodilution
9. Linton R, Band D, O’Brien T, Jonas MM & Leach R. (1997) Lithium dilution cardiac output measurement: A comparison with thermodilution. Critical Care Medicine; 25: 1796-1800
10. Jonas MM, Kelly FE Linton RAF, Band DM, O’Brien TK, Linton NWF. (1999) A comparison of lithium dilution cardiac output measurements made using central and antecubital venous injection of lithium chloride. Journal of Clinical Monitoring & Computing, 15: 525-528
11. Mason D, O’Grady M, Woods P, McDonell W. (2002) Effect of background serum lithium concentrations on the accuracy of lithium dilution cardiac output determination in dogs. American Journal of Veterinary Research; 63: 1048 – 1052
12.Garcia-Rodriguez C, Pittman J, Cassell CH, Sum-Ping J, El-Moalem H, Young C, Mark JB. (2002) Lithium dilution cardiac output measurement: A Clinical assessment of central venous and peripheral venous indicator injection. Crit Care Med Vol. 30, No. 10 p2199-2204
13. Kurita T, Morita K, Kawasaki H, Fujii K, Kazama T, Sato S. (2002) Lithium Dilution Cardiac Output Measurement in Oleic Acid-Induced Pulmonary Edema. Journal of Cardiothoracic and Vascular Anesthesia, Vol 16, No 3 (June): pp 334-337
14. Corley K, Donaldson L, Furr M. (2002) Comparison of lithium dilution and thermodilution cardiac output measurements in anaesthetised neonatal foals. Equine Vet J 2002 Sept;34 (6) 598-601
15.Durando M, Corley K, Boston R, Birks E. (2008) Cardiac output determination by use of lithium dilution during exercise in horses. American Journal Veterinary Research; 69 : 1054 – 1060