MicrodialysisBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7337.588 (Published 09 March 2002) Cite this as: BMJ 2002;324:588
- Markus Müller, associate professor ()
- Department of Clinical Pharmacology, Vienna University School of Medicine, Vienna General Hospital, Allgemeines Krankenhaus-AKH, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Monitoring tissue chemistry in patients by microdialysis is likely to become routine in clinical practice
Many diagnostic and therapeutic decisions in medical practice are based on measuring blood concentrations of endogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Assessing tissue chemistry should theoretically provide more accurate data, and this can now be achieved relatively cheaply and minimally invasively with microdialysis. This review describes the technique of microdialysis and its application in clinical research, drug monitoring, and drug development. It also discusses how, in the future, measurement of tissue rather than blood chemistry may become the standard for some clinical investigations.
Microdialysis enables the in vivo measurement of tissue chemistry in humans and is feasible in virtually every human organ
It is currently being used to monitor brain ischaemia and metabolic control
The technique is set to become a standard tool in drug monitoring and development
In the future “bedside” microdialysis will allow monitoring of tissue metabolism in a wide range of diseases
This article is based on 10 years of personal experience of using microdialysis to monitor tissue chemistry in various clinical settings and on a comprehensive study of the literature. A Medline search at the time of writing provided 1020 articles for “microdialysis and human” and 7277 articles for “microdialysis.”
Principles of microdialysis
In vivo microdialysis measures the chemical composition of the interstitial tissue fluid—that is, the fluid to which cells and other target structures are directly exposed. In contrast to imaging techniques or biosensors, which serve as detecting tools, microdialysis is a sampling tool and needs to be linked to an analytical device. Depending on the availability of an appropriate analytical assay, virtually every soluble molecule in the interstitial space fluid can be measured by microdialysis. In recent years the use of microdialysis has moved from preclinical evaluation and validation to clinical application, reflected by a considerable growth in the literature.1–5 This development was catalysed by the increasing availability of extremely sensitive chemical detectors and detectors that require only a few microlitres of fluid.
The concept of microdialysis goes back to the early 1960s, when push-pull cannulas, dialysis sacs, and dialytrodes were inserted into animal tissues to study tissue biochemistry directly.5 In 1974 Ungerstedt and Pycock reported on the use of “hollow fibers.” These fibres were steadily improved and eventually resulted in the needle probe (fig 1) which is inserted by means of a guide cannula into the tissue. Today, several companies offer commercial microdialysis kits, and there are probes available that are EU approved for studies in human soft tissues and human brain. The cost of a disposable kit is roughly €250 (£150, $220).
Microdialysis is based on sampling of soluble molecules from the interstitial space fluid by means of a semipermeable membrane at the tip of a probe (fig 2). The probe is constantly perfused with a physiological solution, and when the probe is implanted into tissue molecules present in the interstitium diffuse across the membrane into the perfusion medium of the probe. Samples are either analysed on line or collected for later analysis. For most analytes the equilibrium between interstitium and the perfusion medium is incomplete, which is why microdialysis probes need to be calibrated.6 Most calibration methods are based on adding the respective analyte to the perfusion medium and measuring its rate of disappearance through the membrane, which is taken as a measure of equilibration between the probe and the tissue. With proper calibration, intraindividual coefficients of variation for microdialysis measurements range around 20% depending on the analyte. Although microdialysis offers many advantages over other techniques, notably its potential to be performed in any clinical centre, it is currently limited by the availability of sufficiently sensitive chemical assays. Microdialysis with conventional dialysis membranes is also limited to dialysable molecules with a molecular weight of no more than about 50 kD, although the use of ultrafiltration membranes and metal meshes could raise this limit.
Initially microdialysis was designed to measure concentrations of neurotransmitters in rat brain, and was gradually adopted in other research.5 The first published application of microdialysis in humans was a study on interstitial glucose in 1987,6 and its use was initially confined to adipose tissue. 6 7 However, numerous reports have since appeared on microdialysis in other human tissues such as brain,8 heart,9 lung,10 and solid tumours.11
From a practical point of view no special skills are required to insert a microdialysis probe. In soft tissues and the skin, the procedure can be managed by any health professional and is no more painful than the placement of an intravenous catheter. After about 10 minutes, most subjects do not report any pain at all. The probes are usually left in situ for several hours, but they can be left in place for up to several weeks. Studies of people during exercise are possible with flexible probes.
Application of microdialysis in clinical research
Currently, microdialysis is most widely used in neurointensive care for monitoring secondary ischaemia, a common complication after brain trauma or intracranial haemorrhage that may seriously affect outcome.12 Microdialysis reveals characteristic changes in the concentrations of energy related metabolites that may serve as earlier and more accurate markers of ischaemic events than brain pressure. Experiments show that an increase in glycerol concentration indicates damage of neuronal membranes and that an increase in the lactate:pyruvate ratio may be an early indicator of brain ischaemia.13 Other studies indicate that reductions in cerebral blood flow are followed by a massive release of potentially neurotoxic excitatory amino acids.14
The potential of microdialysis to closely monitor patients with brain trauma led to its routine use as a clinical tool in Sweden, notably in Lund and Stockholm in the mid-1990s. Microdialysis monitoring has become part of the “Lund concept” for treating traumatic brain injury, which has dramatically reduced mortality in patients with severe head injuries.15 This concept is based on physiological principles of volume regulation in the brain and on surgical and pharmacological interventions aimed at keeping capillary hydrostatic pressure and brain pressure low. The experience gained in Sweden provides evidence that microdialysis yields sensitive and early markers for secondary brain injury and helps to indicate whether therapeutic interventions are effective.15 On the basis of these encouraging results, many academic centres for neurosurgery worldwide are about to implement microdialysis in routine care. Thus microdialysis will probably become fully integrated in routine monitoring procedures in intensive care.
Microdialysis has also been used to monitor concentrations of cardiac troponin T and aspartate transaminase for up to 100 hours after patients have undergone heart surgery.9 Increased myocardial concentrations of these markers correlate with electrocardiographic changes and precede peak levels in serum by an hour. Gut ischaemia is another serious and difficult to diagnose complication, at least in preclinical settings, that can be monitored by microdialysis.16 For plastic surgery, microdialysis monitoring has been shown to be useful for indicating imminent ischaemia in myocutaneous flaps used in reconstructions.17
Since publication of the diabetes control and complications trial (DCCT) the importance of long term metabolic control in patients with diabetes has been well recognised. Several devices have been developed for closely monitoring tissue glucose, including a portable microdialysis system that allows continuous measurement of subcutaneous glucose concentrations for up to several days.7 Such devices offer the benefit of glucose analysis without the need for repeated invasive measurements and may be used to improve glycaemic control (fig 3). Ambulatory glucose monitoring with microdialysis is particularly suitable for patients with labile glycaemic control.7 Although the lack of suitable automated online glucose analysers hampers its routine application, microdialysis can be used in selected patients to improve metabolic control.
Current clinical research applications of microdialysis
Elucidating the chemical basis for initiation of seizures (such as pre-epileptic increase in glutamate and a consecutive surge in γ-aminobutyric acid8)
Studying neurochemical patterns in defined brain areas (such as increased dopamine release in human amygdala during performance of cognitive tasks19)
Measuring peptides and metabolites at site of action or release and describing paracrine regulations in select organs or tissues such as the ovary and subcutaneous fat20
Administering drug locally by microdialysis without inducing systemic side effects and simultaneously measuring the corresponding tissue response, such as catecholamine induced lipolysis20
The role of microdialysis in clinical pharmacology
Antibiotic drug research
Because microdialysis measures concentrations of unbound (that is, pharmacologically active) drugs in the interstitium (the target site for many bacterial infections) the technique has led to a reappraisal of concepts of “tissue-penetration” by antimicrobial drugs. 25 26 Microdialysis data indicate that in healthy people interstitial concentrations of β-lactams are in the range of free serum concentrations, whereas interstitial levels of chinolones and macrolides are considerably lower than those predicted from biopsies. For several conditions, notably septicaemia and septic shock, tissue concentrations of antibiotics such as piperacillin may be subinhibitory even though effective concentrations are attained in serum. 26 27 This may explain therapeutic failures and the emergence of drug resistant bacteria that were exposed to subinhibitory drug concentrations in tissue.
Microdialysis studies of tumours are of considerable interest with the recognition that insufficient drug penetration into the interstitium of solid tumours represents a rate limiting step in clinical response to chemotherapy.28 Microdialysis studies in patients with breast cancer and melanoma revealed no association between serum concentrations of anticancer drugs and tumour exposure to the drugs. 11 25 However, there is preliminary evidence that the concentrations of cytotoxic drugs in a tumour may correlate with response to chemotherapy.11 These findings cast doubt on the use of serum drug concentrations to predict response and corroborate previous findings of a high variability of drug penetration into tumours. Microdialysis may therefore prove to be a good method for selecting compounds with favourable penetration characteristics and may help to identify patients who are unlikely to benefit from chemotherapy because of poor drug penetration.
Additional educational resources
Lönnroth P. Microdialysis—a new and promising method in clinical medicine. J Intern Med 1991;230:363-4
Ungerstedt U. Microdialysis—principles and applications for studies in animals and man. J Intern Med 1991;230:365-73
Elmquist WF, Sawchuk RJ, eds. Use of microdialysis in drug delivery studies [theme issue] Advanced Drug Delivery Reviews 2000;45(2-3)
Hillered L, Persson L. Neurochemical monitoring of the acutely injured human brain. Scand J Clin Lab Invest Suppl 1999;229:9- 18
Lafontan M, Arner P. Application of in situ microdialysis to measure metabolic and vascular responses in adipose tissue. Trends Pharmacol Sci 1996;17:309- 13
American Association of Pharmaceutical Scientists (AAPS), Microdialysis Focus Group (http://www.aapspharmaceutica.com/resources/focus/microdial.asp)
A useful and frequently updated commercial website about basic methods and latest developments in microdialysis research
Cutaneous Microdialysis Club (http://www.physiologie1.uni-erlangen.de/)
Topical application of drugs is an attractive way to circumvent systemic side effects, but it is often not clear whether adequate drug concentrations are reached in the tissue. Microdialysis permits this issue to be addressed and could be used to identify formulations and doses of topically applied non-steroidal anti-inflammatory drugs that produce effective local concentrations.29 The use of microdialysis in topical drug research may thus lead to a critical reappraisal of cost benefit ratios of topically administered drugs.
Drugs in the central nervous system
Microdialysis has been used to measure several drug concentrations directly in human brain parenchyma25 and may help to define optimal drug penetration across the blood-brain barrier for patients such as those infected with HIV. The success of preclinical microdialysis indicates ample opportunity for clinical neuropharmacological studies. In contrast to preclinical studies, however, there are serious ethical limitations for human drug studies, mainly the small number of clinical settings where such studies would be ethically appropriate.
Given the recent developments in microdialysis techniques, it seems likely that microdialysis will become available for a broad range of diagnostic applications. Besides its role as a research tool, it will become an integral part of neurointensive care monitoring and standard for measuring drug distribution in drug development. Miniaturisation and online automisation of chemical assays will ultimately allow “bedside microdialysis” for assessing antibiotic penetration of infected organs and monitoring tissue metabolism in disease states.
Competing interests None declared.