Monitoring in chronic disease: a rational approach
1 University of Oxford, Department of Primary Health Care, Oxford OX3 7LF UK,2 Screening and Test Evaluation Program, School of Public Health, University of Sydney, Camperdown, NSW 2006, Australia
Introduction
"Know which abnormality you are going to follow during treatment. Pick something you can measure."
Meador C. A Little Book of Doctors' Rules.
Lyons: IARC Press, 1999.
, http://www.100md.com
The ritual of routine visits for most chronic diseases usually includes monitoring to check on the progress or regress of the disease and the development of complications. Such checks require that we choose what to monitor, when to monitor, and how to adjust treatment. Poor choices in each can lead to poor control, poor use of time, and dangerous adjustments to treatment. For example, an audit of serum digoxin monitoring in a UK teaching hospital more than 20 years ago showed that the logic behind more than 80% of the tests requested could not be established, the timing of tests reflected poor understanding of the clinical pharmacokinetics, and about one result in four was followed by an inappropriate clinical decision.1 Improvements are possible. For example, a computerised reminder of inappropriate testing reduced the volume of testing for the concentration of antiepileptic drugs by 20%2; a decision support system for anticoagulation with warfarin led to an improvement from 45% to 63% of patients being within target range3; and quality control charts for peak flow measurements for people with asthma could detect exacerbations four days earlier than conventional methods.4 Given the extent of monitoring, even modest improvements are likely to improve benefits for patients and may reduce costs.
, 百拇医药
Monitoring is periodic measurement that guides the management of a chronic or recurrent condition. It can be done by clinicians, patients, or both. In Australia, monitoring comprises between a third and half of all tests ordered in general practice and outpatients (Pirozzo, personal communication, 2002). Despite the considerable staff time and resources involved, monitoring is a surprisingly understudied area. We review the current literature (based on a Medline search using the terms "monitor", "therap" or "treat"; "limit" or "threshold"; "chronic" and a check of references of relevant papers found) on the clinical uses of monitoring, and develop some principles for good monitoring strategies.
, 百拇医药
Should we monitor at all
Although intuitively monitoring should be beneficial, clinicians accept non-monitoring in many areas. Aspirin, for example, is used to prevent stroke without assessing platelet aggregation. Establishing benefit for patients is important, as it must be balanced against the downsides of monitoring, such as the inconvenience and costs, and the impact of false positive and false negative (monitoring) results that can lead to inappropriate or delayed actions. As with other interventions, this ideally requires a randomised controlled trial. The benefit should preferably be measured by outcomes that are relevant to patients rather than time spent in the target range (a surrogate marker). For example, in a trial of drug monitoring in epilepsy, monitored patients were more often within control limits than unmonitored patients (8% v 25%), but the proportion remaining free of seizures did not change (38% v 41%).5 However, few monitoring practices have undergone such trials.
, 百拇医药
Monitoring is a complex intervention. It can have an impact through several means, including improvement of adherence, better selection of treatments based on individual response, better titration of treatment, and patients' learning about non-treatment factors that alter the condition's control. Because of this complexity, any trial should be preceded by developmental work to understand the optimal strategies.
Monitoring and adjustment may be controlled by clinicians or patients. For patients, monitoring may provide a signal for action or simply provide motivation to adhere to treatment. For example, a recent trial in which some diabetes patients were randomised to self monitoring of risk factors showed a better achievement of target measurements of blood pressure, low density lipoprotein cholesterol, and HbA1c; and a reduction in clinical events.6 However, a randomised trial of the motivational effect of cholesterol measurement in general practice in the United Kingdom showed only negligible benefit—a difference of 0.1 mmol/l in total cholesterol measurements.7
, http://www.100md.com
The optimal process is not straightforward. A recent study compared three modes of peak flow monitoring in childhood asthma: regular daily measurements, measurement only when symptomatic, and monitoring only at times of symptoms. The second group—children randomised to measure their peak expiratory flow rate only when symptomatic—had lower asthma severity scores, fewer days of symptoms, and fewer healthcare visits than children randomised to either daily peak flow monitoring or monitoring only at times of symptoms.8 The study showed that peak flow monitoring is helpful but that the less intensive monitoring regimen is preferable.
, http://www.100md.com
The phases of monitoring
The objective and methods of monitoring change over the course of treatment. This course of monitoring can be usefully divided into the five phases listed in table 1.
The objectives for the five phases of monitoring
Pretreatment monitoring
Monitoring before treatment should establish the need for treatment and then a baseline to judge the response to treatment or changes in the patient's condition. Treatment should not start until sufficient measurements for a firm baseline have been obtained. This firm baseline confirms that the degree of abnormality is beyond the initiation threshold. Serial measurements often "normalise" before treatment for several reasons, such as training effects (for example, with a peak flow meter), accommodation to measurement (for example, with blood pressure measurement), and, perhaps most importantly, regression to the mean (the tendency of repeat tests to be closer to normal9). For example, in the first biennial check in the Framingham study, the average blood pressure fell by 3.4 mm Hg systolic and 2.4 mm Hg diastolic.10 Among 99 Dutch patients with apparently raised blood pressure, re-measurement resulted in average reductions of 9 mm Hg systolic and 4 mm Hg diastolic.11 The same study showed that two measurements were sufficient to establish the need for treatment in patients who were well above the initiation threshold. For borderline patients, even four measurements resulted in substantial misclassification.
, 百拇医药
Initial titration: response, control, and safety
After establishing the baseline, we should set a target and start titration to achieve that target. However, achieving the target is just one of several objectives of the initial titration phase, which should include checking the individual's response to treatment, detecting unacceptable adverse effects, and achieving the desired target range.
This initial monitoring checks adequate response to treatment—that is, whether it "works" as expected on the basis of clinical trials in other patients. Sometimes individual response to treatment can be predicted by other measurements, such as genetic testing (for example, the dose requirement on initiating warfarin treatment is strongly related to CYP2C9 gene variants12). Sometimes it can be predicted by pharmacokinetic studies—for example, in initiating tricyclic antidepressants, short term measurement of the drug concentration can characterise individual metabolism and guide the long term dose used.13 However, personalising treatment usually requires some pragmatic trial and error. We can therefore think of this phase as an "n = 1" trial.14 Ideally, the estimate of effect will be based on both the measurements in that patient and the known effect from trials.15
, http://www.100md.com
The initiation phase should also detect immediate or short term adverse effects.16 Measures of potential harm should hence be assessed and monitored. Almost half of the medicines in the electronic Medicines Compendium (www.medicines.org.uk) include a suggestion for some monitoring. Many drugs affect renal function, and regular monitoring of creatinine and electrolytes is widely recommended. A more specific example is treatment with clozapine, for which white cell counts are measured on a weekly basis for the first few months to detect agranulocytosis, which occurs in 0.8% of patients. However, the rationale for the timing of measurement is seldom explicit. The criteria for monitoring for adverse effects are similar to those for screening, including that the effect is serious, that a simple test is available, that earlier detection is predictive, and that change in treatment leads to a better outcome.17
, http://www.100md.com
Monitoring during treatment
Once the target is achieved, the objective of monitoring is to ensure that measurements stay within reasonable limits, called control limits. The control limits ensure that we detect real changes in the level of the target measure while minimising false positives resulting from variable measurements in the short term or errors in the technical measurement. The degree of short term variation can be estimated from population studies, subpopulations, or from the individual's own measurements. Because extreme measurements are unlikely to be due to variability of short term measurements, they may justify action to re-establish control. One approach suggested by statistical control theory is to consider that a shift from control has occurred if a single measurement is outside an upper and lower control limit of 3 standard deviations, or if two or three successive measurements are more than 2 standard deviations from the target.18 Figure 1 shows these two sets of action thresholds; one for action (SD 3) and one for re-measurement (SD 2), with action if the repeat result is also more than 2 standard deviations from target.
, 百拇医药
Monitoring during treatment can be less frequent than during the initiation phase. The interval depends on the probability of being outside the control limits, which in turn depends on both random drift and systematic changes (progression or regression of disease).
The measurements intervals may be shorter than the decision interval. For example, monitoring measurements of blood pressure might be done daily by patients, but the decision made at a monthly consultation with the doctor. This is illustrated in figure 1, where multiple measures (3(b)—small arrows) occur between the decision points (3(a)—large arrows). Ideally a graphical presentation, such as a control chart, should be used to aid recording and deciding treatment changes.
, 百拇医药
Adjustment to re-establish control
When a clear drift beyond the control limits occurs, we should re-establish control. As in the initiation phase, a shorter measurement interval is generally warranted until control is re-established.
We have already cited several examples (for example, monitoring digoxin therapy) in which audits have shown that clinical decisions taken as a result of monitoring are suboptimal—sometimes tending to the conservative. A New Zealand study of digoxin monitoring showed that 53% of ordered measurements were inappropriately timed and that 5% of the ordered measurements led to inappropriate dose adjustments.19 Patients too find this difficult: a survey of diabetes educators showed that correct adjustment of insulin dosage is the single hardest skill to teach.20 This may be because of the lack of a planned and explicit response to test results or because the tests are seldom considered in context—they usually arrive as a single value, without reference to past values or a clear and useful statement about the variability of measurements. The appropriate degree of adjustment may be helped by nomograms or computer algorithms.
, 百拇医药
Cessation of treatment
Most therapies are not lifelong. Monitoring should inform stopping decisions. Again, such decisions are usually based on a threshold level—either a negative outcome (such as an adverse effect on renal function or frequency of epileptic seizures exceeding a threshold), or a positive outcome (such as pain relief) that falls below a minimum threshold. However, the precise thresholds chosen and the monitoring interval depend on the phase of treatment. Cessation of treatment mirrors the first phases of pre-treatment and initiating treatment. A decision to stop based on current risks and control is made, treatment is withdrawn (perhaps in stages), and, after a "washout" period, the patient is rechecked to ensure that treatment does not need to be restarted.
, http://www.100md.com
Monitoring strategy
For all phases, several choices have to be made in devising a good monitoring strategy: whether to monitor at all, the choice of measurement(s), the choice of target range, the choice of measurement interval, and who should monitor.
Which measurement
Monitoring the wrong target is obviously a fundamental error. Often various possible monitoring tests will be available, and there are advantages to choosing one main measurement (or a composite measure of several) to guide changes in management (fig 2). The criteria for the choice of measurement include the following.
, 百拇医药
Is it a good predictor of clinically relevant outcomes Monitoring measurements are surrogate markers for the patient relevant outcomes.21
Can it detect changes in risk early Risk predictors will vary in their responsiveness to the beneficial impact of treatment, with a good monitoring measurement providing an early indication of risk change.22
Is the random variability acceptable or can it be made acceptable by repeated measurements
, 百拇医药
Is it sufficiently affordable, accessible, and acceptable to patients
Choosing the monitoring interval
The different phases require different monitoring intervals (table 1). The interval is shortest for the pretreatment phase, longest for the maintenance phase, and intermediate for the other three phases.
For the pretreatment phase, measurements need to be far enough apart to make allowance for the short term variability within and between days. For example, the multiple readings taken when monitoring blood pressure for 24 hours give an accurate picture over a full day but do not capture some patients' considerable variability from day to day. For remeasurement during the treatment phases, we must know the time to therapeutic response (allowing for both pharmacokinetics and pharmacodynamics)—for example, the interval for statins is about six weeks23 and for angiotensin converting enzyme inhibitors for blood pressure about three weeks.24
, 百拇医药
Who should monitor
Self monitoring by patients is becoming more common. Such monitoring may be for motivation—for example, by using pedometers to monitor physical activity or home blood glucose measurement for people with non-insulin dependent diabetes25; for providing a clinician with between visits measurements—for example, home blood pressure monitoring26, or home glucose monitoring; or for self adjustment of therapy—for example, peak flow rates to trigger actions in asthma patients27 or home blood glucose for insulin adjustments. As the examples show, monitoring of patients can be done for all three purposes.
, http://www.100md.com
Discussion
Although monitoring is common in clinical practice, the principles of monitoring have not been well conceptualised, which in turn has led to suboptimal care. Chronic care could potentially be improved (and often at reduced costs) if for each chronic disease we determined whether and how monitoring was necessary, set explicit monitoring ranges and provided appropriate graphical representations that aided decision making, recognised the need for different optimal intervals for different phases, and understood better when and how to adjust treatment to avoid the increases in variability caused by overadjustment. Health professionals working in chronic care need to understanding these principles better, and systems needs to be improved, including use of appropriate decision aids that have been shown to improve monitoring care.28
, 百拇医药
Additional educational resources
For patients and clinicians
National electronic Library for Health (www.nelh.nhs.uk)—contains UK relevant guidelines on monitoring for many areas. A search on "monitoring" and choosing "evidence" provides the evidence base for a number of monitoring topics
The BTS/SIGN British Guideline for Asthma (www.brit-thoracic.org.uk/sign/index.htm)—few long term conditions have appropriate monitoring charts, but asthma is one of the better served. A printable peak flow diary is downloadable from the websites of the British Thoracic Society and Scottish Intercollegiate Guidelines Network (www.brit-thoracic.org.uk/sign/mainframe_download.html)
, http://www.100md.com
For researchers
Westgard QC (www.westgard.com)—a website for laboratory tests, which includes a database of within person variation for over 100 tests (see "Biologic Variation Database"), and the Westgard rules for detect readings beyond control limits
Summary points
Monitoring aims to establish the response to treatment, detect the need to adjust treatment, and detect adverse effects
, 百拇医药
Monitoring is not always necessary or beneficial and can lead to inappropriate changes
Control charts help distinguish natural variability from true change and reduce unnecessary adjustment
Monitoring for both benefit and harm is important, preferably with a single measurement
The interval between measurements varies between phases and is shorter after changes in treatment
, 百拇医药
We thank Andrew Farmer, Jeffrey Aronson, and Tom Fahey for detailed comments on various drafts, and Susan Jack who help with initial searches and problem formulation.
Contributors: PG conceived the study, and all authors contributed to the ideas and writing. PG is guarantor.
Funding: PG and LI were in part funded by the Australian National Health and Medical Research Council for this work, as part of a programme grant 211205 on testing.
, 百拇医药
Competing interests: None declared.
References
Clague HW, Twum-Barima Y, Carruthers SG. An audit of requests for therapeutic drug monitoring of digoxin: problems and pitfalls. Ther Drug Monit 1983;5: 249-54.
Chen P, Tanasijevic MJ, Schoenenberger RA, Fiskio J, Kuperman GJ, Bates DW. A computer-based intervention for improving the appropriateness of antiepileptic drug level monitoring. Am J Clin Pathol 2003;119: 432-8.
, 百拇医药
Ryan PJ, Gilbert M, Rose PE. Computer control of anticoagulant dose for therapeutic management. BMJ 1989;299: 1207-8.
Gibson PG, Wlodarczyk J, Hensley MJ, Murree-Allen K, Olson LG, Saltos N. Using quality-control analysis of peak expiratory flow recordings to guide therapy for asthma. Ann Intern Med 1995;123: 488-92.
Jannuzzi G, Cian P, Fattore C, Gatti G, Bartoli A, Monaco F, Perucca E. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy. Epilepsia 2000;41: 222-30.
, 百拇医药
Rachmani R, Levi Z, Slavachevski I, Avin M, Ravid M. Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with Type 2 diabetes mellitus—a randomized prospective study. Diabet Med 2002;19: 385-92.
Robertson I, Phillips A, Mant D, Thorogood M, Fowler G, Fuller A, Yudkin P, Woods M. Motivational effect of cholesterol measurement in general practice health checks. Br J Gen Pract 1992;42: 469-72.
, 百拇医药
Yoos HL, Kitzman H, McMullen A, Henderson C, Sidora K Symptom monitoring in childhood asthma: a randomized clinical trial comparing peak expiratory flow rate with symptom monitoring. Ann Allerg Asthma Immunol 2002;88: 283-91
Bland JM, Altman DG. Regression towards the mean. BMJ 1994;308: 1499.
Dauber TR. The Framingham study: the epidemiology of atherosclerotic disease. Cambridge, MA: Harvard University Press, 1980.
, http://www.100md.com
Brueren MM, Petri H, van Weel C, van Ree JW. How many measurements are necessary in diagnosing mild to moderate hypertension Fam Pract 1997;14: 130-5.
Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM. CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulation therapy. Clin Pharmacol Ther 2004;75: 198-203.
Braithwaite RA, Dawling S, Montgomery SA. Prediction of steady-state plasma concentrations and individual dosage regimens of tricyclic antidepressants from a single test dose. Ther Drug Monit 1982;4: 27-31.
, 百拇医药
Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med 1990;112: 293-9.
Irwig L, Glasziou P, Wilson A, Macaskill P. Estimating an individual's true cholesterol level and response to intervention. JAMA 1991;266: 1678-85.
Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003;327: 1222-5.
, 百拇医药
Pirmohamed M, Ferner RE. Monitoring drug treatment. BMJ 2003;327: 1179-81.
Boggs PB, Hayati FH, Washburne WF, Wheeler DA. Using statistical process control charts for the continual improvement of asthma care. J Qual Improve 1999:25: 163-81.
Sidwell A, Barcaly M, Begg E, Moore G. Digoxin therapeutic monitoring: an audit and review. N Z Med J 2003;116: U704.
Bonnet C, Gagnayre R, d'Ivernois JF.Learning difficulties of diabetic patients: a survey of educators. Patient Educ Couns 1998;35: 139-47.
, 百拇医药
Begg CB, Leung D. On the use of surrogate end points in randomized trials. J R Stat Soc A 2000;163: 15-28
Irwig L. This added to my multiple myopia. BMJ 2003;326: 1336.
Scottish Intercollegiate Guidelines Network. Lipids and the primary prevention of coronary heart disease. Edinburgh: SIGN, 1999. www.sign.ac.uk/guidelines/fulltext/40/index.html (accessed 5 Jan 2005).
Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol 2000;40: 1380-90.
, http://www.100md.com
Lowy. A memorable patient: Home glucose monitoring, who started it BMJ 1998;316: 1467.
Cappuccio FP, Kerry SM, Forbes L, Donald A. Blood pressure control by home monitoring: meta-analysis of randomised trials. BMJ 2004;329: 145-8.
Thoonen BP, Schermer TR, van Den Boom G, Molema J, Folgering H, Akkermans RP, et al. Self-management of asthma in general practice, asthma control and quality of life: a randomised controlled trial. Thorax 2003;58: 30-6
Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care Systematic review of randomized controlled trials. Arch Intern Med 2004;164: 722-32., 百拇医药(Paul Glasziou, Les Irwig,)
Introduction
"Know which abnormality you are going to follow during treatment. Pick something you can measure."
Meador C. A Little Book of Doctors' Rules.
Lyons: IARC Press, 1999.
, http://www.100md.com
The ritual of routine visits for most chronic diseases usually includes monitoring to check on the progress or regress of the disease and the development of complications. Such checks require that we choose what to monitor, when to monitor, and how to adjust treatment. Poor choices in each can lead to poor control, poor use of time, and dangerous adjustments to treatment. For example, an audit of serum digoxin monitoring in a UK teaching hospital more than 20 years ago showed that the logic behind more than 80% of the tests requested could not be established, the timing of tests reflected poor understanding of the clinical pharmacokinetics, and about one result in four was followed by an inappropriate clinical decision.1 Improvements are possible. For example, a computerised reminder of inappropriate testing reduced the volume of testing for the concentration of antiepileptic drugs by 20%2; a decision support system for anticoagulation with warfarin led to an improvement from 45% to 63% of patients being within target range3; and quality control charts for peak flow measurements for people with asthma could detect exacerbations four days earlier than conventional methods.4 Given the extent of monitoring, even modest improvements are likely to improve benefits for patients and may reduce costs.
, 百拇医药
Monitoring is periodic measurement that guides the management of a chronic or recurrent condition. It can be done by clinicians, patients, or both. In Australia, monitoring comprises between a third and half of all tests ordered in general practice and outpatients (Pirozzo, personal communication, 2002). Despite the considerable staff time and resources involved, monitoring is a surprisingly understudied area. We review the current literature (based on a Medline search using the terms "monitor", "therap" or "treat"; "limit" or "threshold"; "chronic" and a check of references of relevant papers found) on the clinical uses of monitoring, and develop some principles for good monitoring strategies.
, 百拇医药
Should we monitor at all
Although intuitively monitoring should be beneficial, clinicians accept non-monitoring in many areas. Aspirin, for example, is used to prevent stroke without assessing platelet aggregation. Establishing benefit for patients is important, as it must be balanced against the downsides of monitoring, such as the inconvenience and costs, and the impact of false positive and false negative (monitoring) results that can lead to inappropriate or delayed actions. As with other interventions, this ideally requires a randomised controlled trial. The benefit should preferably be measured by outcomes that are relevant to patients rather than time spent in the target range (a surrogate marker). For example, in a trial of drug monitoring in epilepsy, monitored patients were more often within control limits than unmonitored patients (8% v 25%), but the proportion remaining free of seizures did not change (38% v 41%).5 However, few monitoring practices have undergone such trials.
, 百拇医药
Monitoring is a complex intervention. It can have an impact through several means, including improvement of adherence, better selection of treatments based on individual response, better titration of treatment, and patients' learning about non-treatment factors that alter the condition's control. Because of this complexity, any trial should be preceded by developmental work to understand the optimal strategies.
Monitoring and adjustment may be controlled by clinicians or patients. For patients, monitoring may provide a signal for action or simply provide motivation to adhere to treatment. For example, a recent trial in which some diabetes patients were randomised to self monitoring of risk factors showed a better achievement of target measurements of blood pressure, low density lipoprotein cholesterol, and HbA1c; and a reduction in clinical events.6 However, a randomised trial of the motivational effect of cholesterol measurement in general practice in the United Kingdom showed only negligible benefit—a difference of 0.1 mmol/l in total cholesterol measurements.7
, http://www.100md.com
The optimal process is not straightforward. A recent study compared three modes of peak flow monitoring in childhood asthma: regular daily measurements, measurement only when symptomatic, and monitoring only at times of symptoms. The second group—children randomised to measure their peak expiratory flow rate only when symptomatic—had lower asthma severity scores, fewer days of symptoms, and fewer healthcare visits than children randomised to either daily peak flow monitoring or monitoring only at times of symptoms.8 The study showed that peak flow monitoring is helpful but that the less intensive monitoring regimen is preferable.
, http://www.100md.com
The phases of monitoring
The objective and methods of monitoring change over the course of treatment. This course of monitoring can be usefully divided into the five phases listed in table 1.
The objectives for the five phases of monitoring
Pretreatment monitoring
Monitoring before treatment should establish the need for treatment and then a baseline to judge the response to treatment or changes in the patient's condition. Treatment should not start until sufficient measurements for a firm baseline have been obtained. This firm baseline confirms that the degree of abnormality is beyond the initiation threshold. Serial measurements often "normalise" before treatment for several reasons, such as training effects (for example, with a peak flow meter), accommodation to measurement (for example, with blood pressure measurement), and, perhaps most importantly, regression to the mean (the tendency of repeat tests to be closer to normal9). For example, in the first biennial check in the Framingham study, the average blood pressure fell by 3.4 mm Hg systolic and 2.4 mm Hg diastolic.10 Among 99 Dutch patients with apparently raised blood pressure, re-measurement resulted in average reductions of 9 mm Hg systolic and 4 mm Hg diastolic.11 The same study showed that two measurements were sufficient to establish the need for treatment in patients who were well above the initiation threshold. For borderline patients, even four measurements resulted in substantial misclassification.
, 百拇医药
Initial titration: response, control, and safety
After establishing the baseline, we should set a target and start titration to achieve that target. However, achieving the target is just one of several objectives of the initial titration phase, which should include checking the individual's response to treatment, detecting unacceptable adverse effects, and achieving the desired target range.
This initial monitoring checks adequate response to treatment—that is, whether it "works" as expected on the basis of clinical trials in other patients. Sometimes individual response to treatment can be predicted by other measurements, such as genetic testing (for example, the dose requirement on initiating warfarin treatment is strongly related to CYP2C9 gene variants12). Sometimes it can be predicted by pharmacokinetic studies—for example, in initiating tricyclic antidepressants, short term measurement of the drug concentration can characterise individual metabolism and guide the long term dose used.13 However, personalising treatment usually requires some pragmatic trial and error. We can therefore think of this phase as an "n = 1" trial.14 Ideally, the estimate of effect will be based on both the measurements in that patient and the known effect from trials.15
, http://www.100md.com
The initiation phase should also detect immediate or short term adverse effects.16 Measures of potential harm should hence be assessed and monitored. Almost half of the medicines in the electronic Medicines Compendium (www.medicines.org.uk) include a suggestion for some monitoring. Many drugs affect renal function, and regular monitoring of creatinine and electrolytes is widely recommended. A more specific example is treatment with clozapine, for which white cell counts are measured on a weekly basis for the first few months to detect agranulocytosis, which occurs in 0.8% of patients. However, the rationale for the timing of measurement is seldom explicit. The criteria for monitoring for adverse effects are similar to those for screening, including that the effect is serious, that a simple test is available, that earlier detection is predictive, and that change in treatment leads to a better outcome.17
, http://www.100md.com
Monitoring during treatment
Once the target is achieved, the objective of monitoring is to ensure that measurements stay within reasonable limits, called control limits. The control limits ensure that we detect real changes in the level of the target measure while minimising false positives resulting from variable measurements in the short term or errors in the technical measurement. The degree of short term variation can be estimated from population studies, subpopulations, or from the individual's own measurements. Because extreme measurements are unlikely to be due to variability of short term measurements, they may justify action to re-establish control. One approach suggested by statistical control theory is to consider that a shift from control has occurred if a single measurement is outside an upper and lower control limit of 3 standard deviations, or if two or three successive measurements are more than 2 standard deviations from the target.18 Figure 1 shows these two sets of action thresholds; one for action (SD 3) and one for re-measurement (SD 2), with action if the repeat result is also more than 2 standard deviations from target.
, 百拇医药
Monitoring during treatment can be less frequent than during the initiation phase. The interval depends on the probability of being outside the control limits, which in turn depends on both random drift and systematic changes (progression or regression of disease).
The measurements intervals may be shorter than the decision interval. For example, monitoring measurements of blood pressure might be done daily by patients, but the decision made at a monthly consultation with the doctor. This is illustrated in figure 1, where multiple measures (3(b)—small arrows) occur between the decision points (3(a)—large arrows). Ideally a graphical presentation, such as a control chart, should be used to aid recording and deciding treatment changes.
, 百拇医药
Adjustment to re-establish control
When a clear drift beyond the control limits occurs, we should re-establish control. As in the initiation phase, a shorter measurement interval is generally warranted until control is re-established.
We have already cited several examples (for example, monitoring digoxin therapy) in which audits have shown that clinical decisions taken as a result of monitoring are suboptimal—sometimes tending to the conservative. A New Zealand study of digoxin monitoring showed that 53% of ordered measurements were inappropriately timed and that 5% of the ordered measurements led to inappropriate dose adjustments.19 Patients too find this difficult: a survey of diabetes educators showed that correct adjustment of insulin dosage is the single hardest skill to teach.20 This may be because of the lack of a planned and explicit response to test results or because the tests are seldom considered in context—they usually arrive as a single value, without reference to past values or a clear and useful statement about the variability of measurements. The appropriate degree of adjustment may be helped by nomograms or computer algorithms.
, 百拇医药
Cessation of treatment
Most therapies are not lifelong. Monitoring should inform stopping decisions. Again, such decisions are usually based on a threshold level—either a negative outcome (such as an adverse effect on renal function or frequency of epileptic seizures exceeding a threshold), or a positive outcome (such as pain relief) that falls below a minimum threshold. However, the precise thresholds chosen and the monitoring interval depend on the phase of treatment. Cessation of treatment mirrors the first phases of pre-treatment and initiating treatment. A decision to stop based on current risks and control is made, treatment is withdrawn (perhaps in stages), and, after a "washout" period, the patient is rechecked to ensure that treatment does not need to be restarted.
, http://www.100md.com
Monitoring strategy
For all phases, several choices have to be made in devising a good monitoring strategy: whether to monitor at all, the choice of measurement(s), the choice of target range, the choice of measurement interval, and who should monitor.
Which measurement
Monitoring the wrong target is obviously a fundamental error. Often various possible monitoring tests will be available, and there are advantages to choosing one main measurement (or a composite measure of several) to guide changes in management (fig 2). The criteria for the choice of measurement include the following.
, 百拇医药
Is it a good predictor of clinically relevant outcomes Monitoring measurements are surrogate markers for the patient relevant outcomes.21
Can it detect changes in risk early Risk predictors will vary in their responsiveness to the beneficial impact of treatment, with a good monitoring measurement providing an early indication of risk change.22
Is the random variability acceptable or can it be made acceptable by repeated measurements
, 百拇医药
Is it sufficiently affordable, accessible, and acceptable to patients
Choosing the monitoring interval
The different phases require different monitoring intervals (table 1). The interval is shortest for the pretreatment phase, longest for the maintenance phase, and intermediate for the other three phases.
For the pretreatment phase, measurements need to be far enough apart to make allowance for the short term variability within and between days. For example, the multiple readings taken when monitoring blood pressure for 24 hours give an accurate picture over a full day but do not capture some patients' considerable variability from day to day. For remeasurement during the treatment phases, we must know the time to therapeutic response (allowing for both pharmacokinetics and pharmacodynamics)—for example, the interval for statins is about six weeks23 and for angiotensin converting enzyme inhibitors for blood pressure about three weeks.24
, 百拇医药
Who should monitor
Self monitoring by patients is becoming more common. Such monitoring may be for motivation—for example, by using pedometers to monitor physical activity or home blood glucose measurement for people with non-insulin dependent diabetes25; for providing a clinician with between visits measurements—for example, home blood pressure monitoring26, or home glucose monitoring; or for self adjustment of therapy—for example, peak flow rates to trigger actions in asthma patients27 or home blood glucose for insulin adjustments. As the examples show, monitoring of patients can be done for all three purposes.
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Discussion
Although monitoring is common in clinical practice, the principles of monitoring have not been well conceptualised, which in turn has led to suboptimal care. Chronic care could potentially be improved (and often at reduced costs) if for each chronic disease we determined whether and how monitoring was necessary, set explicit monitoring ranges and provided appropriate graphical representations that aided decision making, recognised the need for different optimal intervals for different phases, and understood better when and how to adjust treatment to avoid the increases in variability caused by overadjustment. Health professionals working in chronic care need to understanding these principles better, and systems needs to be improved, including use of appropriate decision aids that have been shown to improve monitoring care.28
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Additional educational resources
For patients and clinicians
National electronic Library for Health (www.nelh.nhs.uk)—contains UK relevant guidelines on monitoring for many areas. A search on "monitoring" and choosing "evidence" provides the evidence base for a number of monitoring topics
The BTS/SIGN British Guideline for Asthma (www.brit-thoracic.org.uk/sign/index.htm)—few long term conditions have appropriate monitoring charts, but asthma is one of the better served. A printable peak flow diary is downloadable from the websites of the British Thoracic Society and Scottish Intercollegiate Guidelines Network (www.brit-thoracic.org.uk/sign/mainframe_download.html)
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For researchers
Westgard QC (www.westgard.com)—a website for laboratory tests, which includes a database of within person variation for over 100 tests (see "Biologic Variation Database"), and the Westgard rules for detect readings beyond control limits
Summary points
Monitoring aims to establish the response to treatment, detect the need to adjust treatment, and detect adverse effects
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Monitoring is not always necessary or beneficial and can lead to inappropriate changes
Control charts help distinguish natural variability from true change and reduce unnecessary adjustment
Monitoring for both benefit and harm is important, preferably with a single measurement
The interval between measurements varies between phases and is shorter after changes in treatment
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We thank Andrew Farmer, Jeffrey Aronson, and Tom Fahey for detailed comments on various drafts, and Susan Jack who help with initial searches and problem formulation.
Contributors: PG conceived the study, and all authors contributed to the ideas and writing. PG is guarantor.
Funding: PG and LI were in part funded by the Australian National Health and Medical Research Council for this work, as part of a programme grant 211205 on testing.
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Competing interests: None declared.
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