POMH-UK Topic 7 Monitoring of patients prescribed lithium Please use the following to cite this report: Prescribing Observatory for Mental Health (2009). Topic 7 baseline report. Monitoring of patients prescribed lithium: baseline. Prescribing Observatory for Mental Health, CRTU069 (data on file).
Clinical background Lithium is licensed for the treatment of bipolar affective disorder and depression. Essentially it is used in three situations the acute treatment of mania, prophylaxis in bipolar disorder and to augment antidepressants in treatment refractory recurrent depression. Its use for these indications is supported by the NICE guidelines for depression (NICE, 2004) and bipolar disorder (NICE, 2006). Lithium also appears to protect against suicidality in both unipolar depression (Guzzetta et al, 2007) and bipolar illness (Goodwin et al, 2003). In addition, lithium is licensed for the treatment of aggressive or self-mutilating behaviour, and is occasionally used to increase the white blood cell count in patients who take clozapine (Paton, 2005). For most patients, lithium is a long-term treatment; in patients with bipolar disorder, it is recommended that lithium should be taken for at least 3 years (Goodwin, 1994). The side-effect profile of lithium is well established. Common side-effects include an upset stomach, fine tremor, polydipsia (thirst), polyuria (passing more urine than usual; Movig et al, 2003; Livingstone & Rampes, 2006), weight gain (Sachs et al, 2006; Livingstone & Rampes, 2006) and hypothyroidism (underactive thyroid). Lithium has a narrow therapeutic range, that is, there is a small margin between an effective dose and a toxic one. The therapeutic range is generally accepted to be 0.4-1.0mmol/L; blood should be taken 12 hours after the last dose. The lower end of this range is used for elderly and infirm patients, and the upper end for younger patients, particularly those being treated for an episode of mania. For the long-term treatment of bipolar disorder, Severus et al (2008) concluded from the available evidence that the optimal serum level range for lithium was between 0.4 1.2 mmol/l, but that when initiating long-term treatment, clinicians should aim for levels of 0.6-0.75 mmol/l, with higher levels possibly being of benefit for patients with predominantly manic symptoms. There is little information to guide choice of lithium level when it is used in treatment refractory depression or its other indications. If the concentration of lithium in the blood is too high, blurred vision, muscle weakness, coarse tremor, slurred speech, confusion, seizures and renal damage may all occur. All patients who take lithium should have regular blood tests to ensure that the amount of lithium in their blood is within the therapeutic range. Lithium is an element, so unlike the majority of drugs is not metabolised by the liver; it is almost wholly excreted in the urine. Any changes in kidney (renal) function, fluid balance (such as dehydration) or electrolyte levels (such as a low level of sodium in the blood - hyponatraemia), can potentially lead to lithium accumulation which in turn can lead to renal damage and toxicity. All patients who receive treatment with lithium should have their renal function (electrolytes and creatinine/e-gfr) checked regularly. Lithium treatment increases the risk of clinical hypothyroidism up to 5-fold, the risk being particularly high in women who are 40-59 years of age (Johnston & Eagles, 1999). The effects of lithium on the thyroid are complex; lithium is thought to interfere with iodine uptake, alter the structure of thyroglobulin,
decrease the release of T4, inhibit the peripheral conversion of T4 to T3 and possibly exacerbate pre-existing autoimmunity (Livingstone & Rampes, 2006). The clinical symptoms of hypothyroidism overlap with those of depression and may therefore remain undiagnosed and untreated unless specific screening tests are undertaken. All patients who receive treatment with lithium should have their thyroid function tests (TFTs) checked regularly. Recommendations for monitoring patients receiving lithium With respect to plasma lithium levels, the NICE guideline for bipolar disorder (2006), Drugs & Therapeutics Bulletin (DTB, 2005), the Summary of Product Characteristics (SPC) for Priadel and the British National Formulary (BNF) all recommend that plasma lithium is checked every 3. The British Association for Psychopharmacology guidelines for bipolar disorder (Goodwin, 2003) recommend every 3-6. With respect to renal and thyroid function, the NICE guideline for bipolar disorder and the DTB recommend that U&Es, creatinine and TFTs are checked every 6, the BNF every 6-12 and the BAP guideline for bipolar disorder recommends every 12. These monitoring recommendations are summarised in the table below. Source Priadel SPC BAP guideline for bipolar disorder 2003 DTB 2005 NICE guideline for bipolar disorder 2006 BNF 2007 Serum lithium -6 Target range (mmol/l) 0.7-1.0 0.5-1.0 (up to 1.5mmol/L in acute mania) U&Es and TFTs Should be reassessed periodically Every 12 0.4-1.0 Every 6 0.6-0.8mmol/L (Option of up to 1.0) Every 6 (U&Es more often if interacting drugs are co-prescribed) 0.4-1.0 Every 6-12 In primary care, the Quality and Outcomes Framework (QOF) sets targets for the monitoring of patients receiving lithium. The measures collected for each practice are the proportion of patients receiving lithium who have had their TFTs and creatinine checked in the previous 15 (mental health standard 4) and have had a plasma lithium level within the therapeutic range documented in the previous 6 (mental health standard 5). Lithium treatment is commonly associated with weight gain, and given the potential adverse consequences for physical health, it is reasonable to expect that weight/bmi checks will form part of the annual physical examination for patients who receive this treatment.
Audit standards 1: The following tests/measures should be completed before initiating treatment with lithium a) Renal function tests; urea and electrolytes (U&Es) including creatinine (or e-gfr or creatinine clearance) b) Thyroid function tests (TFTs) c) Weight or BMI or waist circumference 2: The following tests/measures should be conducted during maintenance treatment a) Serum lithium level every 3 b) U&Es and TFTs every 6 c) Weight or BMI or waist circumference during the last year Monitoring lithium in clinical practice There are a number of published audits of lithium monitoring. These audits cover all care groups; children and adolescents (Craig et al, 2006), adults (Butler & Taylor, 2000), the elderly (Olugbemi & Katona, 1998; Head & Denning, 1998) and people with learning disabilities (Buckley & Sharrand, 2003). All report that practice could be improved. For example, Craig et al (2006) found that a third of patients did not have baseline laboratory tests before lithium was prescribed, Butler & Taylor (2000) that 7% of patients had not had a plasma lithium level measured for over a year and Glover & Lawley (2005) that a third of patients had no recorded results for U&Es or TFTs in the last year. Glover & Lawley (2005) also reported that 75% of patients considered that they had not received enough information about lithium treatment. Despite the recognised need for lithium monitoring, and the availability of national guidelines and Trust prescribing frameworks, local audits tend to find that lithium monitoring is inadequate. Lithium Related Patient Safety Incidents Reported to the National Patient Safety Agency (NPSA) The National Patient Safety Agency (NPSA) is a Special Health Authority which was established in 2001 to coordinate efforts to identify and learn from patient safety incidents. Its roles include the following: Collect and analyse information on adverse events Assimilate other safety-related information Learn lessons and ensure that they are fed back into practice Where risks are identified, to work with partners to produce solutions to prevent harm.
How incidents are reported The information the NPSA uses is gathered from a variety of sources, the mainstay of which is the Reporting and Learning System (RLS). This is the system through which anybody can report patient safety incidents to the NPSA, and it is through these reports that it can identify trends and patterns and analyse what is going on throughout the NHS. The RLS is not intended to replace or duplicate the work of the Medicines and Healthcare Regulatory Authority (MHRA) in identifying and/or quantifying adverse reactions to prescribed medicines that are used appropriately in routine clinical practice. The focus of the RLS is to identify systems errors that may be preventable. Reports are received in a number of ways: Local NHS Trusts are linked via local risk management systems to the NPSA and so incidents reported to those trusts are forwarded to the NRLS automatically. Practitioners and staff can choose to report directly to the NPSA using the form on the agency s website, and in this case have the choice whether or not to share that report with their local trust. In the case of large community pharmacy chains, most choose to send reports directly from head office once they have been reported from branches using internal reporting mechanisms. Patients and carers can also report using the web based form. The NPSA also receives information from other agencies such as the Medicines and Healthcare Regulatory Authority, the Healthcare Commission, the NHS Litigation Authority and various professional indemnity organisations such as the Chemist Defence Association and the Medical Defence Union. Finally, the NPSA receives information from international partners all across the world. All of these information sources put together represent a vast array of information from which the NPSA tries to get to the root of what is going wrong and do something about it. The NPSA currently receives up to 100,000 error reports a month from the NHS, and of these up to 10,000 reports a month relate to medication incidents. A review of medication incidents related to the use of lithium reported to the RLS identified a total of 567 incidents. The majority of these incidents were submitted from within mental health services (see table below) Care Setting Total Mental health service 317 Acute / general hospital 160 Learning disabilities 32 Community nursing, medical and therapy service (incl. community hospital) 30 Community pharmacy 23 General practice 5 Total 567
Out of the total of 567 incidents, two were identified as resulting in severe harm to the patient, 34 in moderate harm, and the remainder in low or no harm. A further analysis of the RLS data allowed a breakdown by Stage during the medication process. This identified that the administration and prescribing stages are the most prone to error (see table below). Stage During Medication Process Total Administration / supply of a medicine from a clinical area 279 Prescribing 115 Preparation of medicines in all locations / dispensing in a pharmacy 107 Monitoring / follow-up of medicine use 27 Other 29 Advice 10 Total 567 By analysing the data further, a breakdown can be made showing the type of error that has been reported. As can be seen by the data in the table below wrong dose or strength was the most commonly reported type of error. This is consistent with all medication data submitted to the RLS. Medication error type Number Wrong / unclear dose or strength 124 Wrong frequency 77 Omitted medicine / ingredient 71 Wrong drug / medicine 74 Other 70 Wrong quantity 46 Mismatching between patient and medicine 29 Contra-indication 23 Wrong / transposed / omitted medicine label 11 Wrong storage 6 Wrong formulation 7 Adverse drug reaction (when used as intended) 9 Wrong / omitted / passed expiry date 8 Unknown 5 Wrong method of preparation / supply 4 Wrong / omitted patient information leaflet 2 Wrong / omitted verbal patient directions 1 Total 567
Perhaps the real learning from reports to the RLS comes from looking at the narrative within the reports. The following are examples of errors relating to the monitoring of lithium that have been reported and are fairly representative of the type of errors that the NPSA receives: 1. Lithium level of 0.97mmol/L treated as normal" in a 61 year old with symptoms of lithium toxicity, as this fell within the local lab range of 0.6-1.2 mmol/l. The patient later developed life threatening toxicity and renal failure. 2. Emergency admission of patient for lithium toxicity in a critical condition. Unfortunately his lithium levels were out of date. The last level (5 old) was within the therapeutic range, hence his lithium was reauthorised. Unfortunately, it appeared his outpatient appointments had been subject to cancellations hence his lithium levels were not being regularly monitored. Patient at time of report was being ventilated. 3. Patient on treatment for depression with lithium which was monitored by his G.P. The lithium level had gone up but it was still within therapeutic levels (but may have been toxic for him). He had a stroke and died. His clinical state may have been worsened by the effects of a high lithium level. The concern was that if the lithium level is not above normal it is not flagged up on the system even though it may have doubled in reality. 4. Patient was seen in community and was diagnosed with lithium toxicity. Lithium levels were three times higher than last time they were checked, and well above therapeutic range. On discovering patient blood results, patient was immediately transferred to A&E before transferring her to the Medical Admissions Unit for treatment for renal failure. 5. Patient on lithium for many years. Discharged on diuretic but lithium dose was not reduced. Readmitted three weeks later with life threatening lithium toxicity. Lithium levels are increased when diuretics are added.