Integrating a pharmacist into the perioperative setting.

This paper describes the integration of a pharmacist into a perioperative environment and the ensuing quality and economic benefits. Deficiencies were identified in medication management in operating theatres (OT) at a large tertiary hospital. A perioperative pharmacist was employed for a 6-month pilot period, with permanent funding dependent on demonstration of agreed economic benefits. A multidisciplinary committee set goals, drove strategic initiatives and was accountable for delivery of outcomes. Pharmaceutical expenditure was analysed and high expenditure items targeted. Cost savings and staff satisfaction were measured at 6 months. Savings of A$63884 were achieved during the pilot period, resulting from optimised pharmaceutical unit pricing, OT medication stock on hand (imprest) review and redesigned medication management strategies. Improvements in medication management included better access to medications in the OT, rationalising available products to minimise wastage and implementation of guidelines and protocols for high-cost and high-risk medications. At 6 months, 97% of theatre staff supported continuation of the role; the project was extended with demonstrated cost savings of A$157265 at 12 months. The integration of a perioperative pharmacist resulted in cost savings and medication management improvements in the OT setting. A permanent position was funded.

Neurotoxicity in chronic lithium poisoning.

BACKGROUND: Lithium-induced neurotoxicity typically occurs with chronic accumulation rather than following acute overdose. There is little emphasis in the literature on the protracted nature of lithium neurotoxicity long after the lithium concentration returns to the therapeutic range. AIMS: To characterise lithium neurotoxicity, with a view of increasing awareness of this important phenomenon. METHODS: This is a retrospective observational study of patients presenting with lithium-induced neurotoxicity over a 5-year period to a clinical toxicology unit. Patients were identified through the unit's database, and clinical notes were analysed. RESULTS: There were 22 patients, with a median age of 65 (range: 36-89) years. Six patients (27%) had previous lithium toxicity, and nine (41%) were regularly prescribed medications that impair lithium excretion. The median lithium concentration on presentation was 2.2 mmol/L, taking a median of 3 days to return to the therapeutic range. Reversible acute kidney injury was observed in 21 patients (95%) on presentation. The median length of stay was 13 (range: 3-95) days due mostly to delayed neurological recovery. Confusion was the predominant symptom, present in 21 (95%) patients, followed by tremors (18(82%)) and ataxia (16(73%)). Multiple investigations were performed to exclude delirium differentials, including 11 computed tomography (CT) and five magnetic resonance imaging (MRI) brain scans, all unremarkable. CONCLUSIONS: Lithium neurotoxicity has a prolonged course. Its severity correlates poorly with lithium concentrations, which normalise quickly. Most poisonings occur in elderly patients with acute kidney injury. Prolonged delirium often prompts multiple unnecessary investigations. Rationalisation of lithium therapy is important in elderly patients.

Using EMR-enabled computerized decision support systems to reduce prescribing of potentially inappropriate medications: a narrative review.

Prescribing of potentially inappropriate medications (PIMs) that pose more risk than benefit in older patients is a common occurrence across all healthcare settings. Reducing such prescribing has been challenging despite multiple interventions, including educational campaigns, audits and feedback, geriatrician assessment and formulary restrictions. With the increasing uptake of electronic medical records (EMRs) across hospitals, clinics and residential aged care facilities (RACFs), integrated with computerized physician order entry (CPOE) and e-prescribing, opportunities exist for incorporating clinical decision support systems (CDSS) into EMR at the point of care. This narrative review assessed the process and outcomes of using EMR-enabled CDSS to reduce the prescribing of PIMs. We searched PubMed for relevant articles published up to January 2018 and focused on those that described EMR-enabled CDSS that assisted prescribers to make changes at the time of ordering PIMs in adults. Computerized systems offering only medication reconciliation, dose checks, monitoring for medication errors, or basic formulary information were not included. In addition to outcome measures of medication-related processes and adverse drug events, qualitative data relating to factors that influence effectiveness of EMR-enabled CDSS were also gathered from selected studies. We analysed 20 studies comprising 10 randomized trials and 10 observational studies performed in hospitals (n = 8), ambulatory care clinics (n = 9) and RACFs (n = 3). Studies varied in patient populations (although most involved older patients), type of CDSS, method of linkage with EMR, study designs and outcome measures. However, assuming little publication bias, the totality of evidence favoured EMR-enabled CDSS as being effective in reducing the prescribing of PIMs in hospitals, although results were more mixed for ambulatory care settings and RACFs. While absolute effects in most positive studies were modest, they suggest EMR-enabled CDSS are feasible and acceptable to clinicians, and if certain design features are adhered to, there is potential for even greater impact.

Prescribing in the oldest old inpatients: a retrospective analysis of patients referred for specialist geriatric consultation.

BACKGROUND: While medications may prolong life and prevent morbidity in older people, adverse effects of polypharmacy are increasingly recognised. As patients age and become frail, prescribing may be expected to focus more on symptom control and minimise potentially harmful preventive medication use that confer little benefit within a short lifespan. Whether prescribing practice shifts to one of symptom controls among the oldest old admitted to hospital remains unclear. AIM: To determine, in the oldest old inpatients, whether preventive versus symptom control medication prescribing was associated with age or level of frailty. METHODS: Retrospective analysis of all patients aged ≥85 years referred for comprehensive geriatric assessment at a tertiary care hospital between May 2006 and December 2014 for whom all prescribed medications were documented. Medication use was assessed according to age group (85-89, 90-94, ≥95) and categories of frailty index calculated for patients based on 52 deficits (fitter, moderately frail, frail and severely frail). RESULTS: Seven hundred and eighty-three inpatients were assessed of mean (SD) age 89.0 (3.4) and mean frailty index 0.45 (SD 0.14) with a median of eight co-morbidities (IQR 6-10) and who were prescribed a mean of 8.3 (SD 3.8) regular medications per day. Polypharmacy (5-9 medications per day) was observed in 406 patients (51.9%) and hyper-polypharmacy (≥10 medications per day) in 268 patients (34.2%). While there was a significant decrease in number of prescribed medications as age increased, there were no differences across age groups or frailty categories in proportions of medications used for prevention versus symptom control. CONCLUSION: Polypharmacy is prevalent in oldest old inpatients and prescribing patterns according to prevention versus symptom control appear unaffected by age and frailty status.

Self-poisoning by older Australians: a cohort study.

OBJECTIVE: To examine the epidemiology and severity of self-poisoning by older people in Australia; to compare these data with those for overdoses in younger adults. DESIGN, SETTING, PARTICIPANTS: A cohort study of people presenting to a tertiary toxicology centre after self-poisoning over 26 years (1987-2012). MAIN OUTCOME MEASURES: Hospital length of stay (LOS); types of drug ingested; intensive care unit (ICU) admissions; in-hospital deaths. RESULTS: Of 17 276 admissions, 626 patients (3.6%) were at least 65 years old. There was a steady decline in the number of overdoses with age. Most self-poisoning by older people was intentional (80% of admissions), but the proportion of unintentional poisonings increased with age (P < 0.001). Median LOS for older patients was 34 h (interquartile range [IQR], 16-75 h), longer than for younger patients (16 h; IQR, 9-25 h; P < 0.001). 133 older patients (21.2%) were admitted to an ICU, compared with 1976 younger patients (11.9%; P < 0.001). 24 older patients (3.8%) and 93 younger patients (0.6%) died; mortality among older patients declined over time. Hypotension and arrhythmias were more common in patients over 65. Benzodiazepines (24%) were the drugs most commonly ingested by older patients, but opioids the most frequently taken drugs in fatal cases. Toxic ingestion of cardiovascular drugs increased threefold over the 26 years; about one-third of poisonings were unintentional or iatrogenic. Recreational drugs were implicated in the admissions of four older patients (0.6%), but in 7.8% of those of people under 65. CONCLUSION: Older patients treated for self-poisoning differ in several important respects from patients under 65. They are more severely affected by self-poisoning: LOS is greater, and ICU admission and mortality rates are higher.

A clinical audit of high-cost and off-label drug use in dermatology.

BACKGROUND/OBJECTIVES: The use of high-cost, off-label, unsubsidised drugs has become valuable in the management of dermatology patients with challenging conditions unresponsive to conventional therapy. Currently, there is no dedicated funding and a paucity of evidence for such drugs. The aim of this audit was to review outcomes and costs. METHODS: A retrospective clinical audit of high-cost off-label dermatology drug applications to the High Cost Drug's Subcommittee was undertaken at a tertiary public hospital in Brisbane, Queensland, between 2002 and 2013. RESULTS: Of 28 applications, 25 were approved. The medications included thalidomide, mycophenolate mofetil, cyclosporin, infliximab, rituximab and adalimumab. Over 70% of patients responded to treatment. Individual annual costs for these medications ranged from $2068 to $36 984. Adverse effects resulted in drug withdrawal in five cases. CONCLUSIONS: Despite the absence of dedicated funding for high-cost drugs and a rigorous committee approval process, most applications were approved, of which >70% benefited from treatment. This audit provides useful clinical experience with off-label use of high-cost drugs in difficult dermatological conditions.

Polypharmacy among inpatients aged 70 years or older in Australia.

OBJECTIVES: To investigate medication changes for older patients admitted to hospital and to explore associations between patient characteristics and polypharmacy. DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: Patients aged 70 years or older admitted to general medical units of 11 acute care hospitals in two Australian states between July 2005 and May 2010. All patients were assessed using the interRAI assessment system for acute care. MAIN OUTCOME MEASURES: Measures of physical, cognitive and psychosocial functioning; and number of regular prescribed medications categorised into three groups: non-polypharmacy (0-4 drugs), polypharmacy (5-9 drugs) and hyperpolypharmacy (≥ 10 drugs). RESULTS: Of 1220 patients who were recruited for the study, medication records at admission were available for 1216. Mean age was 81.3 years (SD, 6.8 years), and 659 patients (54.2%) were women. For the 1187 patients with complete medication records on admission and discharge, there was a small but statistically significant increase in mean number of regular medications per day between admission and discharge (7.1 v 7.6), while the prevalence of medications such as statins (459 [38.7%] v 457 [38.5%] patients), opioid analgesics (155 [13.1%] v 166 [14.0%] patients), antipsychotics (59 [5.0%] v 65 [5.5%] patients) and benzodiazepines (122 [10.3%] v 135 [11.4%] patients) did not change significantly. Being in a higher polypharmacy category was significantly associated with increase in comorbidities (odds ratio [OR], 1.27; 95% CI, 1.20-1.34), presence of pain (OR, 1.31; 1.05-1.64), dyspnoea (OR, 1.64; 1.30-2.07) and dependence in terms of instrumental activities of daily living (OR, 1.70; 1.20-2.41). Hyperpolypharmacy was observed in 290/1216 patients (23.8%) at admission and 336/1187 patients (28.3%) on discharge, and the proportion of preventive medication in the hyperpolypharmacy category at both points in time remained high (1209/3371 [35.9%] at admission v 1508/4117 [36.6%] at discharge). CONCLUSIONS: Polypharmacy is common among older people admitted to general medical units of Australian hospitals, with no clinically meaningful change to the number or classification (symptom control, prevention or both) of drugs made by treating physicians.

Deciding when to stop: towards evidence-based deprescribing of drugs in older populations.

Minimising the harm from inappropriate prescribing in older populations is a major urgent concern for modern healthcare systems. In everyday encounters between prescribers and patients, opportunities should be taken to identify patients at high risk of harm from polypharmacy and reappraise their need for specific drugs. Attempts to reconcile life expectancy, comorbidity burden, care goals and patient preferences with the benefits and harms of medications should be made in every patient at significant risk. Drugs identified by this process of reconciliation as conferring little or no benefit and/or excessive risk of harm should be candidates for discontinuation. Evidence supporting a structured approach to drug discontinuation (or deprescribing) is emerging, and while many barriers to deprescribing exist in routine practice, various enabling strategies can help overcome them.

Off-label use of recombinant factor VIIa in two tertiary hospitals in Queensland.

BACKGROUND: Recombinant factor VIIa (rFVIIa) is used for many off-label indications without high quality evidence to support its efficacy. The aim of this study was to determine indications for use of off-label rFVIIa, efficacy and safety, and adherence to institutional guidelines. METHODS: We performed a retrospective review of off-label rFVIIa at two tertiary hospitals from 2007 to 2010. RESULTS: One hundred forty-five administrations were identified and analysed. Haemorrhage associated with cardiac surgery made up one-third of all rFVIIa usage, with trauma (20%) and other surgery (11%) the next most frequent indications. Compared with all others, cardiac surgery patients were older (60.0 years versus 47.4 years, P < 0.001) and had lower pre-rFVIIa transfusion requirements, a higher subjective response rate (88% versus 46%, P < 0.001) and lower mortality rates (6.1% versus 33%, P < 0.001), but higher rates of arterial thrombormbolic events (16.7% versus 2.1%, P = 0.002). Most patients received only one or two doses (n = 137; 95%), with no subject receiving a third or subsequent dose having an appreciable reduction in bleeding. Only a small number of patients (n = 15; 10.3%) had rFVIIa administered in accordance with our institutions' guidelines. CONCLUSION: Patients administered rFVIIa for haemorrhage not associated with cardiac surgery were severely unwell. Despite lack of evidence, administration of rFVIIa may be justified by the high mortality rate, but more than two doses are unlikely to provide further benefit. The high rate of arterial thromboembolism in cardiac surgical patients raises risk-benefit considerations. Adherence to our institutions' guidelines was poor.

Association of pre-transplant statin use with delayed graft function in kidney transplant recipients.

BACKGROUND: Administration of HMG-CoA reductase inhibitors (statins), prior to ischemia or prior to reperfusion has been shown to decrease ischemia-reperfusion renal injury in animal studies. It is unknown whether this protective effect is applicable to renal transplantation in humans. The aim of this study was to determine the relationship between prior statin use in renal transplant recipients and the subsequent risk of delayed graft function. METHODS: All patients who underwent deceased or living donor renal transplantation at the Princess Alexandra Hospital between 1 July 2008 and 1 August 2010 were included in this retrospective, observational cohort study. Graft function was classified as immediate graft function (IGF), dialysis-requiring (D-DGF) and non-dialysis-requiring (ND-DGF) delayed graft function. The independent predictors of graft function were evaluated by multivariable logistic regression, adjusting for donor characteristics, recipient characteristics, HLA mismatch and ischaemic times. RESULTS: Overall, of the 266 renal transplant recipients, 21% exhibited D-DGF, 39% had ND-DGF and 40% had IGF. Statin use prior to renal transplantation was not significantly associated with the risk of D-DGF (adjusted odds ratio [OR] 1.05, 95% CI 0.96 - 1.15, P = 0.28). This finding was not altered when D-DGF and ND-DGF were pooled together (OR 0.98; 95% CI 0.89-1.06, p = 0.56). CONCLUSIONS: The present study did not show a significant, independent association between prior statin use in kidney transplant recipients and the occurrence of delayed graft function.

Therapeutic drug monitoring of tacrolimus by liquid chromatography-tandem mass spectrometry: is it truly a routine test?

Therapeutic drug monitoring of tacrolimus by high-performance liquid chromatography-tandem mass spectrometry has become standard practice. We report on the long-term (4.5 years) use of one such method. Whole blood samples (25 µL) were treated with zinc sulphate (100 µL) and acetonitrile containing ascomycin (internal standard, 250 µL). A high-performance liquid chromatography-tandem mass spectrometer operating in positive ion mode with an electrospray interface was used. Chromatography was performed on a TDM C(18) cartridge column (10 mm × 2.1 mm, 10 µm, Waters) using a switch gradient. A total of 4029 batches were analyzed for tacrolimus; this comprised of 81950 analyses of which 61027 were patient samples. Calibration curves (1.0-50 µg/L) were run on 1765 occasions (mean r(2)=0.999; range r(2)=0.988-0.999). Inter-batch accuracy and imprecision of the method (2.5, 12.5 and 30.0 µg/L), when in routine use, was 97.6-98.5% and <8.0%, respectively (n=4031). Evaluation of the method against other methods in an external quality control scheme revealed good agreement by linear regression analysis (y=0.924x+0.196, r(2)=0.985). The percentage difference between our results and that of all methods revealed a mean bias of -6.3% and a range of -33.3% to 11.1%. During the evaluation period, four batch failures occurred (0.1% failure rate) and greater than 1000 samples per analytical column was achieved. In conclusion, the described method is ideally suited as a routine test for tacrolimus in the clinical setting.

Outcomes in patients with gram-negative sepsis treated with gentamicin.

OBJECTIVE: Recent changes to therapeutic drug monitoring (TDM) of gentamicin have been advocated in Australia. It remains uncertain whether these will have an effect on hard clinical endpoints. The aim of this study was to determine clinical outcomes in patients with gram-negative infections treated with gentamicin. METHODS: Microbiology results of patients with confirmed gram-negative cultures were retrospectively reviewed and those treated with gentamicin included. Medical records were reviewed and patient demographics, diagnosis, renal function, comorbidities, gentamicin doses, duration, monitoring, concomitant antibiotics, antimicrobial sensitivity and clinical and microbiological outcomes recorded. RESULTS: A total of 100 patients were included in the study: 52% were male, median age 64 years (17-97). Total body weight was recorded in 56% (median 74.5 kg, range 35-134 kg). Most patients had two or more important comorbidities. A total of 72% received empiric and 28% directed treatment. The organism was identified on blood culture in 45%, urine culture in 43% and aspiration of liver abscess in 12%; 95% of organisms were sensitive to gentamicin. Baseline renal function was normal in 62%. Mean gentamicin dose was 3.9 ± 0.9 mg/kg and mean duration 2.9 ± 2.5 days. Only 21% had optimal TDM. Clinical outcome was favourable in 90%. There were no cases of preventable serious toxicity. CONCLUSIONS: Despite the modest doses of gentamicin used in an elderly population with comorbidities, as well as the absence of optimal TDM, outcomes were favourable without preventable serious toxicity.

Severe acute liver injury associated with lumiracoxib.

BACKGROUND AND AIM: Significant elevations in liver transaminases were noted in some patients during pre-marketing clinical trials with lumiracoxib, a selective COX-2 inhibitor. It was withdrawn from the Australian market in August 2007, because of an association with severe liver injury. We describe in detail three cases of severe liver injury in patients taking lumiracoxib METHODS: Three patients admitted to our hospital with severe liver injury and taking lumiracoxib are described in detail, together with information on a further six cases reported to the Australian Therapeutics Goods Administration (TGA), none of whom had pre-existing liver disease or obvious risk factors for liver disease. RESULTS: Liver histology showed severe hepatic necrosis. One patient required liver transplantation and another died. Autoantibodies were detected in all three patients. As with the other six cases reported to the TGA, all were females who had been taking lumiracoxib 200-400 mg daily, typically for a few months, for osteoarthritis. CONCLUSIONS: Lumiracoxib can be associated with severe liver injury. The presence of a variety of positive auto-antibodies suggests an altered immune response may be contributory.

Use and monitoring of low dose rituximab in myasthenia gravis.

BACKGROUND: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Rituximab (RTX), a monoclonal antibody to CD20, leads to B lymphocyte depletion and has been used in some autoimmune disorders, including small case series of myasthenia gravis patients. METHODS: A retrospective analysis was performed of all patients with acetylcholine receptor (AChR) (11 subjects) or muscle specific kinase antibody (MuSK) positive myasthenia gravis (three subjects), who had been treated with RTX in Brisbane, Australia. In most patients 1 g of RTX, in two divided doses, was given. Patients were monitored by serial clinical assessments, flow cytometry of peripheral blood B lymphocytes and antibody testing. RESULTS: RTX led to a significant improvement in symptoms in 11 of 14 patients. Doses of immunosuppressive medications were able to be reduced in 12 of 14 patients but medications could be completely ceased in only one patient. A demonstrable reduction of autoantibody levels was found in only three AChR positive patients and one MuSK positive patient, independent of clinical improvement. Peripheral blood B lymphocyte depletion was achieved in 13 out of 14 patients. B lymphocyte recovery occurred between 9 and 30 months post RTX (median 12.3 months) and was consistently associated with worsening of clinical symptoms. CONCLUSION: Rituximab at a dose of 1 g appears to be beneficial in the treatment of patients with severe myasthenia gravis. Serial monitoring of peripheral blood B lymphocytes appears to be useful in guiding the need for further RTX therapy.

The current role of liquid chromatography-tandem mass spectrometry in therapeutic drug monitoring of immunosuppressant and antiretroviral drugs.

Therapeutic drug monitoring of critical dose immunosuppressant drugs is established clinical practice and there are similar good reasons to monitor antiretrovirals. The aim of this article is to review the recent literature (last five years), with particular reference to the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS offers many potential advantages. The superior selectivity of LC-MS/MS over immunoassays for immunosuppressant drugs has been widely reported. Simultaneous measurement of a number of drugs can be performed. It is currently routine practice for the four major immunosuppressants (cyclosporin, tacrolimus, sirolimus and everolimus) to be simultaneously measured in whole blood. While up to 17 antiretroviral drugs have been simultaneously measured in plasma. The exquisite sensitivity of LC-MS/MS also provides the opportunity to measure these drugs in alternative matrices, such as dried blood spots, saliva, peripheral blood mononuclear cells and tissue. However, the clinical utility of measuring these classes of drugs in alternative matrices is still to be determined.

Measurement of urinary oxypurinol by high performance liquid chromatography-tandem mass spectrometry.

Oxypurinol is the active metabolite of allopurinol which is used to treat hyperuricaemia associated with gout. Both oxypurinol and allopurinol inhibit xanthine oxidase which forms uric acid from xanthine and hypoxanthine. Plasma oxypurinol concentrations vary substantially between individuals and the source of this variability remains unclear. The aim of this study was to develop an HPLC-tandem mass spectrometry method to measure oxypurinol in urine to facilitate the study of the renal elimination of oxypurinol in patients with gout. Urine samples (50 microL) were prepared by dilution with a solution of acetonitrile/methanol/water (95/2/3, v/v; 2 mL) that contained the internal standard (8-methylxanthine; 1.5 mg/L), followed by centrifugation. An aliquot (2 microL) was injected. Chromatography was performed on an Atlantis HILIC Silica column (3 microm, 100 mm x 2.1mm, Waters) at 30 degrees C, using a mobile phase comprised of acetonitrile/methanol/50 mM ammonium acetate in 0.2% formic acid (95/2/3, v/v). Using a flow rate of 0.35 mL/min, the analysis time was 6.0 min. Mass spectrometric detection was by selected reactant monitoring (oxypurinol: m/z 150.8-->108.0; internal standard: m/z 164.9-->121.8) in negative electrospray ionization mode. Calibration curves were prepared in drug-free urine across the range 10-200 mg/L and fitted using quadratic regression with a weighting factor of 1/x (r(2) > 0.997, n=7). Quality control samples (20, 80, 150 and 300 mg/L) were used to determine intra-day (n=5) and inter-day (n=7) accuracy and imprecision. The inter-day accuracy and imprecision was 96.1-104% and <11.2%, respectively. Urinary oxypurinol samples were stable when subjected to 3 freeze-thaw cycles and when stored at room temperature for up to 6h. Samples collected from 10 patients, not receiving allopurinol therapy, were screened and showed no significant interferences. The method was suitable for the quantification of oxypurinol in the urine of patients (n=34) participating in a clinical trial to optimize therapy of gout with allopurinol.