Orbital myositis secondary to statin therapy

A 45-year-old man presented with a 3-month history of diplopia and pain on left downgaze, increasing left upper lid oedema, and erythema. Eye movements were full and visual acuity and intraocular pressure normal. His regular medications, both commenced 4 months before presentation, were simvastatin (20 mg/day) and aspirin (100 mg/day). A complete blood count, thyroid function and auto-antibodies, inflammatory markers and creatine kinase were all unremarkable, as was an autoimmune screen. Orbital computed tomography showed left medial rectus and superior oblique enlargement.

Simvastatin was ceased, and all symptoms resolved within 3 weeks. Diplopia recurred 4 weeks after a rechallenge with 10 mg simvastatin daily, and resolved almost immediately after withdrawing the statin. The man subsequently elected to control his cholesterol levels with lifestyle modifications.

Orbital myositis is inflammation of one or more extraocular muscles, characteristically presenting with diplopia and orbital pain exacerbated by eye movement. Restriction of eye movement, exophthalmos, conjunctival inflammation and erythema may occur;1 imaging indicates muscle and tendon enlargement. It is usually idiopathic, but can occur in association with a range of inflammatory conditions, including sarcoidosis, systemic lupus erythematosus, Crohn’s disease and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.1

Statins are usually well tolerated medications, but myopathy occurs in 1%–5% of participants in clinical trials, and in 10%–15% of patients in observational studies.2 Statins can affect the extraocular muscles, and orbital myositis should be considered in patients experiencing orbital symptoms during statin treatment.3 The metabolic requirements of extraocular muscles are enormous, but their glycogen content is limited, which may make them more vulnerable to the GTP depletion and myopathy associated with statin use.4 Such patients may present to any of a range of clinicians, and lack of awareness of this complication can mean that cessation of statin therapy is not tried, or that inappropriate treatment is given.

We reviewed VigiBase (the World Health Organization global individual case safety reports database) and two subsets of this adverse drug reaction database (the Medicines and Healthcare Products Regulatory Agency [United Kingdom] and the Therapeutic Goods Administration [Australia]) for all reported ocular complications associated with atorvastatin, simvastatin, rosuvastatin and pravastatin. These databases contained a total of 452 reports suggestive of orbital myositis (Box), including subjective and objective symptoms and signs, and one instance specifically described as an “extraocular muscle disorder”. The databases rarely record dechallenge or rechallenge data, nor do they record relevant investigations and clinical follow-up data. However, as most complications are unreported by patients and their clinicians, the true incidence of side effects is likely to be far higher than that reported.

We would encourage others to use scales such as the Naranjo algorithm, which incorporates important data such as rechallenge and the results of investigations, to calculate adverse drug reaction probabilities.5 Using this scale, our case achieved a score of 9, indicating a “definite” adverse drug reaction.

Box –
Summary of the 452 adverse events recorded in event notification databases

	Diplopia	Exophthalmos	Ophthalmoplegia

TGA (15 reports)
Atorvastatin	7	—	—
Simvastatin	5	—	—
Rosuvastatin	2	—	—
Pravastatin	1	—	—
MHRA (30 reports)
Atorvastatin	8	1	—
Simvastatin	11	1	—
Rosuvastatin	—	1	—
Pravastatin	7	1	—
WHO (407 reports)
Atorvastatin	107	3	22
Simvastatin	95	—	30
Rosuvastatin	49	—	18
Pravastatin	69	1	13
Total	361	8	83

TGA = Therapeutic Goods Administration Database of Adverse Event Notifications (Australia); MHRA = Medicines and Healthcare Products Regulatory Agency (United Kingdom); WHO = VigiBase, World Health Organization, Uppsala Monitoring Centre (Sweden).

Antibiotic resistance changing management of urinary tract infections in aged care

In the lead up to the global Antibiotic Awareness Week (16–22 November), it is timely to focus on the fact that bacterial infections that were once easily cured with antibiotics, such as those affecting the urinary tract, are becoming harder to treat.

Urinary tract infections (UTIs) are common in adults, and are prevalent in both hospital and community settings.

Escherichia coli bacteria — responsible for 80%–90% of uncomplicated UTIs — can display multidrug resistance.

UTIs can result in significant symptoms. When these are present, antibiotic treatment is typically indicated. However, for many people, including those in residential aged care facilities, asymptomatic bacteriuria has not been shown to be harmful. For this reason, routine testing for, or treatment of, asymptomatic UTIs in residential aged care facilities is not beneficial, except in catheterised patients at risk of complications, such as those with neutropenia.

Promoting the appropriate use of antibiotics for UTIs is an important consideration for residents in aged care facilities as excessive use — in the context of asymptomatic bacteriuria — may be contributing to the high prevalence of multidrug-resistant E. coli seen in this group.

In 2012, NPS MedicineWise began a 5-year campaign to reduce antibiotic prescribing in Australia, to bring it in line with the OECD (Organisation for Economic Co-operation and Development) average. The campaign encourages all Australians to use antibiotics responsibly. For health professionals, this means the judicious use and prescribing of antibiotics, and adherence to the principles of antimicrobial stewardship.

Health professionals can consolidate their knowledge on treating UTIs and minimising antibiotic resistance, and brush up on current guidelines and practices at www.nps.org.au/utis.

Ethics and compliance hurdles in conducting multicentre low-risk research

It is over 10 years since Roberts and colleagues1 highlighted difficulties in conducting research across multiple sites. However, the process still remains complex. Our study involved a retrospective data review (2012–2013) across multiple Australian public hospital pharmacy departments to identify the extent of compounding of pharmaceutical products at each site. With no requirement for patient participation (or for patient health details), the project was classified as low or negligible risk. The only participants involved were pharmacists who were provided with the opportunity to raise any concerns related to compounding practices. Ethics approval was obtained from the host university, and from a South Australian hospital site. Despite this, the pathway to gaining ethics approval from the other public hospitals involved multiple procedures.

Gaining ethics approval at one ethics committee involves effort, but in multicentre research projects, the effort is multiplied with non-concordant approval requirements. Extensive paperwork, the need for a local contact person at each site and the delay in obtaining signatures from departmental heads were the major issues, despite utilising the researchers’ professional networks. Human research ethics committee (HREC) meeting schedules varied from 1 to 2 months, with little flexibility to accept proposals if an agenda was full.

After 6 months’ work, we received approval from seven of the 10 HRECs approached. However, one pharmacy department subsequently refused involvement. A summary of major concerns encountered at the six sites at which the research was conducted is shown in the Box.

Delays, repetition of effort, variation in ethics committees’ requirements and inconsistent compliance processes have been previously recognised1 and the role of ethics committees in directing institutional research has been debated by researchers.1–3 These concerns and the often extensive period of time taken to obtain ethics approvals are likely to discourage researchers from conducting multicentre studies, hindering valuable research. The National Ethics Application Form, National Approach to Single Ethical Review of Multi-centre Research, and National Mutual Acceptance of ethical and scientific review for multi-centre clinical trials, have been recently introduced to reduce these hurdles; this has certainly streamlined — at least potentially — the process of the ethics review. It would be useful if a similar streamlined process for site-specific assessment could also be introduced, leading to a once-only approval process for multisite research. However, with separate governance requirements (including legal compliance, data storage and insurance) at each site and in different states across Australia,4,5 this seems to be still a tantalisingly long way off.

Box –
Summary of major concerns encountered at the six sites at which the research was conducted

Issues

HREC 1

HREC 2

HREC 3

HREC 4

HREC 5

HREC 6

Application form type/page count

Audit application (5 pages)

Online NEAF form (15 pages)

Ethics review of low-risk project (6 pages)

LNR application form (10 pages)

Single ethical and scientific review — online LNR application (11 pages)

Governance Evidence Knowledge Outcomes audit system: 2 sections of the 3 (online)

Supporting documents (extra to information sheet, protocol and consent form)

Nil

Covering letter to head of departmentEthics approvals from previous site

Ethics approvals from previous sites

Cover letterCV of all non-staff researchersEthics approvals from previous sites

Ethics approvals from previous sitesCover letter to ethics officer

Nil

Number of contacts (phone/email) to gain approval

5 emails

15–20 emails4–5 phone calls

10–15 mails2 phone calls

10–15 emails

15–20 emails

10 emails6–8 phone calls

Time taken to gain approvals

1 month

3 months

4 months

3 months

2 months

Special requests during approval process

2, 4, 5

1, 2, 3, 4, 5 (principal investigator needed to be a campus staff member)

2, 4, 5 (declaration from HOD)

HOD to lodge audit

Major cause of delay

Nil

Email and signature from HOD

Principal declaration from HOD

Declaration from line manager

Signature and authorisation from HOD

Contacting staff onsite to agree to lodge research project

HREC = human research ethics committee. NEAF = National Ethics Application Form. LNR = low or negligible risk. HOD = head of department, pharmacy. Special requests during approval process: 1 = signed approval from the line manager, 2 = signature from HOD, 3 = CV of the researchers, 4 = need for site-specific consent and information sheet, 5 = need for local contact person for the study.

Renowned clinician next MJA Editor in Chief

Influential medical clinician and researcher, Laureate Professor Nicholas Talley, has been appointed as the new Editor in Chief of the Medical Journal of Australia.

AMPCo Board Chair Richard Allely said Professor Talley, who is currently Pro Vice Chancellor, Global Research, at the University of Newcastle and a part-time staff specialist gastroenterologist at the John Hunter Hospital, came to the position with a wealth of local and international experience in medical research, practice and publishing.

“Professor Nick Talley is a clinician, educator, writer, author, researcher, and editor, with a strong track record in medical practice, medical education, and medical publishing, in Australia and overseas,” Mr Allely said.

As well as having authored 800 original and review articles in peer-reviewed academic journals, Professor Talley is currently Co-Editor in Chief of the international journal Alimentary Pharmacology and Therapeutics (a position he will relinquish soon after he takes up the MJA post on 1 December), and served for six years as Co-Editor in Chief of the American Journal of Gastroenterology.

“He brings significant experience, knowledge and expertise to the MJA, and is perfectly suited to guiding Australia’s leading medical journal at a time of rapid change, innovation and technological revolution in media and publishing,” Mr Allely said.

In addition to his ongoing academic, clinical and publishing work, Professor Talley is President of the Royal Australasian College of Physicians and Chair-elect of the College of Presidents of Medical Colleges.

He also holds several international adjunct appointments, including Professor of Medicine and Professor of Epidemiology at the Mayo Clinic, and Foreign Guest Professor at Stockholm’s Karolinska Institute.

Professor Talley’s appointment was announced soon after it was revealed that AMA Federal Councillor and former Australian Medical Students’ Association President Jessica Dean had been recruited to the Board of mental health organisation beyondblue.

beyondblue Chairman Jeff Kennett said Ms Dean’s experience as a young doctor would be “invaluable” for his organisation as it sought to work with medical students and practitioners at risk of experiencing depression and anxiety.

Ms Dean has been a member of beyondblue’s Victorian Doctors’ Mental Health Advisory Group, and earlier this year addressed a meeting of senior Victorian doctors, health officials and administrators about the mental health of medical practitioners and the culture in which they work.

Adrian Rollins

Safety of opioid patch initiation in Australian residential aged care

Opioid analgesics are recommended for the treatment of cancer pain and for short-term treatment of moderate to severe acute pain.1,2 The number of opioid prescriptions in Australia reimbursed by the Pharmaceutical Benefits Scheme increased from 2.4 million in 2002 to 7.0 million in 2007.3 Much of this increase is probably driven by the increased administration of opioids for chronic non-cancer pain,3,4 but such use remains controversial, especially in older people, as they are more susceptible to adverse drug events.5–7

Transdermal opioid patches have been designed to provide long-lasting therapy for patients with chronic pain. Two opioids are available for administration via transdermal patches: fentanyl and buprenorphine. Fentanyl patches have a duration of action of 3 days, while buprenorphine patches are active for 7 days.1 In addition to an extended duration of action, transdermal opioids also have a slower onset of action, making them unsuitable for the management of acute pain.1

For chronic, non-cancer pain, Australian guidelines recommend a stepwise approach, with an initial trial of non-opioid analgesics followed by weak opioids if simple analgesics are not effective.8,9 Oral morphine or oxycodone and transdermal buprenorphine are considered first-line options for chronic non-cancer pain. For frail or older patients, a low dose of immediate-release opioid may be used to assess responsiveness;8,9 once initial dosing requirements have been determined, sustained-release preparations, including transdermal buprenorphine patches, may increase patient compliance, as the frequency of administration is reduced compared with other dosing forms.7,10

Potent opioids, such as fentanyl, are only recommended for patients with chronic severe and disabling pain who exhibit tolerance for opioids and do not respond to non-narcotic analgesics.1,10,11 The margin between the therapeutic and toxic doses of fentanyl is small, and it has been associated with a number of fatalities in opioid-naive patients.12,13 Guidelines recommend that fentanyl is most appropriate in the treatment of opioid-tolerant palliative care patients and patients with cancer.8 Fentanyl patches should not be used in opioid-naive patients, and the equianalgesic opioid dose should be determined before initiation of the patch.8,11

Given the difficulties with the dose titration of transdermal buprenorphine preparations and concerns about the safety of fentanyl in opioid-naive patients, the use of transdermal preparations in older patients should be limited to opioid-tolerant patients with stable opioid requirements.

The aim of our study was to explore analgesic use before and after the initiation of transdermal opioid patches in residents of Australian aged care facilities. The specific objectives were to determine the proportion of people who were opioid-naive or opioid-tolerant prior to initiation of the transdermal product, and to determine how initiation of transdermal opioids affected the use of other opioids.

Methods

Data source

De-identified pharmacy data on all medicines supplied in dose administration aids to 60 residential aged care facilities in New South Wales during the period 1 July 2008 to 30 September 2013 were analysed. All medications supplied to residents in these facilities, including over-the-counter products, must be packed in a dose administration aid that comprises blisters containing all medications administered at a single dosing point, enabling assessment of intended co-administration. The blisters also reflect any changes made to any medicine in the weekly supply, so that all changes are identified at the time they occur.

The database therefore provides complete medication records for all residents, including a unique resident identifier, sex, date of birth, date of death, generic and brand medication names, duration for which each medicine was dispensed, strength, dose and dosage instructions for each medicine, and pro re nata use (“as needed”).

Analgesic medicines included in the analyses

Included in the analyses were narcotic analgesics (opioids: codeine, codeine with paracetamol, methadone, morphine, hydromorphone, oxycodone, tramadol, pethidine, dextro-propoxyphene, fentanyl and buprenorphine), simple analgesics (paracetamol) and oral non-steroidal anti-inflammatory drugs (NSAIDs: including COX-2 selective inhibitors, but excluding topical preparations).

Patch initiation and previous analgesic use

A cross-sectional cohort study was undertaken to determine the use of analgesics in the 4 weeks prior to initiation of fentanyl and buprenorphine transdermal patches. Incident opioid patch use was defined as the first (index) dispensing of a fentanyl or buprenorphine patch between 1 July 2008 and 30 September 2013, with no use during the previous year. Patients who received their index opioid patch at the time of their admission to the residential aged care facility were excluded, because their analgesic use in the previous year could not be established. The proportions of residents initiated on patches who were naive to all analgesics or to opioids and those who were opioid-tolerant were determined. Opioid-naive users were defined as those who had not received an opioid analgesic (but may have received other simple or NSAID analgesics) in the 4 weeks prior to their first patch. Opioid-tolerant residents were those who had received an opioid, either regularly or pro re nata, in the 4-week period before patch initiation. The initiation strength of the patches was also determined.

Patch initiation and opioid use

The proportion of residents starting on a fentanyl or buprenorphine patch who received opioids (regularly or pro re nata) during the 30 days before or after patch initiation was calculated as a percentage of the entire sample of patch initiators.

Daily doses of regular opioids other than patches, when used concurrently with the patches, were calculated for the 30 days before and the 30 days after patch initiation. The dose of each generic agent in combination products was determined separately. The daily dose of each medicine on a given day was calculated from the product of the strength of the medicine and the dosage instructions (eg, oxycodone 10 mg twice a day = daily dose of 20 mg). Opioid strengths, including transdermal patches, were converted to oral morphine equivalents using opioid equianalgesic conversion ratios.14 Transdermal fentanyl was converted to the lowest daily oral morphine dose in the range provided (ie, 12 µg/h fentanyl to 30 mg morphine, and 25 µg/h fentanyl to 60 mg morphine).

The mean daily dose was calculated for each patch and for the opioids in total. For the dose calculation, as-needed use was excluded because of the lack of information about the actual daily usage.

Statistical analyses

The Pearson χ² test and the Student t test were applied to compare cohort characteristics and proportions. Linear regression trend lines were fitted to the trends in daily dose after initiation of the patches. Analyses were performed with the SAS 9.4 statistical package (SAS Institute).

Ethics

This study was approved by the Sydney Local Health District Human Research Ethics Committee, Concord Repatriation General Hospital (CH62/6/2010-49 HREC/10/CGRH/57).

Results

Patch initiation and previous analgesic use

The dataset included 5297 residents who received at least one medication between 1 July 2008 and 30 September 2013. Fentanyl patches were initiated in 137 individuals (2.6%) and buprenorphine patches in 459 (8.7%). The mean age was similar in both treatment groups, and 74% were women (Box 1).

More than a third (34%, 46 of 137) of residents who began using a fentanyl patch and almost half (49%, 224/459) of those who began using a buprenorphine patch were opioid-naive (Box 2).

Of the opioid- or analgesic-naive residents who received a fentanyl or buprenorphine patch, 87% (46 of 53) and 92% (229 of 250), respectively, commenced on the lowest available strength (12 µg/h fentanyl; 5 µg/h buprenorphine). Further, more than 80% of those who had received opioids before a transdermal patch were also started on the lowest strength dose (69 of 84 for fentanyl; 168 of 209 for buprenorphine). No opioid- or analgesic-naive residents who received a fentanyl patch were initiated on the highest strength (50 µg/h), and only three of the 250 opioid- or analgesic-naive patients who received a buprenorphine patch were initiated on the highest strength (20 µg/h).

Patch initiation and opioid use

After patch initiation, residents receiving fentanyl and buprenorphine were up-titrated to higher doses (Box 3).

Just under 30% of fentanyl initiators had used regular opioids (Box 4) and just under 25% had been using as-needed opioids in the 4 weeks before patch initiation (Box 5). About 20% of buprenorphine initiators had previously used regular opioids (Box 4) and about 18% had received them as needed (Box 5). Most residents were receiving oral formulations. The most commonly used opioids before patch initiation were oxycodone and codeine.

After patch initiation, the proportion of those who continued to receive regular opioids concurrently with their patch was about 15% (21 of 137) for fentanyl users and 10% (47 of 459) for buprenorphine users (Box 4). In residents receiving fentanyl, the total daily dose of regular opioids increased immediately after patch initiation and then declined over time; in residents with a buprenorphine patch, the total daily opioid dose increased slightly after patch initiation and then continued to increase over the next 30 days (Box 6). In both groups, the proportion of people who received opioids as needed increased immediately after patch initiation, but then decreased by day 30 to 30% (41 of 137) for fentanyl and to 23% (106 of 459) for buprenorphine (Box 5).

Discussion

The availability of transdermal opioid formulations provides increased analgesic options for the management of chronic pain. However, initiation of transdermal opioids requires additional caution with the appropriate choice of agent and dose titration, especially in older patients. Our results indicate that fentanyl patches were initiated in 2.6% of aged care residents, and buprenorphine patches in 8.7%. While the use of transdermal buprenorphine is recommended for the management of chronic pain, when commencing opioids in older patients a low-dose immediate-release preparation is recommended once their opioid requirements have been ascertained, and the dose should then be titrated accordingly.8,9 Transdermal fentanyl is not recommended in opioid-naive individuals because of its high potency. In this study, a relatively high use of both fentanyl and buprenorphine patches in opioid-naive aged care residents was observed, and this raises safety concerns.

Fentanyl is a highly potent opioid. It is not appropriate for opioid-naive patients because of the risk of toxicity, including respiratory depression and overdose-related mortality.12,13 The United States Food and Drug Administration released a number of safety communications regarding the dangers of fentanyl patches in opioid-naive patients.15 In Australia, the Pharmaceutical Benefits Scheme allows a restricted benefit for the treatment of chronic severe disabling pain that does not respond to non-narcotic analgesics. In our study, a third of aged care residents who were commenced on a fentanyl patch were opioid-naive. Our findings in residents who had previously used opioids are similar to those of a Dutch study which reported that 60% of patients who began using fentanyl patches had previously used other opioids.16 If fentanyl patches are to be used in opioid-naive patients with cancer pain, they should not be initiated at doses greater than 25 µg/h.11 We found that no opioid- or analgesic-naive patients were initiated with fentanyl patches at doses higher than this.

Commencement of any opioid in older patients requires a “start low and go slow” approach.7 A low initial opioid dose followed by cautious upward titration to achieve adequate analgesia is the strategy recommended by the current Australian guidelines.8,9 One limitation of transdermal patches is the lack of flexibility in dosing titration.17 Use of transdermal buprenorphine in opioid-naive aged care residents, although pharmacologically appropriate for managing chronic pain, does not allow adequate titration and may result in over- or underdosing. In our study, doses of regular concurrent opioids continued to increase after initiation of transdermal buprenorphine in aged care residents, suggesting that underdosing and inadequate pain relief may be problems.

Similar studies that have explored prior opioid use in people first prescribed transdermal buprenorphine reported much higher proportions of opioid-tolerant patients. In our aged care residents, 45% of patients prescribed a buprenorphine patch were opioid-tolerant prior to initiation. A US study found that 92% of patients commencing buprenorphine were opioid-tolerant,18 while a German postmarketing surveillance study found that 70% of new users were opioid-tolerant.19 However, these studies were not conducted in residential aged care settings.

Although transdermal opioid patches are being prescribed for opioid-naive aged care residents, it appears that the “start low and go slow” adage is being followed. The adverse effects of opioids are dose-related2; excessive daily opioid doses for non-malignant pain is strongly associated with opioid-related mortality.6 Lower starting doses and slow dose titration need to be considered, to take into account the patient’s individual tolerance.7 We found that most residents were starting at the lowest doses of each patch type and the dose was then slowly up-titrated, consistent with findings in primary care in the United Kingdom.20

Breakthrough pain is an exacerbation of otherwise well managed chronic pain. Guidelines indicate that if transdermal opioid patches are initiated, additional, immediate-release analgesics may be co-dispensed in the case of breakthrough pain.1 Non-opioid analgesic options may be considered in people without cancer, while short-action opioids should be used as needed in those with cancer.2,10 Even though opioid use decreased after patch initiation, we found that 15% of fentanyl users and 10% of buprenorphine users were still taking regular opioids concurrently with their patches. This is similar to a postmarketing surveillance study which reported that 14% of patients needed concomitant opioids after starting buprenorphine therapy.19 We found that the required doses of regular concurrent opioids decreased after patch initiation in those receiving fentanyl, while they increased in those receiving buprenorphine. Further, a third of fentanyl users and a quarter of buprenorphine users received concomitant oral or parenteral opioids on an as-needed basis 1 month after patch initiation.

Study strengths and limitations

The dataset used in this study provided a complete medication history for each resident in 60 aged care facilities. All medications, including those purchased over the counter, are captured in the dataset. This is important, as many paracetamol and NSAID preparations are available over the counter in Australia. While a complete medication history was available for each resident, the dataset does not contain any clinical information, such as indication, so that it is possible that some of the analgesics were used for acute or cancer pain, or for palliative care. Problems of safety and adequate pain control in opioid-naive patients are not related to the indication for which they are taken, so that the absence of data on indication is unlikely to affect our results. A second limitation was the lack of dosing information for as-needed medicines. As-needed opioids were included in all our analyses, except when calculating the total daily opioid dose.

Conclusion

Our results suggest a certain degree of inappropriate initiation of opioid patches in Australian residential aged care. Contrary to best practice, a third of residents commencing fentanyl patches and almost half of those commencing buprenorphine patches were opioid-naive in the 4 weeks before initiation of the transdermal patch.

Box 1 –
Characteristics of aged care residents in whom transdermal opioid patches were initiated

	Fentanyl initiators	Buprenorphine initiators	P

Number	137	459
Mean age at initiation, years (SD)	86 (8.4)	87 (7.6)	0.148^*
Sex
Male	30 (22%)	126 (27%)	0.194^†
Female	107 (78%)	333 (73%)

*Student t test. †χ² test.

Box 2 –
Analgesic use prior to patch initiation

* P < 0.05 for difference between fentanyl and buprenorphine initiators (χ² test).

Box 3 –
Daily dose of fentanyl or buprenorphine, presented as morphine equivalents*

* As-needed opioids were excluded from analysis because of the lack of information on the dose administered.

Box 4 –
Proportion of residents receiving regular opioids before and after patch initiation*

* After-patch initiation use denotes regular opioid use concurrent with transdermal patch use.

Box 5 –
Proportion of residents receiving as-needed opioids before and after patch initiation*

* After-patch initiation use denotes as-needed opioid use concurrent with transdermal patch use.

Box 6 –
Daily dose of regular opioids, presented as morphine equivalents*

* After-patch initiation use denotes as-needed opioid use concurrent with transdermal patch use. As-needed opioids have been excluded from analysis because of the lack of information on administered dose.

Beware of blotting paper hallucinogens: severe toxicity with NBOMes

Clinical record

16-year-old male presented to the emergency department after ingesting what he believed to be LSD (lysergic acid diethylamide) on red blotting paper while camping with friends in rural New South Wales in late 2014. He had no past medical or mental health history, and was taking no regular medications. He had three seizures before arriving in the ED, where his Glasgow coma scale score was 9. He had a fourth seizure about 1 hour after presenting, and was given 5 mg midazolam intravenously. His initial venous blood gas parameters were: pH 6.93 (reference range [RR], 7.35–7.45); PCO₂, 120 mmHg (RR, 35–48 mmHg); and base excess, −7 (RR, 0.5–1.6). He was then intubated, ventilated, paralysed with rocuronium, and sedated with morphine/midazolam for transfer to a tertiary intensive care unit. His heart rate was 70 bpm, his blood pressure 130/60 mmHg, and he was afebrile after intubation. Over the next 3 hours and before medical retrieval, his blood gases normalised with improved ventilation (pH 7.4; PCO₂, 29.6 mmHg).

He had no further seizures after his transfer to the tertiary intensive care unit. His overnight urine output was initially reduced; this improved with increased fluid replacement. On arrival at the intensive care unit, his blood parameters were: white cell count, 16.3 × 10⁹/L (RR, 4–11 × 10⁹/L); neutrophils 12.1 × 10⁹/L (RR, 1.7–8.8 × 10⁹/L); haemoglobin, 136 g/L (RR, 130–180 g/L); platelets, 198 × 10⁹/L (RR, 150–400 × 10⁹/L); sodium, 142 mM (RR, 134–145 mM); potassium, 3.9 mM (RR, 3.5–5.0 mM); and creatinine, 108 mM (64–104 mM). He remained haemodynamically stable and was extubated the following day. He was transferred to the paediatric ward, and on Day 2 his creatinine and creatine kinase levels were rising, with normal urine output (Figure). Except for some initial nausea that lasted for 24 hours after extubation, he had no other symptoms over the next 3 days, and experienced no hallucinations or agitation. His creatinine levels peaked at 246 mM [RR, 64–104 mM] 37.5 hours after ingestion, and his creatine kinase levels peaked at 34 778 U/L (RR, 1–370 U/L) 90 hours after ingestion. He was discharged well on Day 5 without complications.

NBOMe assays are not currently part of routine emergency toxicology testing; worldwide, only a few forensic and commercial laboratories offer qualitative NBOMe testing in blood or urine. Blood specimens from the patient were sent to the Department of Pathology at Virginia Commonwealth University (USA) for NBOMe detection and quantification. The specimens were tested by previously validated high-performance liquid chromatography/mass spectrometry assays.1,2 25B-NBOMe was detected in the blood specimen at a concentration of 0.089 μg/L, 22 hours after ingestion.

Dimethoxyphenyl-N-[(2-methoxyphenyl)methyl]ethanamine derivatives (NBOMes) are a novel class of potent synthetic hallucinogens originally developed as 5-HT₂ receptor agonists for research purposes, but which have become available as recreational drugs in the past few years.3 They are available under a number of street names, including “N-bombs”, and are often sold as “acid” or “LSD” on blotting paper, as a powder, or as blue tablets (“blue batman”). They have been increasingly associated over the past 2 years with deaths and severe toxicity in North America and Europe.3–5 Most reports have concerned 25I-NBOMe intoxication, and there is much less information on the 25B- and 25C-NBOMe derivatives.2,6,7 While difficult to assess because of the sparse number of reports, 25B-NBOMe may be more toxic than the more commonly reported 25I-NBOMe.3,4 Our case is consistent with previous reports of severe NBOMe toxicity, with agitation, tachycardia and mild hypertension, seizures, rhabdomyolysis and acute kidney injury.3

There have been few reports of NBOMe poisoning in Australia, and only one report of a fatality.8 Most reports in Australia have been in the popular media, describing the presence of NBOMes in this country. There is limited information available to health care professionals about their potential toxicity. An international online survey in 2012 found that NBOMes were being used in Australia, although not as commonly as in the United States.5 NBOMes are reported to be relatively inexpensive, and are usually purchased over the internet. For this reason, as in our case, intoxicated NBOMe users may present to rural and smaller regional hospitals. As in other reports, our patient believed he had taken “acid” or LSD. The one reported death in Western Australia involved a woman who had inhaled a white powder she thought to be “synthetic LSD”; she began behaving oddly, before collapsing and dying.8 In comparison with the dramatic systemic effects seen in our case and those described in the literature, LSD is not associated with such severe medical complications.9

NBOMe toxicity is characterised by hallucinations and acute behavioural disturbance, with seizures, rhabdomyolysis and acute kidney injury in more severe cases.3,4,6,9,10 Our patient was postictal when he presented, and required immediate sedation and intubation, after which he was reported to have a normal heart rate and blood pressure. Rising creatinine and creatine kinase levels were recognised on the medical ward after the patient had been extubated.

Previous reviews3,4 suggested that there are two different presentation types of NBOMe toxicity: one form dominated by hallucinations and agitation, and another involving more severe medical complications. Patients presenting with the first type should be managed in a similar manner to other patients with acute behavioural disturbance, including verbal de-escalation and oral or parenteral sedation as required.11 In many cases, these patients will present with undifferentiated behavioural disturbance, and only the persistence of hallucinations or agitation and the history given by the patient will suggest the diagnosis. In patients with more severe medical complications, directed supportive care is appropriate, including intubation and ventilation for coma, and fluid replacement for rhabdomyolysis and acute renal impairment. Serial electrolyte, creatinine and creatine kinase measurements should be made in all cases to identify these complications and to monitor the progress of the patient. Further, such investigations may potentially play a role in identifying NBOMe as a cause in patients who present with undifferentiated agitation and hallucinations lasting 24 hours or more.

Lessons from practice

Dimethoxyphenyl-N-[(2-methoxyphenyl)methyl]ethanamine derivatives (NBOMes) are hallucinogenic substances that have become available as drugs of misuse in the past few years.
NBOMe toxicity can cause acute behavioural disturbance, and in severe cases can cause seizures, rhabdomyolysis and acute kidney injury.
NBOMes may be distributed as lysergic acid diethylamide (LSD) or “acid” on blotting paper.
Treatment is supportive, including sedation for agitation and intravenous fluid therapy for rhabdomyolysis and acute renal failure.

Clinicians need to be aware that newer synthetic hallucinogens, such as NBOMes, are available in Australia, and that patients may believe them to be “acid” or LSD. NBOMes cause prolonged agitation and hallucinations and, in more severe cases, seizures, rhabdomyolysis and acute kidney injury.

Figure

Serial measurements of creatinine and creatine kinase levels in our patient after ingesting NBOMe.

Sudden sensorineural hearing loss secondary to metronidazole ototoxicity

A 30-year-old Indian gentleman presented to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, with a history of bilateral profound deafness, tinnitus and headache associated with upper- and lower-limb paraesthesia and myalgia. He had been taking metronidazole (400 mg tds) and amoxycillin (500 mg tds) over the preceding 4 days to treat gingivitis. Further questioning revealed that his maternal uncle had experienced identical symptoms while taking metronidazole. Consequently, his metronidazole was immediately discontinued.

After 2 days, he was able to hear faint sounds, and audiography revealed a symmetrical moderate-to-profound sensorineural hearing loss (SNHL) (Box, A). As per our hospital protocol for SNHL management, oral prednisolone was administered (50 mg daily), followed by a slow wean over 3 weeks.

After 8 days, subjective hearing and paraesthesia had improved, and his headache had abated. Audiometry indicated moderate SNHL up to 2000 Hz, with persisting severe high-frequency SNHL (Box, B).

At 6 weeks, repeat audiogram indicated that hearing was normal up to 2000 Hz, but severe-to-profound high-frequency SNHL persisted (Box, C).

Metronidazole is a nitroimidazole antibiotic widely used in various medical specialties. Common side effects include nausea, diarrhoea and abdominal discomfort. Patients receiving high or intravenous doses may experience neurotoxicity, but it is uncommon to suffer ototoxicity.

The first documented case of metronidazole-induced ototoxicity was reported in 1984.1 Since then there have been infrequent but typical reports of SNHL associated with metronidazole. In 1999, two cases of SNHL following about 2 days of treatment with metronidazole for dental sepsis were described.2 More recently, sudden bilateral SNHL after 4 days of metronidazole treatment for diarrhoea has been reported.3

We can only speculate about the mechanism of metronidazole-induced ototoxicity. The clear familial link in our case suggests a potential genetic susceptibility, similar with other ototoxic agents, such as susceptibility for the ototoxic effects of aminoglycosides associated with the mitochondrial A1555G deletion.

Several neurotoxic effects of metronidazole have been hypothesised, including toxic excitation of NMDA receptors leading to production of free radicals and cell death, as well as effects on GABAergic transmission and direct RNA-binding effects.4 Whether or not there is a genetic susceptibility for its effects has not yet been investigated, but it is reported that the onset of neurotoxicity is more rapid and occurs at lower doses in patients of Indian descent than in those of European origin.5

In conclusion, metronidazole is a known neurotoxic antibiotic that can be ototoxic, if only rarely. These adverse effects are reversible after withdrawing the drug. Given its widespread use, it is important that prescribers are aware of these severe adverse reactions.

A: Initial audiogram, showing profound bilateral sensorineural deafness. B: Audiogram, 8 days after cessation of metronidazole, showing improvement in pure tone audiometry at frequencies up to 2000 Hz. C: Audiogram, 6 weeks after cessation of metronidazole, showing near-normal hearing at frequencies up to 2000 Hz, with severe high-frequency hearing loss.

Substandard medication-related processes in primary care costing millions

Poor medication-related processes in the primary care setting is resulting in hospital admissions that could be costing hundreds of millions of dollars, a study has found.

Researchers Dr Gillian Caughey and colleagues from the University of South Australia and the BUPA Health Foundation analysed the hospital admissions of 83 430 older patients between July 2007 and June 2012.

They used data from the Department of Veterans’ Affairs and found that a quarter of admissions were due to substandard medication related processes.

The results have been published in the Medical Journal of Australia.

They found that for those who were hospitalised for fractures after a fall, 85.4% of those patients aged 65 or over had been prescribed a falls-risk medicine before admission.

For patients hospitalised for chronic heart failure, 17% hadn’t been dispensed an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) in the previous 3 months prior.

Similarly, “about one in 10 admissions for renal failure occurred in patients with a history of diabetes who had not received a renal function test in the year before admission and were not dispensed an ACEI or ARB,” the authors wrote.

The authors say the study highlights conditions where there are gaps in medication management in the older population.

“The results could be used to inform and focus the development of interventions and efforts to improve the quality of health care delivery, potentially reducing morbidity and health care costs,” they write.

To read the full study, visit the Medical Journal of Australia website.

Latest news:

Summary statement: new guidelines for the management of paracetamol poisoning in Australia and New Zealand

A large proportion of accidental paediatric exposures and deliberate self-poisoning incidents involve paracetamol; it is the leading pharmaceutical agent responsible for calls to Poisons Information Centres in Australia and New Zealand. Management of paracetamol poisoning has altered since the previous guidelines were published in 2008, so that they do not reflect current practice by clinical toxicologists. The key changes from the previous guidelines concern the indications for administration of activated charcoal; the management of patients taking large or massive overdoses; modified-release and supratherapeutic ingestions; and paediatric liquid paracetamol ingestion.

Main recommendations

The management of patients with paracetamol overdose is usually straightforward. Acute deliberate self-poisoning, accidental paediatric exposure and inadvertent repeated supratherapeutic ingestions all require specific approaches to risk assessment and management.

Each initially involves a risk assessment (Box 1). The key factors to consider in paracetamol poisoning are the ingested dose and serum paracetamol concentration (early), or clinical and laboratory features suggesting liver damage (late). Serum paracetamol concentration should be used to assess the need for acetylcysteine administration in all patients presenting with deliberate self-poisoning with paracetamol, regardless of the stated dose. The management of acute paracetamol exposure with known time of ingestion is summarised in a management flow chart (Box 2) and the management of supratherapeutic ingestion is shown in Box 3.

It is important to note that the paracetamol treatment nomogram has not changed, and that the acetylcysteine regimen remains the same as in the previous guidelines.

Changes in management

Gastric decontamination

It was previously recommended that activated charcoal be administered within 1 hour of paracetamol ingestion. The current guideline advises that 50 g activated charcoal should be administered to a cooperative, awake adult within 2 hours of ingestion of a toxic dose of immediate-release paracetamol, and within 4 hours of modified-release paracetamol ingestion (Box 2).

For immediate-release paracetamol overdoses of greater than 30 g, activated charcoal should be administered up to 4 hours after ingestion. For massive modified-release paracetamol overdoses, absorption may continue until 24 hours after ingestion, and patients may still benefit from activated charcoal treatment after more than 4 hours.

Modified-release paracetamol

As per the previous guideline, acetylcysteine treatment should be started immediately if more than 200 mg/kg or 10 g (whichever is lower) has been ingested. Two assessments of serum paracetamol concentration 4 hours apart are required, the first at least 4 hours after ingestion.

The recommendation about when to discontinue acetylcysteine infusion has changed. Serial paracetamol concentrations, measured 4 hours apart, must be below the nomogram line and decreasing. Further, near the completion of acetylcysteine infusion (ie, 2 hours before completion of infusion), serum alanine aminotransferase (ALT) and paracetamol concentrations should be measured. Acetylcysteine infusion should be continued if the ALT level is increasing (greater than 50 U/L) or the paracetamol concentration is greater than 10 mg/L (66 μmol/L).

Large or massive paracetamol overdoses

Patients who ingest large or massive doses of paracetamol were not discussed in previous versions of the guidelines. Most patients ingest less than 30 g of paracetamol, with only a small percentage of overdoses having a paracetamol concentration greater than double the nomogram line. Those who ingest greater doses may have decreased paracetamol clearance and increased risk of hepatotoxicity despite treatment, and may benefit from modifying the standard paracetamol management. Patients considered at high risk of hepatotoxicity are those with high initial paracetamol concentrations.

Although no randomised control trials have investigated optimum acetylcysteine dosage in these patients, it is the practice of many clinical toxicologists to adjust the dose in large paracetamol overdoses. Who might benefit from an increase in acetylcysteine dose and the optimum dose have not yet been determined. One approach, in patients with a paracetamol concentration more than double the nomogram line, is to double the concentration of the 16-hour infusion of acetylcysteine from 100 mg/kg (current standard acetylcysteine third-bag infusion) to 200 mg/kg intravenous acetylcysteine. Serum ALT and paracetamol levels should be checked near the completion of acetylcysteine infusion. Acetylcysteine should be continued if the ALT level is increasing (greater than50 U/L) or the paracetamol concentration is greater than 10 mg/L (66 μmol/L). The Poisons Information Centre or a clinical toxicologist may be consulted for the most current advice on managing these patients, including the optimal acetylcysteine regimen.

Liquid paracetamol ingestion by children under 6 years of age

No recommendations were made in the previous guideline. When ingestion of more than 200 mg/kg of liquid paracetamol by a child under 6 years of age is suspected (in obese children, this should be based on an ideal body weight), serum paracetamol concentration should be measured at least 2 hours after ingestion. If the concentration 2 to 4 hours after ingestion is less than 150 mg/L (1000 μmol/L), acetylcysteine is not required. If the 2-hour paracetamol concentration is greater than 150 mg/L (1000 μmol/L), it should be measured again 4 hours after ingestion, and acetylcysteine infusion commenced if the value is still greater than 150 mg/L (1000 μmol/L), as per the paracetamol nomogram.

The 2-hour paracetamol concentration should only be used to guide management in a healthy child less than 6 years of age, after an isolated liquid paracetamol ingestion. In all other cases, such as children who present later than 4 hours after ingestion, and children who are older than 6 years of age, treatment is the same as that for acute paracetamol exposure in adults.

Repeated supratherapeutic ingestion

Patients should have serum paracetamol and ALT concentrations measured if they meet the criteria for supratherapeutic ingestion (Box 1). The main changes in the guidelines concern the criteria for assessment in those who have ingested more than 100 mg/kg/day or 4 g/day (whichever is lower) per 24-hour period for longer than 48 hours. Patients only require assessment if they have symptoms such as abdominal pain or nausea or vomiting. Management is outlined in Box 3.

Acetylcysteine dosing recommendation

The guideline essentially remains unchanged, except that dosing should be based on actual body weight rounded up to the nearest 10 kg, with a ceiling weight of 110 kg.

Hepatotoxicity

This was not discussed in detail in the previous guidelines. Acetylcysteine should be continued until the patient is clinically improving, ALT levels are decreasing, the international normalised ratio (INR) is improving and less than 2, and the paracetamol concentration is less than 10 mg/L (66 μmol/L). Regular clinical review and 12-hourly (or more frequent) blood tests are recommended if there is clinical deterioration.

A liver transplant unit should be consulted if any of the following criteria are met:

INR >3.0 at 48 hours or >4.5 at any time;
oliguria or creatinine >200 μmol/L;
persistent acidosis (pH < 7.3) or arterial lactate >3 mmol/L;
systolic hypotension with blood pressure less than 80 mmHg, despite resuscitation;
hypoglycaemia;
severe thrombocytopenia;
encephalopathy of any degree, or any alteration of consciousness (Glasgow coma scale <15) not associated with co-ingestion of sedatives.

Conclusions

This is a summary of the updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. The full guidelines are available on the website of the Medical Journal of Australia (www.mja.com.au/sites/default/files/issues/203_05/Guidelines_paracetamol_Aus_NZ_2015.pdf).

Where there are any concerns regarding the management of paracetamol ingestion, advice can always be sought from a clinical toxicologist or the Poisons Information Centre (telephone: 13 1126 in Australia, 0800 764 766 [0800 POISON] in New Zealand).

Box 1
Paracetamol dosing that may be associated with hepatic injury

Adults and children >6 years of age

Children (aged 0–6 years)∗

Acute single ingestion

>200 mg/kg or 10 g (whichever is lower) over a period of <8 hours

>200 mg/kg over a period of <8 hours

Repeated supratherapeutic ingestion

>200 mg/kg or 10 g (whichever is lower) over a single 24-hour period

>200 mg/kg over a single 24-hour period

>150 mg/kg or 6 g (whichever is lower) per 24-hour period for the preceding 48 hours

>150 mg/kg per 24-hour period for the preceding 48 hours

>100 mg/day or 4 g/day (whichever is lower) per 24-hour period, for more than 48 hours in those who also have symptoms indicating possible liver injury (eg, abdominal pain, nausea or vomiting)

>100 mg/kg per 24-hour period for more than 48 hours

∗For obese children, the body weight used for calculations should be an ideal body weight.

Box 2
Management flow chart for acute paracetamol exposure with known time of ingestion

ALT = serum alanine aminotransferase.

Box 3
Management flow chart for repeated supratherapeutic paracetamol ingestion

ALT = serum alanine aminotransferase.

Suboptimal medication-related quality of care preceding hospitalisation of older patients

Chronic diseases are the leading cause of death and disability worldwide, and their prevalence is increasing, particularly in the older population.1 In Australia, chronic diseases account for 70% of total health expenditure, costing $91.2 billion in the 2010–11 financial year.2 Optimal management of chronic disease therefore has significant potential to reduce health care expenditure, as well as to improve health outcomes for individuals.

In Australia, it is estimated that between 2% and 3% of all hospital admissions are medication related.3 There were 9.3 million hospital separations in Australia during 2011–2012 at an average cost of $5204 per separation; this suggests that there are about 232 500 medication-related admissions per year at an annual cost of $1.2 billion.4 Many of these hospitalisations could potentially be prevented by delivery of appropriate primary care.3

To facilitate the reduction of medication-related morbidity, clinical indicators have been developed that assess processes of care associated with medication use and ensuing adverse outcomes of hospitalisation.5,6 These medication-related clinical indicator sets were originally developed more than 10 years ago by expert panels in the United States, United Kingdom and Canada, based on the principles that medication-related problems are recognisable, that the adverse outcomes are foreseeable, and that their causes and outcomes are identifiable and controllable. On the basis of these clinical indicators, it has been reported that between 3% and 20% of hospitalised patients had suboptimal care before admission, depending on the country and population studied.7–9

Clinical indicators have been widely adopted as a measure of health system performance and quality of care provided to patients, ranging from the acute care to primary care settings, across a number of disease states.10 Use of clinical indicators to determine the appropriateness and timeliness of care for patients with chronic disease and associated medication use is a potentially underused measure for assessing health system performance. Such indicators may facilitate the identification of areas with potential for improving health care and health outcomes, as well as reducing the frequency of adverse events.

We have developed evidence-based medication-related indicators of suboptimal processes of care before hospitalisation that are specific to the Australian health care setting.11 The indicators are based on Level III or greater evidence, and were validated by an expert panel as aspects of medication use that clinicians should be able to identify and resolve in primary care.12 The aim of this study was to apply these medication-related clinical indicators to investigate the prevalence of suboptimal medication-related processes of care preceding hospitalisation of older patients.

Methods

Ethics approval for this study was obtained from the Human Research Ethics Committees of the University of South Australia (protocol number 0000025588) and the Department of Veterans’ Affairs (DVA) (protocol number E012/003).

Data source

We analysed DVA administrative health claims data to determine the prevalence of clinical indicators of suboptimal medication-related processes of care before hospitalisation in a treatment population of about 300 000 veterans during the study period (1 July 2007 to 30 June 2012). The DVA claims database contains patient-specific demographic data, including date of birth, date of death, sex, level of entitlement and residential status, as well as details of all prescription medicines, medical and allied health services, and hospitalisations provided to veterans for which the DVA pays a subsidy. Medicines are coded in the dataset according to the World Health Organization anatomical and therapeutic chemical (ATC) classification13 and the Pharmaceutical Benefits Schedule (PBS) item codes.14 Services are coded according to the Medicare Benefits Schedule (MBS),15 and hospitalisations are coded according to the World Health Organization International Classification of Diseases, 10th revision, Australian modification (ICD-10-AM).16

Prevalence of clinical indicators in the DVA database

Details of the development of the clinical indicators of suboptimal medication-related processes of care before hospitalisation have been published elsewhere.11 As an example of an indicator where the outcome of interest is hospitalisation for acute coronary syndrome, the associated process of care is defined as the combination of “patient has coronary artery stent (in 1 year before admission)” and “no use of aspirin or clopidogrel (in 12 months before admission)”.11

We reviewed the clinical indicators to identify those that were suitable for testing with the DVA administrative health claims data. As the DVA database is an administrative claims dataset, it contains records only for medicines and health services that attract a subsidy. Health care activities that do not have an individual funding item number, such as blood pressure measurement, are not recorded in the administrative claims database. While the use of health services (such as testing for glycated haemoglobin [HbA_1c] levels) can be determined from the claims data, the test results are not available. The criteria for appropriate use of health services as part of the process of care adopted by the indicators were based on practice recommendations in Australian evidence-based guidelines.11 Some of the validated indicators included processes of care that could not be identified in the administrative claims database, and therefore had to be excluded from this analysis. A total of 21 of the 29 validated indicators included medication-related processes of care that could be identified in the claims database and were therefore included in this analysis. They were drawn from six disease groupings: cardiovascular disease, respiratory disease, gastrointestinal disease, osteoporosis or fracture, renal disease, and diabetes. Of these 21 indicators, 13 are based on Level I evidence.11 Indicators that could not be included related to conditions that could not be accurately identified in the data: moderate to severe chronic obstructive pulmonary disease with frequent exacerbations, dyspepsia, and positive test results for Helicobacter pylori; influenza and pneumococcal vaccinations are not recorded in the database, nor are the doses of medicines used (corticosteroids) or the measurement of vitamin D or calcium levels.11

Data rules were developed for identifying each pattern of care and hospitalisation outcome for each indicator in the administrative claims dataset. These data rules included ICD-10-AM codes that identified each hospitalisation outcome, ATC or PBS item codes that identified medications, and MBS codes that identified testing procedures or claims related to the process of care. DVA administrative health claims between 1 July 2007 and 30 June 2012 were analysed to identify all hospitalisations with a primary diagnosis for the outcomes, and all MBS and PBS claims were analysed for patterns of care for the clinical indicator set.

We calculated the prevalence of hospitalisations with suboptimal medication-related processes of care before hospitalisation, as defined by the clinical indicator set. The prevalence was defined as the proportion of individuals with both the pattern of care and the associated hospitalisation divided by the total number of hospitalisations for that indicator. Demographic data were obtained for patients at study entry. All analyses were undertaken with SAS for Windows, v9.4 (SAS Institute).

Results

There were 164 813 hospitalisations for the conditions included in the clinical indicator set over the 5-year study period, encompassing 83 430 patients. The median age of the study population was 81 years (interquartile range, 78–84 years); 54.5% were men, and 6.9% resided in an aged care facility at the time of admission (Box 1).

Box 2 contains the final list of clinical indicators included in the study and the prevalence of suboptimal medication-related processes of care preceding hospitalisation. More than one-third (34.5%) of the study population had at least one hospitalisation and 10.4% had two or more hospitalisations where there had been suboptimal medication-related processes of care before admission (Box 1). The overall proportion of hospitalisations that were preceded by suboptimal medication-related processes of care was 25.2% (41 546 hospitalisations). The most common hospitalisations were for cardiovascular disease (including acute coronary syndromes and heart failure), fracture and gastrointestinal conditions. Fracture and congestive heart failure (CHF) caused the highest numbers of hospitalisations that were preceded by suboptimal medication-related processes of care (Box 2). Of the fracture hospitalisations, 85.4% were for patients aged 65 years or older who had been dispensed a falls-risk medicine before admission; 19.7% and 17.2% of fracture hospitalisations were for men and women, respectively, who had a history of fracture or osteoporosis but had not received a medicine for osteoporosis. There were 4744 CHF admissions (17.1%) of patients with a history of CHF who had not been dispensed an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) in the 3 months before admission. More than one in 10 admissions for gastrointestinal bleeding or ulcer were associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). About one in 10 admissions for renal failure occurred in patients with a history of diabetes who had not received a renal function test in the year before admission and were not dispensed an ACEI or ARB (Box 2).

Although there were more than 33 363 hospitalisations for acute coronary syndromes during the study period, less than 2% involved individuals with a history of myocardial infarction or who had received cardiac stents and had not been dispensed acute coronary syndrome medicines recommended by the guidelines. Similarly, although there were more than 17 149 hospitalisations for gastrointestinal bleeding, ulcer or gastritis during the study period, less than 1% involved patients with a prior history of gastrointestinal bleeding or ulcer who had been dispensed an NSAID without a concurrent gastroprotective agent (Box 2). There were 1751 admissions for hyperglycaemia or hypoglycaemia; only 209 of these patients (11.9%) were prescribed insulin and had not received an HbA_1c test in the 6 months before admission.

Discussion

This is the first study to examine suboptimal medication-related processes of care before hospitalisation. We applied newly developed evidence-based clinical indicators specific to the Australian health care setting and found that 25.2% of hospitalisations for conditions identified in the clinical indicator set were preceded by suboptimal medication-related processes of care. Of the 28 807 patients in the study who had hospitalisations preceded by suboptimal medication-related processes of care, 30% (8640 patients) had multiple such hospital admissions. At least one in 10 hospitalisations for CHF, ischaemic stroke, asthma, gastrointestinal ulcer or bleeding, fracture, renal failure or nephropathy, hyperglycaemia or hypoglycaemia were preceded by suboptimal medication-related processes of care that clinicians should be able to identify and avoid. The frequency of falls-risk medicine use before hospitalisation for a fracture was particularly high (85.4%), highlighting the need to review appropriate prescribing of these medications for older people, who may be particularly vulnerable to their adverse effects.

A recent Australian study (CareTrack) examined the provision of appropriate health care. The investigation was based on medical records from health care practices (primary and secondary care) and hospitals, and it found that 43% of Australian patients had not received appropriate care.17 The CareTrack study examined process indicators only, and these were not linked to outcome measures, such as hospitalisation. The indicators included in the study were either consensus or evidence-based in nature, and were related to individual patient data. Gaps in the provision of appropriate care for specific conditions were identified (including for diabetes, osteoporosis, asthma and stroke), consistent with the results of our study.

Many of the conditions for which suboptimal processes of care were identified by our study fall within National Health Priority Areas for Australia or are associated with a high disease burden in Australia.18 This highlights the potential suitability of the medication-related indicators for monitoring appropriate provision of health care in Australia.

Other studies have highlighted the suitability of clinical indicators as quality indicators for monitoring health system performance and assessing the quality of patient care.5,7,10 Our study showed that administrative health databases can be used to investigate suboptimal medication-related processes of care before hospitalisation through the application of clinical indicators, and to assess the appropriateness of health care in current clinical practice. Routine prospective monitoring of trends in suboptimal processes of care associated with medicine use, and using the indicators in administrative health datasets or as data-mining tools in primary care, could provide a valuable tool for both monitoring and improving health system performance. Primary care interventions, such as patient-specific feedback to medical practitioners, could be focused on improving processes of care that have known and significant risks for patient outcomes and health care expenditure.

The suboptimal processes of care associated with the medication-related indicators applied in our study were validated by an expert panel as problems that clinicians should be able to recognise as suboptimal, with adverse outcomes that are foreseeable, and which could be both identified and controlled. Collaborative home medicines reviews that involve the patient, the pharmacist and the general practitioner have been shown to increase the identification and resolution of medication-related problems,19 and to reduce hospitalisation of patients with heart failure20 and those taking warfarin.21 The suboptimal care processes leading to hospitalisation outcomes in our study are the types of problems that could be identified and potentially resolved with a medication review (eg, reviewing the use of laxatives by chronic users of opioids or of falls-risk medications). Future research could be conducted to confirm whether such reviews are effective in reducing the incidence of suboptimal medication-related processes of care.

A limitation of our study is that we did not assess whether implementation of appropriate care processes would have avoided hospitalisation. It may be that hospitalisations would still have occurred even if the appropriate pattern of care had been implemented. Of interest for future studies would be an examination of the occurrence and effect on hospital admissions of the care processes defined by the indicator set. In addition, there could have been a subset of patients in the study population for whom certain medications were contraindicated, possibly related to comorbid conditions that we were not able to identify. An additional limitation was the inability to distinguish between individuals with diastolic and systolic heart failure on the basis of the available data; we acknowledge that the evidence base for the efficacy of ACEIs and ARBs in reducing long-term morbidity and mortality in those with diastolic heart failure is currently lacking.22 Furthermore, we were unable to assess the use of over-the-counter medicines.

Our study analysed DVA administrative data, which cover an older population of patients with a median age of 81 years. However, our results are probably applicable to other older Australians. Age-specific comparisons of DVA Gold Card holders (those eligible for all health services subsidised by the DVA) without service-related disability with the wider Australian population have found similar rates of GP visits, filling of prescriptions, and hospitalisations per year.23

Although differences in the definitions of clinical indicators may limit their applicability to other population groups, the indicators we employed are based on high-level evidence for common chronic conditions and are linked to patient outcomes. More than 60% of the indicators examined were based on Level I evidence, which, where applicable, included clinical studies of those aged 75 years or older (eg, the use of anti-osteoporosis medicines to reduce the incidence of fractures).11

In summary, this study highlights conditions associated with suboptimal medication-related processes of care in the primary care setting. The patterns of care on which the indicators are based incorporate high-level evidence and are therefore likely to be applicable internationally. Failure to implement appropriate patterns of care suggests that an opportunity to improve health care outcomes is being missed. Routine prospective monitoring of the prevalence of suboptimal processes of care and adverse outcomes in the Australian health care system using clinical indicators may provide a means for assessing the appropriateness of care for common chronic conditions, and for identifying evidence–practice gaps in primary care. The results could be used to inform and focus the development of interventions and efforts to improve the quality of health care delivery, potentially reducing morbidity and health care costs.

Box 1
Demographics of the study population: hospitalisation for diagnoses in the medication-related clinical indicator set (n = 83 430)

Age, median (interquartile range)	81 years (78–84 years)
Sex, n (%)
Male	45 456 (54.5%)
Female	37 974 (45.5%)
Location of residence, n (%)
Residential aged care facility	5725 (6.9%)
Community	77 705 (93.1%)
Hospitalisations with suboptimal processes of care before admission, n (%)
0	54 623 (65.5%)
1	20 167 (24.2%)
≥2	8640 (10.4%)

Box 2
Prevalence of hospitalisations after suboptimal processes of care as defined by the medication-related clinical indicator set

No.

Hospitalisation outcome

Process of care (preceding hospitalisation)

Total hospitalisations (TH)

Hospitalisations after suboptimal care [% TH, 95% CI]

Cardiovascular disease indicators

Acute coronary syndrome

History of myocardial infarction (in 2 years before admission)
Not on aspirin, β-blocker, ACEI or ARB and statin (in 3 months before admission)

33 363

567 [1.69%, 1.56%–1.84%]

Acute coronary syndrome

Patient has coronary artery stent (in 1 year before admission)
No use of aspirin or clopidogrel (in 12 months before admission)

33 363

640 [1.91%, 1.75%–2.05%]

CHF

History of CHF (in 2 years before admission)
Not on an ACEI or ARB (in 3 months before admission)

27 828

4744 [17.05%, 16.66%–17.54%]

CHF or heart block

History of CHF and heart block or advanced bradycardia (in 2 years before admission)
Use of digoxin (in 6 months before admission)

31 039

195 [0.63%, 0.54%–0.72%]

Ischaemic stroke

History of chronic atrial fibrillation or ischaemic stroke (in 2 years before admission)
No use of warfarin or aspirin (in 3 months before admission)

6637

677 [10.20%, 9.47%–10.93%]

Respiratory disease indicators

Asthma

History of asthma
Use of short-acting β-agonist more than three times per week
No use of inhaled corticosteroids

1335

214 [16.03%, 14.13%–18.07%]

Asthma

History of asthma
Use of long-acting β-agonist
No use of inhaled corticosteroids

1335

10 [0.75%, 0.32%–1.28%]

Gastrointestinal disease indicators

Gastrointestinal bleed, perforation or ulcer or gastritis

History of gastrointestinal ulcer or bleeding
NSAID use for at least 1 month
No use of gastroprotective agent (eg, proton pump inhibitor)

17 149

107 [0.62%, 0.48%–0.72%]

Chronic constipation or impaction

Regular use of a strong opioid analgesic (fentanyl, oxycodone, morphine)
No concurrent use of a laxative

6780

604 [8.91%, 8.22%–9.58%]

Gastrointestinal ulcer or bleed

Patient with osteoarthritis
Dispensed long-term NSAID therapy (including cyclooxygenase-2 inhibitors)

17 125

2166 [12.65%, 12.20%–13.20%]

Osteoporosis or fracture indicators

Fracture

Female patient
History of osteoporosis or fracture
No use of hormone replacement therapy, bisphosphonate, teriparatide, selective oestrogen receptor modulators or strontium

20 213

3467 [17.15%, 16.68%–17.72%]

Fracture

Male patient
History of osteoporosis or fracture
No use of bisphosphonate or teriparatide

12 231

2406 [19.67%, 18.98%–20.38%]

Fracture

Patient aged 65 years or older
Use of a falls-risk medicine6,7,24 (eg, long-acting hypnotic or anxiolytic, tricyclic antidepressant)

31 486

26 892 [85.41%, 85.01%–85.79%]

Renal disease indicators

Renal failure or nephropathy

History of diabetes
Microalbuminuria and plasma creatinine not monitored in previous 12 months
Patient not on ACEI or ARB

7335

665 [9.07%, 8.44%–9.76%]

Renal failure

NSAID use for >&nbsp3 months
Serum creatinine not monitored in the previous 12 months

7113

102 [1.43%, 1.13%–1.67%]

Diabetes indicators

Hyperglycaemia

Use of an oral hypoglycaemic agent
HbA_1c level not monitored in previous 6 months

223

42 [18.83%, 13.67%–23.93%]

Hypoglycaemia

Use of a long-acting oral hypoglycaemic agent (glibenclamide or glimepiride)
HbA_1c level not monitored in the previous 6 months

1528

67 [4.38%, 3.37%–5.43%]

Hyperglycaemia or hypoglycaemia

Use of insulin
HbA_1c level not monitored in the previous 6 months

1751

209 [11.94%, 10.38%–13.42%]

Hyperglycaemia or hypoglycaemia

Use of insulin or oral hypoglycaemic medicines
Use of medicines that may alter blood glucose concentration
HbA_1c level not monitored in the previous 6 months

1751

103 [5.88%, 4.80%–7.01%]

Hypoglycaemia

Use of glibenclamide or glimepiride
Renal function not monitored in the previous year

1528

42 [2.75%, 1.97%–3.63%]

Cardiovascular disease

History of diabetes
Not on lipid-lowering drug

67 177

2541 [3.78%, 3.66%–3.94%]

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CHF = congestive heart failure; HbA1c = glycated haemoglobin; NSAID = non-steroidal anti-inflammatory drug.