Volume 211 Issue 5

More research is needed to understand the barriers to optimal adolescent immunisation for students with disabilities

Jenny O'Neill · Fiona Newall · Giuliana Antolovich · Sally Lima · Margie H Danchin

The medical and moral imperative that palliative care be integrated into standard responses to humanitarian crises can be fulfilled through basic training and an essential set of medicines, equipment, social supports and protocols

Eric L Krakauer · Bethany‐Rose Daubman · Tammam Aloudat

Machine learning has huge potential to enhance clinical decision making, but there are still many limitations

Ian A Scott · David Cook · Enrico W Coiera · Brent Richards

A 76- year- old man from rural Victoria presented with 4 months of difficulty swallowing due to a painful, large, non-healing tongue ulcer

Michael B MacIsaac · Sasha R Fehily · Stephen Muhi · Linda Yang · Penelope A McKelvie · Cameron J Jeremiah · Barbara Demediuk

W here there is no psychiatrist, 2nd edition

Mathew Coleman

Accurate diagnosis and staging of invasive melanoma requires an appropriate biopsy and technical proficiency

Michael A Rtshiladze · Jonathan R Stretch · Richard A Scolyer · Pascale Guitera

Paracetamol remains one of the drugs most frequently implicated in deliberate self- poisoning overdoses in Australia

Andis Graudins · Anselm Wong

Excisional biopsy remains the most appropriate diagnostic biopsy technique for invasive melanoma

Sara L de Menezes · John W Kelly · Rory Wolfe · Helen Farrugia · Victoria J Mar

The availability of paracetamol needs to be restricted to stem the increasing number of overdoses

Rose Cairns · Jared A Brown · Claire E Wylie · Andrew H Dawson · Geoffrey K Isbister · Nicholas A Buckley

Management should be individualised, using a multidisciplinary approach

Mathis Grossmann · Sabashini K Ramchand · Frances Milat · Amanda Vincent · Elgene Lim · Mark A Kotowicz · Jill Hicks · Helena J Teede

As a result of their widespread use, elucidating the influence of DMTs on fertility, pregnancy and breastfeeding is critical for assisting physicians and patients in weighing up the relative risks and benefits of continuing therapy. International pregnancy registries have a key role to play, and neurologists should be encouraged to contribute to these when possible. Furthermore, family planning counselling may be useful for patients with multiple sclerosis to help alleviate fears and concerns and to enable more informed decision making. A multidisciplinary approach, involving collaboration between neurologists, obstetricians, midwives, anaesthesiologists and fertility specialists (when required), is also recommended to help optimise outcomes for both the patient and the child. Decision making should be a shared experience between patient and physician, with a personalised approach developed to meet the unique needs of each individual patient.

Anneke Van Der Walt · Ai‐Lan Nguyen · Vilija Jokubaitis

To the Editor: We read with interest the article regarding Australia's approach to managing the challenges of pharmaceutical opioid utilisation.1 The various regulatory, service delivery and educational activities described would appear to provide a comprehensive response to this problem. However, we were surprised to note the absence of any reference to the potential of pharmacogenomics in identifying patients at increased risk of opioid toxicity. Various factors dictate how much opioid reaches the brain, how long it stays there, and how sensitive a patient may be to central nervous system (CNS) depression. Many risk factors for opioid toxicity are familiar to doctors. These include high daily opioid dose, extremes of age (neonates and older patients), comorbid conditions (eg, liver, kidney and respiratory disease), concomitant CNS depressants (sedatives and alcohol), and strong inhibitors or inducers of metabolism. In contrast, pharmacogenomics is unfamiliar to many Australian doctors. A recent position statement from major medical colleges describes a coordinated effort by doctors to develop the role of pharmacogenomics in Australian clinical practice.2 Codeine is converted to the active metabolite morphine by the cytochrome P450 enzyme encoded by the gene CYP2D6. Due to variants in CYP2D6, some patients are poor metabolisers (5–10%), have low CNS exposure to morphine, and are unlikely to benefit from or be harmed by codeine. Conversely, other patients are ultrarapid metabolisers of codeine (up to 10%), resulting in high and prolonged CNS exposure to morphine and an increased risk of CNS depression.3 There is an ongoing debate about the place of pharmacogenomics in managing the prescribing of opioids. There is strong support for testing children and nursing mothers taking codeine due to fatal cases of respiratory failure in ultrarapid metabolisers.4 International clinical guidelines recommend that codeine be avoided in poor metabolisers and ultrarapid metabolisers because of lack of efficacy and risk of CNS depression, respectively.3 Considerable research is underway to determine whether pre‐emptive pharmacogenomic testing can help with the pharmaceutical opioid problem.5 To reduce harm from opioids, we recommend testing for CYP2D6 variants as part of a benefit–risk assessment when prescribing codeine, especially for patients with other risk factors for opioid toxicity.

Thomas Polasek · Melody Caramins · Graeme Suthers

In reply

Gabrielle Campbell · Briony Larance · Nicholas Lintzeris

To the Editor: Sodium–glucose cotransporter type 2 (SGLT2) inhibitors — dapagliflozin, empagliflozin and now ertugliflozin — have become established second line options for type 2 diabetes, with favourable potential for weight loss and cardiovascular protection.1 However, it soon became clear post‐marketing that they had potential for several pronounced side effects, including euglycaemic ketoacidosis — an unusual form of diabetic ketoacidosis where blood sugar levels remained relatively normal.2 The Therapeutic Goods Administration (TGA) first sent an alert about euglycaemic ketoacidosis in relation to SGLT2 inhibitors in 2015; subsequent alerts in 2018 from the TGA and the Australian Diabetes Society warned specifically about periprocedural risks.3,4 Austin Health has a well developed culture of adverse drug reaction reporting. A multidisciplinary committee includes representation from pharmacy, clinical pharmacology, dermatology and infectious diseases. During 2018, our adverse drug reaction committee forwarded 302 reports to the TGA, estimated to be around 15% of all reports received from Australian hospitals. Since 2016, our adverse drug reaction committee has received 12 reports of patients with diabetic ketoacidosis related to SGLT2 inhibitors, including eight in 2018. The growth in incidence locally in such a short period is alarming. Most patients (75%) had a blood sugar level of 11 mmol/L or lower at presentation. Our committee reviewed the cases in the Box to evaluate severity and causality. SGLT2 inhibitors were considered a probable cause in ten cases; the reaction was considered severe in nine cases, with one death during admission. We report our cases with the aim of increasing awareness around contributing factors, particularly concurrent illness resulting in poor oral intake. Only two of the 12 cases related to a perioperative setting, and in neither situation was the SGLT2 inhibitor withheld prior to surgery. We remind clinicians that the precipitants for diabetic ketoacidosis extend beyond the perioperative period. We advise caution when patients are experiencing other contributing factors illustrated by our case series, including acute illness, reducing insulin doses, poor oral intake, severe dehydration and low carbohydrate diet. Patients should be counselled about the signs of ketoacidosis and advised to seek medical help if they occur. SGLT2 inhibitors should be withheld if a patient is acutely unwell or undergoing surgery, and should only be restarted when the patient is eating and drinking normally.5 Box – Cases of ketoacidosis related to sodium–glucose cotransporter type 2 inhibitors Case Year Medication Dose Severity Causality Potential contributing factors 1 2016 Empagliflozin 10 mg daily Moderate Probable Low dietary intake in perioperative setting 2 2016 Dapagliflozin 5 mg twice a day Severe Probable Perioperative setting 3 2017 Dapagliflozin 10 mg daily Severe Probable Unwell for 3 days prior to presentation — patient had type 1 diabetes 4 2017 Empagliflozin 10 mg daily Severe Possible Concurrent influenza 5 2018 Empagliflozin 10 mg daily Severe Probable Narcosis leading to poor oral intake 6 2018 Empagliflozin 12.5 mg twice a day Severe Probable Weight loss since commencing — worse in the month prior to admission 7 2018 Empagliflozin 25 mg daily Moderate Probable Concurrent pneumonia 8 2018 Dapagliflozin 10 mg daily Moderate Possible Low carbohydrate diet 9 2018 Empagliflozin 10 mg daily Severe Probable Patient unwell with some vomiting for several days before admission 10 2018 Dapagliflozin 5 mg twice a day Severe Probable 5–7 days of loss of appetite 11 2018 Dapagliflozin 10 mg daily Severe (died during admission) Probable Illness for 10 days before admission Pancreatitis 12 2018 Empagliflozin 25 mg daily Severe Probable 5 days of gastroenteritis before admission Weaning insulin doses

Gina McLachlan · Claire Keith · Albert Frauman