Objectives Despite recognition of clinical deterioration and medication-related harm as patient safety risks, the frequency of medication-related Rapid Response System activations is undefined. We aimed to estimate the incidence and preventability of medication-related Medical Emergency Team (MET) activations and describe the associated adverse medication events.
Methods A case review study of consecutive MET activations at two acute, academic teaching hospitals in Melbourne, Australia with mature Rapid Response Systems was conducted. All MET activations during a 3-week study period were assessed for a medication cause including identification of the contributing adverse medication event and its preventability, using validated tools and recognised classification systems.
Results There were 9439 admissions and 628 MET activations during the study period. Of these, 146 (23.2%) MET activations were medication related: an incidence of 15.5 medication-related MET activation per 1000 admissions. Medication-related MET activations occurred a median of 46.6 hours earlier (IQR 22–165) in an admission than non-medication-related activations (p=0.001). Furthermore, this group also had more repeat MET activations during their admission (p=0.021, OR=1.68, 95% CI 1.09 to 2.59). A total of 92 of 146 (63%) medication-related MET activations were potentially preventable. Tachycardia due to omission of beta-blocking agents (10.9%, n=10 of 92) and hypotension due to cumulative toxicity (9.8%, n=9 of 92) or inappropriate use (10.9%, n=10 of 92) of antihypertensives were the most common adverse medication events leading to potentially preventable medication-related MET activations.
Conclusions Medications contributed to almost a quarter of MET activations, often early in a patient’s admission. One in seven MET activations were due to potentially preventable adverse medication events. The most common of these were omission of beta-blockers and clinically inappropriate antihypertensive use. Strategies to prevent these events would increase patient safety and reduce burden on the MET.
- Patient safety
- Adverse events, epidemiology and detection
- Hospital medicine
- Medical emergency team
- Medication safety
Data availability statement
No data are available. Not applicable.
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- Patient safety
- Adverse events, epidemiology and detection
- Hospital medicine
- Medical emergency team
- Medication safety
WHAT IS ALREADY KNOWN ON THIS TOPIC
Medications have been shown to contribute to clinical deterioration of patients in hospital; however, the incidence and preventability of medication-related Medical Emergency Team activations have not been quantified.
WHAT THIS STUDY ADDS
Almost a quarter of Medical Emergency Team activations were medication related and more than half of these were preventable.
Omission and inappropriate use of cardiovascular medications were the most common causes of potentially preventable medication-related Medical Emergency Team activations.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY
Prevention and increased recognition of medication-related Medical Emergency Team activations, particularly early in a patient’s hospital stay, present opportunities to improve patient safety and relieve pressure on the Medical Emergency Team.
Intervention strategies to prevent the most common medication-related Medical Emergency Team activations should be designed and tested.
Patient safety is a global health priority.1 Clinical deterioration and medication-related harm are recognised risks to patient safety.2–4 Understanding the nature, aetiology and potential preventability of patient harms is necessary to design solutions that increase patient safety as well as reduce the burden on healthcare providers and systems.
Medical Emergency Teams (METs) respond to episodes of clinical deterioration detected by the Rapid Response System (RRS) to stabilise and triage patients.5 METs have been demonstrated to reduce in-hospital cardiac arrest and mortality.6–9 Despite this, patients who require MET activation have an advanced degree of deterioration and an increased risk of dying in hospital.10 Thus, strategies that identify potential for deterioration prior to MET activation are desirable.11
Harm resulting from adverse medication events may contribute to up to one-third of clinical deterioration in acute hospitals.12 The most accurate estimate to date of 33% arises from a large (n=830) multicentre case review study.13 This study used a broad definition of clinical deterioration, likely reflective of local contemporaneous practice, which included 115 MET activations not requiring intensive care unit (ICU) transfer combined with a much larger number of patients requiring unplanned admission to the ICU.13 Hence, it provided an incidence of medication-related clinical deterioration but not specifically MET activations. The contribution of medications to clinical deterioration leading to MET activation is less defined.12 Reports of medication-related MET activation rates have varied more than 10-fold, and have been limited to single-centre studies.12
Many adverse medication events, particularly errors, are considered highly preventable.14–16 However, the preventability of medication-related MET activations is not known.12 A small observational study of surgical Rapid Response Team activations assessed almost all activations due to medication errors as preventable.17 These findings are limited by the small, selective sample and a focus only on errors. Marquet et al 16 found a similarly high proportion of preventable errors contributed to clinical deterioration. They did not assess adverse medication reactions for preventability. The interpretation of these findings is limited by the risk of classification error with retrospective review and the potential that some adverse medication reactions are preventable.18 19 Development of strategies to prevent medication-related MET activations requires more generalisable data from larger cohorts of patients requiring MET activation.
The aim of this study was to provide a more robust estimate of the incidence of medication-related MET activations. Further, this study aimed to determine the preventability of these activations and describe the medications and adverse medication events leading to medication-related MET activations.
This was an observational cohort study involving retrospective case review of a prospectively identified sample of consecutive MET activations from two tertiary hospitals.
The study sites were the acute hospitals of two academic health services in Melbourne, Australia. Both hospitals had approximately 400 beds and offered a full range of medical, surgical and psychiatric services as well as tertiary and quaternary referral services including solid organ and bone marrow transplantation. One hospital had no electronic medical records at point of care and one had manual electronic documentation of nursing observations and medication prescribing and administration without decision support. At both hospitals, records were scanned at the end of care episodes to provide an electronic history.
Clinical pharmacy and medication management services at both hospitals were delivered according to national standards and were considered practice leading.20 Clinical pharmacists achieved medication reconciliation rates within 24 hours of admission exceeding 80%, charted admission medications for some medical teams, provided daily inpatient clinical reviews and were integrated into multidisciplinary team rounds. Both hospitals had multidisciplinary medication safety teams and practices that met national accreditation standards.21 Routine practices included barcode scanning for dispensed patient medications, use of smart pump technology with drug libraries for all infusion administration and medication incident reporting, investigation and targeted improvement initiatives.
Both study sites had very similar, mature two-tier RRSs with mandatory activation against specified criteria (online supplemental file 1).22–25 No automated monitoring or early warning systems were in place. Any staff member could activate the RRS, for an inpatient in any location in the hospital, 24 hours a day, via the hospital switchboard which sent MET personnel pages and overhead address across the hospital. At low levels of physiological abnormality, an ‘urgent clinical review’ was triggered; this involved a time-critical review by the treating medical and nursing team within 15 minutes. At higher levels of abnormality or concern, there was mandatory activation of the MET for immediate attendance (online supplemental file 1).
The MET was led by a critical care-trained doctor and senior critical care nurse and also included treating team senior medical and nursing staff. Neither site had pharmacist or other allied health MET members. At both study sites, the MET responded to all patients admitted to the hospital. Admissions included multiday encounters (>24 hours) and same-day encounters (ie, day cases or up to 23-hour stays), but excluded ambulatory outpatients. A separate code blue team responded to arrest calls as well as deterioration of outpatients, staff and visitors. These practices were consistent with national guidelines and standards.21 26 27
Both sites maintained a prospective database where for each activation, MET clinicians captured the triggers, clinical assessment, management and immediate outcome and disposition of patients. The dataset also captured factors potentially contributing to clinical deterioration, including a medication-related flag, repeat activations and logistical data such as attendees and delays.
All consecutive MET activations for adult patients (≥18 years) during the study period were included. MET activations for paediatric patients (<18 years) and other RRS activation types (code blue or urgent clinical reviews) were excluded. Based on the annual MET activation rate at each hospital, a sample size of 371 activations across both study sites was calculated to provide a statistically representative sample with a margin of error less than 5%. This equated to approximately 17 days, so a 3-week study period was used. No power calculation was undertaken. Each hospital nominated its own study period that occurred on 21 consecutive days between April and June 2018, late autumn to early winter in Australia, thus excluding the winter peak period but avoiding holiday periods with reduced activity.
MET activation data were extracted from each hospital’s existing database. Case reviews were completed using clinical information sourced from the MET database and medical records. These medical records included ambulance, emergency department and ward medical and nursing notes, physiological observations, investigations and therapies including medications, medication reconciliation at admission, operative reports and discharge documentation. Clinical records from outside the treating hospital (eg, primary care, other hospital) were not available. A case report form (online supplemental file 2) guided the case reviews including patient demographics and clinical data from: admission to hospital including best possible medication history; prior to MET activation including significant events, medications prescribed and administered in the previous 24 hours and the last set of observations recorded prior to deterioration; and at and during MET activation including observations, assessment and management.
Case reviews of all activations were conducted by an experienced clinical pharmacist investigator (XX). A senior intensivist investigator (XX, XX) from each site conducted an independent, blinded case review of approximately 40% of activations comprising all activations identified as medication related by the pharmacist reviewer, plus any activations flagged by clinicians as medication related, plus a random 10% sample of other activations. This additional random sample ensured reliability of the review process and blinding of intensivist review. Prior to undertaking case reviews, reviewers were provided with the case report forms as a spreadsheet and briefed on accessing any available clinical information and use of the study tools.
For each case, reviewers assessed (1) whether the activation was medication related, (2) the contributing medication(s) and adverse medication event, and (3) the preventability of the activation. For determining whether an activation was medication related, reviewers used the 6-point causality scale from landmark adverse event studies,28 29 with a score of 4 or more considered medication related. All adverse medication events were rated for preventability using the previously published methodology by Marquet et al 16 based on the landmark studies,28 29 with a rating of four or more considered preventable. The two reviewers resolved any rating disagreements by discussion and review of all available information. Other patient and admission data linked to each MET activation were provided directly from each hospital’s administration systems.
The primary outcome was the frequency of medication-related MET activations per 1000 admissions. The secondary outcomes included the proportion of these activations that were potentially preventable, differences in characteristics between medication-related and non-medication-related activations and description of medications and adverse medication events contributing to medication-related MET activations.
Data handling and analysis
Data were extracted into Microsoft Excel (Office 2019, Microsoft Corporation, Redmond, California, USA) for cleaning and coding. Where multiple activation triggers were recorded, the trigger matching the patient’s clinical condition and vital signs at the time of the activation was analysed. Medications were coded using the WHO Anatomical Therapeutic Chemical (ATC) categories (https://www.whocc.no/atc_ddd_index/Accessed 19 May 2021). Adverse medication events were categorised using 14 categories as described previously.30 For adverse medication reactions, an international standard classifying six types of reactions (A–F) was used.19 Medication errors were classified using local adaptations of the nursing rights of medication safety 31 that had seven classifications: incorrect patient, incorrect drug, incorrect dose, incorrect time/frequency, incorrect route/formulation, omission and incorrect clinical scenario. The latter is when a medication was prescribed and/or administered when a clinical parameter or diagnosis would have precluded its use, for example, an antihypertensive being administered despite evidence of shock. An additional category of other adverse medication event included patient-initiated actions such as self-medication.
Statistical analyses were completed using IBM SPSS Statistics V.26 (IBM Corporation). Categorical data were presented as counts (%) and distributed data as median (IQR or range). Differences were assessed with the Χ2 test for proportions and Mann-Whitney U tests for continuous data. Agreement between case reviewers was assessed dichotomously using Fleiss’ multirater kappa. A two-sided p<0.05 was considered statistically significant.
During the study periods, there were 9439 admissions across the two hospitals (figure 1). There were 628 MET activations for 403 patients during 406 admissions included for analysis. The MET activation incidence was 66.5 per 1000 admissions. The most common activation triggers were low blood pressure (n=167 of 628, 26.6%) and high heart rate (n=125 of 628, 19.9%). After the majority of MET activations (n=565 of 628, 90%), patients remained on the ward.
In total, 43.6% (n=274 of 628) MET activations were reviewed by two reviewers, including 187 (n=187 of 628, 29.8%) activations flagged by the pharmacist reviewer as potentially medication related. Initial agreement between case reviewers on causality and preventability was low (kappa=0.143 and kappa=0.069). However, agreement for all reviewed cases (n=274) was reached following discussion between reviewers. By the end of the case review process, 133 (n=133 of 187, 71.1%) cases flagged by the pharmacist reviewer were confirmed as potentially medication related.
Medication-related MET activations
There were 146 (n= 146 of 628, 23.2%) medication-related MET activations identified (figure 1), with an incidence of 15.5 medication-related MET activations per 1000 admissions. The most common triggers were low blood pressure (n=63 of 146, 43.2%) and high heart rate (n=18 of 146, 12.3%) (table 1).
Comparisons of activation, patient and admission factors
Compared with non-medication-related MET activations, medication-related MET activations occurred a median of 46.6 hours earlier in a patient’s admission (p=0.001) (table 1). Repeat MET activations during an admission were more likely for patients who experienced a medication-related MET activation (OR=1.68, 95% CI 1.09 to 2.59). There were no other differences in patient characteristics, disposition or outcomes (table 1).
Medications and adverse medication events
Medications from nine of the 14 anatomical/pharmacological ATC first level categories contributed to the 146 medication-related MET activations (figure 1). The most common ATC first level categories were cardiovascular system (ATC C) (n=81 of 146, 55.5%) and nervous system (ATC N) (n=37 of 146, 25.3%).
The most common ATC second level category medications were beta-blocking agents (C07) (n=25 of 146, 17.1%), analgesics (N02) (n=20 of 146, 13.7%), diuretics (C03) (n=20 of 146, 13.7%) and agents acting on the renin–angiotensin system (C09) (n=17 of 146, 11.6%).
Medication errors contributed to 81 (n=81 of 146, 55.5%,) medication-related MET activations (figure 1). Errors of omission (n=47 of 146, 32.2%) were the most common adverse medication events leading to MET activation (online supplemental file 3). Cardiovascular system (ATC C) medication omission (n=29 of 146, 19.9%) was the most common of these. Specifically, 7.5% (n=11 of 146) of medication-related MET activations were due to omission of one beta-blocking agent (ATC C07), metoprolol (table 2). Medication-related MET activations for hypotension due to inappropriate use of cardiovascular (ATC C) medications during acute illness (error=incorrect clinical scenario, n=13 of 146, 8.9%) were common.
Adverse medication reactions contributed to 63 (n=63 of 146, 43.2%) medication-related MET activations (figure 1). Dose-related (type A) reactions (n=27 of 146, 18.5%) and dose and time-related (type C) reactions (n=26 of 146, 17.8%) commonly contributed to medication-related MET activations (online supplemental file 3). These were due to predominantly cardiovascular system (ATC C) medications (type A n=14 of 146, 9.6% and type C n=15 of 146, 10.3%) (table 2). Hypotension was the trigger for the 15 (n=15 of 146, 10.3%) medication-related MET activations due to cumulative toxicity (type C) of cardiovascular (ATC C) medications.
Of the 146 medication-related MET activations, 92 (n=92 of 146, 63%) activations were rated as preventable (figure 1). This gave an incidence of 9.7 potentially preventable medication-related MET activations per 1000 admissions, or one in seven MET activations were due to potentially preventable adverse medication events.
The most common MET activation triggers for potentially preventable medication-related MET activations were low blood pressure (n=35 of 92, 38%) and high heart rate (n=15 of 92, 16.3%) . Five (n=5 of 92, 5.4%) of these activations resulted in patients needing escalation of care to high dependency care or the ICU.
The most common medications (ATC first level categories) leading to potentially preventable medication-related MET activations were cardiovascular system (ATC C) agents (n=55 of 92, 59.8%) (figure 2). The most common ATC second level category medications were beta-blocking agents (C07) (n=19 of 92, 20.7%), analgesics (N02) (n=13 of 92, 14.1%), agents acting on the renin–angiotensin system (C09) (n=12 of 92, 13%) and diuretics (C03) (n=11 of 92, 12%) (table 2).
Medication errors contributed to 66 (n=66 of 92, 71.7%) potentially preventable medication-related MET activations (figure 1). Potentially preventable medication-related MET activations due to omission (n=42 of 92, 45.7%) were most common. Cardiovascular system (ATC C) medications (n=27 of 92, 29.3%) were most commonly omitted (figure 2). Ten (n=10 of 92, 10.9%) of these events were omission of metoprolol leading to tachycardia; the remaining omission of a beta-blocking agent (C07), also metoprolol, leading to tachycardia was rated non-preventable.
Adverse medication reactions contributed to 24 (n=24 of 92, 26.1%) potentially preventable medication-related MET activations (figure 1). Dose and time-related (type C) reactions (n=15 of 92, 16.3%) were the most common. Cardiovascular system (ATC C) medications leading to hypotension contributed to nine (n=9 of 15, 60%) of these events (figure 2).
Errors of cardiovascular system (ATC C) medication use in incorrect clinical scenarios (n=10 of 92, 10.9%) were also common potentially preventable adverse medication events (figure 2). All of these were hypotension due to inappropriate use of medications with antihypertensive effects during acute illness (table 2).
Two (n=2 of 92, 2.2%) potentially preventable medication-related MET activations for change in conscious state were due to patient actions: self-administered oxazepam or zopiclone not prescribed for use during their hospital admission.
This study of 628 MET activations in a heterogeneous population from two hospitals identified almost a quarter of MET activations as medication related. At a rate of almost seven medication-related MET activations per day across the two hospitals, this presents a considerable burden to patients and healthcare resources. These events occurred almost 2 days earlier in a patient’s hospital stay than MET activations unrelated to medications, and these patients were more than 50% more likely to require repeat MET activations.
One in seven MET activations was due to a potentially preventable medication adverse event. Almost all omissions of cardiovascular medications were rated as preventable and the most common were MET activations for tachycardia due to omission of one beta-blocker, metoprolol, the most commonly used beta-blocker in both institutions. As the biggest contributor to medication-related MET activations, these omissions, along with hypotension due to inappropriate use of antihypertensive medications, presented targets for interventions to improve patient safety and reduce burden on the RRS.
Comparison with other literature
We are aware of only one previous multicentre study that provided an estimate of medication-related clinical deterioration.13 They defined clinical deterioration as unplanned ICU admission or MET activation, and observed over one-third of clinical deterioration to be medication related.13 While not specific to MET activations, this estimate is slightly higher than our finding of 23.2%, considering the relative similarity of the methods used in both studies this difference may relate to our specific inclusion of only MET activations. Our study hospitals would have very few unplanned admissions to the ICU without a MET activation occurring first. This is reinforced by the lower rate of escalation of care than observed by Marquet et al 16 in their substudy, suggesting the RRS may have detected these patients early and MET activation allowed prompt management. Differences in healthcare delivery between the two countries, particularly the types of patients eligible for RRS activation, mandatory MET activation and clinical pharmacy services, may have also contributed.
The remaining previous reports provided specific estimates of medication-related MET activations from single-centre studies and all reported lower proportions of medication-related MET activations.12 30 The MET activation rates in these studies were generally comparable with those in our study, suggesting this was unlikely a dilution effect. Studies that relied on data collected by clinicians during the activation30 32 33 likely captured only the most obvious associations with medications. Studies using case review methodologies focused on adverse medication reactions when categorising activations according to clinical syndromes.34 35 Therefore, these estimates did not include MET activations due to medication errors, which were the largest group of adverse medication events detected in our study.
Our finding that medication-related MET activations occurred earlier in a patient’s hospital stay was consistent with our previous results.30 Transitions of care such as hospital admission are recognised as high risk for medication-related harm.4 36 Therefore, this observation is important as early in an admission, patients are generally less stable so less able to tolerate adverse events. This finding is a key consideration for designing strategies to prevent medication-related MET activation.
We believe ours is the first study to quantify the preventability of medication-related MET activations in a non-selective acute hospital population. A small study of surgical patients requiring Rapid Response Team activations found approximately 90% of the errors involving medications were thought to be preventable17 but did not assess adverse reactions. Similarly, the substudy of adverse medication events by Marquet et al 16 classified adverse drug reactions as not preventable and all other adverse medication events as preventable by definition. In our study, medication-related MET activations due to any type of adverse medication event were assessed for preventability and almost 40% of activations due to adverse medication reactions were rated as preventable. One in five medication errors were rated as not preventable.
Strengths and limitations
This study exceeded, almost by double, the required sample size ensuring a highly representative sample of consecutive MET activations and a high level of accuracy to avoid selection bias and to increase the generalisability of the findings. However, the sample could not account for seasonal effects or other variations over time. Blinded, independent case review and validated tools to systematically detect medication-related MET activations were used to increase reliability. All events were assessed for preventability avoiding bias introduced by classification error that may have occurred due to the acknowledged lack of distinction between some medication errors and adverse medication reactions.18 19 The use of internationally recognised medication and adverse medication event classification systems further increases generalisability of our findings, and with the expression of incidence per 1000 admissions, allows for future comparisons.
The study design has limitations. Case review studies rely on secondary use of clinical information. Hence, reviews may have been compromised by poor documentation. The impact of this was minimised by allowing reviewers to use any clinical information available. The subjectivity of the medication-related causality and preventability assessments cannot be discounted.37 38 Low agreement between reviewers was overcome with case discussion to reach consensus which was more likely reflective of multidisciplinary clinical decision-making. The sample size and inclusive population of the study prevented the calculation of the total number of medications or medication doses prescribed or administered during the study. Without this denominator, we were unable to quantify the proportion of all medications used that resulted in medication-related MET activations. These data would be important for assessment of the feasibility and efficacy of interventions to prevent specific adverse medication events. The study was conducted in two government-funded, academic teaching hospitals in Melbourne, Australia, with mature RRSs and comprehensive clinical pharmacy services, and did not analyse variables such as patient case-mix, and clinical service standards or practices. Thus, the findings may not be directly applicable but warrant investigation in other settings, particularly as our study setting represented a ‘better case’ scenario than institutions with less resources, different safety cultures, non-mandatory RRS activation and less integrated clinical pharmacy services.
Implications for practice and future research
The findings of this study highlighted that medications are a major contributor to clinical deterioration leading to MET activation. The potential preventability of so many activations, particularly early in a patient’s hospital stay, presents the opportunity to improve patient safety and relieve pressure on the MET. In the study hospitals where clinical pharmacy services had a heavy focus on patient admission, clinical pharmacists likely had already influenced these rates, but also could play an important role in these improvements.
Intervention strategies to prevent the most common medication-related MET activations should be designed and tested. In this study, these activations were (1) omission of metoprolol leading to MET activations for tachycardia and (2) cumulative toxicity and inappropriate continuation of cardiovascular agents with antihypertensive effects. These are logical targets for clinical improvements focusing on medication management early in a patient’s admission. However, caution and careful evaluation is necessary as strategies to encourage changes in prescribing or administration of medications may have unintended consequences, including increasing MET activations for other triggers such as bradycardia, hypertension, high respiratory rate or even tachycardia. This evaluation could be achieved using either clinical trial or quality improvement methodologies.
The considerable contribution of medications to MET activation in this study and the lower frequency found in studies relying on clinician detection30 32 33 suggest clinicians need support to recognise medication-related MET activations at the bedside. Increased awareness through education may have short-term effects. Ideally, more durable interventions should be implemented to ensure medications are routinely considered in differential diagnoses for patients who clinically deteriorate. This may present a role for clinical pharmacists either working as part of the attending MET or a prompted follow-up review of patients who triggered a MET activation. Either service could be prioritised by MET activation trigger as the findings of this study demonstrated medication-related activations were commonly triggered for high heart rate and fluctuations in blood pressure and conscious state. The local priorities of clinical pharmacy services would influence the development of these roles. However, these considerations should also be influenced by the potential impacts of undetected medication-related causes of MET activations, and the risk of adverse medication events occurring during MET activations particularly as a result of emergent situations where a team unfamiliar with each other and the patient are working in an unfamiliar environment.39
Medications contribute to almost a quarter of MET activations, often early in a patient’s admission. One in seven MET activations were due to potentially preventable medication adverse events. These events were most commonly beta-blocker omission or clinically inappropriate antihypertensive use. Strategies to prevent the most common medication-related MET activations would increase patient safety and reduce patient morbidity as well as reduce burden on the MET.
Data availability statement
No data are available. Not applicable.
Patient consent for publication
This study received institutional approval and need for consent was waived by the reviewing ethics committee (The Alfred Ethics Committee HREC/17/Alfred/192, Alfred Health SSA/18/Alfred/48, Austin Health SSA/18/Austin/133, Monash University Human Research Ethics Committee 12577).
The authors acknowledge the contribution of XXXX to supporting the case reviews. The authors also acknowledge the work of the nurses and doctors of the METs at the two sites where this study was conducted: XXXX and XXXX.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Contributors All authors have made substantial contributions to the planning and conduct of this study and drafting and revision of the manuscript. Bianca J Levkovich is the guarantor of the study.
Funding BIanca J Levkovich was supported by an Australian Government Research Training Programme Scholarship. D James Cooper was supported by an Australian National Health and Medical Research Council Practitioner.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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