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Ischemic stroke
Original research
The detrimental clinical impact of severe angiographic vasospasm may be diminished by maximal medical therapy and intensive endovascular treatment
  1. Alex Mark Mortimer1,
  2. Brendan Steinfort1,
  3. Ken Faulder1,
  4. Celia Bradford2,
  5. Simon Finfer2,
  6. Nazih Assaad3,
  7. Timothy Harrington1
  1. 1Department of Radiology, Royal North Shore Hospital, Sydney, Australia
  2. 2Department of Intensive Care Medicine, Royal North Shore Hospital, Sydney, Australia
  3. 3Department of Neurosurgery, Royal North Shore Hospital, Sydney, Australia
  1. Correspondence to Dr A M Mortimer, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia; alex_mortimer{at}hotmail.com

Abstract

Objective Severe angiographic vasospasm (aVSP) is a risk factor for poor functional outcome following subarachnoid hemorrhage. We investigated the impact of angiographic surveillance and intensive endovascular treatment using transluminal balloon angioplasty (TBA) and/or verapamil infusion for severe aVSP through comparison of clinical outcomes in patients of similar presenting grade but with no/mild vasospasm.

Methods This was an analysis of prospectively acquired clinical trial data. World Federation of Neurosurgical Societies (WFNS) grade 1–2 patients presenting within 72 h were included. Angiographic screening for vasospasm was undertaken at days 5–7 or in response to clinical deterioration. Severe aVSP was defined as >50% luminal narrowing on digital subtraction angiography. Treatment was instituted on the basis of radiographic findings and/or clinical deterioration. Discharge destination and favorable clinical outcomes (discharge Glasgow Outcome Score (GOS) 4–5, 90 day modified Rankin Scale (mRS) score 0–2, and GOS 4–5) for patients with severe aVSP were compared with those without significant vasospasm. Statistical analysis was undertaken using Fisher's exact test.

Results 63 WFNS grade 1–2 patients with minimal vasospasm were compared with 17 WFNS grade 1–2 patients with severe aVSP treated with induced hypertension and endovascular therapy. Results were available in 62 and 16 patients, respectively. Rates of favorable outcome did not differ significantly between the two groups. For patients with treated severe vasospasm, 90 day mRS 0–2 was seen in 15/17 (88.2%) and GOS 4–5 was achieved in 16/17 (94.1%).

Conclusions An intensive endovascular approach of TBA and/or intra-arterial verapamil in combination with induced hypertension for severe aVSP may result in comparable clinical outcomes to those without vasospasm.

  • Aneurysm
  • Angiography
  • Angioplasty
  • Balloon
  • Blood Flow

https://doi.org/10.1136/neurintsurg-2014-011403

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    Introduction

    Angiographic vasospasm (aVSP) is an independent predictor of poor outcome following subarachnoid hemorrhage (SAH).1 There is a strong correlation between the severity of aVSP and the incidence of cerebral infarction,2 which itself is strongly associated with poor outcome following SAH.3 ,4 The majority of delayed infarcts are related to severe aVSP,2 ,5–7 which results in the most severe perfusion deficits.7–10 The goal of endovascular therapy, using either transluminal balloon angioplasty (TBA) or intra-arterial vasodilators, is to improve cerebral blood flow and therefore to reduce the risk of infarction. Endovascular methods are most commonly employed as ‘rescue’ procedures. This has been shown to be effective in case series but neurological improvement is maximal if treatment is performed early in this setting.11 ,12 Delayed endovascular treatment following development of symptoms is probably of limited clinical benefit.13 The use of prophylactic TBA undertaken prior to development of vasospasm has also been investigated in a multicenter randomized trial.14 Although there were significant reductions in the rate of patients requiring rescue therapy in the treatment arm and possible outcome benefits in the good grade patients, overall clinical outcome was not significantly different in those treated with prophylactic TBA.

    An alternative approach is to screen for vasospasm at or just before the time when the majority of patients develop symptoms.15 ,16 The goal of this practice is to identify those patients with significant angiographic vasospasm who may benefit from treatment prior to development of symptoms or who are at risk of silent infarction as they are clinically too difficult to accurately assess.17 We routinely undertake a program of angiographic surveillance at days 5–7 post ictus, at or just before the time point that most patients become symptomatic,15 ,16 with subsequent endovascular treatment and multiple procedures where necessary based not only on symptomology but also on radiographic features.

    We analyzed prospectively collected trial data obtained at our institution to assess the clinical efficacy of this approach through comparison of outcomes of patients with treated severe aVSP with those of similar presenting grade who did not develop significant aVSP.

    Methods

    Study design and inclusion/exclusion criteria

    This was an analysis of prospectively acquired clinical trial data obtained primarily for the assessment of clinical outcomes and aVSP severity and incidence in patients treated with magnesium following aneurysmal SAH.18 The primary aim of this study was to compare clinical outcomes for patients with either no aVSP or mild aVSP (<25% arterial narrowing) treated with medical therapy only, with those patients with severe aVSP (>50% arterial narrowing) treated using an intensive combined medical and endovascular approach involving induced hypertension, TBA, and/or intra-arterial infusion of verapamil.

    Patients admitted to a tertiary hospital (Royal North Shore Hospital) between April 1, 2005 and February 1, 2010, presenting within 72 h of SAH confirmed by CT, were included. The study was confined to those presenting with World Federation of Neurosurgical Societies (WFNS) grades 1–2 to minimize the confounding impact of poor grade/acute injury on outcomes. Exclusion criteria included age <18 years, serum creatinine >200 µmol/L, if death was thought imminent within 72 h, if the patient had myasthenia gravis or was pregnant, or if aVSP was present prior to inclusion in the study. The study was approved by the Northern Sydney Ethics Committee and written informed consent was obtained from each patient or legal surrogate.

    Patient management

    All patients were managed on the neurointensive care unit with routine insertion of arterial and central lines. After admission, digital subtraction angiography or CT angiography was performed, and the aneurysm responsible for the bleeding was occluded by operative or endovascular means within 48 h. Following clipping or coiling of the aneurysm, systolic blood pressure was maintained between 120 and 150 mm Hg. A nimodipine infusion of 20 µg/kg/h was commenced on arrival in the ICU. All patients received nimodipine for 21 days, with at least 10 days of intravenous administration. For body temperature, the aim was to maintain the temperature below 37.5°C. Oxygen saturation was monitored continuously by pulse oximetry and maintained at >95%. Angiographic screening for vasospasm was performed routinely at days 5–7. In the event that vasospasm was suspected at an earlier time point, hydrocephalus was excluded with CT and angiographic investigation was brought forward. If felt to be clinically deteriorating secondary to aVSP, patients were managed with adequate hydration, systolic blood pressure maintained between 140–160 mm Hg, and continued nimodipine infusion.

    Endovascular technique

    Digital subtraction angiography was performed via a femoral approach using a 5 F system. Vasospasm was defined as none, mild (<25%), moderate (25–50%), and severe (>50%) by two neuroradiologists by consensus. If significant aVSP was identified, this was treated using either chemical or balloon angioplasty, and a repeat angiogram was undertaken the following day. In cases of severe refractory vasospasm, multiple treatments were undertaken. Angiography was repeated daily until either aVSP was no longer significant or aVSP proved to be unsatisfactorily treated with this regimen. In the event that multiple treatments were required, the groin sheath was sutured in situ, replaced at each sitting, and femoral angiography was performed at daily intervals to screen for external iliac artery dissection. The side of the sheath was routinely changed after 4 days if further treatments were required.

    The decision to treat and mode of treatment were based on the degree and site of arterial narrowing in conjunction with the clinical state of the patient, with treatment generally reserved for moderate–severe aVSP. Severe proximal aVSP involving the vertebral artery (VA), basilar artery, internal carotid artery (ICA), M1 middle cerebral artery, or A1 anterior cerebral artery was treated with TBA where possible. M2 middle cerebral artery and distal vasospasm was treated with intra-arterial vasodilators. Verapamil was delivered via a 5 F catheter positioned in the proximal ICA or VA at a rate of 1 mg/min, typically 10–15 mg total to a maximum dose of 25 mg per territory. Papaverine (used as a secondline agent) was delivered via a microcatheter positioned proximally within the target vessel. Arterial monitoring was used during the procedure to augment blood pressure control through slowing of the vasodilator administration and/or titration of inotropic support.

    Patients undergoing TBA were systemically anticoagulated using intravenous heparin (typically 5000 U total) with a goal of doubling baseline activated clotting time. A guiding catheter was placed on heparinized saline drip in either the cervical ICA or cervical VA. Next, a compliant balloon microcatheter (HyperGlide, ev3, Irvine, California) was navigated over a compatible 0.010 inch microwire to the most distal aspect of the spastic vessel segment to be treated (ie, the smallest spastic arterial branch farthest from the femoral access site). A single, gentle, brief (<30 s) inflation with iodinated contrast material were performed to achieve at least 70% of the expected baseline vascular luminal diameter. If the response was inadequate, further balloon inflations were performed.

    Data collected and analysis

    Baseline variables were collected, including demographic data, history of smoking, hypertension, use of statins, use of trial magnesium, previous SAH or stroke, and Acute Physiology and Chronic Health Evaluation (APACHE II) score. WFNS grade was assessed at admission. Aneurysm site and presence of hydrocephalus were recorded through assessment of angiographic and CT imaging, respectively. Clinical outcomes, including discharge Glasgow Outcome Score (GOS), discharge destination, and 90 day GOS and modified Rankin Scale (mRS) score were obtained, acquired by independent assessors. Secondary outcome measures, including length of ITU stay and length of hospital stay, were also assessed.

    Statistical analysis was performed using Medcalc statistical software. Non-parametric data (sex, WFNS grade, history of smoking, hypertension, SAH, cardiovascular event, magnesium or statin use, hydrocephalus, aneurysm location, and aneurysm securing modality) were compared using Fisher's exact test, and parametric data (age, APACHE II score, ITU days, ventilated days, hospital days, and noradrenaline dose) were compared using analysis of variance. Statistical significance was defined as p<0.05.

    Results

    Analysis of the trial database identified 80 patients; 63 patients with either no aVSP or mild aVSP who were treated with medical therapy only and 17 patients with severe aVSP who were treated with medical therapy and endovascular treatment. Fifteen patients with moderate aVSP were also identified but these patients were variably treated with endovascular therapy and were therefore not included in the analysis. Two patients with severe vasospasm who were not treated using endovascular therapy were not included in the analysis. Baseline variables are displayed in table 1. There was no significant difference in baseline characteristics between the two groups, including sex, age, history of smoking, hypertension, previous stroke or SAH, magnesium or statin use, APACHE II score, or incidence of hydrocephalus (table 1). Patients in the severe aVSP group tended to be younger, although this did not reach statistical significance. There were significantly more WFNS grade 2 patients in the severe aVSP group. No significant difference in the distribution of responsible aneurysm or aneurysm securing treatment method (endovascular vs surgical clipping) was demonstrated.

    View this table:
    Table 1

    Baseline characteristics

    Patients with severe aVSP had a significantly greater ITU and hospital stay and spent significantly more days ventilated. They had a significantly increased total noradrenaline dose (table 2). The mean first day of vasospasm treatment following hemorrhage was 6.6±1.5. For those with severe aVSP, mean duration of aVSP was 6.5±2.5 days. Of those with severe aVSP, 8/17 patients (47%) underwent TBA with a total of 15 procedures. Seventeen patients underwent verapamil chemical angioplasty with a total of 67 procedures. The mean total dose of verapamil that any one patient received at each procedure was 20.3 ±2.3 mg (range 5–40 mg). Four patients were additionally treated with intra-arterial papaverine (mean dose 90 mg; range 60–120 mg) with a total of eight infusions. The distribution of severe vasospasm and treatment employed for each patient in the study population are shown in table 3.

    View this table:
    Table 2

    Differences in care between the two populations studied

    View this table:
    Table 3

    Distribution of vasospasm and treatments used

    Clinical outcome data are shown in tables 4 and 5 and figures 1 and 2. Clinical outcomes were available for 62 patients with none or mild aVSP and for 16 patients with treated severe vasospasm. No significant difference in discharge GOS, proportion of patients discharged home, mortality, 90 day GOS, or 90 day mRS was demonstrated between the two groups if favorable outcome was dichotomized as GOS 4–5 or mRS 0–2. Patients with no/mild aVSP achieved a 90 day GOS 4–5 and mRS 0–2 of 83.9% and 82.2%, respectively. Of those with aggressively treated severe vasospasm, 90 day GOS and mRS were 94.1% and 88.2%, respectively. If favorable outcome was dichotomized as mRS 0–1, there tended to be more favorable outcomes in the no/mild vasospasm group but this did not reach significance (p=0.2693). However, there were significantly more WFNS grade 2 patients in the severe aVSP group (10/17, 64.7% v 17/63, 30%) confounding this. When outcomes were assessed by grade, this difference was less apparent (see table 6). For example, for WFNS grade 2 patients without significant spasm, favorable outcome was 7/17 (41.2%) mRS 0–1 and 13/17 (76.5%) mRS 0–2. Outcomes for WFNS grade 2 patients with treated severe aVSP were 4/11 (36.4%) mRS 0–1 and 10/11 (90.9%) mRS 0–2. Furthermore, if favorable outcome was dichotomized by GOS 5, no significant difference was demonstrated.

    View this table:
    Table 4

    Outcomes for each of the two populations studied

    View this table:
    Table 5

    Clinical outcomes at 90 days by modified Rankin Scale and Glasgow Outcome Scale

    View this table:
    Table 6

    Favorable outcomes by World Federation of Neurosurgical Societies grade

    Figure 1
    Figure 1

    Ninety day Glasgow Outcome Score for patients with minimal or severe vasospasm.

    Figure 2
    Figure 2

    Ninety day modified Rankin Scale score for patients with minimal or severe vasospasm.

    Complications included one thromboembolic event treated using intravenous abciximab with prompt angiographic resolution. This equated to a procedural risk of 1.5% and a patient specific risk of 5.9% but there was no permanent morbidity or mortality related to the treatment.

    Discussion

    We have demonstrated that for good grade SAH patients (WFNS 1–2) who subsequently develop the complication of severe cerebral vasospasm and are treated aggressively with a combination of induced hypertension and intensive endovascular management, comparable clinical outcomes can be obtained with patients who do not develop this complication. No significant difference in discharge GOS, the proportion of patients discharged home, 90 day mRS, or 90 day GOS was demonstrated for those with severe vasospasm undergoing treatment compared with those without vasospasm, whose outcomes were in line with those published in previous trials.19 Of patients with severe vasospasm, 88% achieved mRS 0–2. Similarly, in a retrospective analysis of the period spanning 2009 and 2013 demonstrated that 84% of WFNS grade 1–2 patients with severe vasospasm achieved mRS 0–2 (Mortimer, unpublished data, 2014). In an earlier study spanning 1992–1998,20 in which a similar protocol based on papaverine angioplasty was used, favorable clinical outcomes for good grade patients who developed significant vasospasm were seen in 93%. There are two possible conclusions that can be drawn from these data. Firstly, it could be argued that angiographic vasospasm has no impact on patient outcome and that these favorable outcomes are incidental. Secondly, it could be argued that intensive efforts to improve cerebral blood flow have a beneficial impact on clinical outcomes in patients afflicted by severe vasospasm.

    Critics of this approach to treating angiographic vasospasm may cite uncertainty regarding the role of aVSP in delayed cerebral ischemia.21 ,22 ,23 A number of clinical trials of pharmaceutical agents have demonstrated improvement in the rate of moderate–severe vasospasm but not in the rate of favorable outcome.24 ,25 Likewise, while nimodipine remains the only pharmacological treatment to improve outcomes, this benefit is achieved without angiographic evidence of cerebral vasodilation.26 ,27 As a result of this, there has recently been much emphasis on the role of alternative mechanisms of delayed ischemia, including microthrombosis and spreading depolarization with cortical ischemia, that may act separately or in combination with aVSP. However, analysis of the CONSCIOUS-1 trial has demonstrated that moderate–severe angiographic vasospasm is an independent predictor of poor functional outcome (OR 2.62 (1.58–4.36), p<0.0001).1 In that study, 46% of patients with moderate to severe aVSP (>33% arterial narrowing) had a poor outcome at 3 months. The International Co-operative Study on the Timing of Aneurysm Surgery found that vasospasm was more often the cause of death or disability than any other factor, including the direct effect of the initial bleed.28

    Intuitively, the impact of vasospasm on outcome stems from an increased risk of cerebral infarction, which itself is strongly associated with poor outcome.3 ,4 There is a strong correlation between the severity of aVSP and the incidence of cerebral infarction.2 The more severe the vasospasm, the more severe the perfusion deficit,7–10 and we believe strongly that the hemodynamic effects of vasospasm are appropriate to target to reduce the risk of associate infarction. While it is commonly quoted that approximately half of patients with vasospasm will be ‘symptomatic’, the severity of vasospasm correlates with symptomology, and even if asymptomatic, angiographic vasospasm can result in infarction.1 ,6 Although we were unable to analyze the rate of aVSP associated infarction in this study, we have analyzed this in a separate cohort of WFNS grade 1–5 patients (Mortimer, unpublished data 2014), and for those presenting within 72 h of ictus, 6.7% suffered proximal vessel infarction if treated using the same regimen used in this study. If smaller perforator infarcts and watershed infarcts were included, the overall rate of infarction was 17.8%, but if this is compared with other reported rates of infarction in the region of 46–81% for severe vasospasm,2 ,6 ,7 the results are promising.

    The Poiseuille equation states that flow is directly proportional to the pressure gradient and radius to the fourth power and inversely proportional to the fluid viscosity and vessel length. This formula forms the basis for hypertensive treatment in the intensive care unit but also for attempts to improve flow through an increase in vessel diameter. While flow will increase with a change in pressure, it will increase markedly with a change in vessel diameter. Both TBA11 ,29 ,30 and (more modestly) verapamil31 have been shown to significantly increase vessel diameter in the setting of aVSP (albeit with a lag of approximately 30 min with the latter). TBA and intra-arterial calcium channel antagonists result in significant improvements in cerebral blood flow.30 ,32–34 While TBA has a relatively durable effect,35 ,36 the duration of action of verapamil on the cerebral circulation remains unknown and further investigation is required to elucidate this. We have evolved a system of performing daily vasodilator infusions where necessary and in a number of patients, multiple procedures, as previously discussed.19 Others have experimented with indwelling microcatheters37 although we are reluctant to employ this approach because of the potential risk of thromboembolic complication.

    In this study, patients with severe angiographic vasospasm had a significantly increased ITU stay and ventilated days. This can be explained partly by the impact of vasospasm on clinical status, partly by local protocols which center on hypertensive therapy in patients with vasospasm, and partly on the need for inotropic support in patients treated with high dose verapamil. Indeed, the total noradrenaline dose was significantly higher for those with severe vasospasm. We were unable to elucidate the relative benefit of endovascular therapy over hypertensive therapy but these finding suggest that a combined approach of endovascular therapy and induced hypertension may have a role in the prevention of delayed cerebral infarction following the development of severe aVSP and further lends support for design of a trial to test this hypothesis and to elucidate the relative impact of each facet of treatment.

    The approach used in the study was different to that often previously published which centers on either prophylactic TBA prior to development of significant vasospasm or rescue therapy in patients who deteriorate despite maximal medical therapy or who cannot tolerate medical therapy. Our aim has been to identify significant vasospasm prior to neurological deterioration. This is controversial but is employed by other centers surveyed in a recent US national questionnaire.38

    The use of prophylactic TBA has been investigated in a multicentre randomized trial.14 Fisher grade 3 patients were randomized to receiving either prophylactic TBA at a mean 51 h (range 19–94 h) post SAH, prior to the typical vasospasm window, or maximal medical therapy. Balloons were inflated to the vessel diameter until apposition of the balloon to the vessel wall was identified fluoroscopically.

    The primary outcome measure (dichotomized GOS score at 3 months after hemorrhage) was no different between patients treated with prophylactic TBA and controls. There was no difference in the secondary outcome measures of vasospasm (defined by transcranial Doppler (TCD), length of stay in the ICU, or total length of hospitalization). However, the secondary outcome measure, incidence of delayed ischemic deficit, trended toward significance, with 24% of prophylactic TBA patients developing a deficit versus 32% of controls. A significant difference was identified in the need for rescue angioplasty, with only 12% of prophylactic TBA patients requiring this procedure compared with 26% of controls, perhaps reflecting a lower incidence of severe medically refractory vasospasm in the prophylactic TBA group. Furthermore, for good grade patients (Hunt and Hess grades 1 and 2), there was a 9.5% reduction in unfavorable outcome.

    We suggest that the treatment algorithm of this trial was suboptimal as it did not select patients with documented cerebral vasospasm for treatment, thereby diluting the treatment effect of prophylactic TBA. Selection based purely on Fisher grade is likely to result in a proportion of patients undergoing unnecessary treatment. Furthermore, 56% of the prophylactic TBA group developed vasospasm by TCD criteria, which suggests that TBA may not be as effective in non-spastic vessels (TBA seems to be effective through stretching and disruption of both the degenerative muscle and the proliferative non-muscle components, mainly in the media of the vasospastic vessels36) and there remains the problem of more distal vasospasm. We suggest that identifying patients with significant angiographic vasospasm and selecting these patients for treatment prior to significant deterioration may be a more suitable approach.

    The approach of reserving endovascular treatment for use as a rescue therapy alone following clinical deterioration suffers from two major limitations. Firstly, the therapeutic window is narrow11 ,12 (this probably accounts for a limited number of patients showing neurological improvement with vasodilator therapy or TBA22 ,23 ,39–43) and secondly, patients may suffer infarction in the absence of acute deterioration (especially if poor grade and difficult to assess) which itself is associated with a poor eventual outcome.16 A process of screening for and treating severe aVSP may allow more timely intervention prior to more severe ischemia but the risks of this approach need to be justified, and critical to this is the safety of the screening method and chemical and balloon angioplasty. In this study, there was one transient thromboembolic complication. This equates to a procedural risk of 1.5% but patient risk of 5.9%, although with no permanent morbidity and mortality relating to the procedure. However, the group sizes in this study are probably too small to draw firm conclusions. The feared complications of TBA are vessel rupture and thromboembolic events. In a recent review of the literature, it has been suggested that the procedural risk of rupture for TBA with modern compliant balloons is approximately 1%, and thromboembolic complications have been reported in 4–5%.35 For chemical angioplasty, the risks are related to the angiographic procedure and also to the agent being used. We now rely on verapamil as the firstline vasodilator. In our experience, it is associated with a low rate of complications but there are reports in the literature of elevated intracranial pressure.39 ,40 We manage these patients with inotropic support as required and titrate the rate of administration of verapamil with blood pressure to limit systemic hypotension. Papaverine use is now secondline both at our institution and at other surveyed centers38 owing to its side effect profile.35

    The approach of investigating for vasospasm with digital subtraction angiography utilizes the gold standard imaging modality for detection of vasospasm and allows therapeutic intervention but does carry with it a small but not insignificant procedural risk. Others have developed local expertise in the use of TCD and CT angiography/perfusion. Each may be a valid method of evaluation either alone or in combination to guide a treatment algorithm of similar philosophy. Both TCD and CT angiography/perfusion are non-invasive tools. TCD is operator dependant and is limited in its ability to assess the anterior cerebral artery and posterior circulation as well as distal vasospasm. CT angiography and CT perfusion may play a more prominent role in vasospasm diagnosis in the future. CT angiography has limits in demonstration of distal vasospasm and vessels adjacent to clip or coil artifact, and CT perfusion can be limited by the amount of brain volume coverage, radiation exposure, and clip or coil artefact.44 ,45 Accurate quantification with CT perfusion is also dependent on an intact blood–brain barrier, which may not be the case with ischemic tissue.

    This was a post hoc analysis of trial data that was not specifically collected to answer the question of the impact of endovascular treatment or hypertensive therapy from available data. The study group with severe aVSP contained a small sample of only 17 patients and there was considerable difference in the size of the study group compared with the control population without spasm, comprising 63 patients. There was no control population with severe aVSP who did not undergo endovascular therapy with which to compare, and as a result we are unable to report on the additional benefit of endovascular treatment over hypertensive therapy.

    Conclusions

    The results of this prospectively acquired single institution study suggest that clinical outcomes for patients with severe angiographic vasospasm are similar to those without vasospasm if treated with induced hypertension and an intensive endovascular regimen of TBA and/or chemical angioplasty based on a verapamil protocol. Further trials are necessary to fully elucidate the individual impact of medical treatment and endovascular therapy on the natural history of vasospasm with patients receiving medical and timely interventional treatment versus matched controls receiving medical management alone.

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    Footnotes

    • Correction notice This article has been corrected since it was published Online First. The 7th author's name has been corrected to Timothy Harrington.

    • Contributors All authors contributed to the study concept, analysis, and final drafting.

    • Competing interests None.

    • Ethics approval The study was approved by the North Sydney and Central Coast Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Parties interested in data sharing can contact Celia Bradford.