Hypertension in the emergency department: A missed opportunity to screen for primary aldosteronism?

Primary aldosteronism (PA) is a common but underdiagnosed secondary cause of hypertension. Emergency departments (EDs) often assess patients with severe hypertension or its sequelae, some of whom have underlying PA. We aimed to determine the proportion of patients presenting to the ED with hypertension who meet the Endocrine Society criteria for PA testing and the proportion who were screened.


INTRODUC TI ON
Primary aldosteronism (PA), also known as Conn syndrome, is an adrenal disorder characterized by autonomous adrenal production of aldosterone inappropriate for the sodium status. 1 This may result in hypertension, hypokalemia, and adverse cardiometabolic sequelae. 2,3 is estimated to affect between 3.2% and 14% of hypertensive patients in primary care and up to 30% of those patients in referral centers or with refractory hypertension. 4,5While traditionally regarded as rare, PA is now increasingly recognized as a common but underdiagnosed secondary cause of hypertension.Data from the United States, Canada, and Australia suggest that less than 1% of hypertensive patients are ever screened for PA 6,7 ; even in those with persistent hypertension and hypokalemia, which are considered hallmarks of PA, only up to 5% are ever screened. 8,9tection and targeted management of PA is pivotal as prolonged exposure to excess aldosterone is associated with significant end-organ damage. 10Patients with PA have two-or fourfold higher risk of cardiovascular, renal, and metabolic disease when compared to those with essential hypertension, even when matched for blood pressure (BP). 3,10PA is specifically treatable with mineralocorticoid receptor antagonists that block the systemic effects of aldosterone or potentially curable with surgical resection of an aldosterone-producing adrenal adenoma. 1 Therefore, timely disease detection is essential to enable targeted treatment and prevention of end-organ damage. 7pertension is a relatively common presentation in the ED.
During a period of 7 years (2006-2012), the Nationwide Emergency Department Sample conducted in the United States found that 23.6% of all ED visits were given a diagnosis code of hypertension as a complaint, while data from 2016 suggest that approximately 1.2 million ED visits had hypertension as the presenting complaint (U.S. National Hospital Ambulatory Medical Care Survey 2016). 11Hence, the ED represents an opportunistic setting in which the diagnosis of PA could be considered, with active screening if feasible or referral for screening in the outpatient setting.Indeed, PA has been documented in patient groups presenting to ED with other primary complaints associated with hypertension, including unexplained atrial fibrillation, 12 hypertensive emergency, or stroke. 13PA was identified in 42%, 12 2.5%, and 4% of these cohorts, respectively. 13It is unknown what proportion of all hypertensive patients who present to ED could be tested for PA.
To address this knowledge gap, we evaluated the proportion of patients who presented to Australian EDs with hypertension who meet the Endocrine Society criteria for PA testing (Figure 1).We also determined the proportion of patients who were actually screened for PA and the factors that led to testing.

Study design
This is a retrospective chart review performed at a tertiary health service.Data collection and waiver of consent were approved by the human research ethics committee given the low-risk and retrospective nature of the study (HREC approval number QA/73930/ MonH-2021-252,112).

Study setting
The study was performed using the information collated from the electronic medical records (EMRs) of three emergency departments (EDs) within a tertiary health service.This service is the largest public health care network in Victoria, Australia.The three EDs had a 2021-2022 annual census of 219,603 visits. 15 The Endocrine Society's current recommendations for patients who should be tested for PA. 14 1.Sustained blood pressure (BP) above systolic 150 or diastolic 100 mm Hg on each of three measurements obtained on different days*; 2. Hypertension (BP > systolic 140 or diastolic 90 mm Hg) resistant to three conventional antihypertensive drugs;

Selection of participants
Patients eligible for inclusion were aged >18 years, had presented to the ED between August 2019 and February 2020, and were coded on the EMR with the ICD-10 code I10 for essential hypertension. 14This EMR utilized a system in which coding occurred by the treating clinician during each patient's ED stay, usually before

Primary outcome measure
This project primarily aimed to evaluate the proportion of patients presenting with the primary diagnosis of hypertension who qualified for PA screening based on the Endocrine Society recommendations (Figure 1).

Secondary outcome measures
The secondary objectives were to determine the proportion of hypertensive patients who were screened for PA.Patients were classified as screened if there was an aldosterone-renin ratio (ARR) test ordered during their time in the ED by any practitioner, a referral to endocrinology for the evaluation of endocrine hypertension, or a specific suggestion for PA testing to occur with the patient's general practitioner (GP) in the discharge note.A further secondary outcome measure was to examine the characteristics of patients who were screened in comparison to those who were not and identify factors associated with screening.Patient characteristics recorded include age, sex, and systolic and diastolic BPs measured while in the ED and documented cardiovascular comorbidities.Other parameters collected include biochemistry results (sodium, potassium levels, renal function); types of antihypertensive medications that the patient was taking before and after presentation; mortality; and disposition.Referrals to other specialties, or recommendations for GP follow-up to further investigate hypertension, or PA specifically, were recorded.The results of PA testing and outpatient clinic records were reviewed to determine the number of new diagnoses of PA from the study cohort.

Study protocol
A structured chart review was performed based on standard methods. 16,17A structured chart review was performed based on standard methods.Data on BP and serum potassium were collected from structured data entry points using the EMR, while data on antihypertensive medications, comorbidities, and family history were extracted from free text in the medical records.The researchers created a data collection instrument in which all study variables were defined and documented in a coding guide, and protocols were developed regarding inclusion and exclusion criteria and missing or conflicting data.The abstractors in the project include two medical students and a medical officer who were not blinded to the intent of the trial and study design.Two abstractors were initially trained using a standard training protocol.Analysis of a randomized pilot data set of 10 entries was performed, and a Cohen kappa score of 0.78 was calculated to assess reliability among raters for the primary outcome. 18Any discrepancies in this set were verbally discussed between abstractors to clarify the data collection protocol for further data collection.The third abstractor was later included in the project, who was also trained to follow the same protocol.Abstractors periodically met to review coding rules and disputes.
Study data were collected and managed securely using REDCap electronic data capture tool hosted and managed by Helix (Monash University) 19 and subsequently encoded and reviewed.Analysis was performed using excel and SPSS (Version 29, SPSS) for all statistics.
Comparison of baseline characteristics was made between patients who met the criteria for PA screening and those who failed to do so and also between patients who were screened for PA and those who were not screened.Continuous variables were reported as mean and standard deviation (SD) or median (25th-75th percentile interquartile range), and groups were compared by rank-sum test.Categorical variables were reported as proportions (%) and groups were compared by chi-square test.Effect size difference with two-sided 95% confidence intervals (CIs) for these comparisons were calculated.

RE SULTS
Of 676 patients who presented to ED with hypertension over a 6-month period, 418 were included in the final analysis (Figure 2).
Among the included patients, 181 (43.3%) fulfilled the criteria for PA screening (Table 1) with resistant hypertension being the most common indication for screening (Table 2) and 79 patients meeting more than one criterion.A total of nine patients (2.2%) were screened for PA, of whom three met the screening criteria.Of the remaining six patients, four had an ARR measured in the ED at the request of a medical team, and two were discharged home with a specific request for their GP to perform PA screening.The reasons for these patients being tested for PA were not specified in the medical records.None of these patients had a confirmed new diagnosis of PA (Table S1).
Screening for PA was more frequent in patients who were referred by ED physicians to medical teams (including endocrinology, cardiology, nephrology, and general medicine; 5/108, 4.6%) compared to those managed entirely by ED clinicians (4/310, 1.0%; effect size 0.10, 95% CI 0-0.20) even though the proportion who fulfilled screening criteria were similar in both groups (48.1% vs. 41.6%).
In terms of follow-up arrangement, 202 patients (48.3%) were discharged with a documented plan for hypertension management including either a recommendation for GP follow-up of hypertension without specific mention of PA or referral to another specialty that was not endocrinology.Of these patients, 82 (40.6%) had at least one indication for PA screening but only four patients (2.0%) were given specific recommendations for PA testing in the discharge letter to the GP.

DISCUSS ION
1][22][23] The patients who were tested for PA in ED were younger and had higher systolic BP upon arrival.This may reflect the tendency for clinicians to not screen patients who are perceived to fit a clinical picture of essential hypertension, i.e., older with less severe hypertension. 24However, in the current study, even high-risk clinical characteristics such as resistant hypertension or hypertension and concurrent hypokalemia were not sufficient to prompt PA testing.Exceedingly low screening rates in other high-risk population have previously been demonstrated, 8,24 suggesting poor awareness and uptake of screening guidelines.Although more complex presentations of PA may warrant specialist input, increased education about clear-cut indications for screening may help trigger appropriate opportunistic testing in the ED.The low rate of PA testing in EDs may be caused by persistent historical perspectives regarding PA as a rare disease. 25Doctors in the ED may be unfamiliar with current diagnostic algorithms for PA that are mostly published in endocrine literature rather than in mainstream hypertension management guidelines.However, the exact barriers to PA screening in the ED remain to be formally investigated.

F I G U R E 2
The logistics of ordering an ARR screening test may also be a barrier to PA testing in the ED.A common reported reason for reluctance to screen is that the ARR can be confounded by commonly used antihypertensive medications. 24ACEi, ARBs, loop diuretics, and thiazide-type diuretics can cause false-negative screening results while beta blockers can cause false-positive results. 26However, these interfering medications were prescribed similarly between screened and unscreened patients in our study, indicating that medication use is not sufficient to explain the low screening rates.In practice, the ARR can be measured without switching medications, at least as an initial test, but the result needs to take the effect of these medications into account. 26other factor influencing Emergency Physcian is that the ARR is typically batched and measured once or twice a week in the health service laboratory; hence the result is unlikely to be available be-

LI M ITATI O N S
A limitation of our study is that only patients coded with a presenting complaint of hypertension were analyzed.Therefore, patients with other coded primary complaints and coexisting hypertension were not included as they may have confounding causes of elevated BP, such as pain and inflammation, or alternative acute primary pathologies.This may have led to selection bias as patients presenting with hypertension as a primary complaint would likely be more thoroughly investigated for secondary causes.However, as our results revealed a low screening rate even in this population, the rate of PA screening in all ED patients with hypertension is expected to be lower.On the other hand, if all hypertensive patients in ED were considered as the denominator for those who meet the criteria for PA screening, then the proportion of patients who meet screening criteria may be lower.
Including only patients with hypertension as their primary complaint may also reduce significant confounding factors for other screening criteria, including hypokalemia, which may be more likely in the setting of other acute presenting complaints.While we acknowledge that some patients had coexisting symptoms that may have caused hypokalemia, our focus on including only patients with hypertension as their coded primary complaint is the closest to capturing presentations that were not confounded by other conditions.
A further limitation of including patients with hypertension as their primary complaint is that some normotensive patients who fulfilled screening criteria would not have been analyzed.This includes normotensive patients using four or more antihypertensive agents and those with normotension who had a family history of PA.This may have underestimated the proportion of patients who fulfilled PA screening criteria.We assumed that patients were taking their medications as prescribed.It is possible that patients who were not taking their antihypertensive medications appeared to have resistant hypertension, when the actual cause was nonadherence.This may have overestimated the number of patients who appeared to have an indication for PA screening due to resistant hypertension.
Within the tertiary health service, we did not have sufficient data to analyze site-specific differences in our outcome of interest.Hypertension and first-degree relatives with PA 0 0 Abbreviation: PA, primary aldosteronism.

3 .
Controlled BP (lower than 140/90 mm Hg) on four or more antihypertensive drugs; 4. Hypertension and spontaneous or diuretic-induced hypokalaemia (<3.5mmol); 5. Hypertension and adrenal incidentaloma; 6. Hypertension and sleep apnoea; 7. Hypertension and a family history of early onset hypertension or cerebrovascular accident at young age (40 years); 8. First-degree relatives of patients diagnosed with PA. *Patients were classified as meeting these criteria if there was hypertension during the analysed ED encounter, and EMR records showing at least two other occasions of hypertension on separate days.
discharge.Patients were excluded if there was no documented BP > 140/90 mm Hg on presentation to the ED (n = 223), if they were pregnant (n = 11), or if they had previous known diagnosis of PA (n = 2).Patients who had repeat presentations to the ED were only entered into the database once based on their first chronological presentation (n = 22).
fore discharge from ED.The inability to review the result may contribute to reluctance in ordering the test due to medicolegal and patient safety concerns regarding follow-up, which may involve referral to endocrinology and confirmatory testing such as oral sodium loading test, saline infusion test, captopril challenge test, and furosemide upright test.Furthermore, aldosterone concentration is best measured in the morning as it decreases during the day much like cortisol.27However, a suppressed renin at any time of the day should raise concern for underlying PA.Depending on the nature of the ED and availability of aldosterone and renin measurements, the screening test can be performed in the ED either to reduce the risk of loss of follow-up or to provide specific advice given to the primary care physician for outpatient screening.Awareness of the positive impact of making a timely diagnosis may prompt increased testing, especially when supported by a reliable strategy for the follow-up of test results.

Did not meet screening criteria (n = 237) Size effect (95% CI)
Flow chart for cohort definition.PA, primary aldosteronism.Demographic and clinical characteristics of patients based on screening criteria and status of PA screening.
TA B L E 2 Number (and percentage) of patients who fulfilled screening criteria and had PA screening test performed.