Real-world treatment of hyperkalemia among patients in emergency department in China (POETRY-E): A study protocol for multicenter,prospective,observational study

Abstract

Objective

HyperkalemiaF is associated with fatal cardiac arrhythmias, all-cause mortality, and frequent emergency department visits among patients with hyperkalemia. A recent Chinese epidemiological study suggested that the severity of hyperkalemia increases with comorbidities. Diagnosis, testing, and overall management of patients with hyperkalemia in the emergency department require strengthening. However, the lack of evidence from the emergency department and consensus guidelines has led to poorly characterized treatment patterns for hyperkalemia. The present study will evaluate the real-world effectiveness of different treatment options among patients with hyperkalemia in the emergency department across China.

Methods

This multicenter, prospective, observational study plans to collect primary data from 600 patients diagnosed with hyperkalemia who present to the emergency department in 15–20 tertiary hospitals across China. Patients aged ≥18 years with serum potassium levels ≥5.5 mmol/L will be included. Patients previously enrolled in any other clinical study within 3 months before enrollment will be excluded. Eligible patients will be enrolled, assessed at baseline, and followed up until discharge from the emergency department or death. The primary objective will be to determine the real-world effectiveness of potassium-lowering treatment (monotherapy/combination therapy), calculated as the mean change in serum potassium levels from baseline to 5 ± 1 h after treatment initiation. The secondary objectives will assess the clinical burden, calculated as the number of patients with baseline serum potassium levels ((5.5, 6.0), (6.0, 6.5), (6.5, 7.0), and (≥7.0) mmol/L), real-world treatment patterns, serum potassium testing, and the duration between baseline testing and treatment initiation. Exploratory objectives will further evaluate clinical outcomes among patients with different baseline serum potassium levels as described above and the proportion of patients recovering to normal serum potassium levels.

Discussion

The POETRY-E study is the first prospective observational study to evaluate the real-world effectiveness of different potassium-lowering treatment regimens among patients with hyperkalemia in the Chinese emergency department setting. This study addresses the overall burden and management among patients with hyperkalemia in China.

Trial registration: Name of the Registry: Chinese Clinical Trial Registry

Registration Number: ChiCTR2100053100

Introduction

Hyperkalemia (HK) is a common acute medical emergency that can precipitate fatal cardiac arrhythmias. Patients with chronic kidney disease (CKD), heart failure, hypertension, and diabetes mellitus are generally at greater risk. HK can also be induced by medications that alter potassium excretion, including renin–angiotensin–aldosterone system inhibitors (RAASi), potassium-sparing diuretics, nonsteroidal anti-inflammatory drugs, succinylcholine, and digitalis.^1–3

It is estimated that approximately 800,000 HK-related emergency department (ED) visits occur annually in the United States (US). ⁴ Therefore, patients with HK are frequently managed in ED. ⁴ A US retrospective study reported that among 100,260 ED visits, serum potassium (sK⁺) was measured in 48,827 patients, of whom 3.6% had elevated sK⁺ levels (>5.0 mEq/L). ⁵ The clinical burden of HK in ED is similar across China, as indicated by a recent epidemiological study, suggesting that approximately 3.52% of patients present with at least one HK event in ED. ⁶

There is no internationally standardized definition for HK; therefore, to aid clinical decision-making, sK⁺ >5.0 mmol/L is typically selected as the diagnostic threshold in China. High sK⁺ levels (sK⁺ >5.0 mmol/L) are associated with an increased risk of mortality and hospitalization. ⁷ A previous study reported a 15% higher in-hospital mortality among patients with sK⁺ >5.5 mEq/L. ⁸ However, in real-world practice, most patients receive potassium-lowering treatment and undergo sK⁺ retesting only when sK⁺ levels are ≥5.5 mmol/L.^1,6 Management of HK requires a multifaceted approach driven by potassium levels and other comorbid conditions. Various therapeutic options are available for maintaining potassium homeostasis, including calcium chloride/gluconate, insulin/glucose, β-adrenergic agonists (albuterol and salbutamol), sodium bicarbonate, loop diuretics or cation-exchanging resins, potassium binders, and dialysis. ⁹ Although these treatments are frequently used as monotherapy or in combination to lower potassium levels, they are associated with potential side effects. ¹⁰

The literature on emergency treatment of HK is limited, as suggested by a Cochrane review. ⁴ Recently, the UK Renal Association published clinical practice guidelines for the treatment of acute HK in hospital and community settings; however, to date, no randomized interventional HK treatment trials have been conducted to support these recommendations. ¹¹ Due to the lack of standardized therapeutic protocols, similar heterogeneity and diverse clinical practices for the management of HK in ED are also observed in China. Therefore, to address these evidence gaps and develop a treatment algorithm for emergency HK management, the present study will be aimed to describe the real-world effectiveness of different potassium-lowering treatment regimens among patients with HK in ED across China.

Methods

Study design

This multicenter, prospective, observational study aims to collect primary data from 600 patients admitted to ED of 15–20 tertiary hospitals across China. Patients will be aged ≥18 years at the time of signing written informed consent and will have documented sK⁺ levels ≥5.5 mmol/L. All patients provided written informed consent prior to inclusion in the study. The consent process included a detailed explanation of the study’s purpose, procedures, potential risks and benefits, confidentiality measures, and the voluntary nature of participation. Patients will be informed of their right to withdraw from the study at any time without any impact on their medical care or legal rights. Patients previously enrolled in the study within the past 3 months will be excluded. Additionally, patients may be excluded under predefined circumstances in which study procedures cannot be safely or feasibly conducted. These circumstances include the following: (a) immediate life‑threatening instability requiring urgent intervention; (b) inability to obtain essential assessments because of the patient’s clinical condition (e.g. severe agitation or altered mental status without a legal representative); (c) concurrent participation in another interventional study that may interfere with data collection; or (d) imminent transfer before any study‑relevant evaluation could be performed. Eligible patients will be enrolled, assessed at baseline, and followed up from the first potassium-testing report at ED admission until discharge or death. The end of follow-up time is defined at the individual patient level as the earliest occurrence of the following: (a) normalization of sK⁺ levels in ED; (b) ED disposition, including discharge home, admission to an inpatient ward or intensive care unit (ICU), or transfer to another facility; or (c) voluntary departure from ED. This approach ensures that follow-up reflects each patient’s actual clinical trajectory (Figure 1). The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki 1975, as revised in 2024, and in compliance with Good Clinical Practice (GCP) and applicable regulatory requirements. The final protocol will be approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) of Peking Union Medical College Hospital, and the ethical approval number will be HS‑3087. The study is registered in the Chinese Clinical Trial Registry (ChiCTR2100053100).

Figure 1.

Study design. (a) Grade I. No symptoms and no limitation in ordinary physical activity, for example, shortness of breath when walking or climbing stairs; Grade II. Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity; Grade III. Marked limitation in activity due to symptoms, even during less-than-ordinary activity (e.g. walking short distances); Grade IV. Severe limitations, including patients experiencing symptoms even at rest and are mostly bedbound. (b) Standard 12-lead ECGs performed according to routine clinical practice; the ECG date, heart rate, overall interpretation, and relevant comments will be collected. (c) Type, dosage, duration, and route of administration; (d) 2–3 times/week or 5 times/2 weeks; (e) amount of dialysis solution used per day and the total duration for retaining dialysis solution in the patient’s abdomen per day; (f) drug name, start and end date/time, dosing information, and routes of administration. ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor neprilysin inhibitor; BUN: blood urea nitrogen; CBC: complete blood count; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disorder; DM: diabetes mellitus; ECG: electrocardiogram; ED: emergency department; eGFR: estimated glomerular filtration rate; Hb: hemoglobin; HD: hemodialysis; HF: heart failure; HTN: hypertension; ICU: intensive care unit; MCV: mean cell volume; MHD: maintenance hemodialysis; MRA: mineralocorticoid receptor antagonist; NYHA: New York Heart Association; PD: peritoneal dialysis; RAASi: renin–angiotensin–aldosterone system inhibitor; TCM: traditional Chinese medicine.

Study objectives and endpoints

The primary objective will be to determine the mean change in sK⁺ levels from baseline to 5 ± 1 h following the initial intervention for HK. The secondary objective will be to assess the clinical burden of HK in ED across various baseline sK⁺ level ranges (5.5, 6.0), (6.0, 6.5), (6.5, 7.0), and (≥7.0) mmol/L. Clinical burden is defined as the short-term impact of HK on the patient’s ED course, as evaluated through the intensity of treatments required, the frequency of sK⁺ monitoring, and any escalation of care such as ICU admission or repeat interventions. Moreover, real-world treatment patterns, potassium-testing patterns, and the duration between the first and second potassium tests among patients with HK in ED, stratified by baseline sK⁺ levels, will also be evaluated. The sK⁺ levels will be measured in the laboratory, including arterial blood gas analysis or biochemical detection. The testing frequency will be once every 2–4 h, depending on patient compliance. Additional objectives will include the assessment of clinical outcomes (mortality, hospital and ICU admission, hemodynamic instability, and cardiac arrest) among patients stratified by different baseline sK⁺ levels as well as the proportion of patients recovering to normokalemia during their stay in the ED. The study endpoints for each objective are described in detail in Table 1.

Table 1.

Study endpoints for POETRY-E.

Primary endpoints

Mean change in blood potassium levels from baseline to 5 ± 1 h after initiating specific potassium-lowering treatment:– Insulin plus glucose (A)– Diuretics (B)– Combination of A and B– Oral potassium binders (CPS, SPS, or SZC)

Secondary endpoints

Proportion of patients with HK at various baseline blood potassium levels ((5.5, 6.0), (6.0, 6.5), (6.5, 7.0), and (≥7.0) mmol/L) Proportion of patients receiving the treatment options described below during the ED stay, either as monotherapy or in combination– Insulin/glucose– Diuretics: furosemide, hydrochlorothiazide, torsemide, and bumetanide– β2-agonist: inhaled salbutamol– Sodium bicarbonate– Dialysis (HD/PD), hemofiltration, and CRRT– Oral potassium binders (CPS, SPS, or SZC) Average number of potassium tests and the time interval between two subsequent tests among patients in the ED with baseline potassium levels ((5.5, 6.0), (6.0, 6.5), (6.5, 7.0), and (≥7.0) mmol/L) Time from reporting the potassium test result to initiation of potassium-lowering treatment in the ED

Exploratory endpoints

Percentage of the outcome events described below among patients with baseline blood potassium levels in ((5.5, 6.0), (6.0, 6.5), (6.5, 7.0), and (approximately ≥7.0) mmol/L)– Death in ED– Hospital and ICU admission– Hemodynamic instability a – Cardiac arrest Proportion of patients recovering to normokalemia during the ED stay– Blood potassium level <5.5 mmol/L– Blood potassium level <5.0 mmol/L

a

Vasoactive medications needed to maintain stable hemodynamics.

CPS: calcium polystyrene sulphonate; CRRT: continuous renal replacement therapy; ED: emergency department; HD: hemodialysis; ICU: intensive care unit; PD: peritoneal dialysis; SPS: sodium polystyrene sulphonate; SZC: sodium zirconium cyclosilicate.

Data collection

The investigator will be responsible for collecting and entering relevant data from eligible patients into the case report form (CRF), including potassium concentrations at multiple time points, strategies used to manage HK, and the timing of each potassium test. All available laboratory test results and outcome events will be collected according to standard clinical practice. Eligible patients will be followed up until leaving the ED or study discontinuation due to any of the following reasons: loss to follow-up, withdrawal of consent, noncompliance with necessary clinical examinations and treatment according to physician advice, or investigator’s decision to exclude the patient from the study. The time of ED discharge will be obtained from medical record files or confirmed by the investigator. The investigator will be responsible for the accuracy and appropriateness of original documents, data, and records related to the study.

The date, time, and route of dosage administration will be recorded for monotherapies with insulin/glucose; diuretics, including furosemide, hydrochlorothiazide, torsemide, and bumetanide; β2-agonists, including inhaled salbutamol; sodium bicarbonate; dialysis modalities, including hemodialysis, peritoneal dialysis, hemofiltration, and continuous renal replacement therapy (CRRT); traditional potassium binders, such as sodium polystyrene sulphonate (SPS) and calcium polystyrene sulphonate (CPS); and novel potassium binder sodium zirconium cyclosilicate (SZC). Combination therapies involving two, three, four, five, or more than five of the above treatments will also be recorded. For patients receiving dialysis, the dialysis modality, along with the start and end date and time, will be documented.

Statistical analysis

All eligible patients will be included in the full analysis set (FAS). Continuous variables will be presented using descriptive statistics, including the number of patients (n), mean, SD, median, minimum, and maximum, whereas categorical variables will be expressed as frequencies and percentages.

For analysis of the primary objective, only the latest potassium-testing results will be used for derivation. Patients without potassium test results will be excluded. The primary endpoint will be summarized as a continuous variable for all patients in the FAS with available postbaseline potassium results. The values will be presented as percentages with 95% confidence intervals (CIs). The proportions of patients in the secondary and exploratory endpoints will also be presented as percentages with 95% CI estimation. The average number of potassium tests during follow-up and the interval time will be summarized using the same method as for continuous variables. The time from reporting of the potassium test result to initiation of potassium-lowering treatment will be summarized using standard descriptive statistics. Time zero will be defined as the timestamp at which the potassium result is reported, and the event will be initiation of potassium-lowering therapy. Kaplan–Meier curves will be used to estimate and visualize the time-to-event distributions. Cox proportional hazards regression will be used to calculate hazard ratios (HRs) and corresponding 95% CIs, comparing the prespecified exposure groups (e.g. HK severity categories).

For exploratory analyses, when multiple records of postbaseline sK⁺ testing are available, both the latest and the lowest values will be considered. Sensitivity analyses with different criteria for normokalemia and subgroups of patients will also be examined. All statistical analyses will be performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). No formal power-based sample size calculation was performed for this descriptive study. A precision-based approach was used to inform the planned sample size, focusing on the estimation of effect measures with adequate CI precision rather than hypothesis testing. Consequently, some analyses may be underpowered to detect statistically significant differences, and findings should be interpreted accordingly.

Sample size

This study used a precision-based approach, which is recommended for descriptive/exploratory research where the primary objective is to estimate parameters with clinically interpretable CIs rather than to perform hypothesis testing.^12–14

For the primary analysis, the treatment options will be divided into four categories: insulin/glucose, diuretics, combination therapy, and oral potassium binders (CPS, SPS, or SZC). Based on published epidemiological data, prior interventional studies in similar populations, ¹⁵ and feasibility assessments from participating centers, we anticipated that each treatment category would comprise approximately 5%–50% of the study population. A total sample size of 600 therefore ensures that the smallest subgroup includes at least 30 patients, which is generally considered the minimum required for generating stable subgroup estimates in descriptive analyses.

For continuous outcomes (e.g. maximum change in sK⁺ within 6 h), the sample size of 120 refers to pooled treatment-level analyses rather than the smallest subgroups. Assuming an SD of 0.4–0.7 mmol/L, a sample size of 120 provides a 95% CI half-width of approximately 0.072–0.125 mmol/L, which is adequate for clinical interpretation. Precision was calculated using the standard formula for the margin of error: 1.96 × SD/√n.

A precision table summarizing expected CI half-widths across sample sizes (N = 30, 60, 120, and 300) is provided in Table 2.

Table 2.

Precision of continuous outcome estimates across sample sizes.

	Precision estimation (half-width of 95% CI)
Expected SD	N = 30	N = 60	N = 120	N = 300
0.4	0.143	0.101	0.072	0.045
0.5	0.179	0.127	0.089	0.057
0.6	0.215	0.152	0.107	0.068
0.7	0.250	0.177	0.125	0.079

CI: confidence interval; N: total no of samples.

Safety

There is no requirement for adverse events (AEs) to be actively collected and reported. However, if any drug-related AEs occur, investigators are encouraged to report them to the sponsor.

Discussion

The incidence of HK ranges from 1.1% to 10% among hospitalized patients. ¹¹ However, the standard of care for the management of HK in ED has been poorly described. ¹⁶ Severe HK may lead to cardiac arrest; therefore, prompt intervention is required. Accordingly, the present study is designed to evaluate the real-world effectiveness of different potassium-lowering treatment regimens among patients with HK in emergency settings. To the best of our knowledge, this is the first prospective observational study addressing evidence gaps in the management among patients with HK across China.

The time window selected for measuring the primary endpoint will be 5 ± 1 h after initiation of potassium-lowering treatment, as this is a typical duration of a patient’s ED visit. This approach is supported by a recent US study on real-world evidence for the treatment of HK in ED (REVEAL–ED), which evaluated changes in sK⁺ levels at 4 h among patients with moderate (≥5.5 to ≤6.0 mmol/L) to severe (≥6.0 mmol/L) HK. ⁴

A recent meta-analysis of 27 diverse cohorts suggested that sK⁺ ≥5.0 mmol/L is associated with a long-term risk of all-cause and cardiovascular mortality. ¹⁷ Similarly, in the present study, to collect sufficient information on HK management for data analysis, the main focus is on patients with sK⁺ ≥5.5 mmol/L.

According to a US report, the therapeutics most frequently used for the acute management of HK include calcium gluconate, insulin plus glucose/dextrose, albuterol, furosemide, and SPS. ¹⁸ Additionally, a recent Chinese epidemiological study suggested that insulin plus glucose is the most common treatment for HK in ED. ⁶ Therefore, in line with these findings, the primary endpoint in the present study will be evaluated across four specific treatment options (Table 1).

Data from a retrospective cohort observational study revealed that sK⁺ levels of 5.5–6.0 were associated with an increased risk of hospitalization, whereas sK⁺ levels of 6.0–6.5 mEq/L were associated with death. ¹⁹ The definition of HK remains debated; therefore, studies employ various thresholds such as 5.0, 5.5, or 6.0 mEq/L. Usually, baseline sK⁺ levels ≥5.0 mEq/L are associated with increased mortality. ²⁰ Accordingly, the present study collects data from predefined baseline sK⁺ levels in the ranges of 5.5, 6.0; 6.0, 6.5; 6.5, 7.0; and ≥7.0 mmol/L.

Notably, the diagnostic rate and potassium-retesting level in ED across China are low. ⁶ Therefore, to address this shortcoming, the present study aims to estimate the average number of potassium tests and the time interval between two subsequent tests among patients with HK in the ED, stratified by different baseline sK⁺ values.

A key strength of this prospective, multicenter observational study is its ability to capture contemporary, real-world HK management across diverse ED settings, thereby improving clinical relevance and external validity. Prior multicenter ED cohorts have demonstrated substantial variability in HK treatment practices, underscoring the need for updated, systematically collected data. The inclusion of multiple heterogeneous sites enhances generalizability and reflects the broad range of patient characteristics and treatment patterns observed in routine care. Additionally, by evaluating treatment choices, monitoring approaches, and short-term outcomes, this study is positioned to inform evidence-based refinements to ED HK management pathways, aligning with established consensus recommendations for rapid assessment, potassium-shifting interventions, and ongoing reassessment.^21,22

This observational study has a limitation in that it will not compare the efficacy among different treatment options. Moreover, a limited number of patients within a specific treatment option may introduce some degree of bias. To minimize selection bias, multiple tertiary hospitals will be selected across different geographical areas. There is also the possibility that the treatment spectrum and the frequency of blood potassium testing may vary across sites or according to disease severity. To address this, results will be examined among patients with different baseline potassium ranges, and sensitivity analyses will be undertaken if required.

Overall, the POETRY-E study intends to describe the real-world effectiveness of varied treatment options for HK and the overall burden among patients with HK in the Chinese ED setting.