Heart Rhythm After Intravenous Methylprednisolone Administration

Increased Heart Rhythm in Response to High-dose Intravenous Methylprednisolone Pulse Therapy of Moderate-to-severe Graves' Orbitopathy

High doses of intravenous (iv.) glucocorticoids (GCs) are commonly used as a treatment for many autoimmune and inflammatory disorders. According to the European Group on Graves' Orbitopathy (EUGOGO) guidelines, intravenous methylprednisolone (IVMP) is an accepted first-line agent for active, moderate-to-severe and very severe Graves' orbitopathy (GO). This treatment is proven to be more efficient and safer than oral GCs. However, some patients may experience adverse cardiovascular effects during the administration of iv. GCs, which in rare cases may even be fatal. There are limited data, mostly obtained from case reports, reporting the occurrence of cardiac arrhythmias, acute myocardial infarction or heart failure. Increased heart rhythm (HR) has drawn attention of researchers as a possible adverse effect correlated with IVMP. During this study, investigators performed 72-hours of Holter ECG and ambulatory blood pressure monitoring (ABPM) to evaluate the impact of IVMP on patients with moderate-to-severe GO, concerning HR and blood pressure (BP) changes. In order to elucidate possible mechanism of observed changes, researchers investigated the level of potassium in serum and urine and catecholamines (epinephrine, norepinephrine) in serum. All patients were treated routinely according to EUGOGO recommendations with standard doses of methylprednisolone with standard recommended schedule. Inclusion criterion for the therapy was according to EUGOGO guidelines active, moderate-to-severe and active GO (12 pulses of IVMP 6x0.5g followed by 6x0.25g every week).

Study Overview

• Status: Completed
• Conditions: Heart Failure; Hypertension; Graves Ophthalmopathy; Graves Disease; Blood Pressure; Heart Rhythm Disorder
• Intervention / Treatment: Drug: Intravenous Methylprednisolone

Detailed Description

The clinical status of patients was evaluated before each pulse, including blood pressure monitoring, glucose level monitoring and symptoms of infection. HR and BP was measured continuously for 3 consecutive days (the day before, the day of IVMP and the day after IVMP) during 1st, 6th and 12th IVMP pulse, using 24-hour Holter ECG and ABMP. Serum laboratory tests for potassium, epinephrine and norepinephrine were measured 3 times the day before and the day of first IVMP pulse and 1 time the second and sixth day after 1st IVMP. Additionally, urine samples for potassium were collected 5 times the day of first IVMP pulse and 1 time the second and sixth day after 1st IVMP.

• Study Type: Observational
• Enrollment (Actual): 40

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients admitted to the clinic for routine treatment of active, moderate-to-severe GO

Description

Inclusion Criteria:

• active, moderate-to-severe GO according to EUGOGO classification
• euthyroidism
• completion of 12 IVMP pulses.

Exclusion Criteria:

• cardiovascular morbidity (such as chronic heart failure and/or coronary heart disease)
• uncontrolled hypertension (defined as systolic blood pressure (SBP) more than 140 mmHg and/or diastolic blood pressure (DBP) more than 90 mmHg)
• contraindications to IVMP therapy
• previous GCs treatment in the last 6 months.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
active, moderate-to-severe GO; Each participant received IVMP according to EUGOGO recommendations (cumulative dose of methylprednisolone 4.5 g, treatment duration 12 weeks in single weekly intravenous pulses, first 6 weeks 0.5g of IVMP, next 6 weeks 0.25g of IVMP).	Drug: Intravenous Methylprednisolone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour Holter ECG Monitoring - 1st pulse mean HR	Analysis of changes in mean HR between day before and day of 1st pulse of IVMP, day of 1st IVMP and day after 1st IVMP, day before and day after 1st IVMP	72 hours
24-hour Holter ECG Monitoring - 6th pulse mean HR	Analysis of changes in mean HR between day before and day of 6th pulse of IVMP, day of 6th IVMP and day after 6th IVMP, day before and day after 6th IVMP	72 hours
24-hour Holter ECG Monitoring - 12th mean HR	Analysis of changes in mean HR between day before and day of 12th pulse of IVMP, day of 12th IVMP and day after 12th IVMP, day before and day after 12th IVMP	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum potassium levels Day 0 - Day 1	Change in value of potassium between day before and day of 1st pulse of IVMP	48 hours
Serum epinephrine levels Day 0 - Day 1	Change in value of epinephrine between day before and day of 1st pulse of IVMP	48 hours
Serum norepinephrine levels Day 0 - Day 1	Change in value of norepinephrine between day before and day of 1st pulse of IVMP	48 hours
Urine potassium levels Day 0	Change in value of potassium during the day of 1st pulse of IVMP	24 hours
72-hour ambulatory blood pressure monitoring (ABPM) - 1st pulse mean BP	Analysis of changes in mean BP between day before and day of 1st pulse of IVMP, day of 1st IVMP and day after 1st IVMP, day before and day after 1st IVMP	72 hours
72-hour ambulatory blood pressure monitoring (ABPM) - 6th pulse mean BP	Analysis of changes in mean BP between day before and day of 6th pulse of IVMP, day of 6th IVMP and day after 6th IVMP, day before and day after 6th IVMP	72 hours
72-hour ambulatory blood pressure monitoring (ABPM) - 12th pulse mean BP	Analysis of changes in mean BP between day before and day of 12th pulse of IVMP, day of 12th IVMP and day after 12th IVMP, day before and day after 12th IVMP	72 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum potassium levels Day 0 - Day 7	Change in value of potassium between day before and sixth day after 1st pulse of IVMP	7 days
Serum potassium levels Day 0 - Day 2	Change in value of potassium between day of 1st IVMP and day after 1st IVMP, day before and day after 1st IVMP	72 hours
Serum epinephrine levels Day 0 - Day 7	Change in value of epinephrine between day before and sixth day after 1st pulse of IVMP	7 days
Serum epinephrine levels Day 0 - Day 2	Change in value of epinephrine between day of 1st IVMP and day after 1st IVMP, day before and day after 1st IVMP	72 hours
Serum norepinephrine levels Day 0 - Day 7	Change in value of epinephrine between day before and sixth day after 1st pulse of IVMP	7 days
Serum norepinephrine levels Day 0 - Day 2	Change in value of norepinephrine between day of 1st IVMP and day after 1st IVMP, day before and day after 1st IVMP	72 hours
Urine potassium levels Day 1- Day 2	Change in value of epinephrine between day of 1st IVMP and day after 1st pulse of IVMP	48 hours
Urine potassium levels Day 3 - Day 7	Change in value of epinephrine between second and sixth day after 1st IVMP	5 days

Collaborators and Investigators

• Sponsor: Medical University of Warsaw

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2011
• Primary Completion (Actual): February 20, 2020
• Study Completion (Actual): February 20, 2020

Study Registration Dates

• First Submitted: May 5, 2020
• First Submitted That Met QC Criteria: May 13, 2020
• First Posted (Actual): May 18, 2020

Study Record Updates

• Last Update Posted (Actual): May 18, 2020
• Last Update Submitted That Met QC Criteria: May 13, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Thyroid Diseases; Eye Diseases, Hereditary; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Eye Diseases; Graves Ophthalmopathy; Arrhythmias, Cardiac; Graves Disease; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: IVMPheartrate

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The collected data will be shared in a publication. It includes all laboratory results from all points of evaluation, results of 72-hour Holter ECG and 72-hour ABPM.
• IPD Sharing Time Frame: The results of the study will be published in 2020

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No