Author's summary
The influence of the degree of cardiovascular support on clinical outcomes remains to be elucidated in patients with fulminant myocarditis. This study showed a significant association between the prognosis and vasoactive inotropic score (VIS) when stratified by venoarterial-extracorporeal membrane oxygenation (VA-ECMO). The study suggests that VIS could serve as a prognostic indicator that can be used in real-world practice as well as in future research to develop treatments for fulminant myocarditis. Additionally, the prognostic value of VIS was more pronounced in patients without VA-ECMO than those with VA-ECMO, warranting the need for different interpretations of VIS depending on VA-ECMO.
Keywords: Myocarditis, Cardiotonic agents, Extracorporeal membrane oxygenation, Prognosis
Abstract
Background and Objectives
This study aimed to evaluate the prognostic value of the vasoactive inotropic score (VIS) in patients with fulminant myocarditis according to the application of venoarterial-extracorporeal membrane oxygenation (VA-ECMO).
Methods
This study retrospectively analyzed 417 patients with biopsy-proven or clinically suspected fulminant myocarditis from 7 hospitals in Korea. The primary outcome was a composite of all-cause death, heart transplantation, or the use of left ventricular assist device (LVAD) at 1 year.
Results
The median VIS was 19.9, and 217 (52.0%) patients received VA-ECMO. The primary outcome occurred in 105 patients (26.7%). All-cause death, heart transplantation, and the implantation of LVAD occurred in 81 (20.7%), 30 (8.7%), and 1 (0.3%) patients, respectively. VIS was associated with the risk of the primary outcome in both patients treated with VA-ECMO (hazard ratio [HR], 1.017 for every 10-point increase; 95% confidence interval [CI], 1.007–1.028; p=0.001) and patients without VA-ECMO (HR, 1.128 for every 10-point increase; 95% CI, 1.079–1.179; p<0.001), but the effect was greater in patients without who did not receive VA-ECMO (interaction p<0.001). Furthermore, the predictive performance of VIS for the primary outcome was significantly lower in patients with VA-ECMO than in those without VA-ECMO (C-index, 0.555 vs. 0.780; p value for C-index comparison, 0.002).
Conclusions
In patients with fulminant myocarditis, the prognostic value of VIS was more prominent in patients without VA-ECMO than in patients with VA-ECMO. These findings suggest that the prognostic value of VIS is weakened under the influence of VA-ECMO.
Trial Registration
ClinicalTrials.gov Identifier: NCT05933902
Graphical Abstract
INTRODUCTION
Myocarditis is an inflammatory disease of the myocardium.1) Myocarditis can manifest in a variety of presentations, from simple chest pain to arrhythmias, conduction abnormalities, acute heart failure, and cardiogenic shock (CS).2) Similarly, the prognosis of myocarditis can vary widely. In uncomplicated cases, the in-hospital mortality rate was approximately 0%, whereas in fulminant myocarditis, the 2-month mortality rate was reported to be approximately 30%.3),4) While the need for cardiovascular support, including inotropes or mechanical circulatory support (MCS), is associated with a poorer prognosis in fulminant myocarditis compared to patients who do not require such support, the influence of the degree of cardiovascular support on clinical outcomes remains to be fully elucidated. Vasopressors and inotropes are inherently arrhythmogenic and increase myocardial ischemia by increasing myocardial oxygen demand, which could interfere with myocardial recovery and lead to adverse outcomes.5) Simultaneously, a substantial portion of fulminant myocarditis patients inevitably require MCS, such as an intra-aortic balloon pump, Impella, or venoarterial-extracorporeal membrane oxygenation (VA-ECMO), due to medically refractory CS or cardiac arrest.3),6) Therefore, in myocarditis, the appropriate use of vasopressors and MCS could have a significant effect on patient prognosis.
The vasoactive inotropic score (VIS) quantifies the degree of cardiovascular support provided by standardizing the administered doses of various vasopressors and inotropic agents.7) The clinical relevance of VIS has been validated in pediatric patients and patients undergoing cardiac surgery, as well as patients with CS from various causes.8),9) Using VIS as a surrogate indicator of the need for cardiovascular support, this study aimed to evaluate the long-term prognostic value of VIS in patients with fulminant myocarditis. The differential value of VIS according to the application of VA-ECMO was also evaluated.
METHODS
Ethical statement
The study protocol was approved by the Institutional Review Board (IRB) of Samsung Medical Center (title: Multicenter Retrospective Observational Study of Acute Myocarditis in Korea, approval number: 2022-01-003, approval date: Jan 27th 2022) and conducted according to the principles of the Declaration of Helsinki, as revised in 2013. The IRB waived the requirement for informed consent because the patients were retrospectively enrolled, and only anonymized data were collected.
Study design and population
The study population was a retrospective cohort gathered from 7 hospitals in Korea (Samsung Medical Center, Chonnam National University Hospital, Asan Medical Center, Keimyung University Dongsan Hospital, Bucheon Sejong Hospital, Korea University Anam Hospital, and Incheon Sejong Hospital) from January 2004 to December 2022 (Multicenter Retrospective Observational Study of Acute Myocarditis in Korea, NCT05933902). This registry included patients who met the European Society of Cardiology position statement diagnostic criteria for clinically suspected or biopsy-proven acute myocarditis and were admitted for treatment.10) Briefly, a diagnosis of clinically suspected myocarditis was defined as the identification of ≥1 clinical presentation and ≥1 diagnostic criterion. The relevant clinical presentations were 1) acute pericarditic or pseudo-ischemic chest pain; 2) new-onset (within days to 3 months) or worsening dyspnea at rest or during exercise; 3) palpitations, unexplained arrhythmia symptoms, syncope, or aborted sudden cardiac death; and 4) unexplained CS. The relevant diagnostic criteria were 1) newly abnormal 12-lead electrocardiography results; 2) elevated troponin T or I; 3) functional and structural abnormalities on echocardiography or cardiac magnetic resonance imaging (MRI); 4) edema or late gadolinium enhancement of the classical myocarditis pattern on cardiac MRI.11) Biopsy-proven myocarditis was defined in accordance with the Dallas criteria.12) There were no age restrictions in the enrollment criteria. Patients with alternate cardiac diagnoses at discharge, including ischemic heart disease and sarcoidosis, were excluded.
For this study, patients with fulminant myocarditis who required inotropes or VA-ECMO were selected from the registry (Supplementary Figure 1). To quantify the degree of cardiovascular support, the maximum VIS within 48 hours after the occurrence of CS during the hospitalization period was calculated as previously described: Dopamine Dose (mg/kg/min) + Dobutamine Dose (mg/kg/min) + 100×Epinephrine Dose (mg/kg/min) + 100×Norepinephrine Dose (mg/kg/min) + 10,000×Vasopressin Dose (unit/kg/min) + 10×Milrinone Dose (mg/kg/min).7) The aim of this study was to investigate the relationship between VIS and the long-term prognosis of patients with fulminant myocarditis.
Patient management
In addition to cardiovascular support using inotropic agents or VA-ECMO, mechanical ventilator, and renal replacement therapy were recommended according to the accompanying organ dysfunction. In cases of refractory CS or cardiac arrest, temporary MCS, such as VA-ECMO or an intra-aortic balloon pump, were considered. VA-ECMO was inserted by percutaneous cannulation using the Seldinger technique or by surgical cannulation using the cut-down method at femoral vessels. All patients on VA-ECMO received unfractionated heparin as an anticoagulant unless there was active bleeding. If weaning from VA-ECMO was not an option, an exit strategy involving the implantation of a left ventricular assist device or heart transplantation was considered after assessing the patient’s eligibility. Arrhythmia management was performed in accordance with the latest guidelines on arrhythmia at the time of care because no specific recommendations for patients with acute myocarditis were available.10) The therapeutic options included antiarrhythmic medication, pacemaker, or defibrillation depending on the patient's clinical condition. The use of immunosuppressive therapy was generally at the discretion of the attending physician because no treatment or robust data to support a specific regimen were established.1)
Data collection, follow-up, and clinical outcomes
The following data were collected retrospectively by reviewing electronic medical records: demographic features, comorbidities, clinical presentation, laboratory findings, electrocardiography, echocardiography, cardiac MRI, cardiac pathologic findings, in-hospital management (including medications and organ-support devices), and clinical outcomes. Additionally, dedicated study coordinators sent queries to individual researchers by Email or telephone to clarify and fill in values missing from the collected data, as necessary. The primary outcome was a composite of all-cause death, heart transplantation, or the implantation of a left ventricular assist device at 1 year. The secondary outcomes were the individual components of the primary outcome and hospitalization for heart failure.
Statistical analyses
Categorical variables are presented as numbers and relative frequencies (percentages) and were compared using the χ2 test. Continuous variables are presented as means ± standard deviations or medians with interquartile ranges and were compared using Student’s t-test or the Mann-Whitney rank-sum test, as appropriate. The cumulative incidence of the endpoints was evaluated using Kaplan-Meier analyses, and significance levels were assessed with the log-rank test. Treatment effects were estimated by Cox proportional hazard regression models in terms of the hazard ratio (HR) and 95% confidence interval (CI). The proportional hazards assumption was evaluated using plots of the log-log survival function and Schoenfeld residuals. The associations between VIS and the risks of clinical outcomes are graphically presented with a penalized spline with 3 degrees of freedom.13) Multivariable Cox proportional hazard models were constructed to identify independent predictors of the primary outcome. Variables were selected considering clinical relevance in previous studies and a significant association with the primary outcome with a p value <0.05 in the univariable analyses.3),4),14),15),16) Variable selection was carefully performed considering sample size limitation, missing value, and multicollinearity (Supplementary Table 1). Variables considered in the multivariable model were age, sex, hypertension, diabetes mellitus, initial creatinine, initial total bilirubin, initial platelet, initial normal sinus rhythm, QRS duration, complete atrioventricular block, pulmonary congestion on chest X-ray, time from symptom onset to admission, left ventricular ejection fraction, application of VA-ECMO, and VIS. The final model was constructed using backward elimination to select the set of variables that made the best information criterion for predicting the primary outcome. An optimal cut-off value of VIS was determined using a receiver operating characteristic (ROC) curve analysis. The diagnostic performance is presented in terms of sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy. The discriminant function is presented and was compared using the C-index and 95% CI. All probability values are 2-sided, and p values <0.05 are considered statistically significant. All statistical analyses were performed using R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Characteristics of the study population
From the registry, 417 patients with fulminant myocarditis who required inotropic agents or VA-ECMO were analyzed in this study. The baseline characteristics according to their survival status are presented in Table 1. The mean age was 37.6±21.1 years, and 49.4% of the patients were female. The median time from symptom onset to admission was 3 (0–6) days. The most frequent symptoms were dyspnea (54.4%), febrile sense (52.3%), and chest pain (48.9%). The mean Sequential Organ Failure Assessment score and median N-terminal prohormone of brain natriuretic peptide were 8.4±5.5 and 13,438.0 (4,199.5–30,000.0), respectively. Compared with survivors, non-survivors were older and had a higher proportion of comorbidities such as hypertension, diabetes mellitus, and chronic kidney disease. Furthermore, non-survivors had worse vital signs, more severe organ damage in laboratory findings, and a higher proportion of abnormal rhythms in electrocardiography at admission than survivors. In echocardiography, non-survivors had lower left ventricular ejection fraction and e’ velocity and higher wall thickness and E/e’ than survivors (Table 2). Endomyocardial biopsy was performed less frequently in non-survivors, and thus the proportion of biopsy-confirmed cases was lower in non-survivors than survivors (Tables 1 and 2). Within the whole patient cohort, the median peak VIS was 19.9 (6.4–42.5), and 217 (52.0%) patients received VA-ECMO. Beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and spironolactone were used less frequently in non-survivors, and amiodarone was used more frequently in non-survivors than survivors. Peak VIS, the proportion of patients receiving VA-ECMO, and organ support using a mechanical ventilator or continuous renal replacement therapy were significantly higher in non-survivors than survivors (Table 3).
Table 1. Baseline characteristics of fulminant myocarditis patients.
| Variables | Total (n=417) | Survivors (n=337) | Non-survivors (n=80) | p value | |||
|---|---|---|---|---|---|---|---|
| Demographics | |||||||
| Age (years) | 37.6±21.1 | 36.4±21.0 | 42.9±20.9 | 0.015 | |||
| Female | 206 (49.4) | 167 (49.6) | 39 (48.8) | 0.897 | |||
| Body mass index (kg/m2) | 22.5±4.2 | 22.4±4.2 | 23.1±4.3 | 0.188 | |||
| Comorbidities | |||||||
| Hypertension | 73 (17.5) | 50 (14.8) | 23 (28.8) | 0.003 | |||
| Diabetes mellitus | 34 (8.2) | 21 (6.2) | 13 (16.3) | 0.003 | |||
| Dyslipidemia | 21 (5.0) | 15 (4.5) | 6 (7.5) | 0.260 | |||
| Chronic kidney disease | 11 (2.6) | 4 (1.2) | 7 (8.8) | 0.001 | |||
| Current smoker | 68 (16.3) | 54 (16.0) | 14 (17.5) | 0.748 | |||
| Malignancy | 20 (4.8) | 13 (3.9) | 7 (8.8) | 0.080 | |||
| Previous history of myocarditis | 2 (0.5) | 1 (0.3) | 1 (1.3) | 0.347 | |||
| Clinical presentation | |||||||
| Symptom onset to admission time (days) | 3.0 (1.0–6.0) | 3.0 (1.0–6.0) | 3.0 (0.2–6.0) | 0.923 | |||
| Chest pain | 204 (48.9) | 173 (51.3) | 31 (38.8) | 0.043 | |||
| Dyspnea | 227 (54.4) | 180 (53.4) | 47 (58.8) | 0.389 | |||
| Syncope | 47 (11.3) | 41 (12.2) | 6 (7.5) | 0.235 | |||
| Respiratory symptoms other than dyspnea | 90 (21.6) | 79 (23.4) | 11 (13.8) | 0.058 | |||
| Febrile sense | 218 (52.3) | 184 (54.6) | 34 (42.5) | 0.051 | |||
| Systolic blood pressure (mmHg) | 76.9±20.0 | 79.6±18.6 | 65.1±21.8 | <0.001 | |||
| Mean blood pressure (mmHg) | 57.5±17.1 | 59.6±16.2 | 48.4±17.6 | <0.001 | |||
| Heart rate (beats per minute) | 100.5±37.0 | 101.2±34.0 | 97.6±47.8 | 0.532 | |||
| Bradycardia | 47/414 (11.4) | 31/335 (9.3) | 16/79 (20.3) | 0.006 | |||
| Tachycardia | 203/414 (49.0) | 163/335 (48.7) | 40/79 (50.6) | 0.752 | |||
| Tachypnea | 187/405 (46.2) | 148/327 (45.3) | 39/78 (50.0) | 0.451 | |||
| Fever | 144 (34.5) | 118 (35.0) | 26 (32.5) | 0.671 | |||
| Cardiac arrest | 95 (22.8) | 50 (14.8) | 45 (56.3) | <0.001 | |||
| Arrest rhythm | 0.320 | ||||||
| Ventricular tachycardia or fibrillation | 47/81 (58.0) | 26/41 (63.4) | 21/40 (52.5) | ||||
| Pulseless electrical activity or asystole | 34/81 (42.0) | 15/41 (36.6) | 19/40 (47.5) | ||||
| Diagnosis methods | 0.001 | ||||||
| Biopsy confirmed | 143 (34.3) | 128 (38.0) | 15 (18.8) | ||||
| Clinically suspected myocarditis | 274 (65.7) | 209 (62.0) | 65 (81.3) | ||||
| P/F ratio | 268.5±176.4 | 275.1±173.5 | 240.7±186.7 | 0.158 | |||
| GCS | <0.001 | ||||||
| Mild (13–15) | 256/412 (62.1) | 235/333 (70.6) | 21/79 (26.6) | ||||
| Moderate (9–12) | 19/412 (4.6) | 16/333 (4.8) | 3/79 (3.8) | ||||
| Severe (3–8) | 137/412 (33.3) | 82/333 (24.6) | 55/79 (69.6) | ||||
| SOFA score | 8.4±5.5 | 7.4±5.1 | 12.6±5.1 | <0.001 | |||
| Laboratory findings | |||||||
| White blood cell (103/mL) | 12.7±7.0 | 12.4±6.5 | 13.9±8.8 | 0.150 | |||
| Lymphocyte (103/mL) | 1.5 (1.1–2.2) | 1.5 (1.0–2.2) | 1.5 (1.1–2.1) | 0.983 | |||
| Hemoglobin (g/dL) | 12.7±2.1 | 12.7±2.0 | 12.4±2.5 | 0.287 | |||
| Platelet (103/mL) | 216.9±105.5 | 221.7±101.0 | 196.5±121.2 | 0.088 | |||
| C-reactive protein (mg/dL) | 3.8 (1.1–10.3) | 3.4 (1.1–9.7) | 5.0 (1.6–12.1) | 0.354 | |||
| Erythrocyte sedimentation rate (mm/hr) | 18.0 (5.0–37.0) | 20.0 (7.0–39.0) | 9.0 (2.0–27.5) | 0.008 | |||
| Total bilirubin (mg/dL) | 0.7 (0.5–1.2) | 0.7 (0.5–1.2) | 0.7 (0.5–1.9) | 0.285 | |||
| AST (U/L) | 127.0 (59.0–275.0) | 113.0 (57.0–233.0) | 217.5 (83.8–590.5) | <0.001 | |||
| ALT (U/L) | 66.0 (34.0–175.0) | 63.0 (33.0–148.0) | 118.0 (47.5–362.5) | 0.001 | |||
| Creatinine (mg/dL) | 1.3±1.1 | 1.1±1.0 | 1.8±1.5 | <0.001 | |||
| Na (mmol/L) | 136.5±5.2 | 136.3±4.5 | 137.7±7.2 | 0.098 | |||
| K (mmol/L) | 4.3±0.8 | 4.2±0.7 | 4.4±1.0 | 0.247 | |||
| Lactic acid (mmol/L) | 5.7±6.0 | 4.2±3.7 | 12.0±8.8 | <0.001 | |||
| Peak troponin T (ng/mL) | 1.9 (0.4–6.0) | 1.8 (0.3–5.1) | 5.0 (1.4–22.4) | 0.050 | |||
| Peak troponin I (ng/mL) | 17.1 (4.4–48.7) | 15.0 (4.3–31.8) | 48.4 (8.9–149.8) | <0.001 | |||
| N-terminal pro-brain natriuretic peptide (pg/mL) | 13,438.0 (4,199.5–30,000.0) | 13,046.5 (4,151.8–29,815.5) | 17,154.0 (5,903.0–31,029.0) | 0.407 | |||
| Pulmonary congestion on chest X-ray | 285 (68.3) | 219 (65.0) | 66 (82.5) | 0.002 | |||
| Electrocardiography | |||||||
| Initial rhythm | <0.001 | ||||||
| Normal sinus rhythm | 301/398 (75.6) | 254/323 (78.6) | 47/75 (62.7) | ||||
| Atrial fibrillation | 14/398 (3.5) | 9/323 (2.8) | 5/75 (6.7) | ||||
| Second- or third-degree atrioventricular block | 32/398 (8.0) | 29/323 (9.0) | 3/75 (4.0) | ||||
| Ventricular tachycardia or fibrillation | 43/398 (10.8) | 29/323 (9.0) | 14/75 (18.7) | ||||
| Asystole | 8/398 (2.0) | 2/323 (0.6) | 6/75 (8.0) | ||||
| QRS duration (ms) | 117.3±35.8 | 114.6±34.4 | 129.5±39.5 | 0.004 | |||
| ST-segment change | 322 (78.5) | 267 (79.9) | 55 (72.4) | 0.147 | |||
| Left or right bundle branch block | 144/412 (35.0) | 116/336 (34.5) | 28/76 (36.8) | 0.702 | |||
Data presented as the mean ± standard deviation, median (interquartile range), or number (%).
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GCS = Glasgow Coma Scale; P/F = arterial pressure of oxygen/fractional inspired oxygen; SOFA = Sequential Organ Failure Assessment.
Table 2. Echocardiographic, cardiac MRI, and pathologic findings.
| Variables | Total (n=417) | Survivors (n=337) | Non-survivors (n=80) | p value | ||
|---|---|---|---|---|---|---|
| Echocardiography | ||||||
| Left ventricular ejection fraction (%) | 34.2±17.7 | 35.7±17.1 | 26.9±19.0 | <0.001 | ||
| Left ventricular end diastolic dimension (mm) | 47.0±8.3 | 47.1±8.0 | 46.8±9.8 | 0.837 | ||
| Left ventricular end systolic dimension (mm) | 37.7±9.4 | 37.6±9.0 | 38.8±11.3 | 0.504 | ||
| Septal wall thickness (mm) | 9.6±2.6 | 9.5±2.6 | 10.4±2.8 | 0.031 | ||
| Posterior wall thickness (mm) | 9.6±2.5 | 9.5±2.5 | 10.5±2.5 | 0.021 | ||
| Left atrial volume index (mL/m2) | 32.4±15.7 | 31.8±14.9 | 36.5±20.7 | 0.478 | ||
| E velocity (m/s) | 0.69±0.25 | 0.69±0.25 | 0.68±0.26 | 0.758 | ||
| A velocity (m/s) | 0.53±0.29 | 0.54±0.31 | 0.49±0.21 | 0.149 | ||
| e’ velocity (cm/s) | 6.6±3.0 | 6.9±3.1 | 5.1±2.0 | <0.001 | ||
| E/e’ | 11.7±5.1 | 11.2±4.9 | 14.6±5.7 | 0.002 | ||
| RVSP (mmHg) | 27.3±11.4 | 26.9±11.2 | 29.5±12.9 | 0.345 | ||
| Pericardial effusion | 199/367 (54.2) | 174/313 (55.6) | 25/54 (46.3) | 0.205 | ||
| Cardiac MRI | ||||||
| Edema | 37/85 (43.5) | 36/82 (43.9) | 1/3 (33.3) | >0.999 | ||
| Late-gadolinium enhancement | 58/85 (68.2) | 56/82 (68.3) | 2/3 (66.7) | >0.999 | ||
| Pericardial effusion | 41/85 (48.2) | 39/82 (47.6) | 2/3 (66.7) | 0.607 | ||
| Endomyocardial biopsy | ||||||
| Performed | 158 (37.9) | 139 (41.2) | 19 (23.8) | 0.004 | ||
| Histologic diagnosis | 0.172 | |||||
| Lymphocytic | 125/158 (79.1) | 112/139 (80.6) | 13/19 (68.4) | |||
| Eosinophilic | 14/158 (8.9) | 13/139 (9.4) | 1/19 (5.3) | |||
| Giant cell | 4/158 (2.5) | 3/139 (2.2) | 1/19 (5.3) | |||
| Non-diagnostic | 15/158 (9.5) | 11/139 (7.9) | 4/19 (21.1) | |||
Data presented as the mean ± standard deviation or number (%).
MRI = magnetic resonance imaging; RVSP = right ventricular systolic pressure.
Table 3. In-hospital management of fulminant myocarditis patients.
| Variables | Total (n=417) | Survivors (n=337) | Non-survivors (n=80) | p value | |||
|---|---|---|---|---|---|---|---|
| Medications | |||||||
| Beta-blocker | 169 (40.5) | 153 (45.4) | 16 (20.0) | <0.001 | |||
| ACEi or ARB | 181 (43.4) | 170 (50.4) | 11 (13.8) | <0.001 | |||
| Furosemide | 340 (81.5) | 278 (82.5) | 62 (77.5) | 0.301 | |||
| Spironolactone | 156 (37.4) | 143 (42.4) | 13 (16.3) | <0.001 | |||
| Non-steroidal anti-inflammatory drugs | 83 (19.9) | 77 (22.8) | 6 (7.5) | 0.002 | |||
| Aspirin | 85 (20.4) | 70 (20.8) | 15 (18.8) | 0.687 | |||
| Colchicine | 17 (4.1) | 16 (4.7) | 1 (1.3) | 0.215 | |||
| Immunosuppressants | 176 (42.2) | 142 (42.1) | 34 (42.5) | 0.953 | |||
| Amiodarone | 118 (28.3) | 82 (24.3) | 36 (45.0) | <0.001 | |||
| Organ supports | |||||||
| Vasopressor or inotropic | 401 (96.2) | 326 (96.7) | 75 (93.8) | 0.205 | |||
| Norepinephrine | 194 (46.5) | 140 (41.5) | 54 (67.5) | <0.001 | |||
| Peak dose (mcg/kg/min) | 0.20 (0.10–0.40) | 0.20 (0.10–0.30) | 0.30 (0.16–0.70) | 0.001 | |||
| Vasopressin | 39 (9.4) | 20 (5.9) | 19 (23.8) | <0.001 | |||
| Peak dose (IU/min) | 0 (0–0.04) | 0 (0–0.04) | 0.02 (0–0.03) | 0.318 | |||
| Epinephrine | 95 (22.8) | 65 (19.3) | 30 (37.5) | <0.001 | |||
| Peak dose (mcg/kg/min) | 0.15 (0.10–0.30) | 0.15 (0.10–0.30) | 0.15 (0.10–0.30) | 0.627 | |||
| Dopamine | 232 (55.6) | 181 (53.7) | 51 (63.8) | 0.104 | |||
| Peak dose (mcg/kg/min) | 10.0 (5.0–15.0) | 10.0 (5.0–15.0) | 10.0 (5.3–18.5) | 0.176 | |||
| Dobutamine | 216 (51.8) | 181 (53.7) | 35 (43.8) | 0.109 | |||
| Peak dose (mcg/kg/min) | 5.5 (4.4–10.0) | 5.5 (4.0–10.0) | 7.0 (5.0–12.5) | 0.431 | |||
| Milrinone | 28 (6.7) | 24 (7.1) | 4 (5.0) | 0.495 | |||
| Peak dose (mcg/kg/min) | 0.438 (0.250–0.550) | 0.362 (0.250–0.500) | 0.550 (0.400–0.684) | 0.245 | |||
| Peak vasoactive inotropic score | 19.9 (6.4–42.5) | 15.0 (6.0–35.0) | 40.3 (15.8–111.6) | <0.001 | |||
| Temporary pacemaker | 49 (11.8) | 40 (11.9) | 9 (11.3) | 0.877 | |||
| Permanent pacemaker | 10 (2.4) | 8 (2.4) | 2 (2.5) | >0.999 | |||
| Mechanical ventilator | 232 (55.6) | 159 (47.2) | 73 (91.3) | <0.001 | |||
| Continuous renal replacement therapy | 93 (22.3) | 48 (14.2) | 45 (56.3) | <0.001 | |||
| VA-ECMO | |||||||
| Insertion of VA-ECMO | 217 (52.0) | 153 (45.4) | 64 (80.0) | <0.001 | |||
| Duration, days | 7.0 (4.0–11.0) | 7.0 (5.0–10.0) | 6.0 (2.5–18.0) | 0.154 | |||
| Distal perfusion | 109/208 (52.4) | 82/147 (55.8) | 27/61 (44.3) | 0.130 | |||
| Left ventricular unloading | 94/211 (44.5) | 65/149 (43.6) | 29/62 (46.8) | 0.675 | |||
| Anticoagulation | 200/208 (96.2) | 145/148 (98.0) | 55/60 (91.7) | 0.046 | |||
Data presented as the median (interquartile range) or number (%).
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; VA-ECMO = venoarterial-extracorporeal membrane oxygenation.
One-year clinical outcomes
In the total study population, the primary outcome occurred in 105 patients (26.7%). All-cause death, heart transplantation, and implantation of a left ventricular assist device occurred in 81 (20.7%), 30 (8.7%), and 1 (0.3%) patients, respectively (Table 4). VIS was significantly associated with the risk of the primary outcome (HR, 1.028 for every 10-point increase; 95% CI, 1.019–1.037; p<0.001) (Figure 1A). When the patients were divided according to the optimal VIS cut-off value for discriminating the primary outcome (derived from a ROC curve analysis), patients whose VIS ≥27.0 had a significantly higher risk of the primary outcome than patients whose VIS <27.0 (40.4% vs. 18.6%; HR, 2.764; 95% CI, 1.875–4.074; p<0.001) (Figures 2 and 3A, Table 4). Additionally, patients treated with VA-ECMO had a higher risk of the primary outcome than patients who did not receive VA-ECMO (41.4% vs. 9.3%; HR, 5.331; 95% CI, 3.171–8.962; p<0.001) (Supplementary Figure 2).
Table 4. One-year clinical outcomes.
| Endpoints | HR (95% CI) | p value | |||||
|---|---|---|---|---|---|---|---|
| Total population | Overall (n=417) | VIS ≥27.0 (n=154) | VIS <27.0 (n=263) | ||||
| Primary outcome | 105 (26.7) | 61 (40.4) | 44 (18.6) | 2.764 (1.875–4.074) | <0.001 | ||
| All-cause death | 81 (20.7) | 51 (33.9) | 30 (12.7) | 3.259 (2.075–5.117) | <0.001 | ||
| Heart transplantation | 30 (8.7) | 13 (10.6) | 17 (7.7) | 1.576 (0.765–3.245) | 0.217 | ||
| Left ventricular assist device | 1 (0.3) | 0 (0) | 1 (0.4) | - | - | ||
| Hospitalization for heart failure | 14 (5.1) | 4 (4.6) | 10 (5.3) | 0.813 (0.255–2.591) | 0.726 | ||
| Patients with VA-ECMO | Overall (n=217) | VIS ≥65.5 (n=56) | VIS <65.5 (n=161) | ||||
| Primary outcome | 88 (41.4) | 31 (55.9) | 57 (36.3) | 2.019 (1.303–3.129) | 0.002 | ||
| All-cause death | 64 (30.2) | 27 (49.0) | 37 (23.7) | 2.726 (1.657–4.484) | <0.001 | ||
| Heart transplantation | 30 (17.1) | 4 (9.2) | 26 (18.8) | 0.590 (0.206–1.692) | 0.326 | ||
| Left ventricular assist device | 1 (0.6) | 0 (0) | 1 (0.7) | - | - | ||
| Hospitalization for heart failure | 10 (7.4) | 1 (5.6) | 9 (7.9) | 0.595 (0.075–4.712) | 0.623 | ||
| Patients without VA-ECMO | Overall (n=200) | VIS ≥15.0 (n=74) | VIS <15.0 (n=126) | ||||
| Primary outcome | 17 (9.3) | 13 (19.0) | 4 (3.6) | 5.893 (1.921–18.076) | 0.002 | ||
| All-cause death | 17 (9.3) | 13 (19.0) | 4 (3.6) | 5.893 (1.921–18.076) | 0.002 | ||
| Heart transplantation | 0 (0) | 0 (0) | 0 (0) | - | - | ||
| Left ventricular assist device | 0 (0) | 0 (0) | 0 (0) | - | - | ||
| Hospitalization for heart failure | 4 (2.8) | 0 (0) | 4 (4.3) | - | - | ||
Cumulative incidence of clinical outcomes is presented as event number (Kaplan-Meier estimates).
CI = confidence interval; HR = hazard ratio; VA-ECMO = venoarterial-extracorporeal membrane oxygenation; VIS = vasoactive inotropic score.
Figure 1. Prognostic value of vasoactive inotropic score according to VA-ECMO.
The association between the risk of the primary outcome and (A) VIS and (B) VIS after patients were stratified by VA-ECMO are presented in the spline plot.
CI = confidence interval; HR = hazard ratio; VA-ECMO = venoarterial-extracorporeal membrane oxygenation; VIS = vasoactive inotropic score.
Figure 2. Discriminant ability and cut-off value of VIS according to VA-ECMO.
Discriminant value and diagnostic performance of VIS in the total study population, patients treated with VA-ECMO, and patients not treated with VA-ECMO.
NPV = negative predictive value; PPV = positive predictive value; VA-ECMO = venoarterial-extracorporeal membrane oxygenation; VIS = vasoactive inotropic score.
Figure 3. Primary outcome according to VIS and VA-ECMO.
Comparison of the cumulative incidence and Kaplan-Meier curves based on (A) a VIS value of 27 and (B) VA-ECMO application and the optimal VIS cut-off value in each subgroup stratified by VA-ECMO.
VA-ECMO = venoarterial-extracorporeal membrane oxygenation; VIS = vasoactive inotropic score.
Differential prognostic value of vasoactive inotropic score according to the application of venoarterial-extracorporeal membrane oxygenation
When the patients were stratified according to the use of VA-ECMO, VIS was associated with the risk of the primary outcome in both patients who received VA-ECMO (HR, 1.017 for every 10-point increase; 95% CI, 1.007–1.028; p=0.001) and patients who did not receive VA-ECMO (HR, 1.128 for every 10-point increase; 95% CI, 1.079–1.179; p<0.001) (Figure 1B). When comparing the risk of the primary outcome based on the optimal VIS cut-off values in each subgroup stratified by VA-ECMO, patients with VIS >65.5 had a higher risk of the primary outcome than those with VIS <65.5 in the VA-ECMO subgroup (55.9% vs. 36.3%; HR, 2.019; 95% CI, 1.303–3.129; p=0.002). Similarly, in the non-VA-ECMO subgroup, patients with VIS >15.0 had a higher risk of the primary outcome than those with VIS <15.0 (19.0% vs. 3.6%; HR, 5.893; 95% CI, 1.921–18.076; p=0.002) (Figures 2 and 3B, Table 4). However, the impact of VIS on the risk of the primary outcome was greater in patients who did not receive VA-ECMO than in those who did receive VA-ECMO (interaction p<0.001) (Figure 1B). Furthermore, the discriminant ability of VIS for the primary outcome was significantly higher in patients who did not receive VA-ECMO than in those who did receive VA-ECMO (C-index 0.780 vs. 0.555; p value for C-index comparison=0.002) (Figure 2).
Independent predictors of the primary outcome
In the total study population, both VIS (HR, 1.012 for every 10-point increase; 95% CI, 1.000–1.023; p=0.045) and VA-ECMO (HR, 3.514; 95% CI, 1.904–6.483; p<0.001) were independent predictors of the primary outcome. However, when patients were stratified by the use of VA-ECMO, VIS was an independent predictor only in patients who did not receive VA-ECMO (HR, 1.184 for every 10-point increase; 95% CI, 1.108–1.264; p<0.001); VIS was not selected in the final model for patients treated with VA-ECMO (Table 5).
Table 5. Independent predictors of the primary outcome.
| Models | Multivariable analysis | ||
|---|---|---|---|
| HR (95% CI) | p value | ||
| Model 1: total population | |||
| VA-ECMO | 3.514 (1.904–6.483) | <0.001 | |
| Vasoactive inotropic score (10-point increase) | 1.012 (1.000–1.023) | 0.045 | |
| Age (year) | 1.016 (1.005–1.028) | 0.007 | |
| Initial creatinine (mg/dL) | 1.212 (1.060–1.385) | 0.005 | |
| Initial total bilirubin (mg/dL) | 1.032 (1.004–1.060) | 0.025 | |
| Left ventricular ejection fraction (%) | 0.986 (0.971–1.001) | 0.060 | |
| Model 2: with VA-ECMO | |||
| Age (year) | 1.012 (0.998–1.026) | 0.094 | |
| Symptom onset to admission time (day) | 1.029 (1.004–1.054) | 0.022 | |
| Initial creatinine (mg/dL) | 1.312 (1.064–1.618) | 0.011 | |
| Left ventricular ejection fraction (%) | 0.980 (0.964–0.996) | 0.017 | |
| Model 3: without VA-ECMO | |||
| Vasoactive inotropic score (10-point increase) | 1.184 (1.108–1.264) | <0.001 | |
| Age (year) | 1.026 (1.006–1.048) | 0.013 | |
| Symptom onset to admission time (day) | 0.856 (0.709–1.034) | 0.106 | |
| Initial creatinine (mg/dL) | 1.287 (1.047–1.582) | 0.016 | |
| Pulmonary congestion on chest X-ray | 0.367 (0.100–1.350) | 0.132 | |
| Left ventricular ejection fraction (%) | 0.959 (0.920–1.000) | 0.048 | |
CI = confidence interval; HR = hazard ratio; VA-ECMO = venoarterial-extracorporeal membrane oxygenation.
DISCUSSION
This study evaluated the mid-term prognostic value of VIS in patients with fulminant myocarditis. The main findings are as follows. First, VIS and the need for VA-ECMO were significantly associated with the risk of the primary outcome in the total population. Second, although VIS was significantly associated with the risk of the primary outcome in patients with and without VA-ECMO, the prognostic value of VIS was greater in patients without VA-ECMO. Third, the discriminant ability of VIS for the primary outcome was significantly higher in patients who did not receive VA-ECMO than in those who did.
The rising incidence of acute myocarditis related to the use of immune checkpoint inhibitors and coronavirus disease 2019 vaccines has caused growing interest in acute myocarditis.17),18) Nevertheless, myocarditis is a rare disease with limited evidence about prognostic factors and no validated standardized treatment. It was only recently shown that hemodynamically unstable patients are associated with poor outcomes. In a multicenter study, myocarditis patients presenting with left ventricular ejection fraction <50%, sustained ventricular tachycardia, or hemodynamic instability had a higher risk of cardiac death or heart transplantation at 5 years than patients without those conditions (14.7% vs. 0%).3) Similarly, among acute myocarditis patients with left ventricular systolic dysfunction, patients with fulminant myocarditis had a worse 7-year prognosis than patients with non-fulminant myocarditis (47.7% vs. 10.4%).4) Currently, no validated objective index or marker exists to predict prognosis and guide management in fulminant myocarditis. To address this unmet need, our study investigated whether VIS could dynamically reflect a patient's evolving clinical status and serve as a long-term prognostic indicator. This could facilitate future research and the development of treatments for fulminant myocarditis.
VIS was developed to objectively quantify the degree of cardiovascular support provided to a patient. Initially, the clinical utility of VIS was validated in pediatric patients undergoing cardiothoracic surgery.7),19) Subsequently, VIS was validated in adult patients, in both post-cardiovascular surgery settings and patients with CS or sepsis.20),21) Two previous studies demonstrated that VIS was associated with in-hospital mortality in patients with CS caused by various etiologies as well as by acute myocardial infarction.20),21) Despite sharing a common pathophysiology and presentation, CS can arise from various etiologies, each with a distinct course and prognosis. However, the prognostic value of VIS has not previously been evaluated in patients with fulminant myocarditis. In addition, previous studies showed variable cut-off values for VIS in different settings and for different target outcomes, and no cut-off value has been validated. Accordingly, it was not certain whether the VIS cut-off value for predicting mortality from fulminant myocarditis would be similar to or different from those used in other causes of CS patients. Therefore, this study evaluated the clinical relevance of VIS in patients with fulminant myocarditis.
In this study cohort, VIS was significantly associated with the risk of all-cause death, heart transplantation, or the implantation of a left ventricular assist device at 1 year. When stratified by the optimal cut-off value of 27 (obtained in this study), patients with high VIS had an approximately 3-fold higher risk of the primary outcome than patients with low VIS. Furthermore, VIS was an independent predictor of prognosis even after adjusting for variables previously proven to be associated with the prognosis of patients with fulminant myocarditis. These findings support the potential of VIS as a marker, dynamically reflecting both a patient's immediate hemodynamic status and their long-term prognosis in fulminant myocarditis. Moreover, the findings from this study have the potential to inform the development of standardized enrollment criteria for future trials. This could significantly expedite the identification of homogeneous patient populations, ultimately paving the way for the development of evidence-based and effective therapies for fulminant myocarditis. Another interesting finding in this study is that the VIS cut-off value of 27 is lower than those in previous studies targeting patients with CS, which reported a VIS cut-off value of 40 for discriminating the risk of in-hospital mortality.20),21) This finding implies that the prognosis of patients with fulminant myocarditis is determined at a less severe stage of hemodynamic instability than in patients with CS from other etiologies. Consistent with these findings, previous studies have shown that patients with fulminant myocarditis have an acute course that can deteriorate rapidly. In those studies, the median time from symptom onset to intensive care unit admission was 3 days, and 10-day mortality was approximately 10%.3),4),6) Moreover, a substantial proportion (25–40%) of these patients develop life-threatening ventricular arrhythmias, which can acutely exacerbate their clinical course.4),6)
In line with previous studies, the prognostic value of VIS was higher in patients who did not receive VA-ECMO than in those treated with VA-ECMO.20),21) In this study, VIS was an independent predictor in patients who did not receive VA-ECMO, but not in patients treated with VA-ECMO. Also, the discriminant ability of VIS was significantly greater in patients who did not receive VA-ECMO than in those who did. This finding aligns with the fundamental role of VIS as a standardized metric quantifying vasoactive inotrope usage, which reflects the severity of hemodynamic instability. Higher VIS values typically indicate greater cardiovascular compromise, logically correlating with worse outcomes. However, the reduced predictive power of VIS in VA-ECMO-supported patients can be explained by VA-ECMO’s ability to provide robust MCS, which stabilizes hemodynamics and diminishes the need for inotropic support. Consequently, VIS may no longer accurately reflect the severity of cardiac dysfunction once VA-ECMO has been initiated. This paradox highlights the limitations of using VIS alone to assess prognosis in VA-ECMO-supported patients. Therefore, in the setting of VA-ECMO, the clinical course and prognosis should be evaluated not solely based on VIS but in conjunction with other clinical parameters, such as biochemical markers, echocardiographic findings, and overall organ perfusion indices.
Due to its observational design, this study cannot provide definite guidance, but it offers insights into the appropriate use of inotropes and VA-ECMO in patients with fulminant myocarditis. While vasopressors and inotropes play a crucial role in supporting cardiac function, they become less effective at high doses and can increase the risk of fatal arrhythmias.22),23) Conversely, VA-ECMO is a potent device that can generate sufficient flow, but it inevitably accompanies fatal complications such as bleeding, limb ischemia, and stroke.24) In this context, determining the optimal timing for transitioning from intravenous inotropes to VA-ECMO support is crucial. In this study, patients with VIS <15 and without VA-ECMO had a favorable prognosis, with the primary outcome occurring in only 3.6%. However, once the VIS score exceeded 15, the risk of poor outcomes increased approximately 6-fold in patients who did not receive VA-ECMO. Additionally, in the overall patient cohort, a VIS score of 27 was identified as the cut-off for predicting the primary outcome. These findings suggest proactive intervention should be prepared and considered when the VIS score exceeds 15. In particular, when the VIS score surpasses 27, VA-ECMO initiation should be actively considered. Given the limited therapeutic options currently available to improve prognosis in fulminant myocarditis, the use of VA-ECMO and endomyocardial biopsy should be strongly considered in these high-risk patients.6)
The following limitations should be considered when interpreting the results of this study. First, this study has all the limitations innate in any retrospective design. Specifically, patient management, including the management of patients treated with VA-ECMO, was left to the discretion of the attending physicians and was not protocolized. Therefore, future prospective protocolized studies with long-term follow-up are required for validation. Second, not all patients were diagnosed using endomyocardial biopsy. Although this study included patients who met the diagnostic criteria outlined in the European Society of Cardiology position statement, there remains a possibility that patients with other conditions mimicking myocarditis were included. Third, VIS was collected only as peak values, and its variations over time were not recorded. Consequently, this study could not assess the prognostic impact of VIS changes over time, nor confirm whether the recorded peak values were obtained before or after VA-ECMO initiation. However, given that vasopressors and inotropes are typically maintained or tapered after VA-ECMO initiation, and that VA-ECMO was initiated within 48 hours of CS in most cases (184/217, 84.8%), the maximum VIS during this period might be considered a surrogate for the maximum VIS prior to VA-ECMO initiation.
VIS was associated with mid-term prognosis in patients with fulminant myocarditis. However, the prognostic value of VIS was more prominent in patients who did not receive VA-ECMO than it was in patients treated with VA-ECMO.
Footnotes
Funding: This study was supported by a research grant from the Korean Cardiac Research Foundation (grant number 202201-01).
Conflict of Interest: The authors have no financial conflicts of interest.
Data Sharing Statement: The data generated in this study is available from the corresponding author upon reasonable request.
- Conceptualization: Hong D, Yang JH.
- Data curation: Hong D, Bak M, Park H, Kim HY, Kim IC, Hyun J, Kim SR, Kim MN, Kim KH, Yang JH.
- Formal analysis: Hong D, Lee S.
- Funding acquisition: Yang JH.
- Investigation: Hong D, Yang JH.
- Methodology: Hong D, Yang JH.
- Project administration: Yang JH.
- Supervision: Yang JH.
- Validation: Bak M, Park H, Kim HY, Lee S, Kim IC, Hyun J, Kim SR, Kim MN, Kim KH, Yang JH.
- Visualization: Hong D.
- Writing - original draft: Hong D.
- Writing - review & editing: Hong D, Bak M, Park H, Kim HY, Lee S, Kim IC, Hyun J, Kim SR, Kim MN, Kim KH, Yang JH.
SUPPLEMENTARY MATERIALS
Univariable analysis
Study flow.
Primary outcome according to VA-ECMO.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Univariable analysis
Study flow.
Primary outcome according to VA-ECMO.