Inotropes improve symptoms in advanced heart failure (HF) but were associated with higher mortality in clinical trials. Recurrent hospitalizations, arrhythmias, and infections contribute to morbidity and mortality, but the risks of these complications with modern HF therapies are not well known. We collected arrhythmia, infection, and hospitalization data on 197 patients discharged from our institution from January 2007 to March 2013 on intravenous inotropes. Patients were followed until they died, received a transplant or left ventricular assist device, were weaned off inotropes, or remained on inotropes at the end of the study. All patients had stage D HF. At baseline, 30% had a history of ventricular tachycardia, 7.1% had a history of cardiac arrest, and 39% had a history of atrial fibrillation. During follow-up, 33 patients (17%) had one or more implantable cardioverter–defibrillator shocks. Of patients who had shocks, 27 patients (82%) had appropriate shocks for ventricular tachycardia/ventricular fibrillation, 3 patients (9%) had inappropriate shocks, and 3 patients (9%) had both appropriate and inappropriate shocks. The risk of implantable cardioverter–defibrillator shock was not related to dose of inotrope (p = 0.605). Fifty-seven patients (29%) had one or more infections during follow-up. Bacteremia was the most common type of infection. Implanted electrophysiology devices did not confer an increased risk of infection. One hundred twelve patients (57%) had one or more hospitalizations during follow-up. Common causes of hospitalizations were worsening HF symptoms (41%), infections (20%), and arrhythmias (12%). In conclusion, arrhythmias, infections, and rehospitalizations are important complications of inotropic therapy.
Inotropic agents have been studied for several decades in heart failure (HF). The early studies showed improvement in hemodynamic profiles. Larger studies such as Prospective Randomized Milrinone Survival Evaluation Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (PROMISE OPTIME-CHF), and the Acute Decompensated Heart Failure National Registry (ADHERE) registry raised concerns about higher mortality with inotrope use and showed that hemodynamic improvement does not necessarily translate into survival benefit. Inotropes are therefore not currently used routinely for acute decompensated HF. The general role of inotropes in current practice is to treat cardiogenic shock and low output states, improve symptoms, optimize hemodynamics, and maintain end-organ function in transplant or left ventricular assist device (LVAD) candidates, or as palliative therapy. Several of the inotrope trials were performed before widespread use of β blockers, aldosterone antagonists, and implantable cardioverter–defibrillators (ICDs) for primary prevention in HF. These treatments used concomitantly with inotropes may impact the risks and complications associated with inotropes. Major issues related to inotrope therapy include infections related to chronic indwelling catheters, arrhythmias, and recurrent hospitalizations, and these have not been analyzed in detail in contemporary cohorts. A detailed examination of these complications would facilitate a more informed discussion with patients and families facing these choices and may identify strategies to decrease these complications and is the focus of this study.
Methods
This study was a retrospective review of all adult patients with advanced HF discharged from one tertiary care institution on milrinone or dobutamine from January 2007 to March 2013. Patients on an inotrope were identified using multiple methods: review of our patient records for 3 of 5 home infusion companies that supplied inotropes during that period, review of the HF clinic charts, query of the hospital discharge, and clinic electronic medical records (EMRs) for patients prescribed dobutamine or milrinone, and review of patients who received LVAD or transplantation during that period. All patients had stage D HF, and were deemed inotrope–dependent and managed by HF specialists. Exclusion criteria included patients who received inotropes after LVAD, patients who received inotropes in the hospital only, patients who received inotropes for congenital heart disease or isolated right ventricular failure, and patients aged <18 year old. Patients were followed until they died, received a transplant or LVAD, were weaned off inotropes, or until the end of the data collection period (January 30, 2014) if they remained on inotropes. Infection and arrhythmia data were collected throughout the follow-up period using the EMR, paper charts, electrophysiologic device interrogation reports, microbiology laboratory data, pharmacy data, and review of any emergency room and/or admission data to other hospitals available in the clinic chart or scanned in our EMR. The institutional review board approved the project.
Continuous variables are presented as mean ± SD. Odds ratios (ORs) are presented with 95% CIs and p values. The t tests and chi-square tests were used to compare continuous and categorical variables, respectively. Univariate logistic regression was used to assess the association between the risk of postinotrope arrhythmias and each of the demographic and baseline characteristics. Any covariates that were statistically significant at p <0.05 were then included in a multivariate logistic regression. Statistical analysis was performed using Statistical Analysis Software (SAS) 9.3.
Results
One hundred ninety-seven patients with stage D New York Heart Association IV HF were placed on inotropes for several reasons: for palliation (98 patients), as a bridge in patients listed for transplant or scheduled for LVAD (60 patients), in patients being evaluated for VAD/transplant (20 patients), for stabilization pending cardiac resynchronization therapy or percutaneous coronary intervention (4 patients), and in patients who were offered LVAD evaluation but preferred inotropes (15 patients). Baseline characteristics are listed in Table 1 . Milrinone was used in 84.8% and dobutamine in 15.2%. The mean discharge dose of milrinone was 0.296 (±0.092) μg/kg/min and mean discharge dose of dobutamine was 4.38 (±1.78) μg/kg/min. Hemodynamic and clinical changes preinotrope and postinotrope and survival in this population has been previously reported.
| Female | 51 (25.8%) |
| Male | 146 (74.1%) |
| Mean Age (years) | 54.4 (14.6) |
| Etiology | |
| Ischemic | 79 (40.1%) |
| Nonischemic | 118 (59.9%) |
| Number of Hospitalizations in Year Prior to Inotrope Initiation | |
| 0 | 17 (8.6%) |
| 1 | 51 (25.9%) |
| 2 | 45 (22.8%) |
| 3 | 19 (9.6%) |
| 4 | 18 (9.1%) |
| Greater than 4 | 33 (16.8%) |
| Unknown | 14(7.1%) |
| Ventricular Tachycardia | 59 (30.0%) |
| History of Cardiac Arrest | 14 (7.1%) |
| Electrophysiology Device | |
| None | 14 (7.1%) |
| Pacemaker only | 3 (1.5%) |
| ICD | 84 (42.6%) |
| Biventricular-ICD | 82 (41.6%) |
| Lifevest | 7 (3.6%) |
| Unknown | 7 (3.6%) |
| Left Ventricular Ejection Fraction (n=131) | 18.7 (8.1) |
| Systolic blood pressure (mmHg) (n=158) | 105.6 (17.0) |
| Diastolic blood pressure (mmHg) (n=158) | 65.5 (11.4) |
| Heart Rate (bpm) (n=157) | 85.3 (15.8) |
| Sodium (mEq/L) (n=160) | 135.2 (4.7) |
| Blood Urea Nitrogen (mg/dL) (n=160) | 31.1 (20.2) |
| Creatinine (mg/dL) (n=159) | 1.6 (0.8) |
| Brain Natriuretic Peptide (pg/ml) (n=96) | 1239.2 (1135.1) |
| Right Heart Catheterization- Fick Cardiac Index (L/min/m 2 ) (n=103) | 1.7 (0.4) |
| Pulmonary capillary wedge pressure (mmHg) (n=107) | 25.6 (8.1) |
Fifty-seven patients (29%) had at least one clinical infection during inotrope therapy. The majority had one infection, and 2% had ≥3 infections. The most common type of infection was bacteremia without a diagnosis of sepsis or septic shock in the hospitalization records, followed by sepsis/shock, access-site infection, and endocarditis ( Table 2 ). Infections were caused most commonly by staphylococcus aureus, coagulase-negative staphylococci, and enterococci ( Table 3 ). Implanted electrophysiology devices (pacemaker, ICD, biventricular-ICD) did not confer an additional risk of infection compared to patients with LifeVest or no implanted devices (p = 0.58).
| Number of patients (%) | |
|---|---|
| Number of Infections | |
| 0 | 140 (71.1%) |
| 1 | 37 (18.8%) |
| 2 | 16 (8.1%) |
| 3 or more | 4 (2.0%) |
| Types of Infection | |
| Access site infection | 8 (9.9%) |
| Bacteremia | 61 (75.3%) |
| Endocarditis | 4 (4.9%) |
| Sepsis/shock | 8 (9.9%) |
| Organism | Frequency |
|---|---|
| Coagulase-negative staphylococcus | 17 (21.25 %) |
| Staphylococcus aureus | 17 (21.25 %) |
| Enterococcus species | 7 (8.75 %) |
| Klebsiella species | 4 (5.0 %) |
| Escherichia coli | 4 (5.0 %) |
| Candida species | 4 (5.0 %) |
| Serratia Marcescens | 3 (3.75 %) |
| Enterobacter species | 3 (3.75 %) |
| Agrobacterium | 2(2.5 %) |
| Diptheroids | 2(2.5 %) |
| Pseudomonas species | 2(2.5 %) |
| Stenotrophomonas maltophilia | 2(2.5 %) |
| Streptococcus species | 2(2.5 %) |
| Proteus mirabilis | 1(1.25 %) |
| Bacillus species | 1(1.25 %) |
| Actinobacter species | 1(1.25 %) |
| Acinetobacter baumannii | 1(1.25 %) |
| Organisms not specified | 7(8.75 %) |
Thirty-three patients (17%) had one or more ICD shocks during follow-up. The shocks were appropriate for ventricular tachycardia/ventricular fibrillation in 27 patients (82%; Table 4 ). The number of shock episodes, total shocks, shock episodes per month, or shocks per month was not statistically different between the different outcome groups ( Table 5 ). Predictors of postinotrope ICD shocks by multivariate logistic regression analysis were LV ejection fraction (OR 0.94, 95% CI 0.88 to 0.996, p = 0.037), a history of ventricular tachycardia preinotrope (OR 2.41, 95% CI 1.07 to 5.43, p = 0.034), and baseline angiotensin-converting enzyme inhibitor use (OR 2.75, 95% CI 1.16 to 6.52, p = 0.021). The risk of ICD shock was not related to the dose of inotrope (p = 0.605).
| Number of patients (%) | |
|---|---|
| Appropriate for ventricular tachycardia/fibrillation | 27 (82%) |
| Inappropriate for atrial fibrillation/flutter | 1 (3%) |
| Inappropriate for sinus tachycardia | 1 (3%) |
| Appropriate and Inappropriate | 3 (9%) |
| Missing | 1 (3%) |
| Total | 33 (100%) |
| Variable | Death (N=68) | Weaned (N=24) | Remained on Inotropes (N=50) | Transplant (N=23) | LVAD (N=32) | p value ∗ |
|---|---|---|---|---|---|---|
| Number of Shock episodes | 2.4(2.5 ) | 1.8 (1.2) | 1.9 (1.4) | 0 | 2.0 (1.3) | 0.895 |
| Number of Total Shocks | 3.7 (3.9) | 1.8(1.2) | 4.2 (3.5) | 0 | 2.7 (1.6) | 0.468 |
| Follow-up time (months) | 6.5 (7.6) | 10.2 (9.0) | 12.2 (11.5) | 3.6 (4.3) | 3.0 (2.7) | <0.001 |
| Shock episodes per month | 1.2 (3.0) | 0.4 (0.6) | 0.1 (0.1) | 0 | 0.5 (0.3) | 0.591 |
| Shocks per month | 1.4 (3.1) | 0.4 (0.6) | 0.2 (0.2) | 0 | 0.7 (0.3) | 0.529 |
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