- Email: [email protected]
Outpatient Continuous Parenteral Inotropic Therapy as Bridge to Transplantation in Children With Advanced Heart Failure
Journal of Cardiac Failure Vol. 12 No. 2 2006
Outpatient Continuous Parenteral Inotropic Therapy as Bridge to Transplantation in Children With Advanced Heart Failure JACK F. PRICE, MD,1,2 JEFFREY A. TOWBIN, MD,1,2 WILLIAM J. DREYER, MD,1,2 BRADY S. MOFFETT, PharmD,2 NAOMI J. KERTESZ, MD,1,2 SARAH K. CLUNIE, RN,2 AND SUSAN W. DENFIELD, MD1,2 Houston, Texas
ABSTRACT Background: Advanced heart failure in children is associated with high morbidity and mortality and is often refractory to standard medical therapy. The purpose of this study was to review our institutional experience with the use of outpatient parenteral inotropic therapy (PIT) for advanced chronic heart failure in children. Methods and Results: We reviewed the medical records of all patients treated with PIT as outpatients. Seven patients received outpatient PIT from 2/99 to 1/05 (mean age was 14.6 years 6 3.7). Median duration of therapy was 10 weeks (range 4–84 weeks). The mean number of emergency department visits per patient was greater before starting PIT than after starting PIT (2.3 6 1.8 versus 1.1 6 2.2, P ! .05). The mean number of hospital admissions from exacerbation of heart failure symptoms decreased after starting PIT (2.1 6 1.3 versus 0.6 6 0.8, P ! .05). Mean EF% in patients with systolic dysfunction improved while on therapy (30 6 14% before versus 39 6 16% after, P ! .05). There was 1 death and 5 complications in 2 patients. Six patients were successfully bridged to transplantation. Conclusion: Outpatient continuous parenteral inotropic therapy may serve as a successful bridge to cardiac transplantation in selected pediatric outpatients. Key Words: Pediatric, heart failure, inotrope, transplant.
parenteral inotropic therapies have been used successfully as a method of alleviating symptoms and bridging patients to cardiac transplantation.1–5 To date, no data exist regarding the use of outpatient inotropic infusions in children with advanced heart failure. In fact, there is no evidence that intravenous inotropes improve symptoms or alter mortality in children hospitalized with decompensated heart failure. Nevertheless, anecdotal experience in pediatric and adult populations have led physicians to routinely treat symptomatic children with intravenous inotropic agents. At our institution, we have used continuous low-dose dopamine and milrinone infusions in selected pediatric outpatients with advanced heart failure to alleviate their symptoms and bridge them to transplantation. We have also speculated that relieving symptoms in this manner would lead to fewer emergency department visits and hospital admissions. The purpose of this study was to review and report our experience using outpatient inotropic agents in children.
Advanced heart failure in children is characterized by worsening symptoms, recurring exacerbations, and frequent emergency department visits and hospital admissions. At end stage, the symptoms of heart failure may become refractory to standard medical therapy. Death is the usual outcome unless the patient undergoes cardiac transplantation. Some patients with decompensated heart failure can receive symptomatic relief with intravenous inotropic agents, only to experience recurrence of symptoms within hours or days of discontinuation of the infusion. Frequently, such ‘‘inotrope-dependent’’ patients are listed for transplantation, and they may require a protracted course of inotropic agents while awaiting a suitable organ. In some adults with chronic heart failure, continuous or intermittent outpatient
From 1Department of Pediatrics (The Lillie Frank Abercrombie Section of Pediatric Cardiology), Baylor College of Medicine, 2Texas Children’s Hospital, Houston, Texas. Manuscript received August 6, 2005; revised manuscript received October 28, 2005; revised manuscript accepted November 1, 2005. Reprint requests: Jack F. Price, MD, Texas Children’s Hospital, 6621 Fannin, MC 19345-C, Houston, TX 77030. 1071-9164/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2005.11.001
Methods Data Collection We reviewed the medical records of all patients who were treated with continuous parenteral inotropic therapy as outpatients at
139
140 Journal of Cardiac Failure Vol. 12 No. 2 March 2006 our institution while awaiting transplantation between February 1999 and January 2005. Any patient older than 21 years of age was excluded from the study. Data collected included patient demographics, type and dose of inotrope used, length of therapy, complications, and the number of emergency department visits and hospital admissions per patient. Preinfusion data were recorded for the same duration that each patient was treated with outpatient inotropic therapy. The most recent estimated ejection fraction measured before starting therapy was compared to the last echocardiogram performed during therapy.
Table 1. Patient Characteristics at Initiation of Inotropic Therapy Age Patient (years)
NYHA Class
Sex
b-blocker, ACEI, diuretic digoxin, ACEI, diuretic, amio
11.7
IV
M
TCAD
2
15.8
IV
M
3
15.8
IV
F
4
16.0
IV
F
5
20.2
III
M
6
13.7
III
M
7
8.5
IV
M
Tricuspid atresia, s/p Fontan Complex digoxin, ACEI, heterotaxy, diuretic s/p Fontan TCAD digoxin, ACEI, diuretic CCTGA b-blocker, digoxin, ACEI, diuretic, amio, ICD Aortic b-blocker, ACEI, stenosis diuretic Idiopathic b-blocker, digoxin, DCM ACEI, diuretic, amio, ICD
Follow-up Each patient was seen in follow-up at least monthly in the outpatient heart failure clinic. A home health nurse visited each patient at least once weekly. The doses of inotropic medications were not adjusted during outpatient therapy.
Other Therapies
1
Inpatient Monitoring Parenteral infusions were initiated while patients were hospitalized and continued for at least 48 hours of inpatient monitoring. Patients were discharged home after their medication doses had been optimized and they demonstrated no hemodynamic or symptomatic instability on a fixed infusion rate of parenteral inotropic therapy.
Etiology of HF
HF, heart failure; M, male; F, female; TCAD, transplant coronary artery disease; ACEI, angiotensin-converting enzyme inhibitor; s/p, status post; amio, amiodarone; ICD, implantable cardio defibrillator; CCTGA, congenitally corrected transposition of the great arteries; DCM, dilated cardiomyopathy.
Catheters All lines were single lumen, peripherally inserted central venous catheters. Most common sites of line insertion were the antecubital, basilic and subclavian veins, with sizes varying from 3 to 5 Fr. Portable infusion pumps could be fastened to a patient’s belt or carried by a patient in a hip satchel. Statistical Analysis The Wilcoxon signed-rank test was used to compare the number of emergency department visits, hospital admissions, and ejection fractions before and after starting outpatient therapy. A p value ! .05 was accepted as statistically significant. Results are reported as a mean 6 SD.
at the time of initiation of inotropic therapy included a diuretic (n 5 7), angiotensin-converting enzyme inhibitor (n 5 7), digoxin (n 5 5), b-blocker (n 5 4), and amiodarone (n 5 3). Six patients were New York Heart Association functional class III or IV, and all were listed for transplant before the initiation of outpatient inotropic therapy. In addition, all patients had been treated with oral medications for at least 4 months before starting parenteral therapy. There was a history of ventricular tachycardia in 3 patients, 2 of whom had received implantable cardioverter defibrillators (ICD). Inotropic Therapy
Results Patient Characteristics
Seven patients were treated with parenteral inotropic therapy as outpatients during the study period. Table 1 illustrates study patient characteristics. Mean age was 14.5 6 3.7 years. The etiology of heart failure included congenital heart disease (n 5 4), ischemic cardiomyopathy (n 5 2), and idiopathic dilated cardiomyopathy (n 5 1). Of the 4 patients with heart failure from congenital heart disease, 2 had undergone staged surgical palliation with a total cavopulmonary anastomosis, and 1 had congenitally corrected transposition. All 3 had developed progressive systemic ventricular systolic dysfunction. One patient who was treated for diastolic dysfunction also had pulmonary hypertension, with a history of aortic valve stenosis that had been repaired surgically. Milrinone was started in that patient for its lusitropic properties.6 The 2 patients with ischemic cardiomyopathy had developed post-transplant coronary artery disease and ventricular dysfunction. Oral agent therapy
Inotropic medications used for PIT included dopamine alone (n 5 1), milrinone alone (n 5 4), and dopamine and milrinone in combination (n 5 2). The mean dose of dopamine used was 2.8 6 0.3 mcg$kg$minute. The mean dose of milrinone was 0.25 6 0.03 mcg$kg$minute. The total duration of therapy was 1386 patient days, with a mean of 198 days (range 27–588 days) (Table 2). Emergency Department Visits and Hospital Admissions
The mean number of emergency department visits per patient was greater before starting outpatient therapy than after starting therapy for the same duration (2.3 6 1.8 before infusion versus 1.1 6 2.2 during infusion, P ! .05) (Table 3). Similarly, the mean number of cardiac hospital admissions was reduced after beginning parenteral therapy (2.1 6 1.3 before infusion versus 0.6 6 0.8 during infusion, P ! .05) (Table 3). The total number of cardiac admissions decreased by 71% during outpatient therapy. The change in mean number of all-cause hospital admissions was not
Outpatient Inotropes in Pediatric Heart Failure
Price et al
141
Table 2. Inotropic Therapy and Complications Patient 1 2 3 4 5 6 7
Inotrope and Dose (mcg$kg$min) Milrinone 0.3 Milrinone 0.2 DA 3.0 and milrinone 0.25 Milrinone 0.2 DA 3.0 Milrinone 0.3 DA 2.5 and milrinone 0.25
Length of Therapy 27 days 50 days 588 days 111 days 392 days 98 days 56 days
Complications
Outcome
None Died at home Occlusion; extravasation (twice) None Leaking catheter; infection None None
Transplant Sudden death Transplant Transplant Transplant Transplant Transplant
DA, dopamine.
significant (2.1 6 1.3 before infusion versus 1.3 6 1.8 during infusion, P 5 .06). Ejection Fraction
Estimated ejection fraction could be calculated in 6 patients. The mean estimated ejection fraction improved during outpatient therapy (30 6 14% before infusion versus 39 6 16% during infusion, P ! .05) (Fig. 1). Catheter Complications
Five catheter complications occurred in 2 patients. These included catheter occlusion (n 5 1), extravasation of the catheter (n 5 2) requiring removal and replacement, and leaking catheter (n 5 1). One patient developed a central line infection. Blood cultures grew alpha hemolytic streptococcus, and the patient was treated with intravenous antibiotics for 10 days after removal of the infected line. A new catheter was placed and inotropic therapy was continued after completion of antibiotic therapy. Outcome
One patient died suddenly at home during parenteral therapy. That patient had undergone a Fontan procedure and had a history of nonsustained ventricular tachycardia for which he was being treated with oral amiodarone. He did not receive an ICD because he was not a candidate for a transvenous system, and the risk associated with surgical placement of an epicardial system was thought to be too great. His last documented episode of ventricular tachycardia occurred 8 weeks before beginning outpatient lowdose milrinone. Although the family was informed of the risks involved, they preferred to wait at home. Two other patients also had a history of ventricular tachycardia and received ICDs before beginning outpatient parenteral therapy. Interrogation of their ICDs demonstrated no device discharges. The 6 surviving patients were maintained on parenteral inotropic therapy until a suitable organ became available and they could then undergo cardiac transplantation.
children. This therapeutic regimen of low-dose dopamine or milrinone appeared to improve heart failure symptoms sufficiently to reduce the frequency of emergency department visits and heart failure related hospital admissions. Ventricular systolic function also improved during outpatient parenteral therapy. Moreover, all patients but 1 were successfully bridged to cardiac transplantation. Outpatient inotropic therapy has become an accepted treatment method for selected adults with end-stage heart failure and inotrope-dependence, both as a bridge to cardiac transplantation and as hospice care. Although intermittent dosing has been more frequently reported, continuous infusions of dopamine, dobutamine and milrinone have been demonstrated to be safe, effective, and cost saving.7–18 Adult candidates for outpatient inotropic therapy are usually characterized as symptomatic at rest and refractory to maximal outpatient medical therapy. Most have experienced a recurrence of their symptoms with attempts at withdrawal from inotropic therapy and require frequent hospitalizations for treatment of symptomatic exacerbations. After starting intravenous inotropes in the outpatient setting, adult patients frequently report symptomatic relief and require fewer emergency department visits, hospital admissions, and days spent in the hospital.13,19 As with adults, this cohort of pediatric patients usually described having heart failure symptoms at rest or with minimal exertional activity. They had all been hospitalized at least once for intravenous therapy prior to receiving outpatient parenteral therapy and they were all listed for cardiac transplantation (Class IB). All but 1 (the patient with diastolic dysfunction) developed recurrence of their symptoms when the inotrope(s) were discontinued or weaned. Reports of symptomatic improvement were not well documented; however, emergency department visits and hospital admissions decreased during outpatient parenteral therapy,
Table 3. Mean Emergency Department Visits, All-Cause, and Cardiac Admissions
Discussion These data represent the first reported use of outpatient parenteral inotropic therapy for advanced heart failure in
Emergency department visits All-cause hospital admissions Cardiac admissions
Before Infusion
During Infusion
P Value
2.3 6 1.8 2.1 6 1.3 2.1 6 1.3
1.1 6 2.2 1.2 6 1.8 0.6 6 0.6
!.05 .06 !.05
142 Journal of Cardiac Failure Vol. 12 No. 2 March 2006 70%
Ejection fraction
60% 50% 40% 30% 20% 10% 0%
Before infusion
During infusion
Fig. 1. Change in estimated ventricular ejection fraction from before starting outpatient therapy to during outpatient therapy (30 6 14% vs. 39 6 16%, P 5 .04).
suggesting that patients received some degree of symptomatic relief. Of those admissions that occurred during outpatient therapy, 44% were due to exacerbations of cardiac symptoms. The remaining admissions were related to problems with the catheters. Ventricular ejection fraction also improved during continuous inotropic infusions, although not necessarily a marker of improved symptomatology. Catheter complications occurred in only 2 patients. One patient became bacteremic during parenteral therapy but was never septic. Partial extravasation of a catheter occurred twice in the same patient, with no untoward hemodynamic effect. If a catheter was temporarily disabled, the patient was admitted to the hospital and continued on their inotropic agent using a peripheral IV until a new venous catheter could be placed. Three patients had ventricular tachycardia documented by Holter monitoring before initiation of outpatient inotropic therapy. One died suddenly at home, 50 days after outpatient therapy was initiated. The child who died was the only patient with ventricular tachycardia who did not receive an ICD. His death was believed to be related to arrhythmia. Although studies in adults with symptomatic heart failure have demonstrated reduced incidence of sudden cardiac death with the use of ICDs, data are lacking in children.20 A case series of pediatric patients awaiting cardiac transplantation attributed up to 25% of deaths to arrhythmia.21 Primary prevention strategies are the subject of ongoing research in children.22 Our current practice is to refer all patients with advanced heart failure and documented ventricular tachycardia for ICD implantation if they are to be discharged home. Patients who meet criteria for ICD implantation, but in whom implantation carries a high risk, are no longer considered candidates for outpatient inotropic therapy. We used low doses of dopamine and milrinone in this cohort in order to provide a degree of symptomatic relief while minimizing the potential risks associated with higher doses of inotropes. Patients tolerated these infusion rates and the doses were not adjusted during outpatient therapy. Oral medications were also well tolerated during followup and could be uptitrated without difficulty.
Normally, we do not discharge our inotrope-dependent transplant candidates home to wait for a suitable organ. However, several medical and social factors reassured us that it would be safe to send these particular patients home while receiving inotropic therapy. None of the patients required a prolonged intensive care unit stay during their hospitalization, and each patient’s symptoms improved during inotropic therapy such that they were all New York Heart Association class II or III before discharge. All patients were receiving and tolerant of standard care oral medical therapy. In addition to having stable hemodynamics while treated with inotropic infusions as inpatients, these children needed to have reliable parents with dependable transportation who lived relatively close to the hospital to ensure good follow-up. These particular patients were older than most of our hospitalized pediatric heart failure patients and we considered them mature enough to alert a parent or home health nurse of a catheter-related problem. We also required at least weekly home health nursing visits for inspection of the catheter and assessment of the patient. In addition, each patient was seen in follow-up in our heart failure clinic no less frequently than every 4 weeks. Our pretransplant heart failure patients do not normally receive regular home nursing visits and assessments; this likely contributed to the clinical improvement observed in this cohort. Finally, we believe that this therapy should be reserved for children with recurrent heart failure symptoms or inotropic sensitive pulmonary hypertension who have received standard maximal oral therapy and are awaiting heart transplant. A treatment regimen including b-blockers and angiotensin-converting enzyme inhibitors, as well as amiodarone, ICDs, and frequent follow-up was the foundation that allowed for survival in this cohort. Outpatient inotropic therapy appeared to improve their symptoms and may have contributed to successful bridge to transplantation. Conclusion
Continuous outpatient parenteral inotropic therapy was well tolerated in this cohort of children with advanced heart failure and may have provided a successful bridge to cardiac transplantation. Symptoms of heart failure appeared to improve during therapy and complications were few. Mortality did not exceed the reported frequency of mortality in pediatric patients awaiting cardiac transplantation. This form of therapy may provide selected patients with sustained symptomatic relief while awaiting transplantation.
References 1. Hodgson JM, Aja M, Sorkin RP. Intermittent ambulatory dobutamine infusions for patients awaiting cardiac transplantation. Am J Cardiol 1984;53:375–6. 2. Miller LW, Merkle EJ, Herrmann V. Outpatient dobutamine for endstage congestive heart failure. Crit Care Med 1990;18:S30–3.
Outpatient Inotropes in Pediatric Heart Failure 3. Collins JA, Skidmore MA, Melvin DB, Engel PJ. Home intravenous dobutamine therapy in patients awaiting heart transplantation. J Heart Lung Transplant 1990;9:205–8. 4. Young JB, Moen EK. Outpatient parenteral inotropic therapy for advanced heart failure. J Heart Lung Transplant 2000;19:S49–57. 5. Sindone AP, Keogh AM, Macdonald PS, McCosker CJ, Kaan AF. Continuous home ambulatory intravenous inotropic drug therapy in severe heart failure: safety and cost efficacy. Am Heart J 1997;134: 889–900. 6. Monrad ES, McKay RG, Balm DS, et al. Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone. Circulation 1984;70:1030–7. 7. Applefeld MM, Newman KA, Grove WR, et al. Intermittent, continuous dobutamine infusion in the management of congestive heart failure. Am J Cardiol 1983;51:455–8. 8. Roffman DS, Applefeld MM, Grove WR, et al. Intermittent dobutamine hydrochloride infusions in outpatients with chronic congestive heart failure. Clin Pharm 1985;4:195–9. 9. Krell MJ, Kline EM, Bates ER, et al. Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure. Am Heart J 1986;112:787–91. 10. Applefeld MM, Newman KA, Sutton FJ, et al. Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients. Am Heart J 1987;114: 589–95. 11. Miller LW. Outpatient dobutamine for refractory congestive heart failure: advantages, techniques and results. J Heart Lung Transplant 1991; 10:482–7. 12. Erlemeier H, Kupper W, Bleifeld W. Intermittent infusion of dobutamine in the therapy of severe congestive heart failuredlong-term effects and lack of tolerance. Cardiovasc Drugs Ther 1992;6:391–8.
Price et al
143
13. Marius-Nunez AL, Heaney L, Fernandez RN, et al. Intermittent inotropic therapy in an outpatient setting: A cost-effective therapeutic modality in patients with refractory heart failure. Am Heart J 1996;132:805–8. 14. Cesario D, Clark J, Maisel A. Beneficial effects of intermittent home administration of the inotrope/vasodilator milrinone in patients with end-stage congestive heart failure: a preliminary study. Am Heart J 1998;135:121–9. 15. Hershberger RE, Nauman D, Walker TL, Dutton D, Burgess D. Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure. J Cardiac Fail 2003;9:180–7. 16. Upadya S, Lee FA, Saldarriaga C, et al. Home continuous positive inotropic infusion as a bridge to cardiac transplantation in patients with end-stage heart failure. J Heart Lung Transplant 2004;23:466–72. 17. Leier CV, Huss P, Lewis RP, et al. Drug-induced conditioning in congestive heart failure. Circulation 1982;65:1382–7. 18. Miller LW, Merkle EJ, Jennison SH. Outpatient use of dobutamine to support patients awaiting heart transplantation. J Heart Lung Transplant 1994;13:S126–9. 19. Harjai KJ, Mehra MR, Ventura HO, et al. Home inotropic therapy in advanced heart failure: cost analysis and clinical outcomes. Chest 1997;112:1298–303. 20. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. 21. Rosenthal DN, Dubin AM, Chin C, et al. Outcome while awaiting heart transplantation in children: a comparison of congenital heart disease and cardiomyopathy. J Heart Lung Transplant 2000;19:751–5. 22. Dubin AM, Berul CI, Bevilacqua LM, et al. The use of implantable cardioverter-defibrillators in pediatric patients awaiting heart transplantation. J Card Fail 2003;9:375–9.
Outpatient Continuous Parenteral Inotropic Therapy as Bridge to Transplantation in Children With Advanced Heart Failure JACK F. PRICE, MD,1,2 JEFFREY A. TOWBIN, MD,1,2 WILLIAM J. DREYER, MD,1,2 BRADY S. MOFFETT, PharmD,2 NAOMI J. KERTESZ, MD,1,2 SARAH K. CLUNIE, RN,2 AND SUSAN W. DENFIELD, MD1,2 Houston, Texas
ABSTRACT Background: Advanced heart failure in children is associated with high morbidity and mortality and is often refractory to standard medical therapy. The purpose of this study was to review our institutional experience with the use of outpatient parenteral inotropic therapy (PIT) for advanced chronic heart failure in children. Methods and Results: We reviewed the medical records of all patients treated with PIT as outpatients. Seven patients received outpatient PIT from 2/99 to 1/05 (mean age was 14.6 years 6 3.7). Median duration of therapy was 10 weeks (range 4–84 weeks). The mean number of emergency department visits per patient was greater before starting PIT than after starting PIT (2.3 6 1.8 versus 1.1 6 2.2, P ! .05). The mean number of hospital admissions from exacerbation of heart failure symptoms decreased after starting PIT (2.1 6 1.3 versus 0.6 6 0.8, P ! .05). Mean EF% in patients with systolic dysfunction improved while on therapy (30 6 14% before versus 39 6 16% after, P ! .05). There was 1 death and 5 complications in 2 patients. Six patients were successfully bridged to transplantation. Conclusion: Outpatient continuous parenteral inotropic therapy may serve as a successful bridge to cardiac transplantation in selected pediatric outpatients. Key Words: Pediatric, heart failure, inotrope, transplant.
parenteral inotropic therapies have been used successfully as a method of alleviating symptoms and bridging patients to cardiac transplantation.1–5 To date, no data exist regarding the use of outpatient inotropic infusions in children with advanced heart failure. In fact, there is no evidence that intravenous inotropes improve symptoms or alter mortality in children hospitalized with decompensated heart failure. Nevertheless, anecdotal experience in pediatric and adult populations have led physicians to routinely treat symptomatic children with intravenous inotropic agents. At our institution, we have used continuous low-dose dopamine and milrinone infusions in selected pediatric outpatients with advanced heart failure to alleviate their symptoms and bridge them to transplantation. We have also speculated that relieving symptoms in this manner would lead to fewer emergency department visits and hospital admissions. The purpose of this study was to review and report our experience using outpatient inotropic agents in children.
Advanced heart failure in children is characterized by worsening symptoms, recurring exacerbations, and frequent emergency department visits and hospital admissions. At end stage, the symptoms of heart failure may become refractory to standard medical therapy. Death is the usual outcome unless the patient undergoes cardiac transplantation. Some patients with decompensated heart failure can receive symptomatic relief with intravenous inotropic agents, only to experience recurrence of symptoms within hours or days of discontinuation of the infusion. Frequently, such ‘‘inotrope-dependent’’ patients are listed for transplantation, and they may require a protracted course of inotropic agents while awaiting a suitable organ. In some adults with chronic heart failure, continuous or intermittent outpatient
From 1Department of Pediatrics (The Lillie Frank Abercrombie Section of Pediatric Cardiology), Baylor College of Medicine, 2Texas Children’s Hospital, Houston, Texas. Manuscript received August 6, 2005; revised manuscript received October 28, 2005; revised manuscript accepted November 1, 2005. Reprint requests: Jack F. Price, MD, Texas Children’s Hospital, 6621 Fannin, MC 19345-C, Houston, TX 77030. 1071-9164/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2005.11.001
Methods Data Collection We reviewed the medical records of all patients who were treated with continuous parenteral inotropic therapy as outpatients at
139
140 Journal of Cardiac Failure Vol. 12 No. 2 March 2006 our institution while awaiting transplantation between February 1999 and January 2005. Any patient older than 21 years of age was excluded from the study. Data collected included patient demographics, type and dose of inotrope used, length of therapy, complications, and the number of emergency department visits and hospital admissions per patient. Preinfusion data were recorded for the same duration that each patient was treated with outpatient inotropic therapy. The most recent estimated ejection fraction measured before starting therapy was compared to the last echocardiogram performed during therapy.
Table 1. Patient Characteristics at Initiation of Inotropic Therapy Age Patient (years)
NYHA Class
Sex
b-blocker, ACEI, diuretic digoxin, ACEI, diuretic, amio
11.7
IV
M
TCAD
2
15.8
IV
M
3
15.8
IV
F
4
16.0
IV
F
5
20.2
III
M
6
13.7
III
M
7
8.5
IV
M
Tricuspid atresia, s/p Fontan Complex digoxin, ACEI, heterotaxy, diuretic s/p Fontan TCAD digoxin, ACEI, diuretic CCTGA b-blocker, digoxin, ACEI, diuretic, amio, ICD Aortic b-blocker, ACEI, stenosis diuretic Idiopathic b-blocker, digoxin, DCM ACEI, diuretic, amio, ICD
Follow-up Each patient was seen in follow-up at least monthly in the outpatient heart failure clinic. A home health nurse visited each patient at least once weekly. The doses of inotropic medications were not adjusted during outpatient therapy.
Other Therapies
1
Inpatient Monitoring Parenteral infusions were initiated while patients were hospitalized and continued for at least 48 hours of inpatient monitoring. Patients were discharged home after their medication doses had been optimized and they demonstrated no hemodynamic or symptomatic instability on a fixed infusion rate of parenteral inotropic therapy.
Etiology of HF
HF, heart failure; M, male; F, female; TCAD, transplant coronary artery disease; ACEI, angiotensin-converting enzyme inhibitor; s/p, status post; amio, amiodarone; ICD, implantable cardio defibrillator; CCTGA, congenitally corrected transposition of the great arteries; DCM, dilated cardiomyopathy.
Catheters All lines were single lumen, peripherally inserted central venous catheters. Most common sites of line insertion were the antecubital, basilic and subclavian veins, with sizes varying from 3 to 5 Fr. Portable infusion pumps could be fastened to a patient’s belt or carried by a patient in a hip satchel. Statistical Analysis The Wilcoxon signed-rank test was used to compare the number of emergency department visits, hospital admissions, and ejection fractions before and after starting outpatient therapy. A p value ! .05 was accepted as statistically significant. Results are reported as a mean 6 SD.
at the time of initiation of inotropic therapy included a diuretic (n 5 7), angiotensin-converting enzyme inhibitor (n 5 7), digoxin (n 5 5), b-blocker (n 5 4), and amiodarone (n 5 3). Six patients were New York Heart Association functional class III or IV, and all were listed for transplant before the initiation of outpatient inotropic therapy. In addition, all patients had been treated with oral medications for at least 4 months before starting parenteral therapy. There was a history of ventricular tachycardia in 3 patients, 2 of whom had received implantable cardioverter defibrillators (ICD). Inotropic Therapy
Results Patient Characteristics
Seven patients were treated with parenteral inotropic therapy as outpatients during the study period. Table 1 illustrates study patient characteristics. Mean age was 14.5 6 3.7 years. The etiology of heart failure included congenital heart disease (n 5 4), ischemic cardiomyopathy (n 5 2), and idiopathic dilated cardiomyopathy (n 5 1). Of the 4 patients with heart failure from congenital heart disease, 2 had undergone staged surgical palliation with a total cavopulmonary anastomosis, and 1 had congenitally corrected transposition. All 3 had developed progressive systemic ventricular systolic dysfunction. One patient who was treated for diastolic dysfunction also had pulmonary hypertension, with a history of aortic valve stenosis that had been repaired surgically. Milrinone was started in that patient for its lusitropic properties.6 The 2 patients with ischemic cardiomyopathy had developed post-transplant coronary artery disease and ventricular dysfunction. Oral agent therapy
Inotropic medications used for PIT included dopamine alone (n 5 1), milrinone alone (n 5 4), and dopamine and milrinone in combination (n 5 2). The mean dose of dopamine used was 2.8 6 0.3 mcg$kg$minute. The mean dose of milrinone was 0.25 6 0.03 mcg$kg$minute. The total duration of therapy was 1386 patient days, with a mean of 198 days (range 27–588 days) (Table 2). Emergency Department Visits and Hospital Admissions
The mean number of emergency department visits per patient was greater before starting outpatient therapy than after starting therapy for the same duration (2.3 6 1.8 before infusion versus 1.1 6 2.2 during infusion, P ! .05) (Table 3). Similarly, the mean number of cardiac hospital admissions was reduced after beginning parenteral therapy (2.1 6 1.3 before infusion versus 0.6 6 0.8 during infusion, P ! .05) (Table 3). The total number of cardiac admissions decreased by 71% during outpatient therapy. The change in mean number of all-cause hospital admissions was not
Outpatient Inotropes in Pediatric Heart Failure
Price et al
141
Table 2. Inotropic Therapy and Complications Patient 1 2 3 4 5 6 7
Inotrope and Dose (mcg$kg$min) Milrinone 0.3 Milrinone 0.2 DA 3.0 and milrinone 0.25 Milrinone 0.2 DA 3.0 Milrinone 0.3 DA 2.5 and milrinone 0.25
Length of Therapy 27 days 50 days 588 days 111 days 392 days 98 days 56 days
Complications
Outcome
None Died at home Occlusion; extravasation (twice) None Leaking catheter; infection None None
Transplant Sudden death Transplant Transplant Transplant Transplant Transplant
DA, dopamine.
significant (2.1 6 1.3 before infusion versus 1.3 6 1.8 during infusion, P 5 .06). Ejection Fraction
Estimated ejection fraction could be calculated in 6 patients. The mean estimated ejection fraction improved during outpatient therapy (30 6 14% before infusion versus 39 6 16% during infusion, P ! .05) (Fig. 1). Catheter Complications
Five catheter complications occurred in 2 patients. These included catheter occlusion (n 5 1), extravasation of the catheter (n 5 2) requiring removal and replacement, and leaking catheter (n 5 1). One patient developed a central line infection. Blood cultures grew alpha hemolytic streptococcus, and the patient was treated with intravenous antibiotics for 10 days after removal of the infected line. A new catheter was placed and inotropic therapy was continued after completion of antibiotic therapy. Outcome
One patient died suddenly at home during parenteral therapy. That patient had undergone a Fontan procedure and had a history of nonsustained ventricular tachycardia for which he was being treated with oral amiodarone. He did not receive an ICD because he was not a candidate for a transvenous system, and the risk associated with surgical placement of an epicardial system was thought to be too great. His last documented episode of ventricular tachycardia occurred 8 weeks before beginning outpatient lowdose milrinone. Although the family was informed of the risks involved, they preferred to wait at home. Two other patients also had a history of ventricular tachycardia and received ICDs before beginning outpatient parenteral therapy. Interrogation of their ICDs demonstrated no device discharges. The 6 surviving patients were maintained on parenteral inotropic therapy until a suitable organ became available and they could then undergo cardiac transplantation.
children. This therapeutic regimen of low-dose dopamine or milrinone appeared to improve heart failure symptoms sufficiently to reduce the frequency of emergency department visits and heart failure related hospital admissions. Ventricular systolic function also improved during outpatient parenteral therapy. Moreover, all patients but 1 were successfully bridged to cardiac transplantation. Outpatient inotropic therapy has become an accepted treatment method for selected adults with end-stage heart failure and inotrope-dependence, both as a bridge to cardiac transplantation and as hospice care. Although intermittent dosing has been more frequently reported, continuous infusions of dopamine, dobutamine and milrinone have been demonstrated to be safe, effective, and cost saving.7–18 Adult candidates for outpatient inotropic therapy are usually characterized as symptomatic at rest and refractory to maximal outpatient medical therapy. Most have experienced a recurrence of their symptoms with attempts at withdrawal from inotropic therapy and require frequent hospitalizations for treatment of symptomatic exacerbations. After starting intravenous inotropes in the outpatient setting, adult patients frequently report symptomatic relief and require fewer emergency department visits, hospital admissions, and days spent in the hospital.13,19 As with adults, this cohort of pediatric patients usually described having heart failure symptoms at rest or with minimal exertional activity. They had all been hospitalized at least once for intravenous therapy prior to receiving outpatient parenteral therapy and they were all listed for cardiac transplantation (Class IB). All but 1 (the patient with diastolic dysfunction) developed recurrence of their symptoms when the inotrope(s) were discontinued or weaned. Reports of symptomatic improvement were not well documented; however, emergency department visits and hospital admissions decreased during outpatient parenteral therapy,
Table 3. Mean Emergency Department Visits, All-Cause, and Cardiac Admissions
Discussion These data represent the first reported use of outpatient parenteral inotropic therapy for advanced heart failure in
Emergency department visits All-cause hospital admissions Cardiac admissions
Before Infusion
During Infusion
P Value
2.3 6 1.8 2.1 6 1.3 2.1 6 1.3
1.1 6 2.2 1.2 6 1.8 0.6 6 0.6
!.05 .06 !.05
142 Journal of Cardiac Failure Vol. 12 No. 2 March 2006 70%
Ejection fraction
60% 50% 40% 30% 20% 10% 0%
Before infusion
During infusion
Fig. 1. Change in estimated ventricular ejection fraction from before starting outpatient therapy to during outpatient therapy (30 6 14% vs. 39 6 16%, P 5 .04).
suggesting that patients received some degree of symptomatic relief. Of those admissions that occurred during outpatient therapy, 44% were due to exacerbations of cardiac symptoms. The remaining admissions were related to problems with the catheters. Ventricular ejection fraction also improved during continuous inotropic infusions, although not necessarily a marker of improved symptomatology. Catheter complications occurred in only 2 patients. One patient became bacteremic during parenteral therapy but was never septic. Partial extravasation of a catheter occurred twice in the same patient, with no untoward hemodynamic effect. If a catheter was temporarily disabled, the patient was admitted to the hospital and continued on their inotropic agent using a peripheral IV until a new venous catheter could be placed. Three patients had ventricular tachycardia documented by Holter monitoring before initiation of outpatient inotropic therapy. One died suddenly at home, 50 days after outpatient therapy was initiated. The child who died was the only patient with ventricular tachycardia who did not receive an ICD. His death was believed to be related to arrhythmia. Although studies in adults with symptomatic heart failure have demonstrated reduced incidence of sudden cardiac death with the use of ICDs, data are lacking in children.20 A case series of pediatric patients awaiting cardiac transplantation attributed up to 25% of deaths to arrhythmia.21 Primary prevention strategies are the subject of ongoing research in children.22 Our current practice is to refer all patients with advanced heart failure and documented ventricular tachycardia for ICD implantation if they are to be discharged home. Patients who meet criteria for ICD implantation, but in whom implantation carries a high risk, are no longer considered candidates for outpatient inotropic therapy. We used low doses of dopamine and milrinone in this cohort in order to provide a degree of symptomatic relief while minimizing the potential risks associated with higher doses of inotropes. Patients tolerated these infusion rates and the doses were not adjusted during outpatient therapy. Oral medications were also well tolerated during followup and could be uptitrated without difficulty.
Normally, we do not discharge our inotrope-dependent transplant candidates home to wait for a suitable organ. However, several medical and social factors reassured us that it would be safe to send these particular patients home while receiving inotropic therapy. None of the patients required a prolonged intensive care unit stay during their hospitalization, and each patient’s symptoms improved during inotropic therapy such that they were all New York Heart Association class II or III before discharge. All patients were receiving and tolerant of standard care oral medical therapy. In addition to having stable hemodynamics while treated with inotropic infusions as inpatients, these children needed to have reliable parents with dependable transportation who lived relatively close to the hospital to ensure good follow-up. These particular patients were older than most of our hospitalized pediatric heart failure patients and we considered them mature enough to alert a parent or home health nurse of a catheter-related problem. We also required at least weekly home health nursing visits for inspection of the catheter and assessment of the patient. In addition, each patient was seen in follow-up in our heart failure clinic no less frequently than every 4 weeks. Our pretransplant heart failure patients do not normally receive regular home nursing visits and assessments; this likely contributed to the clinical improvement observed in this cohort. Finally, we believe that this therapy should be reserved for children with recurrent heart failure symptoms or inotropic sensitive pulmonary hypertension who have received standard maximal oral therapy and are awaiting heart transplant. A treatment regimen including b-blockers and angiotensin-converting enzyme inhibitors, as well as amiodarone, ICDs, and frequent follow-up was the foundation that allowed for survival in this cohort. Outpatient inotropic therapy appeared to improve their symptoms and may have contributed to successful bridge to transplantation. Conclusion
Continuous outpatient parenteral inotropic therapy was well tolerated in this cohort of children with advanced heart failure and may have provided a successful bridge to cardiac transplantation. Symptoms of heart failure appeared to improve during therapy and complications were few. Mortality did not exceed the reported frequency of mortality in pediatric patients awaiting cardiac transplantation. This form of therapy may provide selected patients with sustained symptomatic relief while awaiting transplantation.
References 1. Hodgson JM, Aja M, Sorkin RP. Intermittent ambulatory dobutamine infusions for patients awaiting cardiac transplantation. Am J Cardiol 1984;53:375–6. 2. Miller LW, Merkle EJ, Herrmann V. Outpatient dobutamine for endstage congestive heart failure. Crit Care Med 1990;18:S30–3.
Outpatient Inotropes in Pediatric Heart Failure 3. Collins JA, Skidmore MA, Melvin DB, Engel PJ. Home intravenous dobutamine therapy in patients awaiting heart transplantation. J Heart Lung Transplant 1990;9:205–8. 4. Young JB, Moen EK. Outpatient parenteral inotropic therapy for advanced heart failure. J Heart Lung Transplant 2000;19:S49–57. 5. Sindone AP, Keogh AM, Macdonald PS, McCosker CJ, Kaan AF. Continuous home ambulatory intravenous inotropic drug therapy in severe heart failure: safety and cost efficacy. Am Heart J 1997;134: 889–900. 6. Monrad ES, McKay RG, Balm DS, et al. Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone. Circulation 1984;70:1030–7. 7. Applefeld MM, Newman KA, Grove WR, et al. Intermittent, continuous dobutamine infusion in the management of congestive heart failure. Am J Cardiol 1983;51:455–8. 8. Roffman DS, Applefeld MM, Grove WR, et al. Intermittent dobutamine hydrochloride infusions in outpatients with chronic congestive heart failure. Clin Pharm 1985;4:195–9. 9. Krell MJ, Kline EM, Bates ER, et al. Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure. Am Heart J 1986;112:787–91. 10. Applefeld MM, Newman KA, Sutton FJ, et al. Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients. Am Heart J 1987;114: 589–95. 11. Miller LW. Outpatient dobutamine for refractory congestive heart failure: advantages, techniques and results. J Heart Lung Transplant 1991; 10:482–7. 12. Erlemeier H, Kupper W, Bleifeld W. Intermittent infusion of dobutamine in the therapy of severe congestive heart failuredlong-term effects and lack of tolerance. Cardiovasc Drugs Ther 1992;6:391–8.
Price et al
143
13. Marius-Nunez AL, Heaney L, Fernandez RN, et al. Intermittent inotropic therapy in an outpatient setting: A cost-effective therapeutic modality in patients with refractory heart failure. Am Heart J 1996;132:805–8. 14. Cesario D, Clark J, Maisel A. Beneficial effects of intermittent home administration of the inotrope/vasodilator milrinone in patients with end-stage congestive heart failure: a preliminary study. Am Heart J 1998;135:121–9. 15. Hershberger RE, Nauman D, Walker TL, Dutton D, Burgess D. Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure. J Cardiac Fail 2003;9:180–7. 16. Upadya S, Lee FA, Saldarriaga C, et al. Home continuous positive inotropic infusion as a bridge to cardiac transplantation in patients with end-stage heart failure. J Heart Lung Transplant 2004;23:466–72. 17. Leier CV, Huss P, Lewis RP, et al. Drug-induced conditioning in congestive heart failure. Circulation 1982;65:1382–7. 18. Miller LW, Merkle EJ, Jennison SH. Outpatient use of dobutamine to support patients awaiting heart transplantation. J Heart Lung Transplant 1994;13:S126–9. 19. Harjai KJ, Mehra MR, Ventura HO, et al. Home inotropic therapy in advanced heart failure: cost analysis and clinical outcomes. Chest 1997;112:1298–303. 20. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. 21. Rosenthal DN, Dubin AM, Chin C, et al. Outcome while awaiting heart transplantation in children: a comparison of congenital heart disease and cardiomyopathy. J Heart Lung Transplant 2000;19:751–5. 22. Dubin AM, Berul CI, Bevilacqua LM, et al. The use of implantable cardioverter-defibrillators in pediatric patients awaiting heart transplantation. J Card Fail 2003;9:375–9.