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Propranolol treatment of congestive heart failure in infants with congenital

heart disease: The CHF-PRO-INFANT Trial. Congestive heart failure in infants
treated with propanol

Article  in  International Journal of Cardiology · August 2001

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 International Journal of Cardiology 1 (2001) 000–000
4 www.elsevier.com / locate / ijcard

11 Propranolol treatment of congestive heart failure in infants with congenital

12 heart disease: The CHF-PRO-INFANT Trial

13 Reiner Buchhorn a , *, Martin Hulpke-Wette a , Reinhard Hilgers b , Dietmar Bartmus a , Armin Wessel a ,
a
14 ¨
Joachim Bursch
a
15 ¨
Abteilung Padiatrische ¨ Gottingen
Kardiologie, Georg-August-Universitat ¨ ¨
, Robert-Koch Str. 40, D-37075 Gottingen , Germany
b
16 ¨
Department of Medical Statistics, Robert-Koch-Str. 40, 37075 Gottingen , Germany

17 Received 24 October 2000; received in revised form 23 January 2001; accepted 14 February 2001

18

19 Abstract

20 Aim: Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure
21 in spite of therapy with digoxin and diuretics. We investigated the effects of b-blockade in infants with severe heart failure. Methods and
22 results: We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n510) in
23 comparison to 10 infants receiving additional b-blocker therapy. After 17 days on average b-blocker treated infants (propranolol:1,6
24 mg / kg / day) improved significantly with respect to Ross heart failure score (3.362.3 vs. 8.361.9, P50.002), lower renin levels
25 (3386236 vs. 7046490 mU / l, P50.008) and lower mean heart rates in Holter ECG (118610 vs. 142611 beats / min, P,0.001). While
26 digoxin and diuretic treated infants had unchanged mean heart rate (14968 vs. 148610 beats / min), less decrease of symptoms (Ross
27 Score: 8.561.7 vs. 6.862.3, P50.02) but a significant increase of renin levels (1396102 vs. 9386607 mU / l, P50.001). Conclusion:
28 Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants
29 with congenital heart disease, who suffer from increased neurohormonal activation.  2001 Published by Elsevier Science Ireland Ltd.

30 Keywords: Heart failure; Pediatrics; Trials; Drugs; Heart septal defects

31

32 1. Introduction therapy by Waagstein et al. in 1975 [7], showed 41

significant clinical benefits in adults with myocardial 42
33 The prevalence of heart failure in patients with failure as shown in large, prospective, randomized 43
34 congenital heart disease is as high as 20%, but studies [8,9] and a small trial in children with 44
35 prospective clinical studies of the medical treatment cardiomyopathies [10]. Recently, we reported about 45
36 are limited. Moreover the small, most of all re- the favorable preliminary results of b-blocker treat- 46
37 trospective studies showed contradictory results for ment in six infants with severe congestive heart 47
38 digitalis [1–4] and angiotensin converting enzyme failure due to left-to-right shunts [11]. Consequently, 48
39 inhibitors [5,6]. we performed the prospective, randomized CHF- 49
40 Beta-blocker treatment, introduced in heart failure PRO-INFANT (Congestive heart failure in infants 50
treated with propranolol) trial in order to confirm the 51
effects of b-blockade with propranolol on clinical 52
5 *Corresponding author. Tel.: 149-551-396-204; fax: 149-551-392-
6 560. signs of heart failure, neurohormonal activation and 53
7 E-mail address: rbuchho@gwdg.de (R. Buchhorn). hemodynamics. This paper focuses on the clinical, 54

1 0167-5273 / 01 / $ – see front matter  2001 Published by Elsevier Science Ireland Ltd.
127 2 R. Buchhorn et al. / International Journal of Cardiology 1 (2001) 000 – 000

81 laboratory and noninvasively obtained hemodynamic achieved. Nine patients coming from outward hospi- 102
82 data during the 1st month of treatment while dosage tals had a Ross score of more than 6 points despite 103
83 was titrated. receiving digitalis and diuretics at trial entry. They 104
were randomized to additional propranolol (n56) and 105
three patients remaining on mere digoxin / diuretics 106
84 2. Methods treatment. 107
Propranolol dosage was increased in 17 days 108
85 2.1. Trial design starting with 1 mg / kg / day aiming at a final dosage of 109
2 mg / kg / day. Clinical response and heart rate guided 110
86 The CHF-PRO-INFANT trial was a prospective, titration of dosage. After reaching the target dose 111
87 randomized, open trial in infants with congenital (digoxin: serum level .0.9 nmol / l; propranolol: a 112
88 heart disease and severe heart failure due to left-to- mean heart rate of 110–120 / min) heart failure score, 113
89 right shunts (Table 1). It conforms with the Declara- hemodynamic measurements by echocardiography, 114
90 tion of Helsinki II and the Note for Guidance on 24 h Holter ECG and clinical laboratory were de- 115
91 Clinical Investigation of Medicinal Products in Chil- termined. 116
92 dren (CPMP/ EWP/ 462 / 95). The local ethics com-
93 mittee approved the protocol. Informed consent was 2.3. Clinical parameters 117
94 obtained.
Severity of congestive heart failure was estimated 118
95 2.2. Patients by the Ross Score [12], which bases on following 119
variables: amount of formula consumed per feeding, 120
96 Twenty infants with an age up to 3 months referred feeding time, respiratory rate and pattern, heart rate, 121
97 to our hospital between 9 / 1997 and 2 / 2000, exceed- peripheral perfusion, diastolic filling sounds and 122
98 ing a score of 6 points using Ross heart failure score hepatomegaly. Modifying the Ross Score slightly 123
99 [12], entered the trial (Fig. 1). The patients were patients who needed a nasogastric feeding-tube be- 124
100 randomized and received digoxin / diuretics therapy cause they were not able to drink an adequate amount 125
101 during a run in phase of 1 week until loading was of formula were scored with 4 points. Two physicians 126

55 Table 1
56 Cardiac and extracardiac diagnosis of patients at study entry a
57
58 Group Cardiac diagnosis Extracardiac diagnosis Operation
59
60 Digoxin / Diuretics Three infants with VSD
61 VSD, Ao-PA Window
62 AVSD
63 AVSD, CoA M.Down CoA repair, PAB
64 AVSD Duodenalstenosis, M.Down Bowel resection
65 AVSD M.Down
66 AVSD Tuberous sclerosis
67 DILV, L-TGA, PS

68 Propranolol Two infants with VSD

69 AVSD
70 ASD, VSD M.Down
71 AVSD M.Down
72 AVSD Duodenalstenosis, M.Down Bowel resection
73 Unbalanced AVSD, CoA Cheilognathopalatoschisis CoA repair, PAB
74 PVA, VSD RV-PA-Conduit
75 TA IB Ao-PA-Shunt
76 TA IC
77
a
78 VSD, Ventricular Septal Defect; ASD, Atrial Septal Defect; AVSD, Atrioventricular Septal Defect; CoA, Aortic Coarctation; PAB, Pulmonary Artery
79 Banding; PVA, Pulmonary Valve Atresia; RV-Pa-Conduit, Valveless Right Ventricular to Pulmonary Artery Conduit; Ao-PA, Aortic to Pulmonary
80 Shunt / Window; TA, Tricuspid Valve Atresia.
181 R. Buchhorn et al. / International Journal of Cardiology 1 (2001) 000 – 000 3

129

130 Fig. 1. Flowchart of CHF-PRO-Infant trial. Trial entry Run in phase with digoxin and Final treatment groups. (N=20) diuretic therapy during first week
131 according to randomization.

132 independently determined the Ross Score 3–5 h after 2.6. Processing and analysis of 24 -h holter 155
133 last medication. recordings and heart rate variability 156

Twenty-four-h Holter recordings using two-chan- 157

134 2.4. Neurohormonal activity and clinical laboratory nel recorders were obtained at trial entry, after the 158
run in phase and in those patients, who received 159
135 Venous blood was drawn from non-sedated infants propranolol at the end of the titration period. Since 160
136 by experienced pediatricians during routine blood 3 / 1998 heart rate variability was analyzed additional- 161
137 specimen collection. Norepinephrine and epinephrine ly in order to estimate sympathetic activation during 162
138 levels were measured by high-performance liquid treatment using a MARS 5000  Holter analysis 163
139 chromatography with fluorescence detection [16]. system (Marquette Hellige Medical systems, Mil- 164
140 Renin-, and aldosterone concentrations were deter- waukee, WI, USA). 165
141 mined with commercially available immuno- Heart rate variability parameters were interpreted 166
142 radiometric assays (Nichols Institute Diagnostika according to the standards of the Task Force of the 167
143 GmbH, Bad Nauheim, Germany). European Society of Cardiology and the North Amer- 168
ican Society of Pacing and Electrophysiology [14]. 169
Normal values in infants were taken from a previous 170
144 2.5. Hemodynamic parameter and ventricular trial [15]. 171
145 function
2.7. Statistical analysis 172
146 Systemic and pulmonary blood flow as well as
147 flow ratio were measured noninvasively, using Dop- We analyzed intra individual effects of digoxin and 173
148 pler velocimetry and 2-dimensional echocardiography diuretics in 11 infants without medical treatment at 174
149 [13]. Pulmonary blood flow was not measured in trial entry and the effect of additional propranolol 175
150 three infants with pulmonary artery trunk banding or therapy in 10 infants by a paired student t-test. We 176
151 aortic to pulmonary shunts. used a Wilcoxon matched pairs test to analyze the 177
152 Ventricular function was calculated by fractional Ross-Score, neurohormonal and heart rate variability 178
153 area change of the systemic ventricle in 2-dimension- data, as Gaussian distribution of these data cannot be 179
154 al echocardiography. assumed. 180
256 4 R. Buchhorn et al. / International Journal of Cardiology 1 (2001) 000 – 000

202 3. Results indicated by significantly higher creatinine values. 230

The effects of additional b-blockade after a titration 231
203 3.1. Clinical data period are displayed in Table 4. Renin- and aldos- 232
terone values decreased by 50% on an average during 233
204 Patients with significant left-to-right shunts but propranolol treatment, but norepinephrine levels re- 234
205 different morphological diagnosis were included into mained elevated. 235
206 the trial (Table 1). Three palliative surgical pro-
207 cedures were performed in the propranolol group
208 compared to one in digoxin / diuretics therapy group. 3.3. Hemodynamic measurements and ventricular 236
209 Table 2 demonstrates uniform distribution of clinical function 237
210 characteristics in both groups. Merely the age at trial
211 entry was slightly higher in the propranolol group. The mean heart rate in 24 h Holter ECG was not 238
212 We used comparable digoxin and diuretic dosages in influenced by digitalis / diuretics therapy (149611 vs. 239
213 both groups. The mean propranolol dosage of 148610) and was significantly reduced by proprano- 240
214 1.660.6 mg / kg / day was slightly lower than the lol treatment (118610). Fractional area change 241
215 target dose of 2 mg / kg / day propranolol, as two (FAC) increased during digoxin / diuretics therapy 242
216 infants developed bradycardia at higher dosages. significantly (43611 vs. 49610) and remained un- 243
217 One patient developed a severe sepsis after bowel changed under propranolol treatment (52613 vs. 244
218 resection during early titration period of propranolol 5269). However, FAC was normal in all treated 245
219 (0.45 mg / kg / day) and his therapy was stopped at the patient groups. 246
220 intensive care unit. We included his data into our
221 analysis by the time.
3.4. Heart rate variability 247
222 3.2. Neurohormonal activity and clinical laboratory
Compared to healthy controls [15] all time domain 248
223 In the group starting without medication (n511) and frequency domain parameters were reduced 249
224 the effects of digoxin and diuretics are displayed in under digoxin / diuretics therapy (Table 5), but mean 250
225 Table 3. Norepinephrine and aldosterone levels were RR intervals were not reduced. We observed a 251
226 significantly elevated at baseline. The most signifi- significant increase of heart rate variability in eight 252
227 cant side effect of diuretic therapy was an increase of infants treated with propranolol, indicated by sig- 253
228 renin levels by 675% on average and hyponatraemia nificantly higher SDNN, rMSSD, pNN50, total 254
229 that was accompanied by impaired renal function, power, low- and high frequency power. 255

182 Table 2
183 Characteristics and drug therapy of patients after randomization into final treatment groups a
184
185 Digoxin / diuretics Propranolol P-value*
186 (n510) (n510)
187
188 Characteristics
189 Age (weeks) 5.362.4 9.264.5 0.03
190 Sex (M / F) 4/6 4/6
191 Weight (g)b 34006500 38006900 0.2
192 Ross Score b 7.262.4 8.361.9 0.4

193 Drug therapy

194 Digoxin level (nmol / l) 1.360.5 1.360.9
195 Furosemide (mg / kg / d) 2.460.6 2.661.2
196 Spironolactone (mg / kg / d) 3.060.4 3.060.4
197 Propranolol (mg / kg / d) – 1.660.6
198
a
199 6values are means6S.D.
b
200 After institution of digoxin / diuretics.
201 *P-value of unpaired student t-test.
315 R. Buchhorn et al. / International Journal of Cardiology 1 (2001) 000 – 000 5

257 Table 3
258 Effects of digoxin and diuretics therapy after run in phase in 11 patients, who did not receive medication at trial entry a
259
260 Variable No medication Digoxin / Diuretics P-value
261 (n511) (n511)
262
263 Ross Score 8.561.7 6.862.3 0.02
264 Bodyweight (g) 37276491 36066490 0.006

265 Hemodynamic parameter

266 Mean heart rate (beats / min) 14968 148610 0.49
267 Qp / Qs b 5.061.9 5.061.7 0.49
268 FAC c (%) 43611 49610 0.03

269 Neurohormonal parameter

270 Norepinephrine (ng / l) 6666322 127261103 0.7
271 Epinephrine (ng / l) 60657 1176168 0.8
272 Renin (mU / ml) 1396102 9386607 0.001
273 Aldosterone (pg / ml) 143761035 226861538 0.16

274 Clinical laboratory

275 Sodium (mmol / l) 13962 13563 0.002
276 Creatinine (mg / dl) 0.3660.12 0.4760.1 0.002
277
a
278 6values are means6S.D.
b
279 Sytemic (Qs) and pulmonary (Qp) flow, measured by Doppler Echocardiography (infants with a turbulent blood flow in the pulmonary artery were
280 excluded).
c
281 FAC, Fractional area change.

308 4. Discussion severe heart failure due to congenital heart disease, 311
CHF-PRO-INFANT is the first prospective, random- 312
309 More than 40 years after introduction of digoxin ized trial investigating the clinical and neurohormonal 313
310 and diuretics in medical treatment of infants with effects of this therapy. Digoxin / diuretics therapy had 314

282 Table 4
283 Effects of propranolol in comparison to mere digoxin / diuretics treatment, evaluation at the end of propranolol titration phase a
284
285 Variable Digoxin / Diuretics b Propranolol P-value
286 (n510) (n510)
287
288 Ross Score 8.361.9 3.362.3 0.002
289 Bodyweight (g) 38006942 39866838 0.04

290 Hemodynamic parameter

291 Mean heart rate (beats / min) 142611 118610 ,0.001
292 Qp / Qs c 4.361.7 3.461.5 0.3
293 FAC d (%) 52613 5269 0.7

294 Neurohormonal parameter

295 Norepinephrine (ng / l) 13036666 9976576 0.07
296 Epinephrine (ng / l) 2326390 1976324 0.1
297 Renin (mU / ml) 7046490 3386236 0.008
298 Aldosterone (pg / ml) 15656896 9216586 0.016
299 Clinical Laboratory
300 Sodium (mmol / l) 13562 13863 0.1
301 Creatinine (mg / dl) 0.4860.04 0.4360.07 0.07
302 Blood Glucose (mg / dl) 75615 74617 0.2
303
a
304 6values are means6S.D.
b
305 Data were determined during digoxin / diuretics one day before starting propranolol.
c
306 Sytemic (Qs) and pulmonary (Qp) flow, measured by Doppler Echocardiography.
d
307 FAC, Fractional area change.
412 6 R. Buchhorn et al. / International Journal of Cardiology 1 (2001) 000 – 000

316 Table 5 pranolol effectively reduced sympathetic activation in 369

317 Effect of digoxin / diuretics and propranolol on heart rate variability a,b
318 these infants indicated by a significant fall of mean 370
319 Variable Healthy control Digoxin / diuretics Propranolol heart rate and an increase of heart rate variability. 371
320 (n570) [15] (n512) (n58)
321 These results demonstrate discrepancies between 372
322 Mean NN (ms) 437640 438640 509651**
the hemodynamic model of heart failure and the 373
323 Time domain neurohormonal model [18]. Leading symptoms of 374
324 SDNN (ms) 57619 35611*** 46620* heart failure like tachypnea and cardiac dystrophy are 375
325 rMSSD (ms) 2269 1365*** 25615* probably explainable by neurohormonal activation 376
326 pNN50 (%) 2.162.8 0.862.0*** 9.0613.0*
but not by hemodynamic indices. As recently demon- 377
327 Frequency domain strated in adults with chronic heart failure an aug- 378
328 VLF (ms) 26.067.1 9.066.1*** 15.368.9 mented peripheral chemosensitivity due to autonomic 379
329 LF (ms) 17.565.1 6.164.0*** 14.7611.6*
330 HF (ms) 10.065.1 4.563.5*** 10.5611.7* imbalance could be the pathophysiological mecha- 380
331 LF / HF 1.860.3 1.560.7 1.760.7 nism responsible for tachypnea. It can be detected by 381
332
333 a
6values are means6S.D. elevated norepinephrine levels and a reduced heart 382
334 b
Mean NN, Mean value of all normal RR intervals during 24 h; rate variability [19]. Similarly failure to thrive is 383
335 SDNN, Standard deviation of all NN intervals; pNN50, Number of pairs more closely associated with hormonal changes than 384
336 of adjacent NN intervals differing by more than 50 ms divided by the
337 total number of all NN intervals; rMSSD, The square root of the mean of with conventional measures of the severity in conges- 385
338 the sum of the squares of differences between adjacent NN intervals; tive heart failure [20]. 386
339 VLF, Very low frequency power spectrum between 0.003 and 0.04 Hz; Based on the neurohormonal model of heart failure 387
340 LF, Low frequency power spectrum between 0.04 and 0.15 Hz; HF, High
341 frequency power spectrum between 0,15 and 0.4 Hz; LF / HF ratio, Ratio
the significant clinical benefits of propranolol in 388
342 of low to high frequency power. infants with left-to-right shunts are explainable by the 389
343 Statistical differences of digoxin / diuretics in comparison to healthy beneficial effect of b-blockade of the highly activated 390
344 control and propranolol in comparison to digoxin / diuretics indicated as: sympathetic and renin-angiotensin-aldosterone sys- 391
345 *P50.01–0.05; **P50.001–0.01; ***P,0.001.
tem. There was no evidence for side effects of 392
propranolol on ventricular function or hemody- 393
346 beneficial effect on ventricular function in accordance namics. 394
347 with previous trials [1,3], but clinical benefit accord-
348 ing to Ross score was limited (Tables 3 and 4). Mean 4.1. Limitations 395
349 heart rate was not reduced by digoxin. As serious
350 side effects, diuretics induced a considerable renin The trial was neither placebo controlled nor double 396
351 release and hyponatraemia with laboratory signs of blinded. It would have been unethical to give infants 397
352 impaired renal function, indicated by higher with severe heart failure a placebo. It is not useful to 398
353 creatinine values. blind an infant and of very limited use to blind an 399
354 In propranolol treated infants we observed a sig- investigator who easily can identify a b-blocker 400
355 nificant improvement of clinical symptoms according treated patient by looking at changes in mean heart 401
356 to Ross score, which cannot be explained by hemo- rate. The subset of nine patients already receiving 402
357 dynamic benefits. medication at study entry may represent a subset of 403
358 A higher mean heart rate in 24 h Holter ECG at patients who had more severe heart failure although 404
359 trial entry and during digoxin / diuretics therapy seem Ross score was not significantly higher (Table 2). 405
360 to be an important risk factor of heart failure symp- They were distributed by randomization on proprano- 406
361 toms in accordance with a previous trial, that also lol (n56) and digoxin / diuretics treatment group (n5 407
362 could not find other hemodynamic correlates of 3). 408
363 clinical severity in infants with ventricular septal
364 defects [17]. Elevated norepinephrine levels and a
365 reduced heart rate variability were evidence for an 5. Conclusions 409
366 autonomic imbalance with sympathetic activation and
367 parasymapthetic withdrawal in these infants. Al- Medical therapy of congenital heart disease re- 410
368 though norepinephrine levels remained elevated pro- mains purely a bridge to surgery. However, persistant 411
491 R. Buchhorn et al. / International Journal of Cardiology 1 (2001) 000 – 000 7

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