Cardiology in the Young (2015), 25, 56–62
© Cambridge University Press, 2013
doi:10.1017/S1047951113001522
Original Article Efficacy of very low-dose prostaglandin E1 in duct-dependent congenital heart disease Ilker K. Yucel, Ayhan Cevik, Mustafa O. Bulut, Reyhan Dedeoğlu, İbrahim H. Demir, Abdullah Erdem, Ahmet Celebi Department of Pediatric Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Center and Research Hospital, İstanbul, Turkey Abstract Aim: The present study aims to define the lowest effective prostaglandin E1 dose in patients with inadequacy of pulmonary blood flow and/or intracardiac blood mixing and those with inadequate systemic blood flow. Methods: Patients with inadequacy of both pulmonary blood flow and/or blood mixing (Group 1) and those with inadequate systemic blood flow (Group 2) were retrospectively evaluated in two separate groups with regard to the prostaglandin E1 starting dose given in the referring facility, the lowest and the highest dose administered in our centre, treatment duration, adverse effects, and administered treatment. Results: No difference between the groups could be detected with respect to sex or birth weight (p = 0.95 and 0.42, respectively). Group 1 and Group 2 were statistically similar in aspect of prostaglandin treatment duration (9.73 ± 0.81 days versus 11.6 ± 1.05 days, p = 0.064). When compared with Group 2, the initial, maintenance and lowest efficient doses of prostaglandin E1 treatment were significantly lower and the titrated dose of prostaglandin E1 was significantly higher in Group 1 (p = 0.001 for each). Conclusion: Our findings indicate that the infusion of prostaglandin at a very low dose (0.003–0.005 mcg/kg/minute) is sufficient to maintain the patency of the ductus arteriosus. A higher dose of prostaglandin E1 may be necessary in patients with inadequate systemic blood flow. Keywords: Prostaglandin E1; congenital heart disease; efficacy; neonatal transport Received: 04 June 2013; Accepted: 28 August 2013; First published online: 29 October 2013
N DUCTUS-DEPENDENT CONGENITAL HEART DISEASE, ductal occlusion leads to disorders of end-organ perfusion and tissue oxygenation through inadequacy of pulmonary flow and intracardiac mixing. Keeping the patency of ductal communication is of vital importance for providing the time necessary to establish an anatomic diagnosis until the surgical or non-surgical intervention can be performed.1,2 Owing to the fact that it is well known that prostaglandin E1 treatment effectively keeps the ductal patency, it is widely used before either open surgery or transcatheter procedure is carried out.3–7 Patients with
I
Correspondence to: A. Cevik, Department of Pediatric Cardiology, Dr. Siyami Ersek Chest, Heart and Vessel Surgery Teaching and Research Hospital, Istanbul, Turkey, Tıbbiye Caddesi, No. 13, Haydarpaşa, Istanbul, Turkey. Tel: 0905326571042; Fax: 02163125626; E-mail: [email protected]
a suspected or established diagnosis of ductus-dependent congenital heart disease are exposed to the risks of transportation to a tertiary health-care centre and the side effects of prostaglandin E1 treatment, until they can be given definitive treatment. Prostaglandin E1 treatment entails certain difficulties in managing these patients. Apnoea, hypoventilation, hypotension, vasodilatation, flushing, diarrhoea, seizures, and hyperpyrexia have been reported among the frequent side effects of short-term, standard dose prostaglandin E1 treatment.8,9 Given the need for mechanically assisted ventilation and neonatal intensive care that arose with prostaglandin E1 treatment, different studies explored prostaglandin E1 treatment at a dose lower than the proposed standard, to reduce adverse effects without loss of efficacy.10–13 It is yet unclear, however, how low the dose can be while continuing
Vol. 25, No. 1
Yucel et al: Prostaglandin E1 in duct-dependent congenital heart disease
to keep the patency of the ductus arteriosus, or how low it should be to be devoid of side effects. The objective of the present study was to determine the lowest effective prostaglandin E1 dose that can be given without adverse effects while ensuring ductus arteriosus patency. Prostaglandin E1 treatment at very low doses may ensure both protection from possible side effects and safe transportation to a tertiary care centre.
Materials and methods Study design The present study retrospectively reviews the records of patients who received prostaglandin E1 infusion after being referred to the study centre between January, 2011 and July, 2012 for interventional heart catheterisation or open surgery because of a diagnosis of ductus-dependent congenital heart disease. Neonates who were younger than 14 days and who had duct-dependent congenital heart disease were included, whereas the remaining were excluded neonates older than 14 days. The recruited patients were allocated into two groups: those with insufficiency of pulmonary blood flow and/or blood mixing (Group 1) and those with insufficient systemic blood flow (Group 2). Records of patients referred to our centre between January, 2011 and July, 2012 for interventional heart catheterisation or open surgery with a diagnosis of ductus-dependent congenital heart disease, who had received prostaglandin E1 infusion, were reviewed for the study. Neonates with duct-dependent congenital heart disease were part of the study if younger than 14 days. The following patients were excluded: neonates older than 14 days; patients necessitating mechanical ventilation or assisted breathing; those with a defect ensuring sufficient intracardiac mixing; patients whose duct-dependent congenital heart disease diagnosis could not be confirmed by echocardiography; neonates who received treatment, intra venously or inhaled, other than prostaglandin E1 – inotropic treatment, oxygen, intravenous fluid for treatment – during transportation; and patients who had undergone balloon atrioseptostomy. Patients were retrospectively evaluated after being allocated to one of two main groups: those with insufficiency of pulmonary blood flow and/or blood mixing (Group 1) and those with insufficient systemic blood flow (Group 2). Patients were later distributed in three groups for evaluation of specific subgroups: Group A: Complete transposition of the great arteries; Group B: Pulmonary flow insufficiency; Group C: Systemic flow insufficiency. Local Ethics Committee approval was obtained before the study.
57
Echocardiographic examinations The paediatric cardiology team at the neonatal intensive care unit of the study centre performed transthoracic echocardiography examination for all of the recruited neonates. In addition to ductal morphology, the degree of support by the ductus arteriosus to pulmonary and systemic circulation was determined to evaluate the patients in distinct groups of ductus-dependent congenital heart disease. Echocardiographic examination was performed with Vivid 3 Pro Echo devices (General Electric Medical Systems, Horten, Norway) using 3 and 7 MHz probes. Images were obtained through a high parasternal imaging window, using a direct inferior or slightly superior position by effecting a counterclockwise rotation in the left second to third intercostal space. Images were acquired by effecting a clockwise or counterclockwise rotation while visualising the aortic arch along its long axis – left or right, according to the direction of the aortic arch – alternatively over the right or left clavicle, over the bifurcation of the main and left pulmonary arteries.14 Ductal morphology was defined by minimal and maximal intraluminal diameter measurements by two-dimensional echocardiography. The smallest measurement obtained at the pulmonary end of the ductus arteriosus by colour-Doppler mapping was defined as ductal diameter.15 The lowest effective prostaglandin E1 dose was defined by periodic serial measurements obtained during prostaglandin E1 treatment, after basal measurements. A narrowing to 0.05 for all) (Table 2). The initial dose and the lowest efficient dose of prostaglandin E1 was significantly higher in Group C, whereas the maintenance dose was significantly higher in Group B (p = 0.001 for each).
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Yucel et al: Prostaglandin E1 in duct-dependent congenital heart disease
Table 2. Demographic and clinical characteristics of patients according to their diagnostic subgroups.
Age (days) Sex (male/female) Weight (kg) Concomitant abnormality Treatment duration Final O2 saturation Initial dose (mcg/kg/minute) Titrated dose (mcg/kg/minute) Maintenance dose (mcg/kg/minute) Lowest dose (mcg/kg/minute) Surgery/transcatheter intervention Mortality
Group A (n = 35)
Group B (n = 33)
Group C (n = 27)
p-value
4.20 ± 1.58a,b 35/9 3.43 ± 0.36a,d 26/35 (74.2%) 6.4 ± 3.04 82.15 ± 2.09a,b 0.05 ± 0.014b,f 0.03 ± 0.015b,f 0.0038 ± 0.001b,f 0.0040 ± 0.001b,f 2/35 (5.7%) 4/35 (11.4%)
6.66 ± 2.62a,c 33/18 2.99 ± 0.3a,e 5/33 (15.1%) 6.24 ± 3.5 86.18 ± 3.29a,e 0.05 ± 0.02e,f 0.036 ± 0.014e,f 0.043 ± 0.0011e,f 0.0041 ± 0.001e,f 20/33 (60.6%) 4/33 (12.1%)
6.44 ± 1.60b,c 27/10 3.28 ± 0.5d,e 16/27 (59.2) 6.07 ± 2.84 91.5 ± 2.56b,e 0.093 ± 0.017b,e 0.057 ± 0.016b,e 0.010 ± 0.011b,e 0.0054 ± 0.001b,e 3/27 (11.1%) 4/27 (14.8%)
0.001* 0.049* 0.001* 0.313 0.907 0.001* 0.001 0.001* 0.001* 0.001* 0.001* 0.918
*p-values 0.05) d Group A versus Group C not statistically significant (p > 0.05) e Group B versus Group C statistically significant (p < 0.001) f Group A versus Group B not statistically significant (p > 0.05)
Table 3. Correlations between prostaglandin E1 doses and other variables.
Age r p Weight r p Treatment duration r p O2 saturation r p
Initial dose
Maintenance dose
Titrated dose
Lowest dose
0.218 0.034*
0.160 0.120
0.310 0.002*
0.155 0.135
0.084 0.420
0.047 0.649
0.110 0.287
0.049 0.634
0.016 0.877
0.056 0.590
0.011 0.914
0.081 0.433
0.549 0.001*
0.382 0.001*
0.515 0.001*
0.417 0.001*
*p-values
© Cambridge University Press, 2013
doi:10.1017/S1047951113001522
Original Article Efficacy of very low-dose prostaglandin E1 in duct-dependent congenital heart disease Ilker K. Yucel, Ayhan Cevik, Mustafa O. Bulut, Reyhan Dedeoğlu, İbrahim H. Demir, Abdullah Erdem, Ahmet Celebi Department of Pediatric Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Center and Research Hospital, İstanbul, Turkey Abstract Aim: The present study aims to define the lowest effective prostaglandin E1 dose in patients with inadequacy of pulmonary blood flow and/or intracardiac blood mixing and those with inadequate systemic blood flow. Methods: Patients with inadequacy of both pulmonary blood flow and/or blood mixing (Group 1) and those with inadequate systemic blood flow (Group 2) were retrospectively evaluated in two separate groups with regard to the prostaglandin E1 starting dose given in the referring facility, the lowest and the highest dose administered in our centre, treatment duration, adverse effects, and administered treatment. Results: No difference between the groups could be detected with respect to sex or birth weight (p = 0.95 and 0.42, respectively). Group 1 and Group 2 were statistically similar in aspect of prostaglandin treatment duration (9.73 ± 0.81 days versus 11.6 ± 1.05 days, p = 0.064). When compared with Group 2, the initial, maintenance and lowest efficient doses of prostaglandin E1 treatment were significantly lower and the titrated dose of prostaglandin E1 was significantly higher in Group 1 (p = 0.001 for each). Conclusion: Our findings indicate that the infusion of prostaglandin at a very low dose (0.003–0.005 mcg/kg/minute) is sufficient to maintain the patency of the ductus arteriosus. A higher dose of prostaglandin E1 may be necessary in patients with inadequate systemic blood flow. Keywords: Prostaglandin E1; congenital heart disease; efficacy; neonatal transport Received: 04 June 2013; Accepted: 28 August 2013; First published online: 29 October 2013
N DUCTUS-DEPENDENT CONGENITAL HEART DISEASE, ductal occlusion leads to disorders of end-organ perfusion and tissue oxygenation through inadequacy of pulmonary flow and intracardiac mixing. Keeping the patency of ductal communication is of vital importance for providing the time necessary to establish an anatomic diagnosis until the surgical or non-surgical intervention can be performed.1,2 Owing to the fact that it is well known that prostaglandin E1 treatment effectively keeps the ductal patency, it is widely used before either open surgery or transcatheter procedure is carried out.3–7 Patients with
I
Correspondence to: A. Cevik, Department of Pediatric Cardiology, Dr. Siyami Ersek Chest, Heart and Vessel Surgery Teaching and Research Hospital, Istanbul, Turkey, Tıbbiye Caddesi, No. 13, Haydarpaşa, Istanbul, Turkey. Tel: 0905326571042; Fax: 02163125626; E-mail: [email protected]
a suspected or established diagnosis of ductus-dependent congenital heart disease are exposed to the risks of transportation to a tertiary health-care centre and the side effects of prostaglandin E1 treatment, until they can be given definitive treatment. Prostaglandin E1 treatment entails certain difficulties in managing these patients. Apnoea, hypoventilation, hypotension, vasodilatation, flushing, diarrhoea, seizures, and hyperpyrexia have been reported among the frequent side effects of short-term, standard dose prostaglandin E1 treatment.8,9 Given the need for mechanically assisted ventilation and neonatal intensive care that arose with prostaglandin E1 treatment, different studies explored prostaglandin E1 treatment at a dose lower than the proposed standard, to reduce adverse effects without loss of efficacy.10–13 It is yet unclear, however, how low the dose can be while continuing
Vol. 25, No. 1
Yucel et al: Prostaglandin E1 in duct-dependent congenital heart disease
to keep the patency of the ductus arteriosus, or how low it should be to be devoid of side effects. The objective of the present study was to determine the lowest effective prostaglandin E1 dose that can be given without adverse effects while ensuring ductus arteriosus patency. Prostaglandin E1 treatment at very low doses may ensure both protection from possible side effects and safe transportation to a tertiary care centre.
Materials and methods Study design The present study retrospectively reviews the records of patients who received prostaglandin E1 infusion after being referred to the study centre between January, 2011 and July, 2012 for interventional heart catheterisation or open surgery because of a diagnosis of ductus-dependent congenital heart disease. Neonates who were younger than 14 days and who had duct-dependent congenital heart disease were included, whereas the remaining were excluded neonates older than 14 days. The recruited patients were allocated into two groups: those with insufficiency of pulmonary blood flow and/or blood mixing (Group 1) and those with insufficient systemic blood flow (Group 2). Records of patients referred to our centre between January, 2011 and July, 2012 for interventional heart catheterisation or open surgery with a diagnosis of ductus-dependent congenital heart disease, who had received prostaglandin E1 infusion, were reviewed for the study. Neonates with duct-dependent congenital heart disease were part of the study if younger than 14 days. The following patients were excluded: neonates older than 14 days; patients necessitating mechanical ventilation or assisted breathing; those with a defect ensuring sufficient intracardiac mixing; patients whose duct-dependent congenital heart disease diagnosis could not be confirmed by echocardiography; neonates who received treatment, intra venously or inhaled, other than prostaglandin E1 – inotropic treatment, oxygen, intravenous fluid for treatment – during transportation; and patients who had undergone balloon atrioseptostomy. Patients were retrospectively evaluated after being allocated to one of two main groups: those with insufficiency of pulmonary blood flow and/or blood mixing (Group 1) and those with insufficient systemic blood flow (Group 2). Patients were later distributed in three groups for evaluation of specific subgroups: Group A: Complete transposition of the great arteries; Group B: Pulmonary flow insufficiency; Group C: Systemic flow insufficiency. Local Ethics Committee approval was obtained before the study.
57
Echocardiographic examinations The paediatric cardiology team at the neonatal intensive care unit of the study centre performed transthoracic echocardiography examination for all of the recruited neonates. In addition to ductal morphology, the degree of support by the ductus arteriosus to pulmonary and systemic circulation was determined to evaluate the patients in distinct groups of ductus-dependent congenital heart disease. Echocardiographic examination was performed with Vivid 3 Pro Echo devices (General Electric Medical Systems, Horten, Norway) using 3 and 7 MHz probes. Images were obtained through a high parasternal imaging window, using a direct inferior or slightly superior position by effecting a counterclockwise rotation in the left second to third intercostal space. Images were acquired by effecting a clockwise or counterclockwise rotation while visualising the aortic arch along its long axis – left or right, according to the direction of the aortic arch – alternatively over the right or left clavicle, over the bifurcation of the main and left pulmonary arteries.14 Ductal morphology was defined by minimal and maximal intraluminal diameter measurements by two-dimensional echocardiography. The smallest measurement obtained at the pulmonary end of the ductus arteriosus by colour-Doppler mapping was defined as ductal diameter.15 The lowest effective prostaglandin E1 dose was defined by periodic serial measurements obtained during prostaglandin E1 treatment, after basal measurements. A narrowing to 0.05 for all) (Table 2). The initial dose and the lowest efficient dose of prostaglandin E1 was significantly higher in Group C, whereas the maintenance dose was significantly higher in Group B (p = 0.001 for each).
Vol. 25, No. 1
59
Yucel et al: Prostaglandin E1 in duct-dependent congenital heart disease
Table 2. Demographic and clinical characteristics of patients according to their diagnostic subgroups.
Age (days) Sex (male/female) Weight (kg) Concomitant abnormality Treatment duration Final O2 saturation Initial dose (mcg/kg/minute) Titrated dose (mcg/kg/minute) Maintenance dose (mcg/kg/minute) Lowest dose (mcg/kg/minute) Surgery/transcatheter intervention Mortality
Group A (n = 35)
Group B (n = 33)
Group C (n = 27)
p-value
4.20 ± 1.58a,b 35/9 3.43 ± 0.36a,d 26/35 (74.2%) 6.4 ± 3.04 82.15 ± 2.09a,b 0.05 ± 0.014b,f 0.03 ± 0.015b,f 0.0038 ± 0.001b,f 0.0040 ± 0.001b,f 2/35 (5.7%) 4/35 (11.4%)
6.66 ± 2.62a,c 33/18 2.99 ± 0.3a,e 5/33 (15.1%) 6.24 ± 3.5 86.18 ± 3.29a,e 0.05 ± 0.02e,f 0.036 ± 0.014e,f 0.043 ± 0.0011e,f 0.0041 ± 0.001e,f 20/33 (60.6%) 4/33 (12.1%)
6.44 ± 1.60b,c 27/10 3.28 ± 0.5d,e 16/27 (59.2) 6.07 ± 2.84 91.5 ± 2.56b,e 0.093 ± 0.017b,e 0.057 ± 0.016b,e 0.010 ± 0.011b,e 0.0054 ± 0.001b,e 3/27 (11.1%) 4/27 (14.8%)
0.001* 0.049* 0.001* 0.313 0.907 0.001* 0.001 0.001* 0.001* 0.001* 0.001* 0.918
*p-values 0.05) d Group A versus Group C not statistically significant (p > 0.05) e Group B versus Group C statistically significant (p < 0.001) f Group A versus Group B not statistically significant (p > 0.05)
Table 3. Correlations between prostaglandin E1 doses and other variables.
Age r p Weight r p Treatment duration r p O2 saturation r p
Initial dose
Maintenance dose
Titrated dose
Lowest dose
0.218 0.034*
0.160 0.120
0.310 0.002*
0.155 0.135
0.084 0.420
0.047 0.649
0.110 0.287
0.049 0.634
0.016 0.877
0.056 0.590
0.011 0.914
0.081 0.433
0.549 0.001*
0.382 0.001*
0.515 0.001*
0.417 0.001*
*p-values
