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Patent ductus arteriosus in preterm infants is associated with cardiac autonomic alteration and predominant parasympathetic stimulation
Early Human Development 89 (2013) 631–634
Contents lists available at SciVerse ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Patent ductus arteriosus in preterm infants is associated with cardiac autonomic alteration and predominant parasympathetic stimulation Sabrina Goudjil a, b,⁎, Fatiha Imestouren a, b, Christèle Chazal a, b, Ghida Ghostine a, b, Fabrice Wallois b, André Leke a, Guy Kongolo a, b a b
Department of Paediatrics, Neonatal Intensive Care Unit, Amiens University Hospital, Amiens, France GRAMFC, INSERM U1105, Jules Verne University of Picardie, Amiens, France
a r t i c l e
i n f o
Article history: Received 24 October 2012 Received in revised form 14 April 2013 Accepted 16 April 2013 Keywords: Autonomic nervous system Heart rate variability Patent ductus arteriosus Preterm infant Spectral analysis
a b s t r a c t Background: Hemodynamic disorders in patent ductus arteriosus (PDA) may alter the stimulation of the autonomic nervous system. Aim: The objective of this study was to analyze the orthosympathetic–parasympathetic balance in preterm infants with PDA. Study design and subjects: Patients were included from consecutive admissions to Amiens University Hospital from 2009 to 2011. We defined a PDA group and a Control group (echographic criteria). For each patient, three 4-minutes segments of ECG were recorded during quiet sleep and the RR chronologic series were extracted, and spectral (Fourier Transform) and time-domain analyses were performed. For each parameter of heart rate variability (HRV), average of three measures was determined and analysed. Results: Forty-four patients were included for analysis. The total HRV power, LF/HF ratio and SDNN were lower in the PDA group (n = 22, gestational age 28.2 w ± 1.9) than in the Control group (n = 22, gestational age 28.8 w ± 2). The decrease in LF power destabilized the autonomic balance in favour of parasympathetic stimulation. After adjustment for postconceptional age, PDA was still associated with parameters of autonomic neural stimulation. Conclusion: These results suggest association of PDA with predominance of parasympathetic stimulation in preterm infants. The mechanisms of homeostasis in patients with PDA are very complex and involve both circulatory adaptations and control by autonomic pathway. If confirmed, our results could be interesting for future researches aiming to verify the interest of new targeted therapies for the management of PDA. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Analysis of heart rate variability (HRV) provides information on the autonomous nervous system in specific physiological and pathological situations, especially in hemodynamic disorders such as arterial hyper and hypotension and hypovolemia. Methods for HRV are presented in the report by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) [1]. Spectral analysis is commonly applied to a series of cardiac cycle RR intervals derived from an electrocardiogram (ECG) signal over a 3- to 15-minutes period [2,1]. Some authors have reported that HRV power is reduced after brain injury, respiratory distress syndrome (RDS), coma and multiple organ failure [3–6]. There are few studies on adaptations of autonomic regulatory responses
⁎ Corresponding author at: CHU Amiens, Médecine Néonatale - Réanimation Pédiatrique Polyvalente, Place Victor Pauchet, F-80054 Amiens Cedex 1, France. Tel.: +33 322 668280; fax: +33 322 668281. E-mail addresses: [email protected], [email protected] (S. Goudjil). 0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.earlhumdev.2013.04.008
during neonatal period—despite the fact that the most radical circulatory changes occur during this period. Patent ductus arteriosus (PDA) is one of the most frequent hemodynamic circulatory disorders in preterm infants. PDA is characterized by an aortopulmonary shunt that causes overload of pulmonary circulation, left atrium and ventricle and hyperflow in the ascending aorta and the aortic arch, and systemic hypoperfusion. The objective of the present study was to analyze the orthosympathetic–parasympathetic balance in premature infants with PDA. 2. Patients and methods 2.1. Study population Patients were included from consecutive admissions to the neonatal intensive care unit at Amiens University Hospital (August 2009 and June 2011). We excluded infants with congenital heart disease, grade 3 or 4 intraventricular haemorrhage, necrotizing enterocolitis, acute neonatal infection.
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S. Goudjil et al. / Early Human Development 89 (2013) 631–634
The study protocol was approved by the Investigational Review Board at Amiens University Medical Center. 2.2. Acquisition and ECG signal processing During the study, the neonate lay in the supine position in an incubator. Only data recorded during quiet sleep (detected by polygraphic 8 electrodes electroencephalogram and breathing movements) were analyzed (Deltamed® SA, Paris, France). The ECG signal was recorded through three chest electrodes with a digital polygraph. The signal was then sampled at 512 Hz, stored on the polygraph's hard disk and extracted later for further analysis. Signal processing was performed with MATLAB® software (Mathworks, Natick, MA, USA). A threshold detection program (adapted from the Pan-Tompkins algorithm) was used to calculate the duration of consecutive cardiac cycles (RR intervals) in the ECG signal. RR series with more than 4% errors in cardiac cycle detection were discarded. For each patient, three 4-minutes segments of ECG were recorded during quiet sleep for the analysis of HRV, and the average of results were calculated. 2.3. Spectral and time-domain analysis of HRV The spectral analysis of the RR series was performed by applying an algorithm of Fourier Transform (MATLAB®) [7]. The goal of spectral analysis was to determine the repartition of power across [1] low frequencies (LFs, 0.04–0.15 Hz) reflecting both the sympathetic and parasympathetic stimulation and high frequencies (HFs, 0.15– 1.5 Hz) reflecting parasympathetic activity in the RR series. The main, specific feature of HRV spectral analysis in the neonate relates to the fact that the upper boundary of the HF power is set at between 1 and 2 Hz, since the respiratory rate is higher in neonates (~ 1 Hz) than in adults (~ 0.3 Hz). The normalized [8] power value was calculated as: HFnu = HF/(LF + HF). Here it was also determined the total power (Ptotal = LF + HF), and the LF/HF ratio, reflecting the orthosympathetic–parasympathetic balance [8,7]. A time-domain analysis was also performed to determine the average RR interval duration, the SDNN, the standard deviation of the RR interval reflecting the total power of the RR, the RMSSD, the root mean squared and SDSD, and the standard deviation of successive RR differences [1,8]. 2.4. Collection of echographic data Data on the diagnostic of PDA and evaluation of severity were derived by echocardiography exam. These were used to classify patient in two groups: (i) PDA group defined as left-to-right shunt + ductus diameter > 2 mm + left atrium/aorta ratio > 1.4 and at least one criterion indicating increased pulmonary vascular overload (i.e. a mean left pulmonary artery (MLPA) > 0.40 m/s; end diastol pulmonary blood flow velocity > 0.20 m/s) and (ii) a Control group defined as closed or restrictive ductus arteriosus. Each echography performed by a neonatologist was confirmed by a paediatric cardiologist. 2.5. Clinical data Obstetrical data, neonates' clinical characteristics at birth and administered care during the day of explorations were collected. The postconceptional age corresponded to gestational age at birth plus postnatal age. 2.6. Statistical analysis Categorical variables were described as the number (percentage) and quantitative variables were described as the mean ± standard deviation. Intergroup comparisons of quantitative variables were performed with Student's t test. The statistical significance was set to p b 0.05.
3. Results In all, 22 patients (F/M gender ratio = 8/14) with significant PDA (PDA group) and 22 patients (F/M gender ratio = 5/17) with closed or restrictive ductus arteriosus (Control group) were included in the study. The two groups did not differ significantly in terms of clinical characteristics other than the postconceptional age, which was a slightly but significantly higher in the Control group (p b 0.05). These characteristics are summarized in Table 1. Fourteen (45.5%) patients in the PDA group and eight (36.4%) patients in the Control group were on tracheal ventilation (p = 0.55). Other patients in the groups were ventilated using a nasal continuous positive airway pressure device (Infant Flow, CareFusion, Yorba Linda, CA, USA). Hemodynamic support was necessary in 4 (18.1%) patients in the PDA group and 3 (13.6%) patients in the Control group (p = 0.68). Two patients in the PDA group and 5 in the Control group were sedated with midazolam (p = 0.22). Sufentanil analgesia was used in 6 patients in the PDA group and in 7 patients in the Control group (p = 0.74). The analysis of the ductus arteriosus characteristics highlighted several differences between the two groups of preterm infants. Neonates in the PDA group had a greater ductal shunt diameter (p b 0.001) and end-diastole pulmonary artery velocity (p b 0.01) than neonates in the Control group. The left ventricular diastole diameter was also higher in the PDA group (p b 0.01) than in the Control group. The ultrasound data are summarized in Table 2. Frequency- and time-domain analyses (Table 3) revealed a significantly less total HRV power (p b 0.01) and a lower SDNN value (p b 0.001) in the PDA group than in the Control group. The LF/HF ratio (p b 0.001) was lower in the PDA group than in the Control group resulting from a decrease in LF power (p b 0.01). The mean postconceptional age was higher in the Control group than in the PDA group. After adjustment, PDA was still independently associated with changes in autonomic neural stimulation parameters such total HRV power (coefficient ± SD: −52 ± 19, p b 0.01), HFnu (coefficient ± SD: 0.13 ± 0.05, p b 0.05), LF/HF (coefficient ± SD: −2.64 ± 0.84, p b 0.01) and SDNN (coefficient ± SD: −5 ± 2, p b 0.01). 4. Discussion In our study, neonates with PDA had a less total HRV power than Control neonates did. The decrease in HF power was proportionally less than that of the LF power between the Control group and the PDA group, leading to a decrease in LF/HF ratio from 5.52 ± 3.28 (Control group) to 2.74 ± 1.67 (PDA group), consistent with parasympathetic dominance. In children and neonates, major reduction in HRV power has been described in intracerebral haemorrhage [9], severe sepsis [10], RDS, the aftermath of Fontan open-heart surgery [11] and pulmonary stenosis [12]. The low HRV power observed in our study in preterm infants with PDA (i.e. a decrease in the total power of the RR signal and a low SDNN value) may therefore reflect decoupling between the sinus node and extrinsic signals. Table 1 Patients' characteristics. Variables
PDA group (n = 22)
Control group (n = 22)
Gestational age (week) Birth weight (g) Postconceptional age (week) IUGR % (n) One-minute Apgar score CRIB II score Vaginal delivery % (n) Antenatal corticosteroids % (n) Chorioamnionitis % (n)
28.25 ± 1.95 1237 ± 429 28.6 ± 1.9 13.6 [3] 7±3 7.6 ± 3.7 59.1 [13] 72.7 [16] 4.5 [1]
28.79 ± 2.04 1182 ± 288 29.9 ± 1.9* 9.1 [2] 8±3 7.3 ± 3.2 45.5 [10] 77.3 [17] 9.1 [2]
PDA, patent ductus arteriosus; CRIB, Clinical Risk Index for Babies II; IUGR, intrauterine growth retardation; * p b 0.05.
S. Goudjil et al. / Early Human Development 89 (2013) 631–634 Table 2 Hemodynamic characteristics (on echography). Variables
PDA group (n = 22)
Control group (n = 22)
Ductus diameter (mm) Left atrium/aorta ratio Flow velocity in the ductus (m/s) LPA mean velocity (m/s) LPA-end diastolic velocity (m/s) LV shortening fraction (%) LV-end diastolic diameter (cm) LV outflow (ml/kg/min)
2.25 1.43 1.39 0.54 0.22 33.3 1.35 216
0.49 1.30 1.70 0.39 0.09 31.4 1.00 208
± ± ± ± ± ± ± ±
0.70 0.28 0.62 0.21 0.08 8.2 0.20 74
± ± ± ± ± ± ± ±
0.90** 0.28 0.96 0.16 0.12* 15 0.43* 80
LV, left ventricle; LPA, left pulmonary artery; PDA, patent ductus arteriosu;**p b 0.001; *p b 0.01.
4.1. Hypotheses concerning the mechanisms of parasympathetic stimulation predominance in PDA The mechanisms of parasympathetic stimulation predominance in PDA are complex and poorly understood. Some authors have suggested that sympathetic neurostimulation's mechanisms are involved in PDA [13], an author has demonstrated this effect just before surgical ligation of the ductus arteriosus in human infants [14]. A study in piglets revealed that PDA was associated with a reduction in sympathetic neural transmission [15]. Here, we observed predominant parasympathetic modulation, as evidenced by the low LF/HF ratio in the PDA group. This predominant parasympathetic activity could result from the activation of intrapulmonary volume receptors and arterial baroreceptors because of vascular overload in pulmonary circulation secondary to the ductal shunt. Volume receptors are present in the left atrium and in the left ventricule and then, they could contribute to the cardio-inhibitor reflex. In our study, infants with PDA had a LV-end diastolic diameter higher than patients in the Control group (Table 2), suggesting a higher stimulation of intracardiac volume receptors. Moreover, stretching of the atrial walls prompts the release of atrial natriuretic factor (ANF) into the blood which acts on the kidney to increase natriuresis and diuresis and maintain homeostasis. Secretion of ANF also has a vasodilatory effect because it decreases peripheral vascular resistance. Previous work has also shown that ANF release slows the heart rate through stimulation of the parasympathetic nervous system [16]. Recent research revealed a relationship between plasma ANF levels and certain HRV parameters in adults; there was a positive correlation with the HF power (reflecting parasympathetic stimulation) and a negative correlation with the LH/HF ratio [17]. 4.2. Factors that influence HRV The explorations in baboon fetuses and in preterm infants less than 33 weeks gestational age, showed that HRV increases along with maturation during development. During the first week of life,
633
HRV is higher in the full-term neonate than in the preterm infant. In our study, patients in the PDA group had a postconceptional age significantly higher (29.9 ± 1.9) than patients in the Control group (28.6 ± 1.9). After adjustment for postconceptional age, the PDA was still independently associated with decrease in LF/HF ratio and increase in HFnu. In preterm infants, RDS is associated with decreased HRV power probably by the reduction in pulmonary compliance [4]. In our study the incidence of patients with RDS wasn't different in the 2 groups: 10 patients were on mechanical ventilation in the PDA group, and 8 in the Control group (p = 0.55). Administration of dobutamine and dopamine may alter the vascular tone, heart rate and autonomic modulation. In our study, treatment with these drugs was seldom prescribed in low dosage b 5 microgram/kg/h and concerned only a few patients. 4.3. Study limitations Diagnosis of PDA is based on echographic criteria [18]. The results of ultrasound measurements show inter- and intra-individual variability. A ductus diameter > 2 mm and a left atrium/aorta ratio > 1.4 are considered as severity criteria [18]. Measurement imprecision of the ductal shunt can have an impact on the classification. The LA/aorta ratio > 1.4 is a late-onset sign that may be absent at the time of classification and can also lead to errors in case of foramen ovale patency [19]. In order to avoid the pitfalls related to these two main criteria, our diagnosis of PDA always combined at least one Doppler criterion. 4.4. Perspectives and therapeutic implications In case of PDA, a dominant parasympathetic stimulation may worsen hypotension, and be regarded as an inappropriate adaptation. The results of this study help us to improve our knowledge of autonomic adaptations in neonates with major hemodynamic disorders. If confirmed by further work, these findings could serve as starting point toward researches trying to verify the interest of vagolytic drugs in the treatment of hemodynamic disorders related to PDA. 5. Conclusion Here we showed that in preterm infants, PDA is associated with autonomic alteration, with lower HRV power and parasympathetic dominance. The ductal shunt activates very complex adaptation responses involving both intrinsic mechanisms such as Franck–Starling reflex and extrinsic principles from the autonomic pathways. The results of our study could be interesting to future researches which aim to optimize strategies for prevention of hemodynamic complications associated with PDA. Conflict of interest statement The authors declare no conflict of interest.
Table 3 Parameters of heart rate variability.
References
Variables
PDA group (n = 22)
Control group (n = 22)
Total power (ms2) LF (ms) HF (ms) HF nu LF/HF Mean RR (ms) SDNN (ms) RMSSD (ms) SDSD (ms)
37 27 10 0.35 2.74 420 8 59 110
94 80 14 0.18 5.52 430 13 69 140
± ± ± ± ± ± ± ± ±
45 11 9 0.21 1.67 40 5 23 70
PDA: patent ductus arteriosus; *p b 0,01; **p b 0,001.
± ± ± ± ± ± ± ± ±
68* 31** 9 0.08* 3.28** 30 5* 22 70
[1] Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93(5):1043–65. [2] Longin E, Schaible T, Lenz T, König S. Short term heart rate variability in healthy neonates: normative data and physiological observations. Early Hum Dev 2005;81(8):663–71. [3] Goldstein B, Kempski MH, DeKing D, Cox C, DeLong DJ, Kelly MM, et al. Autonomic control of heart rate after brain injury in children. Crit Care Med 1996;24(2):234–40. [4] Rosenstock EG, Cassuto Y, Zmora E. Heart rate variability in the neonate and infant: analytical methods, physiological and clinical observations. Acta Paediatr 1999;88(5):477–82. [5] Godin PJ, Buchman TG. Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 1996;24(7):1107–16.
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[6] Schmidt H, Müller-Werdan U, Hoffmann T, Francis DP, Piepoli MF, Rauchhaus M, et al. Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med 2005;33(9):1994–2002. [7] Välimäki I, Rantonen T. Spectral analysis of heart rate and blood pressure variability. In: S-Bada-Ellzey H, editor. Clinics in Perinatology, 26. W.B. Saunders Company; 1999. p. 967–80. [8] Burr RL. Interpretation of normalized spectral heart rate variability indices in sleep research: a critical review. Sleep 2007;30(7):913–9. [9] Tuzcu V, Nas S, Ulusar U, Ugur A, Kaiser JR. Altered heart rhythm dynamics in very low birth weight infants with impending intraventricular hemorrhage. Pediatrics 2009;123(3):810–5. [10] Pontet J, Contreras P, Curbelo A, Medina J, Noveri S, Bentancourt S, et al. Heart rate variability as early marker of multiple organ dysfunction syndrome in septic patients. J Crit Care 2003;18(3):156–63. [11] Dahlqvist JA, Karlsson M, Wiklund U, Hörnsten R, Strömvall-Larsson E, Berggren H, et al. Heart rate variability in children with Fontan circulation: lateral tunnel and extracardiac conduit. Pediatr Cardiol 2012;33(2):307–15. [12] Dzimiri N, Galal O, Moorji A, Bakr S, Abbag F, Fadley F, et al. Regulation of sympathetic activity in children with various congenital heart diseases. Pediatr Res 1995;38(1):55–60.
[13] Capozzi G, Santoro G. Patent ductus arteriosus: patho-physiology, hemodynamic effects and clinical complications. J Matern Fetal Neonatal Med 2011;24(Suppl. 1):15–6. [14] Wu RZ, Rong X, Ren Y, He XX, Xiang RL. Heart rate variability, adrenomedullin and B-type natriuretic peptide before and after transcatheter closure in children with patent ductus arteriosus. Zhonghua Xin Xue Guan Bing Za Zhi 2010;38(4):334–6. [15] Jim WT, Chiu NC, Chen MR, Hung HY, Kao HA, Hsu CH, et al. Cerebral hemodynamic change and intraventricular hemorrhage in very low birth weight infants with patent ductus arteriosus. Ultrasound Med Biol 2005;31(2):197–202. [16] Atchison DJ, Ackermann U. The interaction between atrial natriuretic peptide and cardiac parasympathetic function. J Auton Nerv Syst 1993;42(1):81–8. [17] Kasamaki Y, Izumi Y, Ozawa Y, Ohta M, Tano A, Watanabe I, et al. Relationship between status of plasma atrial natriuretic peptide and heart rate variability in human subjects. Heart Vessels 2012. [18] Skinner J. Diagnosis of patent ductus arteriosus. Semin Neonatol 2001;6(1):49–61. [19] Evans N, Iyer P. Incompetence of the foramen ovale in preterm infants supported by mechanical ventilation. J Pediatr 1994;125(5 Pt 1):786–92.
Contents lists available at SciVerse ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Patent ductus arteriosus in preterm infants is associated with cardiac autonomic alteration and predominant parasympathetic stimulation Sabrina Goudjil a, b,⁎, Fatiha Imestouren a, b, Christèle Chazal a, b, Ghida Ghostine a, b, Fabrice Wallois b, André Leke a, Guy Kongolo a, b a b
Department of Paediatrics, Neonatal Intensive Care Unit, Amiens University Hospital, Amiens, France GRAMFC, INSERM U1105, Jules Verne University of Picardie, Amiens, France
a r t i c l e
i n f o
Article history: Received 24 October 2012 Received in revised form 14 April 2013 Accepted 16 April 2013 Keywords: Autonomic nervous system Heart rate variability Patent ductus arteriosus Preterm infant Spectral analysis
a b s t r a c t Background: Hemodynamic disorders in patent ductus arteriosus (PDA) may alter the stimulation of the autonomic nervous system. Aim: The objective of this study was to analyze the orthosympathetic–parasympathetic balance in preterm infants with PDA. Study design and subjects: Patients were included from consecutive admissions to Amiens University Hospital from 2009 to 2011. We defined a PDA group and a Control group (echographic criteria). For each patient, three 4-minutes segments of ECG were recorded during quiet sleep and the RR chronologic series were extracted, and spectral (Fourier Transform) and time-domain analyses were performed. For each parameter of heart rate variability (HRV), average of three measures was determined and analysed. Results: Forty-four patients were included for analysis. The total HRV power, LF/HF ratio and SDNN were lower in the PDA group (n = 22, gestational age 28.2 w ± 1.9) than in the Control group (n = 22, gestational age 28.8 w ± 2). The decrease in LF power destabilized the autonomic balance in favour of parasympathetic stimulation. After adjustment for postconceptional age, PDA was still associated with parameters of autonomic neural stimulation. Conclusion: These results suggest association of PDA with predominance of parasympathetic stimulation in preterm infants. The mechanisms of homeostasis in patients with PDA are very complex and involve both circulatory adaptations and control by autonomic pathway. If confirmed, our results could be interesting for future researches aiming to verify the interest of new targeted therapies for the management of PDA. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Analysis of heart rate variability (HRV) provides information on the autonomous nervous system in specific physiological and pathological situations, especially in hemodynamic disorders such as arterial hyper and hypotension and hypovolemia. Methods for HRV are presented in the report by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) [1]. Spectral analysis is commonly applied to a series of cardiac cycle RR intervals derived from an electrocardiogram (ECG) signal over a 3- to 15-minutes period [2,1]. Some authors have reported that HRV power is reduced after brain injury, respiratory distress syndrome (RDS), coma and multiple organ failure [3–6]. There are few studies on adaptations of autonomic regulatory responses
⁎ Corresponding author at: CHU Amiens, Médecine Néonatale - Réanimation Pédiatrique Polyvalente, Place Victor Pauchet, F-80054 Amiens Cedex 1, France. Tel.: +33 322 668280; fax: +33 322 668281. E-mail addresses: [email protected], [email protected] (S. Goudjil). 0378-3782/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.earlhumdev.2013.04.008
during neonatal period—despite the fact that the most radical circulatory changes occur during this period. Patent ductus arteriosus (PDA) is one of the most frequent hemodynamic circulatory disorders in preterm infants. PDA is characterized by an aortopulmonary shunt that causes overload of pulmonary circulation, left atrium and ventricle and hyperflow in the ascending aorta and the aortic arch, and systemic hypoperfusion. The objective of the present study was to analyze the orthosympathetic–parasympathetic balance in premature infants with PDA. 2. Patients and methods 2.1. Study population Patients were included from consecutive admissions to the neonatal intensive care unit at Amiens University Hospital (August 2009 and June 2011). We excluded infants with congenital heart disease, grade 3 or 4 intraventricular haemorrhage, necrotizing enterocolitis, acute neonatal infection.
632
S. Goudjil et al. / Early Human Development 89 (2013) 631–634
The study protocol was approved by the Investigational Review Board at Amiens University Medical Center. 2.2. Acquisition and ECG signal processing During the study, the neonate lay in the supine position in an incubator. Only data recorded during quiet sleep (detected by polygraphic 8 electrodes electroencephalogram and breathing movements) were analyzed (Deltamed® SA, Paris, France). The ECG signal was recorded through three chest electrodes with a digital polygraph. The signal was then sampled at 512 Hz, stored on the polygraph's hard disk and extracted later for further analysis. Signal processing was performed with MATLAB® software (Mathworks, Natick, MA, USA). A threshold detection program (adapted from the Pan-Tompkins algorithm) was used to calculate the duration of consecutive cardiac cycles (RR intervals) in the ECG signal. RR series with more than 4% errors in cardiac cycle detection were discarded. For each patient, three 4-minutes segments of ECG were recorded during quiet sleep for the analysis of HRV, and the average of results were calculated. 2.3. Spectral and time-domain analysis of HRV The spectral analysis of the RR series was performed by applying an algorithm of Fourier Transform (MATLAB®) [7]. The goal of spectral analysis was to determine the repartition of power across [1] low frequencies (LFs, 0.04–0.15 Hz) reflecting both the sympathetic and parasympathetic stimulation and high frequencies (HFs, 0.15– 1.5 Hz) reflecting parasympathetic activity in the RR series. The main, specific feature of HRV spectral analysis in the neonate relates to the fact that the upper boundary of the HF power is set at between 1 and 2 Hz, since the respiratory rate is higher in neonates (~ 1 Hz) than in adults (~ 0.3 Hz). The normalized [8] power value was calculated as: HFnu = HF/(LF + HF). Here it was also determined the total power (Ptotal = LF + HF), and the LF/HF ratio, reflecting the orthosympathetic–parasympathetic balance [8,7]. A time-domain analysis was also performed to determine the average RR interval duration, the SDNN, the standard deviation of the RR interval reflecting the total power of the RR, the RMSSD, the root mean squared and SDSD, and the standard deviation of successive RR differences [1,8]. 2.4. Collection of echographic data Data on the diagnostic of PDA and evaluation of severity were derived by echocardiography exam. These were used to classify patient in two groups: (i) PDA group defined as left-to-right shunt + ductus diameter > 2 mm + left atrium/aorta ratio > 1.4 and at least one criterion indicating increased pulmonary vascular overload (i.e. a mean left pulmonary artery (MLPA) > 0.40 m/s; end diastol pulmonary blood flow velocity > 0.20 m/s) and (ii) a Control group defined as closed or restrictive ductus arteriosus. Each echography performed by a neonatologist was confirmed by a paediatric cardiologist. 2.5. Clinical data Obstetrical data, neonates' clinical characteristics at birth and administered care during the day of explorations were collected. The postconceptional age corresponded to gestational age at birth plus postnatal age. 2.6. Statistical analysis Categorical variables were described as the number (percentage) and quantitative variables were described as the mean ± standard deviation. Intergroup comparisons of quantitative variables were performed with Student's t test. The statistical significance was set to p b 0.05.
3. Results In all, 22 patients (F/M gender ratio = 8/14) with significant PDA (PDA group) and 22 patients (F/M gender ratio = 5/17) with closed or restrictive ductus arteriosus (Control group) were included in the study. The two groups did not differ significantly in terms of clinical characteristics other than the postconceptional age, which was a slightly but significantly higher in the Control group (p b 0.05). These characteristics are summarized in Table 1. Fourteen (45.5%) patients in the PDA group and eight (36.4%) patients in the Control group were on tracheal ventilation (p = 0.55). Other patients in the groups were ventilated using a nasal continuous positive airway pressure device (Infant Flow, CareFusion, Yorba Linda, CA, USA). Hemodynamic support was necessary in 4 (18.1%) patients in the PDA group and 3 (13.6%) patients in the Control group (p = 0.68). Two patients in the PDA group and 5 in the Control group were sedated with midazolam (p = 0.22). Sufentanil analgesia was used in 6 patients in the PDA group and in 7 patients in the Control group (p = 0.74). The analysis of the ductus arteriosus characteristics highlighted several differences between the two groups of preterm infants. Neonates in the PDA group had a greater ductal shunt diameter (p b 0.001) and end-diastole pulmonary artery velocity (p b 0.01) than neonates in the Control group. The left ventricular diastole diameter was also higher in the PDA group (p b 0.01) than in the Control group. The ultrasound data are summarized in Table 2. Frequency- and time-domain analyses (Table 3) revealed a significantly less total HRV power (p b 0.01) and a lower SDNN value (p b 0.001) in the PDA group than in the Control group. The LF/HF ratio (p b 0.001) was lower in the PDA group than in the Control group resulting from a decrease in LF power (p b 0.01). The mean postconceptional age was higher in the Control group than in the PDA group. After adjustment, PDA was still independently associated with changes in autonomic neural stimulation parameters such total HRV power (coefficient ± SD: −52 ± 19, p b 0.01), HFnu (coefficient ± SD: 0.13 ± 0.05, p b 0.05), LF/HF (coefficient ± SD: −2.64 ± 0.84, p b 0.01) and SDNN (coefficient ± SD: −5 ± 2, p b 0.01). 4. Discussion In our study, neonates with PDA had a less total HRV power than Control neonates did. The decrease in HF power was proportionally less than that of the LF power between the Control group and the PDA group, leading to a decrease in LF/HF ratio from 5.52 ± 3.28 (Control group) to 2.74 ± 1.67 (PDA group), consistent with parasympathetic dominance. In children and neonates, major reduction in HRV power has been described in intracerebral haemorrhage [9], severe sepsis [10], RDS, the aftermath of Fontan open-heart surgery [11] and pulmonary stenosis [12]. The low HRV power observed in our study in preterm infants with PDA (i.e. a decrease in the total power of the RR signal and a low SDNN value) may therefore reflect decoupling between the sinus node and extrinsic signals. Table 1 Patients' characteristics. Variables
PDA group (n = 22)
Control group (n = 22)
Gestational age (week) Birth weight (g) Postconceptional age (week) IUGR % (n) One-minute Apgar score CRIB II score Vaginal delivery % (n) Antenatal corticosteroids % (n) Chorioamnionitis % (n)
28.25 ± 1.95 1237 ± 429 28.6 ± 1.9 13.6 [3] 7±3 7.6 ± 3.7 59.1 [13] 72.7 [16] 4.5 [1]
28.79 ± 2.04 1182 ± 288 29.9 ± 1.9* 9.1 [2] 8±3 7.3 ± 3.2 45.5 [10] 77.3 [17] 9.1 [2]
PDA, patent ductus arteriosus; CRIB, Clinical Risk Index for Babies II; IUGR, intrauterine growth retardation; * p b 0.05.
S. Goudjil et al. / Early Human Development 89 (2013) 631–634 Table 2 Hemodynamic characteristics (on echography). Variables
PDA group (n = 22)
Control group (n = 22)
Ductus diameter (mm) Left atrium/aorta ratio Flow velocity in the ductus (m/s) LPA mean velocity (m/s) LPA-end diastolic velocity (m/s) LV shortening fraction (%) LV-end diastolic diameter (cm) LV outflow (ml/kg/min)
2.25 1.43 1.39 0.54 0.22 33.3 1.35 216
0.49 1.30 1.70 0.39 0.09 31.4 1.00 208
± ± ± ± ± ± ± ±
0.70 0.28 0.62 0.21 0.08 8.2 0.20 74
± ± ± ± ± ± ± ±
0.90** 0.28 0.96 0.16 0.12* 15 0.43* 80
LV, left ventricle; LPA, left pulmonary artery; PDA, patent ductus arteriosu;**p b 0.001; *p b 0.01.
4.1. Hypotheses concerning the mechanisms of parasympathetic stimulation predominance in PDA The mechanisms of parasympathetic stimulation predominance in PDA are complex and poorly understood. Some authors have suggested that sympathetic neurostimulation's mechanisms are involved in PDA [13], an author has demonstrated this effect just before surgical ligation of the ductus arteriosus in human infants [14]. A study in piglets revealed that PDA was associated with a reduction in sympathetic neural transmission [15]. Here, we observed predominant parasympathetic modulation, as evidenced by the low LF/HF ratio in the PDA group. This predominant parasympathetic activity could result from the activation of intrapulmonary volume receptors and arterial baroreceptors because of vascular overload in pulmonary circulation secondary to the ductal shunt. Volume receptors are present in the left atrium and in the left ventricule and then, they could contribute to the cardio-inhibitor reflex. In our study, infants with PDA had a LV-end diastolic diameter higher than patients in the Control group (Table 2), suggesting a higher stimulation of intracardiac volume receptors. Moreover, stretching of the atrial walls prompts the release of atrial natriuretic factor (ANF) into the blood which acts on the kidney to increase natriuresis and diuresis and maintain homeostasis. Secretion of ANF also has a vasodilatory effect because it decreases peripheral vascular resistance. Previous work has also shown that ANF release slows the heart rate through stimulation of the parasympathetic nervous system [16]. Recent research revealed a relationship between plasma ANF levels and certain HRV parameters in adults; there was a positive correlation with the HF power (reflecting parasympathetic stimulation) and a negative correlation with the LH/HF ratio [17]. 4.2. Factors that influence HRV The explorations in baboon fetuses and in preterm infants less than 33 weeks gestational age, showed that HRV increases along with maturation during development. During the first week of life,
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HRV is higher in the full-term neonate than in the preterm infant. In our study, patients in the PDA group had a postconceptional age significantly higher (29.9 ± 1.9) than patients in the Control group (28.6 ± 1.9). After adjustment for postconceptional age, the PDA was still independently associated with decrease in LF/HF ratio and increase in HFnu. In preterm infants, RDS is associated with decreased HRV power probably by the reduction in pulmonary compliance [4]. In our study the incidence of patients with RDS wasn't different in the 2 groups: 10 patients were on mechanical ventilation in the PDA group, and 8 in the Control group (p = 0.55). Administration of dobutamine and dopamine may alter the vascular tone, heart rate and autonomic modulation. In our study, treatment with these drugs was seldom prescribed in low dosage b 5 microgram/kg/h and concerned only a few patients. 4.3. Study limitations Diagnosis of PDA is based on echographic criteria [18]. The results of ultrasound measurements show inter- and intra-individual variability. A ductus diameter > 2 mm and a left atrium/aorta ratio > 1.4 are considered as severity criteria [18]. Measurement imprecision of the ductal shunt can have an impact on the classification. The LA/aorta ratio > 1.4 is a late-onset sign that may be absent at the time of classification and can also lead to errors in case of foramen ovale patency [19]. In order to avoid the pitfalls related to these two main criteria, our diagnosis of PDA always combined at least one Doppler criterion. 4.4. Perspectives and therapeutic implications In case of PDA, a dominant parasympathetic stimulation may worsen hypotension, and be regarded as an inappropriate adaptation. The results of this study help us to improve our knowledge of autonomic adaptations in neonates with major hemodynamic disorders. If confirmed by further work, these findings could serve as starting point toward researches trying to verify the interest of vagolytic drugs in the treatment of hemodynamic disorders related to PDA. 5. Conclusion Here we showed that in preterm infants, PDA is associated with autonomic alteration, with lower HRV power and parasympathetic dominance. The ductal shunt activates very complex adaptation responses involving both intrinsic mechanisms such as Franck–Starling reflex and extrinsic principles from the autonomic pathways. The results of our study could be interesting to future researches which aim to optimize strategies for prevention of hemodynamic complications associated with PDA. Conflict of interest statement The authors declare no conflict of interest.
Table 3 Parameters of heart rate variability.
References
Variables
PDA group (n = 22)
Control group (n = 22)
Total power (ms2) LF (ms) HF (ms) HF nu LF/HF Mean RR (ms) SDNN (ms) RMSSD (ms) SDSD (ms)
37 27 10 0.35 2.74 420 8 59 110
94 80 14 0.18 5.52 430 13 69 140
± ± ± ± ± ± ± ± ±
45 11 9 0.21 1.67 40 5 23 70
PDA: patent ductus arteriosus; *p b 0,01; **p b 0,001.
± ± ± ± ± ± ± ± ±
68* 31** 9 0.08* 3.28** 30 5* 22 70
[1] Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93(5):1043–65. [2] Longin E, Schaible T, Lenz T, König S. Short term heart rate variability in healthy neonates: normative data and physiological observations. Early Hum Dev 2005;81(8):663–71. [3] Goldstein B, Kempski MH, DeKing D, Cox C, DeLong DJ, Kelly MM, et al. Autonomic control of heart rate after brain injury in children. Crit Care Med 1996;24(2):234–40. [4] Rosenstock EG, Cassuto Y, Zmora E. Heart rate variability in the neonate and infant: analytical methods, physiological and clinical observations. Acta Paediatr 1999;88(5):477–82. [5] Godin PJ, Buchman TG. Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 1996;24(7):1107–16.
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[6] Schmidt H, Müller-Werdan U, Hoffmann T, Francis DP, Piepoli MF, Rauchhaus M, et al. Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med 2005;33(9):1994–2002. [7] Välimäki I, Rantonen T. Spectral analysis of heart rate and blood pressure variability. In: S-Bada-Ellzey H, editor. Clinics in Perinatology, 26. W.B. Saunders Company; 1999. p. 967–80. [8] Burr RL. Interpretation of normalized spectral heart rate variability indices in sleep research: a critical review. Sleep 2007;30(7):913–9. [9] Tuzcu V, Nas S, Ulusar U, Ugur A, Kaiser JR. Altered heart rhythm dynamics in very low birth weight infants with impending intraventricular hemorrhage. Pediatrics 2009;123(3):810–5. [10] Pontet J, Contreras P, Curbelo A, Medina J, Noveri S, Bentancourt S, et al. Heart rate variability as early marker of multiple organ dysfunction syndrome in septic patients. J Crit Care 2003;18(3):156–63. [11] Dahlqvist JA, Karlsson M, Wiklund U, Hörnsten R, Strömvall-Larsson E, Berggren H, et al. Heart rate variability in children with Fontan circulation: lateral tunnel and extracardiac conduit. Pediatr Cardiol 2012;33(2):307–15. [12] Dzimiri N, Galal O, Moorji A, Bakr S, Abbag F, Fadley F, et al. Regulation of sympathetic activity in children with various congenital heart diseases. Pediatr Res 1995;38(1):55–60.
[13] Capozzi G, Santoro G. Patent ductus arteriosus: patho-physiology, hemodynamic effects and clinical complications. J Matern Fetal Neonatal Med 2011;24(Suppl. 1):15–6. [14] Wu RZ, Rong X, Ren Y, He XX, Xiang RL. Heart rate variability, adrenomedullin and B-type natriuretic peptide before and after transcatheter closure in children with patent ductus arteriosus. Zhonghua Xin Xue Guan Bing Za Zhi 2010;38(4):334–6. [15] Jim WT, Chiu NC, Chen MR, Hung HY, Kao HA, Hsu CH, et al. Cerebral hemodynamic change and intraventricular hemorrhage in very low birth weight infants with patent ductus arteriosus. Ultrasound Med Biol 2005;31(2):197–202. [16] Atchison DJ, Ackermann U. The interaction between atrial natriuretic peptide and cardiac parasympathetic function. J Auton Nerv Syst 1993;42(1):81–8. [17] Kasamaki Y, Izumi Y, Ozawa Y, Ohta M, Tano A, Watanabe I, et al. Relationship between status of plasma atrial natriuretic peptide and heart rate variability in human subjects. Heart Vessels 2012. [18] Skinner J. Diagnosis of patent ductus arteriosus. Semin Neonatol 2001;6(1):49–61. [19] Evans N, Iyer P. Incompetence of the foramen ovale in preterm infants supported by mechanical ventilation. J Pediatr 1994;125(5 Pt 1):786–92.