Original Paper Received: April 9, 2013 Accepted after revision: August 20, 2013 Published online: November 1, 2013
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
Effect of Positive End-Expiratory Pressure on Ductal Shunting and Systemic Blood Flow in Preterm Infants with Patent Ductus Arteriosus Maria Florencia Fajardo a Nelson Claure a Sethuraman Swaminathan b Sumbal Sattar b Amelia Vasquez b Carmen D’Ugard a Eduardo Bancalari a
Divisions of a Neonatology, and b Cardiology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Fla., USA
Key Words Patent ductus arteriosus · Positive end-expiratory pressure · Left to right shunt · Systemic blood flow · Premature infant
modest decrease in L-R ductal shunting as indicated by a lower LVO/SVC flow ratio. The higher PEEP did not have a significant effect on cerebral perfusion or oxygenation. © 2013 S. Karger AG, Basel
Abstract Background: Left to right (L-R) shunting through a patent ductus arteriosus (PDA) can reduce systemic and cerebral blood flow in preterm infants. To minimize this, the positive end-expiratory pressure (PEEP) is often raised to increase pulmonary vascular resistance and reduce L-R shunting. The effects of this maneuver on systemic and cerebral hemodynamics and oxygenation are not well documented. Objective: To compare the effects of different PEEP on the left ventricular output (LVO), superior vena cava (SVC) flow, LVO/SVC flow ratio, cerebral oxygenation (CrSO2) and gas exchange in mechanically ventilated preterm infants with PDA. Methods: Sixteen mechanically ventilated infants of 23–30 weeks’ gestational age with L-R shunting through the PDA were studied. Ultrasound measurements of LVO and SVC flow, CrSO2, arterial oxygen saturation and transcutaneous CO2 tension (TcPCO2) obtained at PEEP of 2 and 8 cm H2O were compared with baseline values at 5 cm H2O. Results: There was a small but significant reduction in LVO and the LVO/SVC flow ratio at PEEP of 8 compared to 5 cm H2O. SVC flow and CrSO2 did not differ significantly. Conclusions: Increasing PEEP to 8 cm H2O in ventilated preterm infants with a PDA produced a
© 2013 S. Karger AG, Basel 1661–7800/14/1051–0009$39.50/0 E-Mail [email protected] www.karger.com/neo
The persistence of a patent ductus arteriosus (PDA) occurs frequently in premature infants and it has been associated with complications, including pulmonary hemorrhage, necrotizing enterocolitis, increased incidence of bronchopulmonary dysplasia and intracranial hemorrhage [1–8]. These complications may be related to the increased pulmonary blood flow due to left to right (L-R) ductal shunting and to the steal of systemic blood flow that can reduce tissue perfusion. In these infants, a higher continuous positive airway pressure could increase pulmonary vascular resistance (PVR) and consequently decrease L-R shunting. If effective, this maneuver could result in a redistribution of the left ventricular output (LVO) in favor of systemic blood flow and more particularly in cerebral and coronary perfusion. The hypothesis of this study was that higher levels of positive end-expiratory pressure (PEEP) in mechanically ventilated preterm infants will reduce L-R ductal shunting through the PDA which will be reflected in a lower LVO to superior vena cava (SVC) flow ratio (LVO/SVC flow). This will be accompanied by increased cerebral oxygenation. Nelson Claure, MSc, PhD Division of Neonatology, Department of Pediatrics University of Miami Miller School of Medicine PO Box 016960 R-131, Miami, FL 33101 (USA) E-Mail nclaure @ miami.edu
The objective of the study was to compare LVO, SVC flow and the LVO/SVC flow ratio as an index of L-R shunt through the ductus, cerebral oxygenation and gas exchange at different levels of PEEP in preterm infants with PDA.
Methods Eligible subjects were clinically stable neonates of gestational age (GA) ≤32 weeks and birthweight (BW) ≤2,000 g with a diagnosis of PDA confirmed by echocardiography and undergoing mechanical ventilation who were admitted to the Jackson Memorial Hospital – University of Miami Newborn Intensive Care Unit. The study was approved by the University of Miami Institutional Review Board and Jackson Health System Clinical Trials Office. Written informed parental consent was obtained before enrollment of each infant. Based on published data on the LVO/SVC flow ratio in infants with PDA [9], a sample size of 16 infants was estimated necessary to detect a 30% difference in the LVO/SVC flow ratio with a higher PEEP level, assuming a power of 80 and 5% significance alpha. The L-R shunting through the PDA was confirmed by echocardiography immediately prior to the start of the study measurements in each infant. The level of PEEP set by the clinical team before the start of the study was considered as the baseline level. PEEP was increased and decreased by 3 cm H2O from each infant’s baseline level without exceeding 8 or decreasing below 2 cm H2O, respectively. The sequence of the three PEEP levels was determined at random. Each PEEP level was maintained for 10–20 min. Measurements were obtained after 10 min of stabilization at each PEEP level. Peak inspiratory pressure (PIP) was adjusted to maintain the difference between PIP and PEEP constant. Echocardiographic evaluation at each PEEP level included two-dimensional, M-mode, color flow and spectral Doppler (Acuson Sequoia, Siemens Medical, Mountain View, Calif., USA) to measure the velocity time integral (VTI) to estimate LVO and SVC flow. Aortic Doppler was done via apical long axis view and the diameter measured via parasternal long axis view and measured immediately proximal and just below the aortic valve annulus. SVC Doppler was evaluated by subcostal sagittal views and the diameter via parasternal 3-vessel view and measured close to the entrance to the right atrium. The VTI (area measured under the Doppler velocity envelope for one heart beat) and cross-sectional area of the vessels were measured to estimate the flow and stroke volume. Five VTI measurements were obtained for each infant at each PEEP level and averaged. A mean SVC diameter was calculated from multiple measurements of the SVC to obtain the cross-sectional area. To avoid the effects of the positive pressure cycles of the ventilator on the echocardiographic measurements, these were obtained only when the airway pressure was at PEEP level. For this, a nonscaled waveform of the airway pressure was fed to the ultrasound machine. The operator was able to exclude those cardiac cycles occurring when airway pressure increased. All echocardiography recordings were obtained by the same investigator and were analyzed by a pediatric cardiologist.
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Neonatology 2014;105:9–13 DOI: 10.1159/000355146
Table 1. Demographic characteristics of study population
Gestational age, weeks BW, g Age at study, days Weight at study, g Ventilator settings at study Mandatory rate, breaths/min PIP, cm H2O PEEP, cm H2O Pressure support, cm H2O MAP, cm H2O FiO2, %
26 (23–30) 710 (470–1,180) 6 (2–71) 730 (483–2,305) 23 (10–45) 18 (15–20) 5 (4–5) 9 (5–12) 8 (6–9) 24 (21–55)
Data are median (range).
Cerebral oxygenation (CrSO2) was evaluated by near-infrared spectroscopy (INVOS 4100 Cerebral Oximeter, Covidien, Boulder, Colo., USA). Arterial oxygen saturation (SpO2) was measured by pulse oximetry (Radical, Masimo, Irvine, Calif., USA). Carbon dioxide tension (TcPCO2) was measured with a transcutaneous monitor (Microgas 7650, Radiometer America, Westlake, Ohio, USA). The fraction of inspired oxygen (FiO2) and mean airway pressure (MAP) were obtained from the ventilator. The ratio between SpO2 and FiO2 was calculated for each infant. Statistical analysis for within-subject comparisons was done by repeated-measures ANOVA with Holm-Sidak post hoc method for pairwise comparisons to a single control for normally distributed data or by the nonparametric Friedman repeated-measures analysis of variance on ranks with Dunn’s post hoc method for pairwise comparisons to baseline of 5 cm H2O.
Results
Sixteen mechanically ventilated infants with documented L-R shunting through a PDA were studied. Their GA, BW, postnatal age and ventilator settings are shown in table 1. All infants had the diagnosis of PDA confirmed immediately prior to the study. The mean PDA diameter of this group of infants was 2.54 ± 0.54 mm. Ten infants were receiving indomethacin or ibuprofen treatment for PDA at the time of the study. Six infants were not receiving treatment. Of these, 3 had received treatment 5 or more days before the study. The baseline PEEP was 5 cm H2O for all infants except for one with a baseline PEEP of 4 cm H2O. The rounded mean values of baseline, high and low PEEP were 5, 8 and 2 cm H2O, respectively. Hemodynamic measurements show a statistically significant reduction in LVO/SVC flow ratio and LVO with PEEP of 8 compared to 5 cm H2O. These reductions were Fajardo/Claure/Swaminathan/Sattar/ Vasquez/D’Ugard/Bancalari
Table 2. Hemodynamic measurements
PEEP
LVO/SVC flow ratio Percent change from baseline LVO, ml/kg/min Percent change from baseline SVC flow, ml/kg/min Percent change from baseline Heart rate, bpm Percent change from baseline
2 cm H2O
5 cm H2O
8 cm H2O
2.54 (1.38 to 2.98) 0.38 (6.99 to 9.23) 326 (302 to 437) –2.87 (–8.85 to 7.27) 168 (141 to 201) –1.23 (–7.19 to 0.72) 146 (144 to 161) –1.78 (–3.21 to 0.0)
2.14 (1.57 to 2.83)
1.96 (1.54 to 2.67)* –13.23 (–19.4 to –4.06) 346 (246 to 393)* –7.79 (–19.90 to –2.04) 164 (139 to 193) 3.53 (–6.60 to 7.02) 149 (146 to 162) –0.95 (–2.11 to 1.37)
361 (305 to 433) 163 (144 to 204) 151 (145 to 161)
Data are median (interquartile range). * p < 0.05 by Friedman repeated-measures analysis of variance on ranks with Dunn’s post hoc method for multiple comparisons vs. baseline (PEEP 5 cm H2O).
40 Change in LVO/SVC flow ratio from baseline of 5 cm H2O (%)
modest (median reduction of 13.23 and 7.79%, respectively) but relatively consistent. LVO/SVC flow decreased in 14 of the 16 infants, but in only 10 of them was the decline >10%. LVO decreased in 13 infants with the higher PEEP compared to baseline, but in only 7 infants was the decrease >10%. LVO and the LVO/SVC flow ratio did not differ with PEEP of 2 compared to 5 cm H2O (table 2). Changes in the LVO/SVC flow ratio during PEEP of 2 and 8 cm H2O as percentage of the baseline PEEP of 5 cm H2O are shown in figure 1. SVC flow did not differ with PEEP of 8 or 2 with respect to PEEP of 5 cm H2O. The effect of the higher PEEP on SVC flow was inconsistent. SVC flow increased in 10 of the 16 infants leading to a median increase of 3.5% for the group, but the increase was >10% in only 2 infants. Heart rate did not differ with PEEP of 8 or 2 with respect to PEEP of 5 cm H2O (table 2). Measurements of CrSO2, SpO2 and FiO2 with PEEP of 2 or 8 did not differ from PEEP of 5 cm H2O (table 3). As expected, the ratio of SpO2/FiO2 was lower at PEEP of 2 compared to PEEP of 5 cm H2O. There was a small but statistically significant increase in TcPCO2 at PEEP of 8 compared to the baseline PEEP of 5 cm H2O. TcPCO2 increased in 13 of the 16 infants with the higher PEEP compared to baseline.
20
0
–20
–40
2 cm H2O
8 cm H2O PEEP
Fig. 1. Changes in the LVO/SVC flow ratio at PEEP of 2 and 8 cm
H2O with respect to the baseline PEEP of 5 cm H2O. A consistent decline in the LVO/SVC flow ratio was observed at the higher PEEP.
These results show that increasing PEEP from 5 to 8 cm H2O in premature infants with a PDA produces a modest but consistent decrease in L-R shunting through the ductus as indicated by a lower LVO/SVC flow ratio. This reduction is in agreement with published data show-
ing a higher LVO/SVC flow ratio in infants with PDA compared to controls [9]. The effect of the higher PEEP in this study was relatively small and of questionable clinical significance. This may be in part due to the fact that the LVO/SVC flow ratio observed at all three PEEP levels in the present study was considerably smaller than the mean levels reported in the previous study (∼4.5). This suggests a smaller L-R shunting through the ductus in the population studied. The LVO/SVC flow ratio has been used to indicate L-R ductal shunting independently of intracardiac shunts through the foramen ovale [9]. A decline in L-R ductal shunt can produce a decrease in LVO due to a reduction
Effect of PEEP in Preterm Infants with PDA
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
Discussion
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Table 3. Cerebral oxygenation and gas exchange
PEEP
CrSO2, % SpO2, % FiO2, % SpO2/FiO2 ratio TcPCO2, mm Hg
2 cm H2O
5 cm H2O
8 cm H2O
65±15 94 (91–96) 25 (21–36) 3.7 (2.6–4.6)* 50 (43–68)
66±15 94 (93–98) 24 (21–33) 3.9 (3.0–4.6) 49 (44–65)
67±14 96 (94–99) 23 (21–29) 4.1 (3.3–4.7) 51 (45–65)*
Data are mean ± SD or median (interquartile range). * p < 0.05 by Friedman repeated-measures analysis of variance on ranks with Dunn’s post-hoc method for multiple comparisons versus baseline (PEEP 5 cm H2O).
in recirculation through the lungs and also produce an increase in systemic flow which should be reflected in a higher SVC flow. The extent to which these mechanisms affect the LVO/SVC flow ratio at increasing levels of PEEP is not entirely clear. In this group of infants, the decrease in the LVO/SVC flow ratio at the higher PEEP was small but relatively consistent. This reduction was mostly due to a decline in LVO rather than an increase in SVC flow. It can be alternatively argued that the increase in PEEP to 8 cm H2O impaired venous return and thus counterbalanced the effects of a reduced L-R shunt through the PDA on LVO and systemic flow. The results of the present study are in agreement with the findings of another study, where an increase in PEEP from 5 to 8 cm H2O did not change SVC flow in a group of infants most of whom had a PDA [10]. Interestingly, these investigators found the higher PEEP resulted in a reduction in venous return. Our findings of modest changes in L-R shunt and an unchanged SVC flow are also in agreement with a study involving lung recruitment by a higher MAP during high-frequency ventilation [11]. The modest effect of the higher PEEP on the LVO/ SVC flow ratio may also be due to the fact that the population studied included mechanically ventilated premature infants with poorly compliant lungs due to the underlying lung disease and possibly due to the PDA itself [12]. Hence, the increase in PEEP to 8 cm H2O may not have produced a sufficiently large increase in lung volume to influence PVR. The effects of the higher PEEP may be more striking in infants with better lung function. By study design, the exposure to each PEEP level was kept relatively brief to avoid the confounding effects of alterations in gas exchange that may become evident over longer periods of time. Hence, these data reflect only the mechanical effects of changing lung volume on PVR for 12
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
modulation of the L-R shunt. Data obtained following a continuous exposure to the high or low PEEP levels that result in alterations in ventilation or gas exchange may uncover additive or counterbalancing effects on L-R shunting, venous return and systemic circulation. The changes in oxygenation observed at the lower PEEP were not expected to occur within the relatively brief exposure period. The slightly lower SpO2/FiO2 ratio at a PEEP of 2 cm H2O was the result of the greater need for oxygen showed by some infants to maintain SpO2. This was likely related to a decrease in end-expiratory lung volume and larger pulmonary shunt at the lower PEEP level. A decrease in oxygenation in infants with reactive pulmonary vasculature can cause some degree of hypoxic pulmonary vasoconstriction and reduce L-R ductal shunting that could counterbalance the effect of a lower PEEP. The extent to which the changes in oxygenation influenced these infants’ hemodynamics is unclear, but they limit the interpretation and generalization of the findings. In this group of infants, the small reduction in L-R shunt by the higher PEEP did not result in a better cerebral perfusion as indicated by the lack of effect on SVC flow and cerebral oxygen saturation. It is also possible that in these infants the cerebral circulation is preserved by autoregulation in spite of a reduced systemic flow. The modest but consistent increase in TcPCO2 at a PEEP of 8 was likely the result of pulmonary overdistension affecting ventilation and dead space. It is unlikely that the small increase in CO2 at the higher PEEP could induce cerebral vasodilation. One important limitation to this study is the variability in the hemodynamic measurements. This variability could potentially exceed the effect of the changes in PEEP. However, it is reassuring that the hemodynamic effects, or lack thereof, correlated with the measurements of cerebral oxygenation. In conclusion, increasing PEEP up to 8 cm H2O in mechanically ventilated infants with PDA produced a modest short-term decrease in L-R shunting as indicated by the lower LVO/SVC flow ratio. This however was not accompanied by an improvement in cerebral perfusion or oxygenation.
Disclosure Statement We declare no conflict of interest exists, real or perceived, for all authors. The study received unrestricted support from the University of Miami Project NewBorn, a philanthropic organization. The study supporter did not participate in any aspect of the research and reporting of the data.
Fajardo/Claure/Swaminathan/Sattar/ Vasquez/D’Ugard/Bancalari
References 1 Kitterman JA, Edmunds LH Jr, Gregory GA, Heymann MA, Tooley WH, Rudolph AM: Patent ductus arteriosus in premature infants. Incidence, relation to pulmonary disease and management. N Engl J Med 1972;287:473–477. 2 Kluckow M, Evans N: Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr 2000;137:68–72. 3 Shimada S, Kasai T, Konishi M, Fujiwara T: Effects of patent ductus arteriosus on left ventricular output and organ blood flows in preterm infants with respiratory distress syndrome treated with surfactant. J Pediatr 1994; 125:270–277. 4 Meyers RL, Alpan G, Lin E, Clyman RI: Patent ductus arteriosus, indomethacin, and intestinal distension: effects on intestinal blood flow and oxygen consumption. Pediatr Res 1991; 29:569–574.
Effect of PEEP in Preterm Infants with PDA
5 Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole N, Silva-Neto G: Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995;126:605– 610. 6 Brown ER: Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. J Pediatr 1979;95:865–866. 7 Evans N, Kluckow M: Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183–F186. 8 Evans N, Kluckow M: Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;82:F188–F194.
9 El Hajjar M, Vaksmann G, Rakza T, Kongolo G, Storme L: Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005; 90:F419–F422. 10 de Waal K, Evans N, Osborn D, Kluckow M: Cardiorespiratory effects of changes in end expiratory pressure in ventilated newborns. Arch Dis Child Fetal Neonatal Ed 2007; 92:F444–F448. 11 de Waal K, Evans N, van der Lee J, van Kaam A: Effect of lung recruitment on pulmonary, systemic, and ductal blood flow in preterm infants. J Pediatr 2009;154:651–655. 12 Gerhardt T, Bancalari E: Lung compliance in newborns with patent ductus arteriosus before and after surgical ligation. Biol Neonate 1980;38:96–105.
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
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Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
Effect of Positive End-Expiratory Pressure on Ductal Shunting and Systemic Blood Flow in Preterm Infants with Patent Ductus Arteriosus Maria Florencia Fajardo a Nelson Claure a Sethuraman Swaminathan b Sumbal Sattar b Amelia Vasquez b Carmen D’Ugard a Eduardo Bancalari a
Divisions of a Neonatology, and b Cardiology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Fla., USA
Key Words Patent ductus arteriosus · Positive end-expiratory pressure · Left to right shunt · Systemic blood flow · Premature infant
modest decrease in L-R ductal shunting as indicated by a lower LVO/SVC flow ratio. The higher PEEP did not have a significant effect on cerebral perfusion or oxygenation. © 2013 S. Karger AG, Basel
Abstract Background: Left to right (L-R) shunting through a patent ductus arteriosus (PDA) can reduce systemic and cerebral blood flow in preterm infants. To minimize this, the positive end-expiratory pressure (PEEP) is often raised to increase pulmonary vascular resistance and reduce L-R shunting. The effects of this maneuver on systemic and cerebral hemodynamics and oxygenation are not well documented. Objective: To compare the effects of different PEEP on the left ventricular output (LVO), superior vena cava (SVC) flow, LVO/SVC flow ratio, cerebral oxygenation (CrSO2) and gas exchange in mechanically ventilated preterm infants with PDA. Methods: Sixteen mechanically ventilated infants of 23–30 weeks’ gestational age with L-R shunting through the PDA were studied. Ultrasound measurements of LVO and SVC flow, CrSO2, arterial oxygen saturation and transcutaneous CO2 tension (TcPCO2) obtained at PEEP of 2 and 8 cm H2O were compared with baseline values at 5 cm H2O. Results: There was a small but significant reduction in LVO and the LVO/SVC flow ratio at PEEP of 8 compared to 5 cm H2O. SVC flow and CrSO2 did not differ significantly. Conclusions: Increasing PEEP to 8 cm H2O in ventilated preterm infants with a PDA produced a
© 2013 S. Karger AG, Basel 1661–7800/14/1051–0009$39.50/0 E-Mail [email protected] www.karger.com/neo
The persistence of a patent ductus arteriosus (PDA) occurs frequently in premature infants and it has been associated with complications, including pulmonary hemorrhage, necrotizing enterocolitis, increased incidence of bronchopulmonary dysplasia and intracranial hemorrhage [1–8]. These complications may be related to the increased pulmonary blood flow due to left to right (L-R) ductal shunting and to the steal of systemic blood flow that can reduce tissue perfusion. In these infants, a higher continuous positive airway pressure could increase pulmonary vascular resistance (PVR) and consequently decrease L-R shunting. If effective, this maneuver could result in a redistribution of the left ventricular output (LVO) in favor of systemic blood flow and more particularly in cerebral and coronary perfusion. The hypothesis of this study was that higher levels of positive end-expiratory pressure (PEEP) in mechanically ventilated preterm infants will reduce L-R ductal shunting through the PDA which will be reflected in a lower LVO to superior vena cava (SVC) flow ratio (LVO/SVC flow). This will be accompanied by increased cerebral oxygenation. Nelson Claure, MSc, PhD Division of Neonatology, Department of Pediatrics University of Miami Miller School of Medicine PO Box 016960 R-131, Miami, FL 33101 (USA) E-Mail nclaure @ miami.edu
The objective of the study was to compare LVO, SVC flow and the LVO/SVC flow ratio as an index of L-R shunt through the ductus, cerebral oxygenation and gas exchange at different levels of PEEP in preterm infants with PDA.
Methods Eligible subjects were clinically stable neonates of gestational age (GA) ≤32 weeks and birthweight (BW) ≤2,000 g with a diagnosis of PDA confirmed by echocardiography and undergoing mechanical ventilation who were admitted to the Jackson Memorial Hospital – University of Miami Newborn Intensive Care Unit. The study was approved by the University of Miami Institutional Review Board and Jackson Health System Clinical Trials Office. Written informed parental consent was obtained before enrollment of each infant. Based on published data on the LVO/SVC flow ratio in infants with PDA [9], a sample size of 16 infants was estimated necessary to detect a 30% difference in the LVO/SVC flow ratio with a higher PEEP level, assuming a power of 80 and 5% significance alpha. The L-R shunting through the PDA was confirmed by echocardiography immediately prior to the start of the study measurements in each infant. The level of PEEP set by the clinical team before the start of the study was considered as the baseline level. PEEP was increased and decreased by 3 cm H2O from each infant’s baseline level without exceeding 8 or decreasing below 2 cm H2O, respectively. The sequence of the three PEEP levels was determined at random. Each PEEP level was maintained for 10–20 min. Measurements were obtained after 10 min of stabilization at each PEEP level. Peak inspiratory pressure (PIP) was adjusted to maintain the difference between PIP and PEEP constant. Echocardiographic evaluation at each PEEP level included two-dimensional, M-mode, color flow and spectral Doppler (Acuson Sequoia, Siemens Medical, Mountain View, Calif., USA) to measure the velocity time integral (VTI) to estimate LVO and SVC flow. Aortic Doppler was done via apical long axis view and the diameter measured via parasternal long axis view and measured immediately proximal and just below the aortic valve annulus. SVC Doppler was evaluated by subcostal sagittal views and the diameter via parasternal 3-vessel view and measured close to the entrance to the right atrium. The VTI (area measured under the Doppler velocity envelope for one heart beat) and cross-sectional area of the vessels were measured to estimate the flow and stroke volume. Five VTI measurements were obtained for each infant at each PEEP level and averaged. A mean SVC diameter was calculated from multiple measurements of the SVC to obtain the cross-sectional area. To avoid the effects of the positive pressure cycles of the ventilator on the echocardiographic measurements, these were obtained only when the airway pressure was at PEEP level. For this, a nonscaled waveform of the airway pressure was fed to the ultrasound machine. The operator was able to exclude those cardiac cycles occurring when airway pressure increased. All echocardiography recordings were obtained by the same investigator and were analyzed by a pediatric cardiologist.
10
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
Table 1. Demographic characteristics of study population
Gestational age, weeks BW, g Age at study, days Weight at study, g Ventilator settings at study Mandatory rate, breaths/min PIP, cm H2O PEEP, cm H2O Pressure support, cm H2O MAP, cm H2O FiO2, %
26 (23–30) 710 (470–1,180) 6 (2–71) 730 (483–2,305) 23 (10–45) 18 (15–20) 5 (4–5) 9 (5–12) 8 (6–9) 24 (21–55)
Data are median (range).
Cerebral oxygenation (CrSO2) was evaluated by near-infrared spectroscopy (INVOS 4100 Cerebral Oximeter, Covidien, Boulder, Colo., USA). Arterial oxygen saturation (SpO2) was measured by pulse oximetry (Radical, Masimo, Irvine, Calif., USA). Carbon dioxide tension (TcPCO2) was measured with a transcutaneous monitor (Microgas 7650, Radiometer America, Westlake, Ohio, USA). The fraction of inspired oxygen (FiO2) and mean airway pressure (MAP) were obtained from the ventilator. The ratio between SpO2 and FiO2 was calculated for each infant. Statistical analysis for within-subject comparisons was done by repeated-measures ANOVA with Holm-Sidak post hoc method for pairwise comparisons to a single control for normally distributed data or by the nonparametric Friedman repeated-measures analysis of variance on ranks with Dunn’s post hoc method for pairwise comparisons to baseline of 5 cm H2O.
Results
Sixteen mechanically ventilated infants with documented L-R shunting through a PDA were studied. Their GA, BW, postnatal age and ventilator settings are shown in table 1. All infants had the diagnosis of PDA confirmed immediately prior to the study. The mean PDA diameter of this group of infants was 2.54 ± 0.54 mm. Ten infants were receiving indomethacin or ibuprofen treatment for PDA at the time of the study. Six infants were not receiving treatment. Of these, 3 had received treatment 5 or more days before the study. The baseline PEEP was 5 cm H2O for all infants except for one with a baseline PEEP of 4 cm H2O. The rounded mean values of baseline, high and low PEEP were 5, 8 and 2 cm H2O, respectively. Hemodynamic measurements show a statistically significant reduction in LVO/SVC flow ratio and LVO with PEEP of 8 compared to 5 cm H2O. These reductions were Fajardo/Claure/Swaminathan/Sattar/ Vasquez/D’Ugard/Bancalari
Table 2. Hemodynamic measurements
PEEP
LVO/SVC flow ratio Percent change from baseline LVO, ml/kg/min Percent change from baseline SVC flow, ml/kg/min Percent change from baseline Heart rate, bpm Percent change from baseline
2 cm H2O
5 cm H2O
8 cm H2O
2.54 (1.38 to 2.98) 0.38 (6.99 to 9.23) 326 (302 to 437) –2.87 (–8.85 to 7.27) 168 (141 to 201) –1.23 (–7.19 to 0.72) 146 (144 to 161) –1.78 (–3.21 to 0.0)
2.14 (1.57 to 2.83)
1.96 (1.54 to 2.67)* –13.23 (–19.4 to –4.06) 346 (246 to 393)* –7.79 (–19.90 to –2.04) 164 (139 to 193) 3.53 (–6.60 to 7.02) 149 (146 to 162) –0.95 (–2.11 to 1.37)
361 (305 to 433) 163 (144 to 204) 151 (145 to 161)
Data are median (interquartile range). * p < 0.05 by Friedman repeated-measures analysis of variance on ranks with Dunn’s post hoc method for multiple comparisons vs. baseline (PEEP 5 cm H2O).
40 Change in LVO/SVC flow ratio from baseline of 5 cm H2O (%)
modest (median reduction of 13.23 and 7.79%, respectively) but relatively consistent. LVO/SVC flow decreased in 14 of the 16 infants, but in only 10 of them was the decline >10%. LVO decreased in 13 infants with the higher PEEP compared to baseline, but in only 7 infants was the decrease >10%. LVO and the LVO/SVC flow ratio did not differ with PEEP of 2 compared to 5 cm H2O (table 2). Changes in the LVO/SVC flow ratio during PEEP of 2 and 8 cm H2O as percentage of the baseline PEEP of 5 cm H2O are shown in figure 1. SVC flow did not differ with PEEP of 8 or 2 with respect to PEEP of 5 cm H2O. The effect of the higher PEEP on SVC flow was inconsistent. SVC flow increased in 10 of the 16 infants leading to a median increase of 3.5% for the group, but the increase was >10% in only 2 infants. Heart rate did not differ with PEEP of 8 or 2 with respect to PEEP of 5 cm H2O (table 2). Measurements of CrSO2, SpO2 and FiO2 with PEEP of 2 or 8 did not differ from PEEP of 5 cm H2O (table 3). As expected, the ratio of SpO2/FiO2 was lower at PEEP of 2 compared to PEEP of 5 cm H2O. There was a small but statistically significant increase in TcPCO2 at PEEP of 8 compared to the baseline PEEP of 5 cm H2O. TcPCO2 increased in 13 of the 16 infants with the higher PEEP compared to baseline.
20
0
–20
–40
2 cm H2O
8 cm H2O PEEP
Fig. 1. Changes in the LVO/SVC flow ratio at PEEP of 2 and 8 cm
H2O with respect to the baseline PEEP of 5 cm H2O. A consistent decline in the LVO/SVC flow ratio was observed at the higher PEEP.
These results show that increasing PEEP from 5 to 8 cm H2O in premature infants with a PDA produces a modest but consistent decrease in L-R shunting through the ductus as indicated by a lower LVO/SVC flow ratio. This reduction is in agreement with published data show-
ing a higher LVO/SVC flow ratio in infants with PDA compared to controls [9]. The effect of the higher PEEP in this study was relatively small and of questionable clinical significance. This may be in part due to the fact that the LVO/SVC flow ratio observed at all three PEEP levels in the present study was considerably smaller than the mean levels reported in the previous study (∼4.5). This suggests a smaller L-R shunting through the ductus in the population studied. The LVO/SVC flow ratio has been used to indicate L-R ductal shunting independently of intracardiac shunts through the foramen ovale [9]. A decline in L-R ductal shunt can produce a decrease in LVO due to a reduction
Effect of PEEP in Preterm Infants with PDA
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
Discussion
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Table 3. Cerebral oxygenation and gas exchange
PEEP
CrSO2, % SpO2, % FiO2, % SpO2/FiO2 ratio TcPCO2, mm Hg
2 cm H2O
5 cm H2O
8 cm H2O
65±15 94 (91–96) 25 (21–36) 3.7 (2.6–4.6)* 50 (43–68)
66±15 94 (93–98) 24 (21–33) 3.9 (3.0–4.6) 49 (44–65)
67±14 96 (94–99) 23 (21–29) 4.1 (3.3–4.7) 51 (45–65)*
Data are mean ± SD or median (interquartile range). * p < 0.05 by Friedman repeated-measures analysis of variance on ranks with Dunn’s post-hoc method for multiple comparisons versus baseline (PEEP 5 cm H2O).
in recirculation through the lungs and also produce an increase in systemic flow which should be reflected in a higher SVC flow. The extent to which these mechanisms affect the LVO/SVC flow ratio at increasing levels of PEEP is not entirely clear. In this group of infants, the decrease in the LVO/SVC flow ratio at the higher PEEP was small but relatively consistent. This reduction was mostly due to a decline in LVO rather than an increase in SVC flow. It can be alternatively argued that the increase in PEEP to 8 cm H2O impaired venous return and thus counterbalanced the effects of a reduced L-R shunt through the PDA on LVO and systemic flow. The results of the present study are in agreement with the findings of another study, where an increase in PEEP from 5 to 8 cm H2O did not change SVC flow in a group of infants most of whom had a PDA [10]. Interestingly, these investigators found the higher PEEP resulted in a reduction in venous return. Our findings of modest changes in L-R shunt and an unchanged SVC flow are also in agreement with a study involving lung recruitment by a higher MAP during high-frequency ventilation [11]. The modest effect of the higher PEEP on the LVO/ SVC flow ratio may also be due to the fact that the population studied included mechanically ventilated premature infants with poorly compliant lungs due to the underlying lung disease and possibly due to the PDA itself [12]. Hence, the increase in PEEP to 8 cm H2O may not have produced a sufficiently large increase in lung volume to influence PVR. The effects of the higher PEEP may be more striking in infants with better lung function. By study design, the exposure to each PEEP level was kept relatively brief to avoid the confounding effects of alterations in gas exchange that may become evident over longer periods of time. Hence, these data reflect only the mechanical effects of changing lung volume on PVR for 12
Neonatology 2014;105:9–13 DOI: 10.1159/000355146
modulation of the L-R shunt. Data obtained following a continuous exposure to the high or low PEEP levels that result in alterations in ventilation or gas exchange may uncover additive or counterbalancing effects on L-R shunting, venous return and systemic circulation. The changes in oxygenation observed at the lower PEEP were not expected to occur within the relatively brief exposure period. The slightly lower SpO2/FiO2 ratio at a PEEP of 2 cm H2O was the result of the greater need for oxygen showed by some infants to maintain SpO2. This was likely related to a decrease in end-expiratory lung volume and larger pulmonary shunt at the lower PEEP level. A decrease in oxygenation in infants with reactive pulmonary vasculature can cause some degree of hypoxic pulmonary vasoconstriction and reduce L-R ductal shunting that could counterbalance the effect of a lower PEEP. The extent to which the changes in oxygenation influenced these infants’ hemodynamics is unclear, but they limit the interpretation and generalization of the findings. In this group of infants, the small reduction in L-R shunt by the higher PEEP did not result in a better cerebral perfusion as indicated by the lack of effect on SVC flow and cerebral oxygen saturation. It is also possible that in these infants the cerebral circulation is preserved by autoregulation in spite of a reduced systemic flow. The modest but consistent increase in TcPCO2 at a PEEP of 8 was likely the result of pulmonary overdistension affecting ventilation and dead space. It is unlikely that the small increase in CO2 at the higher PEEP could induce cerebral vasodilation. One important limitation to this study is the variability in the hemodynamic measurements. This variability could potentially exceed the effect of the changes in PEEP. However, it is reassuring that the hemodynamic effects, or lack thereof, correlated with the measurements of cerebral oxygenation. In conclusion, increasing PEEP up to 8 cm H2O in mechanically ventilated infants with PDA produced a modest short-term decrease in L-R shunting as indicated by the lower LVO/SVC flow ratio. This however was not accompanied by an improvement in cerebral perfusion or oxygenation.
Disclosure Statement We declare no conflict of interest exists, real or perceived, for all authors. The study received unrestricted support from the University of Miami Project NewBorn, a philanthropic organization. The study supporter did not participate in any aspect of the research and reporting of the data.
Fajardo/Claure/Swaminathan/Sattar/ Vasquez/D’Ugard/Bancalari
References 1 Kitterman JA, Edmunds LH Jr, Gregory GA, Heymann MA, Tooley WH, Rudolph AM: Patent ductus arteriosus in premature infants. Incidence, relation to pulmonary disease and management. N Engl J Med 1972;287:473–477. 2 Kluckow M, Evans N: Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr 2000;137:68–72. 3 Shimada S, Kasai T, Konishi M, Fujiwara T: Effects of patent ductus arteriosus on left ventricular output and organ blood flows in preterm infants with respiratory distress syndrome treated with surfactant. J Pediatr 1994; 125:270–277. 4 Meyers RL, Alpan G, Lin E, Clyman RI: Patent ductus arteriosus, indomethacin, and intestinal distension: effects on intestinal blood flow and oxygen consumption. Pediatr Res 1991; 29:569–574.
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5 Rojas MA, Gonzalez A, Bancalari E, Claure N, Poole N, Silva-Neto G: Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr 1995;126:605– 610. 6 Brown ER: Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. J Pediatr 1979;95:865–866. 7 Evans N, Kluckow M: Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183–F186. 8 Evans N, Kluckow M: Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;82:F188–F194.
9 El Hajjar M, Vaksmann G, Rakza T, Kongolo G, Storme L: Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005; 90:F419–F422. 10 de Waal K, Evans N, Osborn D, Kluckow M: Cardiorespiratory effects of changes in end expiratory pressure in ventilated newborns. Arch Dis Child Fetal Neonatal Ed 2007; 92:F444–F448. 11 de Waal K, Evans N, van der Lee J, van Kaam A: Effect of lung recruitment on pulmonary, systemic, and ductal blood flow in preterm infants. J Pediatr 2009;154:651–655. 12 Gerhardt T, Bancalari E: Lung compliance in newborns with patent ductus arteriosus before and after surgical ligation. Biol Neonate 1980;38:96–105.
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