Dopamine and Neonatal Pulmonary Hypertension—Pressing Need for a Better Pressor?
2022; Elsevier BV; Volume: 246; Linguagem: Inglês
10.1016/j.jpeds.2022.03.022
ISSN1097-6833
AutoresPatrick J. McNamara, Regan E. Giesinger, Satyan Lakshminrusimha,
Tópico(s)Congenital Heart Disease Studies
ResumoDespite scientific advancement, hypoxemic respiratory failure remains a major challenge in contemporary neonatal intensive care. Dysregulation of the pulmonary vascular bed and failure of the normal postnatal decline in pulmonary vascular resistance (PVR) lead to acute pulmonary hypertension (aPH), traditionally referred to as persistent pulmonary hypertension (PH) of the newborn. The hemodynamic consequences of excessive right ventricular (RV) afterload due to elevated PVR include RV dysfunction, reduced left ventricular (LV) preload, low cardiac output, and systemic hypoperfusion with associated low systemic arterial pressure (SAP). The philosophical approach to low SAP in the setting of critical hypoxemia is based either on the correction of mean SAP, which is lower than the gestational age equivalent to restore cardiac output,1Stranak Z. Semberova J. Barrington K. O'Donnell C. Marlow N. Naulaers G. et al.International survey on diagnosis and management of hypotension in extremely preterm babies.Eur J Pediatr. 2014; 173: 793-798Crossref PubMed Scopus (67) Google Scholar or the pursuit of an artificial threshold (based on clinician-estimated pulmonary arterial pressure [PAP]) that will reverse a right-to-left shunt across the patent ductus arteriosus to alleviate hypoxemia.2Siefkes H.M. Lakshminrusimha S. Management of systemic hypotension in term infants with persistent pulmonary hypertension of the newborn: an illustrated review.Arch Dis Child Fetal Neonatal Ed. 2021; 106: 446-455Crossref PubMed Scopus (6) Google Scholar, 3Lakshminrusimha S. Mathew B. Leach C.L. Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide.Semin Perinatol. 2016; 40: 160-173Crossref PubMed Scopus (64) Google Scholar, 4Lakshminrusimha S. Keszler M. Persistent pulmonary hypertension of the newborn.NeoReviews. 2015; 16: e680-e692Crossref PubMed Scopus (55) Google Scholar As neither approach have been formally tested against outcome in the setting of aPH, the possibility that treatment may have unintended consequences is high. In addition, overemphasis on this strategic approach distracts the clinician away from consideration of the primary physiologic disturbance, namely elevated PVR and its negative effects on RV function, RV–LV interaction, and the adequacy or preductal (hence brain) cardiac output. Like many cardiovascular disease states in neonates, arbitrary blood pressure targets represent the contemporary mainstay of assessing systemic hemodynamics and upon which a determination is made regarding health vs disease. Nevertheless, low SAP is a frequent observation in the setting of aPH and the primary driver of cardiovascular drug selection. Typically, intravenous dopamine is the initial pressor of choice for neonatal systemic hypotension, oftentimes irrespective of the underlying physiology and without due consideration of its variance in pharmacologic effects.1Stranak Z. Semberova J. Barrington K. O'Donnell C. Marlow N. Naulaers G. et al.International survey on diagnosis and management of hypotension in extremely preterm babies.Eur J Pediatr. 2014; 173: 793-798Crossref PubMed Scopus (67) Google Scholar,5Nakwan N. Chaiwiriyawong P. An international survey on persistent pulmonary hypertension of the newborn: a need for an evidence-based management.J Neonatal Perinatal Med. 2016; 9: 243-250Crossref PubMed Scopus (15) Google Scholar,6Giesinger R.E. Levy P.T. Lauren Ruoss J. El Dib M. Mohammad K. Wintermark P. et al.Cardiovascular management following hypoxic-ischemic encephalopathy in North America: need for physiologic consideration.Pediatr Res. 2021; 90: 600-607Crossref PubMed Scopus (4) Google Scholar In a population-based study from Norway, 42.1% of patients in the neonatal intensive care unit (NICU) with aPH received inotropes and ∼90% of neonates on inotropic/vasopressor therapy received dopamine.7Burns M.L. Stensvold H.J. Risnes K. Guthe H.J. Astrup H. Nordhov S.M. et al.Inotropic therapy in newborns, a population-based national registry study.Pediatr Crit Care Med. 2016; 17: 948-956Crossref PubMed Scopus (19) Google Scholar The familiarity with dopamine, increase in SAP at relatively low doses,8Padbury J.F. Neonatal dopamine pharmacodynamics: lessons from the bedside.J Pediatr. 1998; 133: 719-720Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,9Seri I. Abbasi S. Wood D.C. Gerdes J.S. Regional hemodynamic effects of dopamine in the sick preterm neonate.J Pediatr. 1998; 133: 728-734Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar simple first-order pharmacokinetics, ability to achieve steady-state levels within 20 minutes of infusion, and a presumed good safety profile10Padbury J.F. Agata Y. Baylen B.G. Ludlow J.K. Polk D.H. Habib D.M. et al.Pharmacokinetics of dopamine in critically ill newborn infants.J Pediatr. 1990; 117: 472-476Abstract Full Text PDF PubMed Scopus (43) Google Scholar have resulted in dopamine being the most commonly used vasopressor and inotrope in the NICU setting.7Burns M.L. Stensvold H.J. Risnes K. Guthe H.J. Astrup H. Nordhov S.M. et al.Inotropic therapy in newborns, a population-based national registry study.Pediatr Crit Care Med. 2016; 17: 948-956Crossref PubMed Scopus (19) Google Scholar Attention to risks and benefits is of relevance as it relates to the commonly used strategy to improve the efficacy of oxygenation by targeting “supranormal” levels of SAP in an attempt to reverse the directionality of the atrial and/or ductal pulmonary to systemic (right-to-left) shunt flow. Anecdotally, this practice has been “normalized” as the standard of care in many NICUs, despite limited physiologic justification or clinical evidence of benefit. The use of dopamine as the universal standard for hemodynamic instability, its biologic and pharmacologic plausibility, and real-world track record in successfully accomplishing these goals need to be questioned.5Nakwan N. Chaiwiriyawong P. An international survey on persistent pulmonary hypertension of the newborn: a need for an evidence-based management.J Neonatal Perinatal Med. 2016; 9: 243-250Crossref PubMed Scopus (15) Google Scholar,6Giesinger R.E. Levy P.T. Lauren Ruoss J. El Dib M. Mohammad K. Wintermark P. et al.Cardiovascular management following hypoxic-ischemic encephalopathy in North America: need for physiologic consideration.Pediatr Res. 2021; 90: 600-607Crossref PubMed Scopus (4) Google Scholar In this commentary, we will review the physiologic contributors to hemodynamic instability in aPH, appraise the biological appropriateness of dopamine as the vasopressor of choice, and discuss the advantages of longitudinal targeted neonatal echocardiography in characterizing the interplay of heart function and pulmonary hemodynamics. Finally, we propose a framework for enhanced precision in the selection of vasopressor agents with favorable pulmonary vascular properties and highlight knowledge gaps and research priorities. In utero, 50% of oxygenated placental return flows right-to-left across the atrial septum to comprise the bulk of LV preload.11Hooper S.B. Te Pas A.B. Lang J. van Vonderen J.J. Roehr C.C. Kluckow M. et al.Cardiovascular transition at birth: a physiological sequence.Pediatr Res. 2015; 77: 608-614Crossref PubMed Scopus (123) Google Scholar Similarly, a high PVR state creates a right to left pressure gradient across the ductus arteriosus. As a result, right to left ductal shunt, which originates in the RV, is an important contributor to post-ductal perfusion and placental return.11Hooper S.B. Te Pas A.B. Lang J. van Vonderen J.J. Roehr C.C. Kluckow M. et al.Cardiovascular transition at birth: a physiological sequence.Pediatr Res. 2015; 77: 608-614Crossref PubMed Scopus (123) Google Scholar Immediately after delivery, the neonate's first breaths aerate the alveoli to initiate a rapid decline in PVR, enabling circulatory redistribution and augmented RV systolic performance, which leads to an increase in pulmonary blood flow.12te Pas A.B. Davis P.G. Hooper S.B. Morley C.J. From liquid to air: breathing after birth.J Pediatr. 2008; 152: 607-611Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Consequently, the augmentation in pulmonary blood flow results in a sufficient rise in pulmonary venous return that it rapidly replaces the right-to-left atrial shunt as the dominant source of left heart preload, thus maintaining cardiac output throughout the postnatal transition. Simultaneously, the newborn's oxygen saturation gradually approaches postnatal norms as pulmonary blood flow increases. The right-to-left ductal shunt declines with incremental reduction in PVR as a greater proportion of alveoli are filled with oxygen and cleared of carbon dioxide.13Crossley K.J. Allison B.J. Polglase G.R. Morley C.J. Davis P.G. Hooper S.B. Dynamic changes in the direction of blood flow through the ductus arteriosus at birth.J Physiol. 2009; 587: 4695-4704Crossref PubMed Scopus (114) Google Scholar The complexity of these changes and the intricate interplay between lung recruitment, PVR, and RV performance places the newly born in a state of vulnerability such that compromise during the birth process or postnatal cardiorespiratory instability may lead to PH. The most common form of aPH occurs when PVR remains elevated after birth (Figure 1, A). This may be due to effects of pulmonary parenchymal disease on appropriate ventilation/perfusion matching, failure of transitional mechanisms, and/or acidosis (such as in patients following perinatal hypoxia–ischemia). In essence, postnatal persistence of in utero pulmonary vasoconstriction leads to an inability of the fetal RV to generate sufficient intracavity pressure to completely eject blood to the pulmonary vascular bed. With each beat, RV emptying is incomplete because there is a lower pressure gradient between the RV cavity, even at maximal contraction, and the pulmonary vascular bed. Of importance, the neonatal RV myocardium is exquisitely sensitive to increased afterload, even more so than the immature left ventricle.14Reller M.D. Morton M.J. Reid D.L. Thornburg K.L. Fetal lamb ventricles respond differently to filling and arterial pressures and to in utero ventilation.Pediatr Res. 1987; 22: 621-626Crossref PubMed Scopus (79) Google Scholar Right-to-left ductal shunt offers a pop-off mechanism limiting RV afterload in the presence of high PVR, albeit still greater than in utero due to the loss of the low-resistance placenta. Thus, even systemic vascular resistance (SVR) that is not augmented by a vasopressor represents an afterload stress on the RV in the transitional period. Afterload stress leads to several changes in RV mechanics that become progressively pathologic. Because blood only flows down a pressure gradient (high pressure to low pressure), increased afterload leads to an early equilibration of pressure between the RV cavity and the main pulmonary artery. Thus, there is an increase in RV end-systolic pressure and, because more blood is left behind at the end of systole (less ejected down the pressure gradient), an increase in RV end-diastolic pressure. These changes may lead to RV dilation, which allows the RV to preserve stroke volume because a larger ventricle needs to eject proportionally less blood. This process is also referred to as heterotrophic adaptation. If progressive, heterotrophic adaptation may become maladaptive; RV dilation places increased wall stress on myocytes, leads to increased myocardial oxygen demand, and has a negative impact on LV mechanics through a variety of mechanisms. These mechanisms primarily relate to either increased RV end-diastolic pressure and/or a reduction in RV myocardial oxygen supply.15Naeije R. Manes A. The right ventricle in pulmonary arterial hypertension.Eur Respir Rev. 2014; 23: 476-487Crossref PubMed Scopus (134) Google Scholar To appreciate the issue of oxygen supply, it is first important to understand coronary flow to the RV and its vulnerability to ischemia. In the normal neonate, RV perfusion occurs in a phasic pattern throughout the cardiac cycle because aortic root pressure remains greater than RV cavity pressure during systole, unlike the LV, where the LV systolic cavity pressure and the aortic root pressure are equal. Patients with aPH have elevated RV systolic pressure and, hence, lose systolic coronary perfusion. A second hit occurs as RV dilation leads to elevated RV end-diastolic pressure, right atrial, and central venous pressure and, therefore, reduction in diastolic coronary flow to the RV. Low coronary root pressure due to low cardiac output and hypotension also may contribute.15Naeije R. Manes A. The right ventricle in pulmonary arterial hypertension.Eur Respir Rev. 2014; 23: 476-487Crossref PubMed Scopus (134) Google Scholar,16Brooks H. Kirk E.S. Vokonas P.S. Urschel C.W. Sonnenblick E.H. Performance of the right ventricle under stress: relation to right coronary flow.J Clin Invest. 1971; 50: 2176-2183Crossref PubMed Scopus (162) Google Scholar In addition, the normally robust neonatal adaptive response to sustained tachycardia is blunted in the presence of cardiac dysfunction, resulting in little, if any, contractile compensation for inadequate filling time.17Schmidt M.R. White P.A. Khambadkone S. Gross G.J. Botker H.E. Vogel M. et al.The neonatal but not the mature heart adapts to acute tachycardia by beneficial modification of the force-frequency relationship.Pediatr Cardiol. 2011; 32: 562-567Crossref PubMed Scopus (5) Google Scholar This may exacerbate coronary hypoperfusion, ischemia, and may contribute to the ongoing vicious cycle of RV dysfunction. RV to pulmonary artery uncoupling, or an alteration in the relationship between RV contractility and afterload, occurs because myocardial ischemia is an independent mediator of RV dysfunction; as a result, relieving the RV afterload, such as with inhaled nitric oxide (iNO), becomes insufficient therapy to normalize RV function. The key role of myocardial ischemia in the progression of circulatory inadequacy is supported by studies demonstrating improved cardiac output, pulmonary blood flow, and clinical markers of cardiovascular stability using norepinephrine18Hirsch L.J. Rooney M.W. Wat S.S. Kleinmann B. Mathru M. Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism.Chest. 1991; 100: 796-801Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar,19Tourneux P. Rakza T. Bouissou A. Krim G. Storme L. Pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension.J Pediatr. 2008; 153: 345-349Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar or vasopressin20Mohamed A. Nasef N. Shah V. McNamara P.J. Vasopressin as a rescue therapy for refractory pulmonary hypertension in neonates: case series.Pediatr Crit Care Med. 2014; 15: 148-154Crossref PubMed Scopus (50) Google Scholar to restore myocardial oxygenation and blood flow. There are several relevant alterations in LV performance in the presence of RV dilation/dysfunction. First, impaired pulmonary venous return induces a low preload state unless there is a large right-to-left atrial level shunt to supplement LA blood flow, albeit with deoxygenated blood. This manifests as impaired LV function due to the Frank-Starling mechanism or low preductal oxygen saturation depending on whether the magnitude of the atrial shunt is small or large enough to cause sufficient mixing. Second, leftward deviation (bowing into the LV) of the septum leads to suboptimal LV conformation. Although ejection fraction may be preserved initially, over time, this will compromise LV systolic performance.21Naeije R. Badagliacca R. The overloaded right heart and ventricular interdependence.Cardiovasc Res. 2017; 113: 1474-1485Crossref PubMed Scopus (100) Google Scholar Third, abnormal septal configuration and compliance reduce the efficacy of systolic ventricular interdependence through which the LV contributes to up to 40% of RV systolic driving force.22Brinker J.A. Weiss J.L. Lappe D.L. Rabson J.L. Summer W.R. Permutt S. et al.Leftward septal displacement during right ventricular loading in man.Circulation. 1980; 61: 626-633Crossref PubMed Scopus (304) Google Scholar,23Bronicki R.A. Anas N.G. Cardiopulmonary interaction.Pediatr Crit Care Med. 2009; 10: 313-322Crossref PubMed Scopus (50) Google Scholar These factors may all contribute to compensatory tachycardia in an effort to maintain cardiac output, which may be ineffective, given the inability of the failing heart to respond to tachycardia by increasing contractility. Finally, myocardial fibers that are shared by the ventricles may contribute to secondary LV dysfunction due to RV myocardial ischemia. Dopamine, a drug with nonselective vasoconstricting actions at a variety of catecholamine receptors in both the pulmonary and systemic circulation, has potential to adversely impact this physiology. Further vasoconstriction of the already compromised pulmonary vascular bed becomes relevant as an adverse effect. In addition, the impact of nonjudicious systemic vasopressor use on SVR and LV mechanics is an oftentimes forgotten consideration; specifically, increased LV afterload may further compromise, not only the adequacy of LV systolic performance but the efficacy of oxygenation. This is secondary to pulmonary venous hypertension through elevating LV end-diastolic pressure. The hemodynamic effects of dopamine have been studied in animal models. The differential response of the systemic and pulmonary vasculature to dopamine appears to be vary between healthy (“control”) animals compared with diseased models. Feltes et al24Feltes T.F. Hansen T.N. Martin C.G. Leblanc A.L. Smith S. Giesler M.E. The effects of dopamine infusion on regional blood flow in newborn lambs.Pediatr Res. 1987; 21: 131-136Crossref PubMed Scopus (29) Google Scholar infused 0-160 μg/kg/min of dopamine in 5- to 12-day-old normal lambs. Dopamine selectively increased SVR without altering PVR. Cheung et al25Cheung P.Y. Barrington K.J. Pearson R.J. Bigam D.L. Finer N.N. Van Aerde J.E. Systemic, pulmonary and mesenteric perfusion and oxygenation effects of dopamine and epinephrine.Am J Respir Crit Care Med. 1997; 155: 32-37Crossref PubMed Scopus (51) Google Scholar infused dopamine (0-32 μg/kg/min) to 1- to 3-day-old piglets and observed an increase in SAP and PAP. The SAP/PAP ratio, however, decreased with high doses of dopamine. Lakshminrusimha26Lakshminrusimha S. The pulmonary circulation in neonatal respiratory failure.Clin Perinatol. 2012; 39: 655-683Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar described the effects of dopamine infusion in both control newly born lambs and lambs with PH induced by antenatal ductal ligation. In control lambs, there was selective increase in SAP (Figure 2, A), with an increase in SAP/PAP ratio (Figure 2, B) without any change in oxygenation (Figure 2, C). In lambs with aPH, PAP was significantly greater compared with control lambs and close to systemic levels at baseline (Figure 2, A), and following dopamine, PAP increased similar to SAP with no significant change in the SAP/PAP ratio (Figure 2). In hypoxic, nonasphyxiated 1- to 3-day-old neonatal pigs, dopamine (2-32 μg/kg/min) increased PAP, negatively impacting the SAP/PAP ratio.27Cheung P.-Y. Barrington K.J. The effects of dopamine and epinephrine on hemodynamics and oxygen metabolism in hypoxic anesthetized piglets.Crit Care. 2001; 5: 158-166Crossref PubMed Scopus (66) Google Scholar Manouchehri et al28Manouchehri N. Bigam D.L. Churchill T. Rayner D. Joynt C. Cheung P.Y. A comparison of combination dopamine and epinephrine treatment with high-dose dopamine alone in asphyxiated newborn piglets after resuscitation.Pediatr Res. 2013; 73: 435-442Crossref PubMed Scopus (9) Google Scholar compared dopamine with dopamine + epinephrine using a piglet asphyxia model where piglets were exposed to 2 hours of hypoxia (PaO2 40 ± 1 mm Hg) followed by 10 minutes of 100% oxygen resuscitation (PaO2 351 ± 15 mm Hg); dopamine (20 μg/kg/min) caused a 101% increase in the PAP/SAP ratio from baseline. Overall, these data suggest that in models without aPH, dopamine in typical pharmacologic doses selectively increases SAP and the SAP/PAP ratio. However, in the presence of aPH and/or remodeled vasculature, dopamine markedly elevates PAP without any positive change to the SAP/PAP ratio and without improvement in oxygenation. Research regarding the biological effects of dopamine in neonates is limited; however, it is reasonable to extrapolate that for patients in whom low SVR is the primary driver of clinical instability, dopamine may be advantageous. However, for infants born at term with pathologically elevated PVR and RV dysfunction, the merits of this approach are questionable. Raising SAP via vasoconstriction may be detrimental to both ventricles, and there are no published studies evaluating the specific role of dopamine in neonatal aPH. Among infants born preterm, there is little controversy around the efficacy of dopamine in increasing SAP,29Valverde E. Pellicer A. Madero R. Elorza D. Quero J. Cabanas F. Dopamine versus epinephrine for cardiovascular support in low birth weight infants: analysis of systemic effects and neonatal clinical outcomes.Pediatrics. 2006; 117: e1213-e1222Crossref PubMed Scopus (92) Google Scholar,30Osborn D. Evans N. Kluckow M. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow.J Pediatr. 2002; 140: 183-191Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar and this approach has become the universal standard. Limited data exist, however, on the potential impact of dopamine on the SAP/PAP relationship. Liet et al31Liet J.M. Boscher C. Gras-Leguen C. Gournay V. Debillon T. Rozé J.C. Dopamine effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus.J Pediatr. 2002; 140: 373-375Abstract Full Text PDF PubMed Scopus (52) Google Scholar performed a comparison of PAP and SAP, assessed by changes in ductal flow velocity, in a cohort of 18 preterm infants before and after treatment of hypotension with dopamine. They identified an overall increase in mean PAP of 43%, which was similar to the increase of 41% in mean SAP; of concern, 50% of the cohort experienced an increase in the mean PAP/SAP ratio. Moreover, almost 20% of infants with exclusively left-to-right flow before dopamine had a shunt that became bidirectional, and 2 patients required escalation of supplemental oxygen to maintain goal saturations.31Liet J.M. Boscher C. Gras-Leguen C. Gournay V. Debillon T. Rozé J.C. Dopamine effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus.J Pediatr. 2002; 140: 373-375Abstract Full Text PDF PubMed Scopus (52) Google Scholar In another study designed to evaluate the role of dopamine as a potential modulator of ductal shunt, a similar cohort of 17 infants with hypotension born preterm with a mean of 28 ± 2 weeks of gestation were serially evaluated before and after dopamine administration.32Bouissou A. Rakza T. Klosowski S. Tourneux P. Vanderborght M. Storme L. Hypotension in preterm infants with significant patent ductus arteriosus: effects of dopamine.J Pediatr. 2008; 153: 790-794Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Dopamine led to an incremental increase in mean PAP and mean PAP to left pulmonary artery flow ratio, which the authors used as a surrogate marker of PVR.32Bouissou A. Rakza T. Klosowski S. Tourneux P. Vanderborght M. Storme L. Hypotension in preterm infants with significant patent ductus arteriosus: effects of dopamine.J Pediatr. 2008; 153: 790-794Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The impact of dopamine on heart function in human neonates with aPH is unknown. We speculate that the magnitude of the positive inotropic effect would have to be marked to outweigh the afterload-mediated decline in RV performance33Bussmann N. El-Khuffash A. Breatnach C.R. McCallion N. Franklin O. Singh G.K. et al.Left ventricular diastolic function influences right ventricular—Pulmonary vascular coupling in premature infants.Early Hum Dev. 2019; 128: 35-40Crossref PubMed Scopus (19) Google Scholar,34Levy P.T. El Khuffash A. Woo K.V. Hauck A. Hamvas A. Singh G.K. A novel noninvasive index to characterize right ventricle pulmonary arterial vascular coupling in children.JACC Cardiovasc Imaging. 2019; 12: 761-763Crossref PubMed Scopus (13) Google Scholar caused by both increased systemic and PVR. Dopamine is a documented chronotrope,31Liet J.M. Boscher C. Gras-Leguen C. Gournay V. Debillon T. Rozé J.C. Dopamine effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus.J Pediatr. 2002; 140: 373-375Abstract Full Text PDF PubMed Scopus (52) Google Scholar,32Bouissou A. Rakza T. Klosowski S. Tourneux P. Vanderborght M. Storme L. Hypotension in preterm infants with significant patent ductus arteriosus: effects of dopamine.J Pediatr. 2008; 153: 790-794Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar which has the potential to exacerbate disease-mediated tachycardia. Importantly, there are no published literature to suggest any documented benefit on either hemodynamics or oxygenation in this patient population. In patients with aPH and significant LV dysfunction, the systemic circulation can become dependent on right-to-left ductal and atrial shunting. Increased left atrial pressure due to LV dysfunction and increased LV afterload due to dopamine can lead to worsening of hypoperfusion, acidosis, and progressive hypoxemia due to pulmonary venous hypertension (Figure 1, B). Acidosis further increases PVR. Animal data suggest that in patients with aPH in whom dopamine infusion is escalated beyond 10 μg/kg/min, there is a risk of marked elevation of PAP. In summary, we were unable to find any evidence in support of dopamine as the vasopressor of choice in the setting of aPH; rather, data from observational studies in both infants born preterm and at term suggest that the effects of dopamine are likely to be unfavorable and are magnified at greater doses. Instead of a focus on the use of vasoconstriction and supranormal SAP to drive blood through the pulmonary vascular bed, it may be prudent to consider the use of cardiovascular agents whose pharmacologic properties are favorable to the pulmonary vascular bed and myocardial systolic/diastolic performance. The 3 main drivers of disease severity in aPH are the magnitude of elevation of PAP, the degree of RV dysfunction, and the presence of a low cardiac output state, which contributes to impaired RV preload, low coronary perfusion pressure, and acidosis. Severe hypoxemia is one resulting clinical phenotype and further aggravates these factors, rather than being the principal driver itself. The approach to restoration of adequate pulmonary blood flow to support systemic oxygen delivery may require consideration of correction of each of these abnormalities. Hence, rather than focusing exclusively on arterial pressure, an approach focused on optimization of PVR, RV health, and improved systemic flow is suggested (Table).TablePhysiological concepts and suggested therapeutic considerations and important exceptionsPhysiologic conceptsTherapeutic approachesHigh PVRSpecific (eg, iNO) or nonspecific (eg, milrinone, sildenafil, PGE) pulmonary vasodilatorsRV systolic and diastolic dysfunctionPositive inotropes (eg, dobutamine, milrinone, epinephrine)Impaired LV filling/systemic blood flowMaintain central venous pressure (eg, volume, PGE) and “PVR-friendly” vasoconstriction (eg, vasopressin or norepinephrine)Low coronary prefusion pressureMaintain adequate diastolic pressure (eg, vasopressin)Physiologic exceptionsTherapeutic cautionsHypertrophic cardiomyopathy (IDM phenotype)Avoid tachycardia or inotropy; vasopressin and volume for hypotensionEncephalopathic patients undergoing therapeutic hypothermiaAvoid drugs with renal clearance (eg, milrinone) give risk of toxic accumulationIDM, infant of mother with diabetes; PGE, prostaglandin. Open table in a new tab IDM, infant of mother with diabetes; PGE, prostaglandin. Provided the LV function is normal, for the coupled RV, in which the decrease in RV performance is proportionate to the elevation in PAP, selective pulmonary vasodilation using iNO may result in a sufficient reduction in PAP35Tworetzky W. Bristow J. Moore P. Brook M.M. Segal M.R. Brasch R.C. et al.Inhaled nitric oxide in neonates with persistent pulmonary hypertension.Lancet. 2001; 357: 118-120Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar to improve RV performance and restore pulmonary blood flow. If this is not sufficient, a careful appraisal with quantification of RV performance using targeted neonatal echocardiography and evaluation for other ambient conditions may guide next steps (Figure 3).36Bischoff A.R. Habib S. McNamara P.J. Giesinger R.E. Hemodynamic response to milrinone for refractory hypoxemia during therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy.J Perinatol. 2021; 41: 2345-2354Crossref PubMed Scopus (9) Google Scholar, 37Toubas P.L. Hof R.P. Heymann M.A. Rudolph A.M. Effects of hypothermia and rewarming on the neonatal circulation.Arch Fr Pediatr. 1978; 35: 84-92PubMed Google Scholar, 38Rubini A. Effect of perfusate temperature on pulmonary vascular resistance and compliance by arterial and venous occlusion in the rat.Eur J Appl Physiol. 2005; 93: 435-439Crossref PubMed Scopus (23) Google Scholar First, iatrogenic blood loss, occult bleeding, or dehydration may need to be corrected to ensure adequate circulating volume. Second, among patients with severe RV d
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