Abstract
A persistent patent ductus arteriosus (PDA) can have significant clinical consequences in preterm infants, depending on the degree of left-to-right shunting, its impact on cardiac performance, and associated perinatal risk factors that can mitigate or exacerbate the shunt. Although the best management strategy remains contentious, PDAs that have contraindications to, or have failed medical management have historically undergone surgical ligation. Recently smaller occluder devices and delivery systems have allowed for minimally invasive closure in the catheterization laboratory even in extremely premature infants. The present review summarizes the pathophysiologic manifestations, treatment options and management of hemodynamically significant PDA in preterm infants. Additionally, we review the available literature surrounding the respiratory support and outcomes of preterm infants following definitive PDA closure.
- patent ductus arteriosus
- prematurity
- surgical ligation
- transcatheter PDA closure
- transport
- anesthesia
- cardiorespiratory instability
- post-ligation cardiac syndrome
- high-frequency ventilation
Introduction
In 1939 Dr Robert E. Gross performed the first successful persistent ductus arteriosus (PDA) ligation, marking the promising start of congenital cardiac surgery. Subsequent innovation has promoted the development of percutaneous techniques that permit minimally invasive closure in most children, except for the smallest infants. Until recently, extremely low birthweight (ELBW <1,000 g) infants have required surgical intervention due to their small size and equipment limitations in the cardiac catheterization laboratory. The morbidity associated with surgical ligation (SL) has led to increasing interest in the use of percutaneous techniques as a less invasive alternative for definitive ductal closure in premature infants.1 In 2019, the United States Food and Drug Administration approved the Amplatzer Piccolo Occluder (Abbott Structural Heart, Plymouth, Minnesota) for transcatheter-PDA closure (TCPC) in infants weighing > 700 g and a postnatal age >3 days.2 Accordingly, the aim of this review is to describe the pathophysiology of the hemodynamically significant PDA in preterm infants, compare definitive treatment options and identify special considerations for the management of ELBW infants undergoing definitive PDA closure.
In utero, oxygenation is dependent upon the placenta for gas exchange as the fetal lungs are fluid-filled and characterized by high pulmonary vascular resistance (PVR) with only 8–20% of combined cardiac output passing through the pulmonary circulation.3 At birth, the onset of ventilation initiates the physiologic transition from fetal circulation to postnatal circulation.4 The rapid reduction of PVR and concurrent increase of systemic vascular resistance (SVR) generally leads to a progressive reversal of blood flow across the PDA, from entirely right-to-left to predominately left-to-right.5 After which, the PDA is exposed to high systemic arterial oxygen concentration and withdrawal of vasodilatory mediators including circulating prostaglandin, nitric oxide and adenosine levels along with concurrent increase of vasoconstrictors such as endothelin-1, catecholamines and contractile prostanoids.6 Collectively, these factors are thought to induce vasoconstriction and functional closure of the PDA in the majority of infants, though often not in extremely premature infants.4 Spontaneous PDA closure occurs in >95% of infants born >28 weeks gestation in the first few days of age.7 In contrast, 70% of preterm infants < 28 weeks and 80% of those born at 24–25 weeks gestation fail to have spontaneous closure within the first 10 days of life.8,9
Hemodynamically Significant PDA
The term hemodynamically significant PDA (HsPDA) is used to differentiate between a small PDA which may have little impact on circulation, from a symptomatic (high shunt volume) PDA that is likely to contribute to hemodynamic instability.5 Therefore, PDA can be conceptualized on a continuum ranging from incidental and hemodynamically insignificant to pathologic in context with age and underlying condition. For example, infants with complex congenital heart disease may require ductal patency to ensure either pulmonary blood flow (eg, pulmonary atresia) or systemic circulation (eg, hypoplastic left heart syndrome) and prevent cardiac compromise until surgical repair. Additionally, maintaining ductal patency in infants with a structurally normal heart complicated by acute pulmonary hypertension (eg, meconium aspiration, congenital diaphragmatic hernia, sepsis) can also be supportive, as the PDA permits right-to-left flow in the setting of right ventricle (RV) dysfunction and systemic pulmonary artery pressure.
Unfortunately, there is no universal definition of HsPDA to guide clinicians in determining whether the PDA requires intervention or will close spontaneously. Many trials have utilized arbitrary cut-offs based on PDA size and clinical symptoms, which may not fully account for the underlying pathologic consequences or short- and long-term outcomes related to HsPDA.10 Classic clinical symptoms of the HsPDA can be interpreted based on the impact on the pulmonary and systemic circulatory effects, and include increased work of breathing, tachypnea, tachycardia, cardiac murmur, hyperactive precordium, bounding pulses, widened pulse pressure, hypotension, increased lactate and decreased urine output. Moreover, HsPDA may be suspected based on radiographic observation of increased pulmonary congestion and cardiomegaly in context with the need for escalation of mechanical ventilation settings or difficulty weaning respiratory support.11 However, these findings lack specificity and cannot accurately diagnose if the PDA is pathologic. The widespread use of serial transthoracic echocardiography has provided significant insight into the clinical evaluation of ductal shunting and quantification of HsPDA.12 Several echocardiographic indices have been proposed to determine hemodynamic significance based on shunt burden, including ductal diameter, flow patterns, evidence of left-sided overload (eg, dilated left atrium [LA] or left ventricle and LA:Ao ratio >1.4) and holodiastolic flow reversal in the abdominal aorta.13
Pulmonary Consequences of a Hemodynamically Significant PDA
Infants with a moderate-large HsPDA can be exposed to high-volume left-to-right shunt for prolonged periods, resulting in increased pulmonary blood flow and edema formation; further reducing the low pulmonary compliance related to the respiratory distress syndrome disease process (Fig. 1, panel A). Progressive reduction in respiratory-system compliance, coupled with worsened gas exchange often necessitates escalation of mechanical ventilation support to maintain adequate oxygenation, ventilation, and pH.14 Consequently, infants with respiratory distress syndrome and concurrent HsPDA are at high risk for prolonged exposure to mechanical ventilation, development of ventilator-induced lung injury (VILI) and definitive treatment of the PDA; a combination which is commonly associated with adverse neonatal outcomes, although the precise mechanisms and causal linkage remains to be established.15,16 Indeed, the inability to separate preterm infants from mechanical ventilation following the failure of pharmacologic interventions to close the PDA is the primary reason (>80%) infants are referred for definitive closure of the PDA.17-19
PDA before and after surgical ligation. A: Schematic of the physiologic impact of prolonged exposure to left-to-right shunt from hemodynamically significant PDA. Pulmonary blood flow is increased as a result of blood being diverted from the systemic to pulmonary circulation. Importantly, the presence of a large shunt reduces left-ventricle afterload and the increases LV preload. The increase in blood flow to the pulmonary arteries and veins results in left atrial and ventricular dilation. B: Schematic of the physiologic manifestations of post cardiac ligation syndrome. Ligation of the PDA results in an immediate decrease in pulmonary blood flow, increased LV afterload and concurrent reduction of LV preload. The premature myocardium is unable to handle this abrupt change in loading conditions and may be further limited by coronary hypoperfusion, ventricular dysfunction and systemic hypoperfusion. PDA = patent ductus arteriosus, PA = pulmonary artery, PV = pulmonary vein, LA = left atrium, LV = left ventricle, Qp = pulmonary blood flow, PV = pulmonary vein, EF = ejection fraction. From Reference 66, with permission.
Interventions to close the PDA aim to improve lung compliance and decrease short- and long- term respiratory morbidities, however, there is limited modern data in this area.20-22 The ability to identify which infants will demonstrate favorable improvements in lung compliance following definitive PDA closure is obfuscated by difficulty in separating the proportion of respiratory insufficiency that is related to HsPDA versus other risk factors associated with prematurity; mainly, evolving chronic lung disease and prolonged mechanical ventilation.18 There is insufficient evidence to determine if the systematic complications associated with HsPDA in ELBW infants result from the PDA itself, or are simply a consequence of prematurity. As such, heterogeneity in birth characteristics, perinatal factors, gestational age, PDA shunt volume and severity of lung disease limit the ability to recommend a single standardized approach to managing mechanical ventilation in preterm infants. Therefore, the care team should consider these factors in context with cardiorespiratory interactions to individualize the mechanical ventilation strategy for each patient. Furthermore, the mode and mechanical ventilation strategy utilized can vary considerable before, during, and after definitive PDA closure.
The Role of Mechanical Ventilation in the Modulation of PDA Flow
Prior to definitive PDA closure, mechanical ventilation strategies can be utilized to influence blood flow through the PDA and help optimize the infant’s pulmonary status while a plan for pharmacologic or procedural ligation is implemented. Modulation of PVR is important, because the gradual reduction in PVR after the first few days of life can lead to overcirculation of the pulmonary vasculature and concomitant hypoperfusion of the systemic circulation. The pulmonary vasculature is responsive to hypoxia, acidosis and intrathoracic pressure, all of which can be manipulated during invasive mechanical ventilation to induce pulmonary vasoconstriction and increase PVR. The approach to modulating the PVR with a HsPDA has been extracted from learned approaches to balance the distribution of pulmonary blood flow () and systemic blood flow (
) in infants with hypoplastic left heart syndrome by mitigating the pressure gradient across the shunt; hence reducing shunt volume. However, it should be noted that extrapolation of these physiologic strategies including the application of elevated mean airway pressure (
) and permissive hypercapnia to reduce transductal flow have not been rigorously investigated in infants with PDA.
Mechanistically, increasing and lung volume above FRC directly influences intrathoracic pressure and variably result in compression of intra-alveolar capillaries by overexpanded alveoli (limiting pulmonary blood flow) and increasing PVR.23 The primary challenge in infants with HsPDA is determining at what threshold does alteration of lung volume (VT, PEEP and
) produce a clinically meaningful reduction of left-to-right flow at the PDA? Small observational studies have evaluated the impact of lung recruitment using higher levels of PEEP or
on pulmonary, systemic, and PDA blood flow.24,25 Fajardo et al26 compared PEEP levels of 5 and 8 cm H2O in preterm infants with PDA and found that mild reductions in left-to-right shunt was associated with PEEP of 8 cm H2O and without impairment of cerebral oxygenation and perfusion. In contrast, de Waal and colleagues25 prospectively studied the effect of lung recruitment in a cohort of mostly premature infants receiving high-frequency oscillatory ventilation (HFOV) and found no significant differences in ductal shunting when comparing a
of 8 cm H2O to 20 cm H2O.
Transductal pressure gradient is a major determinant of ductal shunting in preterm infants. One aim of non-pharmacologic management of a HsPDA is to balance the pulmonary and systemic circulation, and some have hypothesized that permissive hypercapnia can mitigate the gradient. Carbon dioxide exerts opposing effects on the pulmonary and systemic vasculature, with hypercapnia resulting in pulmonary vasoconstriction and systemic vasodilation.27 While the physiologic basis of utilizing hypercapnia to induce pulmonary vasoconstriction is sound, it is unclear what increment of Pco2 change is needed to produce a substantial or small proportionate change to PVR.28 Moreover, it is plausible that hypercapnia and PVR elevating techniques could contribute to pulmonary hypertensive crisis following SL or TCPC. Lastly, there have been no studies to date investigating the impact of permissive hypercapnia on HsPDA.27
Modes of Mechanical Ventilation
Several randomized control trials and subsequent meta-analytic studies have compared volume-targeted ventilation with traditional pressure-controlled modes of ventilation and found important safety benefits associated with volume-targeted ventilation including reduced hypocapnia, risk of neurologic sequelae (eg, periventricular leukomalacia or grade 3–4 intraventricular hemorrhage), bronchopulmonary dysplasia, pneumothorax and shorter duration of mechanical ventilation.29 Although high-level evidence supports utilizing volume-targeted ventilation over other modes of pressure-controlled ventilation in preterm infants; diffusion of volume-targeted ventilation into clinical practice has been limited by heterogeneity in ventilator capabilities, uncertainty about appropriate VT, endotracheal tube leak, institutional preference, and lack of training, experience or clinical practice guidelines.30
In our center, heated humidified circuits are used for all patients and we routinely monitor end-tidal carbon dioxide (ETCO2) with larger infants (>2kg) and less frequently in smaller infants; where ETT leak may negate accuracy or the excess weight from the ETCO2 may pose safety risks. Since infants are routinely muscle-relaxed and sedated during the procedure (TCPC or SL), it is important to distinguish some technical differences between pressure control ventilation and volume-targeted ventilation. As the patients’ spontaneous inspiratory efforts cease and FRC diminishes with anesthesia, the consequent reduction of lung compliance may result in reduced VT during PC-IMV or higher peak inspiratory pressures (to deliver the set VT) for those on volume-targeted ventilation.30 Moreover, preterm infants have highly compliant thoracic cages and low lung compliance, making them prone to developing atelectasis and ventilation-perfusion mismatch following induction of anesthesia.31 Regardless of ventilation mode, it imperative to anticipate this reduction of FRC and adjust ventilator settings accordingly to ensure similar minute volume and .
Collectively, randomized control studies comparing high-frequency ventilation (HFV) to conventional mechanical ventilation in preterm infants have not reported tangible improvement in outcomes for elective or rescue use.32,33 Notably, the larger HFV studies were conducted over 30 years ago and did not include extremely preterm infants, making these anachronistic findings difficult to interpret in contemporary neonatal intensive care units. A number of centers utilize HFV as the primary mode of ventilation in extremely preterm infants,34 however, in many cases HFV is reserved as a rescue modality for infants with persistent respiratory failure (eg, set breathing frequency >40 breaths/min, pH <7.25, PCO2 > 60 mm Hg, or hypoxia, sustained FIO2> 0.60) despite optimization of conventional lung-protective ventilation strategies.35-40
The choice of HFV type may be driven by several factors including, the level of conventional ventilator support, institutional experience, mechanical differences between HFV devices, patient size and underlying condition. While not specific to PDA, early studies evaluating high-frequency jet ventilation (HFJV) in infants with congenital heart disease demonstrated favorable hemodynamics and similar gas exchange with a lower compared to conventional mechanical ventilation.41-44 In contrast, those with anasarca or comorbidities including necrotizing enterocolitis, spontaneous intestinal perforation and abdominal surgery often require higher
and may be better supported with HFOV. The mechanical differences and relative advantages/disadvantages between HFJV and HFOV have been discussed at length in other publications and are summarized in (Table 1).39,40,45,46
Mechanical differences between HFJV and HFOV
Considerations Prior to Definitive Closure
Transport of critically ill preterm infants from the NICU to the catheterization laboratory is necessary for controlling the environment during PDA closure, however, transport also incurs risk of potential harm from adverse events most commonly, hypothermia, respiratory complications, and hemodynamic instability.47-49 Other risk factors include lower birthweight, older postnatal age, longer duration of transport, presence of central venous line and hemodynamic support,50 unplanned extubation or ETT malposition during transport.47,51 Moreover, infants requiring high PEEP, HFV, and vasoactive infusions are at particularly high-risk for adverse events and pose logistical challenges to transport.52,53 Further, in the presence of a large ETT leak (eg, >50%), the risks versus benefits of upsizing or changing to a cuffed ETT should be discussed.
It is important to mention that in some centers, PDA ligation is performed at the bedside which mitigates many of the variables associated with transport. Noonan et al54 sought to evaluate if conversion from HFJV to conventional ventilation during bedside PDA ligation was necessary and found no differences in morbidity or mortality with lower in HFJV managed infants (48 vs 54 mm Hg, P = .006). In contrast, other institutions exclusively perform SL in the operating room and TCPC in the catheterization laboratory.55 For infants managed with HFV prior to PDA closure, in our hospital we typically attempt a trial of conventional mechanical ventilation to assess clinical stability and blood gas values before transport to the catheterization laboratory or operating room. As a standard, the conventional ventilator from the NICU is used for transport and during the case to reduce variability in pressures, tidal volume, and gas exchange.56 In addition to traveling on the ICU ventilator, transport checklists are used to define roles and verify that all appropriate staff and necessary equipment are present.57-59 Collectively, these factors must be discussed with various team members including neonatology, nursing, anesthesia and respiratory therapy to minimize the potential for adverse events. Finally, Willis et al60 demonstrated a 100% procedural success of performing TCPC in ELBW infants without any hemodynamic compromise during transport, but acknowledged that successful transfer is only accomplished safely with multi-disciplinary safety protocols in place.
Treatment Options
The need for PDA treatment continues to be a controversial topic given the high rate of spontaneous closure, moderate efficacy of pharmacologic treatment, and concerns that the adverse effects of treatment may outweigh benefits. Historically, all PDAs were treated early with either pharmacologic or surgical intervention without assessment of hemodynamic impact. Over time, mounting evidence of adverse neonatal outcomes related to pharmacologic and surgical PDA management has led to skepticism about universal treatment; as this approach unnecessarily exposes some infants to potential harm.61 A recent Vermont Oxford Network study included (n = 291,292) VLBW infants and reported diagnosis of PDA (25%) of which (21%) were treated (18% pharmacologic, 2% invasive and 3% received both).62 Therefore, trends in management have become more conservative, with decision to treat being deferred and re-evaluated based on the risks/benefit profile of each individual patient.
Conservative treatment is an umbrella term for the combination of several non-pharmacologic strategies aimed at decreasing the magnitude of left-to-right shunt burden and is contingent upon the possibility of the PDA closing naturally without treatment. Mechanical ventilation strategies using moderate levels of PEEP, permissive hypercapnia, and low are used to increase PVR and minimize left-heart loading to mitigate pulmonary edema formation. Fluid restriction and diuresis have also been traditionally employed to mitigate pulmonary overcirculation and offset heart failure symptomatology, but recent data has questioned this practice for its potential impact on the systemic circulation as well.27 Additionally, targeting higher hematocrit levels 35–40% to increase oxygen carrying capacity and blood viscosity may also be beneficial in some infants.27
Available data on conservative management suggests ∼65–70% of preterm infants have spontaneous closure by 30 postnatal days.63,64 In a recent multi-center prospective study of preterm infants discharged with PDA, Tolia and colleagues65 found that spontaneous ductal closure occurred in 47% by 12-months and 58% at 18 months; of which, 8% ultimately required SL or TCPC.
Infants with persistent PDA after a month of conservative management may be treated with indomethacin, ibuprofen (cyclooxygenase inhibitors) or acetaminophen (peroxidase inhibitor) however, the window of efficacy for these agents is unclear. Open SL and TCPC are more invasive and often reserved for when pharmacologic interventions to close the PDA have failed or are contraindicated. The relative advantages and disadvantages of each treatment are summarized in (Table 2) and have been eloquently described elsewhere.6,13,66
A Comparison of treatment options for HsPDA
Surgical PDA Ligation
The rates of PDA ligation have declined over the past ten years, but surgical ligation (SL) of a hemodynamically significant PDA still occurs in 5–8% of ELBW infants.1,65,67 More recently many centers have shifted away from SL toward catheter-based interventions to close the PDA68,69 including our institution (Fig. 2). Open SL predominantly occurs in ELBW infants who fail or have contraindications to medical management and those who do not meet criteria for TCPC (eg, active infection, ductal characteristics or size limitations).70 Accordingly, the medical, procedural, respiratory, and anesthetic approaches for SL or TCPC require a comprehensive understanding of the unique physiological considerations in ELBW infants.1
Trend of surgical ligation and transcatheter device closure of patent ductus arteriosus at Boston Children’s Hospital.
Thoracotomy and SL can disrupt respiratory mechanics and negatively impact gas exchange. To facilitate exposure to the PDA, infants are placed in a lateral position with manual retraction of the left lung resulting in potential trauma to fragile lung tissue already predisposed to prematurity-related alveolar hypoplasia and surfactant deficiency. Compression of one lung can lead to additional alveolar stretch and barotrauma of the ventilated lung in an attempt to maintain adequate oxygenation and ventilation. Escalation of mechanical ventilation settings and can potentially increase the risk of hyperoxia mediated lung damage and VILI.70 In addition, cytokine cascades can result from the compression of the lung tissue and activate inflammatory pathways that will exacerbate underlying lung disease and could further contribute to the development of bronchopulmonary dysplasia. Although observational studies have demonstrated an association with an increased risk of bronchopulmonary dysplasia, retinopathy of prematurity, and neurodevelopmental impairment following SL, the increased morbidity may be due to bias confounded by indication for ligation.70
Beyond the pulmonary complications, SL has been associated with chylothorax, vocal cord paralysis, diaphragm paresis, bleeding, infection, inadvertent ligation of the left pulmonary artery or aorta, and scoliosis.70 Furthermore, the surgery can result in intra-operative fluid loss, hypothermia and postoperative pain. Fluid restriction and diuretic therapy are often used in the preoperative management of heart failure symptoms from increased pulmonary blood flow and may contribute to the development of perioperative hypovolemia and hypotension. As a result of both the respiratory and metabolic consequences from this stress response, it is recognized that the anesthetic technique and agents may exacerbate the aforementioned perturbations and could have important impact on outcome.71,72 There is no ideal anesthetic regimen identified for SL, and wide variation exists between centers and anesthesiologists with the use of opioids, sedatives, and muscle relaxation when appropriate.71,73 Despite potential intra-operative physiological insults related to prematurity, studies have shown that ELBW infants remain hemodynamically stable, even after receiving large boluses of fentanyl.71 It has been extrapolated that starting low dose opioids or increasing current opioid regiments by 5–10% following closure could prevent some of the physiology changes relating to post-closure low cardiac output and pulmonary vasculature reactivity. Since the clinical deterioration occurs with rising SVR, care is taken to avoid medications that would raise systemic afterload and optimize those medications that limit increases in SVR. Taken altogether, the anesthetic and analgesia approach is an important component of an infant’s stability during surgical closure of the PDA and multidisciplinary guidelines need to be established to study the unique anesthetic roles in the postoperative period.
Transcatheter PDA Closure
First introduced by Werner Porstmann for adults in 1966 and subsequently by William Rashkind for infants in 1979,74 TCPC is among the safest of interventional cardiac procedures and has been the standard of care for PDA closure in infants >5 kg for decades.75 Over the past several years, technological advances have provided PDA occlusion devices small enough to safely close the PDA in ELBW infants.76 In 2019, the United States Food and Drug Administration approved the Amplatzer Piccolo Occluder (Abbott Structural Heart, Plymouth, Minnesota) for TCPC in infants weighing > 700 g and a postnatal age >3 days.2 These devices are delivered with the use of venous access alone and deployed under transthoracic echocardiogram and fluoroscopic guidance, removing the need for arterial instrumentation.1
A recent meta-analysis by Rahde Bischoff et al76 evaluated the technical success of TCPC in (n = 373 infants ≤ 1.5 kg and n = 1,794 ≤ 6 kg) and observed overall success at 96% with a 27% incidence of adverse events. Although 8% were major/catastrophic events, they were all from early studies. Additionally, these authors found that procedural success improved over time despite a progressive increase in the number of procedures performed in younger and smaller infants. Catheter-based PDA closure and avoidance of thoracotomy appear to circumvent many of the respiratory complications of SL. Pulmonary risks are avoided as baseline mechanical ventilation can be maintained throughout the procedure without the need for increased peak pressures to compensate for single lung ventilation, reducing dead-space ventilation. Although, is briefly increased during deployment of the device to compensate for transient ventilation-perfusion mismatch and hypotension related to the catheter tenting open the tricuspid valve, continuously high levels of oxygen are avoided since gas exchange is not impaired by lung compression. Several cohort studies have described a more rapid return to baseline pulmonary status after device closure;77-79 whereas, surgically ligated infants were more likely to require increased respiratory and vasoactive support postoperatively.76,80,81
Transcatheter closure is certainly not devoid of risk with (<3%) major procedural complications being reported including device embolization and migration.2,76 Embolization generally occurs during or shortly after the procedure and is most commonly directed toward the pulmonary artery where it can be retrieved with a vascular snare (>95% of cases).82 In the infrequent occurrence of arterial embolization or inability to pursue percutaneous retrieval, surgical intervention may be required to explant the device. The occlusion device can also be malpositioned or migrate causing aortic arch or left pulmonary artery obstruction if not appropriately seated within the PDA; however, in most cases mild protrusion of the device into the aorta or pulmonary artery is well tolerated and does not require intervention.2,76,83 The risk of low cardiac output syndrome (LCOS) is still present (∼8%), though appears lower than ligation, with recent data reporting decreased LV systolic function (30% vs 5%, P <.01) and oxygenation failure (28% vs 8%, P <.01) following TCPC in infants< 3kg and >3kg, respectively.84 Future research is needed to characterize the different respiratory and cardiovascular phenotypes of LCOS with percutaneous intervention.
Mechanical Ventilation During PDA Closure
The ability to precisely control and monitor VT within a narrow range is desirable to provide lung-protective ventilation and has been recognized as an essential component in limiting VILI. There are several limitations and performance differences between anesthesia machines and critical care ventilators, which have important safety implications for preterm infants. Discrepancies between the set and delivered VT can result from several factors including device specifications, type and location of the flow sensor, ETT (eg, cuffed vs cuffless), leak, fresh gas flow, compressible volume loss within the circuit and whether the breathing circuit was expanded prior to running the compliance test.85 Others have shown that disassociation between inhaled and exhaled VT values were influenced by ventilator type (anesthesia machine vs critical care ventilator), mode of ventilation and more pronounced with smaller size, weight, and worsening lung disease (eg, ELBW with HsPDA and respiratory distress syndrome).86-88 89 90 These important limitations should be carefully considered prior to transport, as critical care ventilators appear to provide more precise control of ventilation in VLBW and ELBW infants. We suggest that strong consideration should be given to utilization of a critical care ventilator in the operating theater or catheterization laboratory to address these limitations and most safely support the ventilatory requirements of this population.
Mechanical Ventilation After PDA Closure
It is important to highlight that many infants, in particular those with a larger PDA may demonstrate improvement in pulmonary compliance following closure, whereas a subset of infants are characterized by either transient or progressive worsening of oxygenation and ventilation. Following definitive closure, the acute increase in SVR (afterload) and simultaneous reduction of LV preload, present increased strain on the preterm LV and upstream impact on the pulmonary vasculature. Elevated pulmonary venous pressure manifests clinically as pulmonary edema with reduced pulmonary compliance, and derangement in gas exchange within hours of PDA closure. Intuitively, a careful assessment of ventilatory support requirements including , Respiratory Severity Score (mean airway pressure ×
), and blood gas values in context with overall hemodynamics before and after PDA closure can provide clinicians helpful insight insofar as patient trajectory and permit timely individualization of the mechanical ventilation strategy.91
Post-Ligation Cardiac Syndrome
Following definitive PDA closure (SL or TCPC) infants may develop significant cardiopulmonary compromise, described as post-ligation cardiac syndrome (PLCS). This represents a form of low cardiac output syndrome that occurs secondary to alterations in loading condition on the left ventricle (decreased preload and increased afterload) and upstream impact on the pulmonary vasculature following abrupt closure of the PDA. The physiologic manifestations of PLCS following SL are depicted in (Fig. 1B).84 PLCS is defined as a composite outcome of systemic hypotension, oxygenation failure and ventilation failure in the absence of any other surgery-related etiology.92 The clinical phenotype of PLCS presents within 6–12 h after SL and had been observed in up to 45% of premature infants with risk factors including lower gestational age and weight at birth, earlier age at ligation, larger PDA size, and elevated preoperative cardiorespiratory support.1
Importantly, PLCS is not the only cause of cardiorespiratory decompensation following PDA closure, as surgical complications including pneumothorax, chylothorax, pulmonary compression or hemorrhage and adrenal insufficiency have been implicated in infants who rapidly deteriorate within 6 h of surgery.14 Ting et al93 found that > 50% of infants who underwent SL subsequently developed oxygenation or ventilation failure and 8% met criteria for PLCS. These findings underscore the need for vigilant monitoring of respiratory mechanics and are likely related to complications from thoracotomy, LV dysfunction, low cardiac output syndrome and pulmonary venous hypertension which present clinically as pulmonary edema and subsequent reduction of pulmonary compliance.
Respiratory Outcomes Following PDA Closure
There are no randomized control trials and few cohort studies that have compared differences in respiratory outcomes between intervention types (SL vs TCPC). Available data suggest that TCPC treated infants have less respiratory instability, wean to extubation more rapidly, require less inotropic support, and experience PLCS less frequently, compared with their surgical ligated counterparts (Table 3).78,80
Comparison of respiratory outcomes between surgical ligation and TCPC
HFV is commonly used before and after SL in the setting of altered respiratory mechanics and derangements of oxygenation and ventilation; with prevalence reported between 20%–67%.80,91,94
Serrano et al80 described postprocedural HFOV requirement between SL and TCPC and reported that 20% of infants who underwent SL received HFV as opposed to none in the TCPC group; with the SL group demonstrating a higher postprocedural (0.64 vs 0.43, P = .004) and a larger total change in peak
(0.23–0.9, P = .008).
Recently, our group studied 110 preterm infants who were mechanical ventilated before and after SL or TCPC closure with the primary (binary) outcome of HFV requirement within 24 h of PDA closure.37 Forty-eight (44%) infants escalated to HFV: (21%) HFOV and (79%) HFJV within 24 h (8% TCPC vs 44% SL, P = .008). In the multivariable model, SL (OR 21.5, 95% CI 1.6 - 284), elevated RSS 1 h post-procedure (OR 1.78, 95% CI 1.07-2.99) and 12 h post-procedure (OR 2.12, 95% CI 1.37-3.26) were independent predictors of HFV. Additionally, we found that RSS > 4 at 1 h following closure may prompt early identification of respiratory compromise and allow for timely adjustment of ventilatory support following definitive PDA closure (Fig. 3). The prevalence of PLCS was lower in infants who remained on conventional ventilation (3% vs 17%, P = .02) compared with those who required HFV. These findings corroborate prior studies that suggest TCPC may afford a more rapid improvement in respiratory outcomes compared with SL; however, larger prospective case-control or randomized controlled trials are needed to answer this question.
Respiratory Severity Score. Predicted probability curves of high-frequency ventilation according to Respiratory Severity Score (RSS) were derived using logistic regression. RSS ranges for individual subjects were 1.47–18.5 and 1.89–17 for 1 h and 12 h post procedure. HFV = high frequency ventilation. From Reference 37, with permission.
Summary
A persistent HsPDA can have clinical consequences in preterm infants and has been implicated in the development of both short- and long- term cardiopulmonary morbidity. Recent innovation has allowed for minimally invasive TCPC closure in ELBW infants with mounting evidence to suggest improvement in respiratory outcomes and less PLCS, compared with SL. More research is now needed to optimize periprocedural respiratory support and describe long-term outcomes in preterm infants following TCPC.
Footnotes
- Correspondence: Craig R Wheeler DHSc RRT RRT-NPS, Department of Respiratory Care, Boston Children's Hospital, Boston, Massachusetts, United States; E-mail: craig.wheeler{at}childrens.harvard.edu
The authors have no conflicts of interest to disclose.
- Copyright © 2022 by Daedalus Enterprises
References
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- 5.↵
- 6.↵
- 7.↵
- 8.↵
- 9.↵
- 10.↵
- 11.↵
- 12.↵
- 13.↵
- 14.↵
- 15.↵
- 16.↵
- 17.↵
- 18.↵
- 19.↵
- 20.↵
- 21.
- 22.↵
- 23.↵
- 24.↵
- 25.↵
- 26.↵
- 27.↵
- 28.↵
- 29.↵
- 30.↵
- 31.↵
- 32.↵
- 33.↵
- 34.↵
- 35.↵
- 36.
- 37.↵
- 38.
- 39.↵
- 40.↵
- 41.↵
- 42.
- 43.
- 44.↵
- 45.↵
- 46.↵
- 47.↵
- 48.
- 49.↵
- 50.↵
- 51.↵
- 52.↵
- 53.↵
- 54.↵
- 55.↵
- 56.↵
- 57.↵
- 58.
- 59.↵
- 60.↵
- 61.↵
- 62.↵
- 63.↵
- 64.↵
- 65.↵
- 66.↵
- 67.↵
- 68.↵
- 69.↵
- 70.↵
- 71.↵
- 72.↵
- 73.↵
- 74.↵
- 75.↵
- 76.↵
- 77.↵
- 78.↵
- 79.↵
- 80.↵
- 81.↵
- 82.↵
- 83.↵
- 84.↵
- 85.↵
- 86.↵
- 87.
- 88.↵
- 89.
- 90.
- 91.↵
- 92.↵
- 93.↵
- 94.↵