Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny

Review

Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise Shahab Noori a, *, Istvan Seri b a

Division of Neonatology and the Center for Fetal and Neonatal Medicine, Department of Pediatrics, Children's Hospital Los Angeles and the LACþUSC Medical Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA b Sidra Medical and Research Center, Doha, Qatar

s u m m a r y Keywords: Cardiac function Echocardiography Hypotension Myocardial dysfunction Sepsis Vascular resistance

With the advances in biomedical research and neonatal intensive care, our understanding of cardiovascular developmental physiology and pathophysiology has significantly improved during the last few decades. Despite this progress, the current management of circulatory compromise depends primarily on experts' opinions rather than high level of evidence. The lack of reliable, accurate, continuous and preferably non-invasive monitoring techniques has further limited our ability to collect the information needed for the design and execution of more sophisticated clinical trials with a better chance to provide the evidence we need. Given the lack of randomized, placebo-controlled trials investigating clinically relevant outcomes of novel treatments of neonatal cardiovascular compromise, we must now use the available lower level of evidence and our present understanding of developmental physiology and pathophysiology when providing cardiovascular supportive care to critically ill neonates. However, with recent advances in cardiovascular monitoring capabilities, direct and more objective assessment of the changes in cardiovascular function, organ blood flow, and tissue oxygenation have become possible. These advances have helped in our clinical assessment and enabled us to start designing more sophisticated interventional clinical trials using clinically relevant endpoints. © 2015 Elsevier Ltd. All rights reserved.

1. Introduction In order to manage circulatory compromise, one must first recognize it. In older children and adults, hypotension is the single most important sign of uncompensated shock. Therefore, it does not come as a surprise that defining hypotension has been a focus of research in neonatology since its inception. Yet, despite decades of research and debate on the topic, we still know very little about what constitutes hypotension in the neonate. Although we have come to understand that blood pressure (BP) has a direct relationship with gestational and postnatal age, controversy continues to surround all other clinically relevant aspects of defining the normal range of BP. Many agree that a definition of hypotension based on the relation between BP and systemic/organ blood flow (especially blood flow to the brain), would be clinically meaningful. However, identifying a threshold below which vital organ

* Corresponding author. Address: Children's Hospital Los Angeles, 4650 Sunset Blvd, MS# 31, Los Angeles, CA 90027, USA. Tel.: þ1 (323) 361 5939. E-mail address: [email protected] (S. Noori).

autoregulation becomes impaired and cellular function disturbed or, even more importantly, permanent organ damage is sustained in a given patient is challenging. Identifying the exact cut-off may be unrealistic as the thresholds likely vary among individuals and may differ in the same patient at different points in time depending on the interplay of many other factors. Considering the uncertainty about the normal range of BP for a given gestational and postnatal age and individual patient characteristics, some have advocated a complete disregard of BP in sick preterm and term neonates. Instead, advocates of this approach only recommend assessment of organ perfusion by clinical and laboratory means to assess the need for provision of cardiovascular supportive care. However, despite its limitations, disregarding BP altogether does not enhance our limited ability to detect circulatory compromise and it ignores the physiologically determined need to maintain appropriate perfusion pressure for the circulation to enable oxygen delivery to the cells. In clinical practice, some clinicians define the lowest acceptable BP by the 5th or 10th percentile of the population-based normative values as, historically, BP values below these cut-off ranges were shown to be associated with brain injury [1]. By another approach, hypotension is defined as the mean BP < 28e30 mmHg in very low

http://dx.doi.org/10.1016/j.siny.2015.03.005 1744-165X/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

2

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

birth weight infants. This definition is based on the limited data demonstrating a loss of cerebral autoregulation at 28e30 mmHg [2,3]. Finally, the arbitrary definition of hypotension by a mean BP value below the numerical value of the gestational age in the given patient is the most widely used definition by clinicians and researchers alike [4]. 2. Why does hypotension matter? Although some studies have shown no difference in outcome of hypotensive preterm infants compared to normotensive patients [5e7], the vast majority of available data point to an association between hypotension, however defined, and poor outcome [1,8e16]. It is not clear, however, whether causality is at play. Given the widespread practice of treating hypotension and the lack of data from randomized controlled trials (RCTs), it remains unknown whether hypotension, its treatment, the underlying pathology leading to hypotension and/or a combination of these factors are the causes of the medium- and long-term hemodynamic and neurodevelopmental adverse effects often seen in critically ill neonates [17]. It is likely that all of the potential causes play a role but the extent of the contribution of each factor to the adverse outcome is not known. Regardless of the controversy about the use or disregard of BP as one of the factors in determining the institution of treatment, low BP does lead to reduced cerebral blood flow (CBF) especially in preterm infants with impaired CBF autoregulation. As in preterm infants the autoregulatory BP range is much narrower than in older children or adults, the preterm infant is more prone to having a pressure-passive CBF. Therefore, concern over cerebral hypoperfusion in the setting of hypotension is often cited as a reason for monitoring BP and treating hypotension. It must be noted that the impact on clinically relevant outcomes of the pace and magnitude of correction of low BP have not been studied. Based on recent data on the changes in CBF and the lack of immediate reestablishment of CBF autoregulation in response to pharmacological normalization of BP in preterm neonates [2], it is tempting to speculate that aggressive treatment of hypotension by whatever means might be as harmful as leaving the brain hypoperfused. The other reason for the need to identify the normal range of BP is to be able to recognize shock earlier. In the case of an event leading to circulatory compromise, such as sepsis, shock progresses through three phases. During the compensated phase, BP is maintained in the “normal range” by neuroendocrine compensatory mechanisms, and oxygen delivery to the vital organs (brain, heart and adrenal glands) remains largely unchanged. In the next, uncompensated state, the compensatory mechanisms fail and hypotension and generalized tissue hypoperfusion develop. If untreated or if the patient is unresponsive to treatment, shock will progress to its final, irreversible phase leading to multi-organ failure and death. In our quest to prevent shock from entering the irreversible phase, we must recognize it during its earlier phases. Hypotension is the main clinical sign that denotes failure of the compensatory mechanisms; therefore defining hypotension is one of the key steps to enable us to recognize the presence of uncompensated shock. 3. Pressure versus flow In recent years, there has been much discussion on whether BP or flow is more important. According to the Poiseuille's law they are related, as flow is directly proportional to the pressure gradient. In other words, BP is the driving force behind moving the blood through the vasculature. Clinically, we use Ohm's law to assess the circulation, where the flow is directly related to the pressure gradient and inversely related to systemic vascular resistance

(SVR). Unfortunately, SVR is a calculated value and cannot be directly measured. Accordingly, BP ¼ cardiac output (CO)  SVR. One can appreciate that BP will not change despite significant alterations in the hemodynamic status if, for example, CO falls by 50% and, at the same time, vascular resistance doubles. Thus, the significant limitation of relying on BP alone in assessing the adequacy of blood flow is clear. Therefore, information about both perfusion pressure and blood flow is required for us to be able to appropriately assess the circulation and gauge the hemodynamic response to treatment. The major function of the circulation is to deliver oxygen and nutrients to the tissue to meet metabolic demands. The interaction between systemic flow and systemic resistance, in the form of maintaining a driving pressure, ensures adequate oxygen delivery. These two relatively independent factors are regulated and controlled by autonomic, endocrine and paracrine factors and affected by a host of other physiologic and pathologic events [18]. Beyond the interaction between systemic flow and SVR in determining perfusion pressure, if compensatory mechanisms start failing to maintain adequate oxygen delivery, capillary recruitment and an increase in oxygen extraction will match oxygen demand with availability for a period. Since we can now continuously assess changes in oxygen extraction using near-infrared spectroscopy (NIRS), we can indirectly follow the progression of shock and/or the response to treatment even if we cannot continuously monitor changes in cardiac output. Although ensuring adequacy of blood flow is our goal, our routinely available clinical and laboratory assessment tools of low blood flow state, such as capillary refill time (CRT) and serum lactate level, respectively have either very limited sensitivity and specificity or have a significant time-lag. These shortcomings render them less helpful in timely recognition of shock [19]. Therefore, more recently many centers have started assessing systemic blood flow by using bedside echocardiography and, less frequently, by electrical impedance velocimetry (EV) along with the information routinely available on systemic BP to better assess cardiovascular function. Of note is that the methods used for the assessment of systemic and organ blood flow and their changes at the bedside (echocardiography, EV and NIRS) all have their own significant limitations as well [18,19]. 4. Evidence-based versus pathophysiology-based approach As is the case with any other conditions, when managing a patient with shock, we should strive to incorporate high-level evidence in our approach to diagnosis and treatment. Unfortunately, high-level evidence is lacking in this area of neonatology. Furthermore, the outlook for establishing treatment strategies and defining the most appropriate subpopulations that would benefit from a given treatment based on findings of RCTs is, at best, grim in the near future. The only study to date that specifically attempted to investigate the effect of untreated hypotension in a randomized fashion found that such a trial was not feasible [20]. In seven neonatal intensive care units (NICUs) and out of 336 eligible extremely preterm infants (23e26 weeks' gestational age), only 10 patients ended up being enrolled and studied during a trial period of one year. The main reason for failure to effectively conduct the study was the inability of the researchers to obtain parental consents in a timely fashion. However, the lack of equipoise by the participating clinicians has also played a significant role. Among patients meeting enrollment criteria but without the parents having been approached for consent, in 65% of these cases the physicians believed that the patients were too sick for enrollment.

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

Indeed, the latter issue poses another problem in conducting RCTs on the treatment of neonatal shock as, even if the study had been completed, the findings would likely only be applicable to less critically ill neonates. At present, there are only two multicenter RCTs registered at ClinicalTrials.gov. One of these studies (Petra Lemmer, Netherlands, NCT01434251) randomizes very preterm infants presenting with hypotension without clinical and/or laboratory evidence of compromised tissue perfusion either to treatment or to no cardiovascular support for hypotension unless their mean BP remains >5 mmHg below the gestational age in weeks for 30 min and/or the patients develop indirect clinical or direct laboratory evidence of tissue hypoperfusion and/or end organ dysfunction. The composite primary outcome measure of the study is mortality or impaired two-year neurodevelopmental outcome. The second study (Gene Dempsey, Ireland, NCT01482559) randomizes hypotensive very preterm infants to dopamine versus a restricted treatment with placebo approach. Both studies will report on the mortality, brain injury, and neurodevelopmental outcome at 24 months. The results of these trials might be helpful in our quest to define the BP and blood flow thresholds for treatment. However, despite the lack of evidence from RCTs, several pieces of information from the literature can guide us concerning the clinical settings when hypotension is more likely to be problematic and when it might be associated with poor outcomes. Therefore, in such instances close observation is warranted and treatment should be considered. For instance, the duration of hypotension has been shown to be an important factor. Although it is not known for how long hypotension needs to persist in a given patient to be associated with harm, the data indicate that the longer it lasts the more likely it is associated with poor outcome [8,9,11]. In one study, hypotension or hypoxemia for more than 1 h was associated with major neurodevelopmental abnormalities at 6e12 months [8]. The probability of bad outcome was even greater if hypotension and hypoxemia were both present. Similarly, presence of signs of poor tissue perfusion such as metabolic acidosis in hypotensive neonates increases the risk of death and/or poor neurodevelopmental outcome [9,21]. Interestingly, epidemiologic studies have shown an association between significant hypo- or hypercapnia and brain injury [22e25]. It has been suggested that the associated cerebral hypo- or hyperperfusion is the mechanism underlying the injury; furthermore, it is conceivable that hypotension, in the setting of hypo- or hypercapnia, might potentiate brain injury by decreasing

3

CBF or attenuating CBF autoregulation, respectively (see S. Noori and I. Seri in this issue for details). Therefore, it seems prudent to be extremely vigilant when hypotension is associated with any of above-mentioned derangements in oxygenation or ventilation. From this discussion, it is clear that there are significant gaps in our knowledge about diagnosis and treatment of hypotension and circulatory failure. Until the time when such data become available, we should apply the principles of developmental physiology and our knowledge of pathophysiology to identify the at-risk neonates and formulate an individualized treatment plan targeting the underlying pathophysiology. 5. Pathophysiology-based approach In this approach, one uses the obstetric and perinatal history, clinical assessment, laboratory tests and, when feasible, additional tools such as echocardiography to define the pathophysiology of circulatory compromise and direct the treatment plan to specifically address the derangement. It is helpful to keep in mind the basic relationship between flow, pressure and resistance whenever we are faced with a patient with circulatory compromise (Fig. 1). Indeed, the circulatory derangement could be the result of abnormal CO (usually low systemic flow), abnormal SVR, or both. As CO is the product of heart rate and stroke volume (SV) and the SV in turn depends on the preload, contractility and afterload, abnormalities of any of these determinants of CO could result in low systemic flow. Similarly, low vascular tone or excessive vasoconstriction can lead to circulatory compromise if the heart cannot compensate for the change in resistance. 5.1. Vascular tone Vasodilation is one of the more frequent causes of shock in neonates, especially in preterm infants. Among infants with septic shock and conditions associated with systemic inflammatory response such as necrotizing enterocolitis (NEC), pathological decrease in vascular tone is the major cause of circulatory compromise. The decrease in vascular tone is largely due to dysregulated production of local nitric oxide and a direct vascular cytokine effect. The concomitant decrease in perfusion pressure is the hallmark of shock in these cases and hypotension develops despite normal or elevated CO. Indeed, a recent study has demonstrated high CO and low calculated SVR in a group of

Figure 1. Cardiac output and systemic vascular resistance are controlled and regulated by autonomic and neuroendocrine systems. Blood pressure is the product of this interaction. Assessment of determinants of cardiac output and systemic vascular resistance is suggested to be useful in diagnosis and treatment of circulatory compromise.

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

4

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

preterm infants presenting with sepsis [26]. It also found that, in patients who did not survive the septic shock, CO only dropped significantly prior to death. In addition to vascular paralysis, myocardial dysfunction may also play a role, especially in Gramnegative sepsis and/or during the late stages of septic shock. It is not known how widespread myocardial dysfunction is in neonates with septic shock, but in older children about half of them have either systolic or diastolic dysfunction [27]. Also, in older children and adults, two different presentations of septic shock have been described and termed “warm” (vasodilatory) and “cold” (vasoconstrictive) shock. One study of children with septic shock found a difference in clinical presentation of shock depending on whether the organism was acquired in the hospital or the community [28]. Children with sepsis acquired in the hospital presented with “warm” shock characterized by high CO and peripheral vasodilation. On the other hand, community-acquired sepsis was more often characterized by low CO and peripheral vasoconstriction (i.e. “cold” shock). This difference may be related to various hemodynamic responses to different bacterial pathogens, as Gram-positive organisms were predominant in patients with hospital-acquired sepsis, whereas Gram-negative bacteria were primarily responsible for community-acquired sepsis. Alternatively, the difference may reflect phases of shock during which patients were first diagnosed, with community-acquired sepsis being diagnosed later and therefore, at a more advanced stage likely associated with myocardial dysfunction. Although the dominant presentation of septic shock in the neonatal period is vasodilatory, there is evidence for cold shock presentation as well. A recent study compared 52 preterm infants with septic shock to 52 control subjects. Left ventricular output was higher in neonates with septic shock. However, in many cases, the high CO was likely secondary to the high incidence of a patent ductus arteriosus (PDA) in patients with septic shock. Indeed, right ventricular output (blood returning from systemic circulation) was normal in neonates with sepsis and was similar to that in the control patients. Furthermore, a large number of neonates with sepsis presented with clinical signs of poor peripheral perfusion suggestive of, but not confirming, peripheral vasoconstriction [29]. Recognition of sepsis in very early stages can reduce mortality. As mentioned above, early clinical detection of shock in neonates, especially during the early postnatal transitional period, is difficult. This is especially true in preterm infants where lack of definition of hypotension often results in a delay in diagnosis until the patient presents with a full-blown, late-stage shock. Alternatively, it may lead to overdiagnosis and use of unnecessary cardiovascular support not without potential side-effects. A recent study showed that paying close attention to the output of the autonomic nervous system by continuously monitoring heart rate characteristics using the HeRO monitor may aid in early recognition of sepsis before progressing to shock [30]. Indeed, mortality rate was lower among neonates with sepsis whose HeRO scores were available to the clinicians (see B.A. Sullivan and K.D. Fairchild in this issue for details) [30]. In addition to specific treatment directed at the cause of circulatory compromise (e.g. antibiotics in case of septic shock), therapeutic strategies aiming at supporting the cardiovascular system by targeting the prominent hemodynamic feature of the cardiovascular compromise should be considered. Here, the reader is referred to a recent review on the most often used cardiovascular medications, their mechanisms of action and side-effects, and on the proposed approach to selecting the medications based on their hemodynamic profile and the underlying pathophysiology [17]. As the most prevalent pathophysiology in neonatal septic shock is vasodilation, after judicious use of volume resuscitation, a medication that could improve the vascular tone is the recommended

first line of treatment. Phenylephrine, an alpha-adrenergic receptor agonist, and vasopressin (V1a receptor agonist) would have the best profile as pure vasopressors. However, given the limited information on the associated risks and benefits and the very limited experience with these medications, their use as the first-line treatment of vasodilatory shock in the neonatal population cannot be recommended at this time. Rather, as the first-line medication in this setting, one of the most widely used vasopressor-inotropes, dopamine or epinephrine, is recommended. In addition to their vasopressor properties, both medications have positive yet somewhat different inotropic effects, potentially beneficial in patients with decreased myocardial contractility associated with septic shock, especially in patients presenting in more advanced stages. As the development of vasopressor resistance is widespread in vasodilatory shock and adrenergic receptor down-regulation plays a significant role in this setting, careful use of a steroid with both gluco- and mineralocorticoid activities, such as hydrocortisone, is recommended to be considered as a second line of treatment [31,32]. On the other hand, in cases of cold shock when vascular resistance is elevated and cardiac output is low, cautious but appropriate volume resuscitation and the use of an inotropic agent such as dobutamine should be considered. Finally, it is important to keep in mind that there is a significant variability in the cardiovascular response among neonates with shock and that peripheral vascular resistance might change over the course of the disease. 5.2. Contractility Systolic dysfunction is a frequent cause of circulatory failure in the neonatal period. Among the causes of systolic dysfunction, asphyxia is the most studied condition. Indeed, myocardial dysfunction is frequent among asphyxiated neonates [33]. Approximately, one-third of asphyxiated neonates have clinical or electrocardiographic evidence of cardiac involvement [34,35]. Studies on the cardiovascular effects of asphyxia have demonstrated variable results (Table 1). Whereas indices of contractility and systolic function have been found to be normal or decreased [36e40], markers of myocardial injury such as troponin T and I and creatine kinase-MB have been consistently reported to be elevated [37,38,41]. Therefore, it is possible that conventional methods used for the assessment of systolic function have low sensitivity in the neonate. Indeed, newer modalities, such as tissue Doppler and strain rate, have been reported to be abnormal whereas measures of systolic dysfunction using the conventional methods remain within normal limits [40,41]. Depending on the severity of

Table 1 Cardiovascular effects of asphyxia. Contractility

Markers

Cerebral

Shortening fraction Ejection fraction Systolic annulus motion Stroke volume Left ventricular output T- and Q-waves, ST segment Troponin T Troponin I CK-MB Doppler flow indices Doppler resistance indices Blood flow: xenon Oxygen extraction: NIRS

Y or ‒ Y or ‒ Y Y or ‒ Y or ‒ Abnormal [ [ [ [ or Y [ or Y e

Y, decrease; [, increase; ‒, no change; troponin T and troponin I, two of the three regulatory proteins of the troponin system; CK-MB, isoenzymes CKM and CKB of phosphocreatine kinase [33e48].

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

asphyxia, findings on electrocardiogram may vary from a flat or inverted T-wave to an abnormal ST segment and the presence of a Q-wave to evidence of frank infarction [35]. As for cerebral hemodynamics, findings on Doppler indices of blood flow and vascular resistance have been contradictory, most likely due to the variability in the severity of the patient populations studied [39,42e44]. Indeed, in severe cases, CBF is high due to vascular paralysis, whereas in less severe cases of asphyxia, CBF might be low due to myocardial dysfunction [45]. More recently, assessment of cerebral tissue oxygenation and fractional oxygen extraction using NIRS showed low oxygen extraction in more severe cases ‒ a finding consistent with the presence of high CBF [46,47]. Therefore, the systemic cardiovascular and cerebral effects of asphyxia depend on multiple factors including the severity of the condition, the timing of the assessment relative to the insult and the methods used. This underscores the importance of the assessment of cardiac function and CBF in asphyxiated neonates as soon as possible after birth [48]. Another group of patients with myocardial dysfunction is the very preterm infant after PDA ligation. Up to 10e30% of patients undergoing ligation develop hypotension following surgery [49,50]. The etiology of the circulatory compromise is multifactorial. Cardiac dysfunction characterized by poor myocardial performance and decreased contractility is one of the underlying causes in a number of patients [51,52]. In this group, the most widely used vasopressor-inotrope, dopamine, appears to be effective in improving the circulatory compromise [50,53]. Prophylactic use of milrinone in a subset of patients with CO < 200 mL/kg/min has been reported to reduce post-ligation hypotension compared to historical controls [54]. The other documented cause of circulatory compromise following PDA ligation is poor vascular tone, likely associated with the presence of adrenal insufficiency. This group of patients does not respond to dopamine or epinephrine and, in most of these patients, hydrocortisone reverses the circulatory compromise [53]. Unfortunately, pre-ligation assessment of adrenal function does not identify this group of patients. However, low serum cortisol levels a few hours after ligation may be helpful in identifying the patient with relative adrenal insufficiency who might benefit from steroid administration [50,53]. Although they do not occur frequently, it is important to mention the issues related to the management of poor myocardial contractility due to dilated cardiomyopathy. In this group of patients, poor myocardial contractility and high afterload (due to the large ventricular cavity) are the underlying causes of low CO. Although inotropic agents such as digoxin are helpful, afterload reducing agents such as angiotensin-converting enzyme inhibitors are the mainstay of treatment in these cases. Myocardial dysfunction associated with septic shock was discussed in the subsection on vascular tone. Poor contractility is also seen in a number of rare conditions including in patients after prolonged tachyarrhythmia or with prolonged hypertension. A discussion on myocardial dysfunction associated with congenital heart defects and following the cardiothoracic surgical intervention is beyond the scope of this review. Whereas poor contractility leads to low CO, a hyperdynamic myocardium can also lead to low CO (see Section 5.3). 5.3. Preload Hypovolemia resulting from blood loss due to perinatal events such as cord avulsion, placental abruption, significant fetomaternal or feto-placental transfusion or subgaleal hemorrhage is relatively rare. However, recent findings of a better hemodynamic status, lower rate of hypotension, and decreased need for

5

cardiovascular support in preterm or term neonates receiving placental transfusion by delaying cord clamping or milking of the cord indicate that low preload likely contributes to circulatory failure in preterm infants (see M. Kluckow and M.B. Hooper in this issue for details). The use of inappropriately high mean airway pressure during provision of respiratory supportive care, or the presence of a tension pneumothorax, pericardial effusion, or pneumopericardium can significantly reduce venous return and are therefore among the causes of reduced preload leading to low CO. Insensible water loss through the skin of extremely premature infants, capillary leak in patients with sepsis, NEC, and postabdominal surgery are other causes of low intravascular volume and resultant low systemic flow. In addition to low volume status and decreased venous return described above, myocardial diastolic dysfunction can also reduce preload. Although the immature myocardium is poorly compliant, the role of this feature limiting diastolic function especially in preterm infants with circulatory compromise is unclear. On the other hand, diastolic dysfunction plays a major role in circulatory compromise associated with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy due to inherited metabolic disease is not frequently observed. However, about one-third of infants born to poorly-controlled diabetic mothers have some degree of hypertrophic cardiomyopathy [55] and a subset of these patients presents with circulatory failure. The causes of circulatory compromise in these neonates include diastolic dysfunction due to small ventricular cavity and hyperdynamic myocardial function. In addition, due to the small ventricular cavity and thick myocardium, these patients also have low afterload accentuating the hyperdynamic state. Furthermore, the outflow-tract obstruction associated with severe septal hypertrophy often worsens due to the contribution from dynamic obstruction stemming from the hypercontractile myocardial function. Therefore, the approach to management of these patients is very different from that in any other neonate with circulatory compromise and focuses on improving diastolic function and decreasing the hyperdynamic myocardial activity. First, liberal use of volume resuscitation and continuous administration of a beta-adrenergic receptor blocker such as esmolol are recommended. These agents decrease the heart rate and the hypercontractile state, which can be helpful in improving diastolic function. In cases resistant to treatment with volume and a beta-adrenergic receptor blocker who present with evidence of low cardiac output and severe hypotension, the use of a “pure” vasopressor such as phenylephrine or vasopressin might be beneficial. It is important to avoid the use of any medication with inotropic effects, as it will exacerbate the cardiovascular compromise. Cases unresponsive to appropriate administration of volume and pharmacotherapy might benefit from veno-arterial extracorporeal membrane oxygenation support. 5.4. Afterload High afterload can also lead to cardiovascular compromise. As discussed earlier, high afterload worsens poor myocardial contractility in infants with dilated cardiomyopathy. In addition, high afterload is postulated to play a role in circulatory compromise prevalent in a subset of preterm infants during the first postnatal day. In this subset of patients, the myocardium is more sensitive to higher afterload and overt myocardial dysfunction can develop leading to low systemic blood flow (also see the subsection on myocardial contractility). Unfortunately, the vulnerability of the immature myocardium is difficult to clinically recognize and treat. Use of the inotropic agent, dobutamine, had little effect in

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

6

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

improving low systemic flow as assessed by changes in superior vena cava flow [56]. Similarly, prophylactic use of the lusitropic agent, milrinone, in high-risk extremely preterm infants did not prevent low systemic blood flow during the first 24 h after birth [57]. However, this study might have been underpowered due to the lower-than-expected incidence of low systemic blood flow in the patients enrolled. 5.5. Heart rate In view of the higher dependency of CO on heart rate in neonates compared to older children and adults, it is intriguing that normal heart rate distribution covers a wide range (i.e. from 80 to 180 beats/min). Whereas bradycardia occurs fairly frequently in preterm infants, it is often transient and is most likely the result of apnea and/or hypoxia. Persistent bradycardia, except for the presence of heart block, is rare and is often associated with terminal events. On the other hand, tachyarrhythmia is not a rare finding. Supraventricular tachycardia and atrial flutter are the most frequently occurring arrhythmias, leading to circulatory failure in the neonatal period. Fortunately, arrhythmias potentially leading to circulatory compromise do not pose a diagnostic challenge in most instances. 6. Direct assessment of cardiac function and hemodynamic monitoring Given the limitations of using BP, laboratory tests, and our clinical examination to assess the adequacy of cardiovascular function and the systemic circulation, we need additional tools to enhance our ability to detect circulatory compromise and aid in the appropriate selection and titration of cardiovascular supportive care (also see Chapter 6). 6.1. TnEcho Functional or targeted neonatal echocardiography (TnEcho) is useful in identifying the underlying pathophysiology of the cardiovascular insufficiency [58]. It has increasingly been used by neonatologists to assist with the decision about selection of the type of cardiovascular support and the response to treatment. However, the neonatologist must acquire the skills to perform and interpret TnEcho, a mentored process that may require 6e12 months (see also A. Jain and P.J. McNamara in this issue). 6.2. Continuous cardiac output monitor Although TnEcho is indispensable in recognizing the underlying cardiovascular pathophysiology, when it comes to the hemodynamic status, it provides only a snapshot of a dynamic process. Electrical impedance cardiometry is a relatively new technique that uses changes in thoracic bioimpedance to continuously estimate CO. Details of this method of estimation of CO are beyond the scope of this review and can be found elsewhere [59]. Suffice to say that the system is very simple to use, as it only requires the application of four regular electrocardiogram electrodes to the skin. Electrical impedance cardiometry has been shown to have a precision similar to that of echocardiography in estimating CO [59]. Further validation of this method is ongoing at the authors' institution. 6.3. Tissue oxygen saturation The ability to reliably and continuously monitor organ blood flow could revolutionize the way we diagnose and treat

circulatory compromise. Near-infrared and visible light spectroscopy can continuously monitor regional tissue oxygenation. There are limited data on visible light spectroscopy in neonates [60]. On the other hand, NIRS has been more widely used in research and also has made its way to clinical care [61]. As 70e80% of blood in the tissue is in the venous system, tissue oxygen saturation primarily reflects venous oxygen saturation. By taking into account the arterial oxygen saturation, one can estimate the changes in tissue oxygen extraction as well, and, from this information, infer the changes in blood flow. However, by using oxygen extraction as a surrogate for blood flow, several assumptions must be made. It is assumed that metabolic rate for oxygen, hemoglobin concentration and the ratio of venous to arterial blood content of the tissue interrogated have all remained constant. If all of the above conditions are met, then changes in tissue oxygen extraction inversely correlate with changes in organ blood flow. If one uses regional tissue oxygen saturation to indirectly assess organ blood flow, arterial oxygen saturation also needs to remain constant. In addition, normative values of regional tissue oxygen saturation and/or tissue oxygen extraction can also be established for the different neonatal subpopulations. Indeed, a recent case‒control study found that, in preterm neonates, cerebral regional oxygen saturation 10% of time during the first three postnatal days is predictive of worse neurodevelopmental outcome at 18 months' corrected age [7]. Although NIRS has already been introduced to the NICU and its utility in assessing changes in organ blood flow and tissue oxygenation is promising, application of NIRS in clinical care remains to be further studied and better defined. 6.4. Other methods Peripheral circulation can be assessed by laser Doppler and orthogonal polarization spectral imaging. However, due to methodological issues, these techniques are not currently used in clinical care. Amplitude-integrated electroencephalogram (aEEG) is another monitoring technique that may be helpful in assessing the impact of circulatory compromise and supportive care on brain function. A detailed discussion on the clinical utility of aEEG is beyond the scope of this review. 7. Conclusion Until data from RCTs are available to guide more appropriately the diagnosis and treatment of neonatal circulatory failure, we need to use the available information on continuous BP and the mostly non-continuous CO measurements; we also need to assess the indirect clinical signs and laboratory evidence of poor perfusion to determine the underlying pathophysiology of shock and the appropriate cardiovascular supportive care required. Perinatal and maternal history is often useful in determining the most likely underlying pathophysiology of the circulatory failure. If feasible, one should directly assess the cardiac function by echocardiography as often as needed so that the suspected underlying pathophysiology and the hemodynamic features of the cardiovascular compromise can be determined with more certainty and so that the response to treatment can be more appropriately followed. The ultimate goal is to develop, test, and then utilize a comprehensive, continuous hemodynamic monitoring and data acquisition system capable of providing reliable information on systemic hemodynamics, organ blood flow, tissue oxygen delivery, peripheral circulation and organ (brain) function in real time. The development and testing of such a system are in progress in the authors' institutions (see T. Azhibekov et al. in this issue for further details).

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

Practice points  Irrespective of the definition of hypotension, hypotensive preterm infants have a higher incidence of adverse neurodevelopmental outcome compared to their normotensive counterparts.  There are no data from RCTs on the impact of untreated hypotension on outcome and, unfortunately, convincing data are unlikely to be available in the near future.  Ongoing RCTs evaluating a higher threshold for administration of cardiovascular supportive measures will be helpful in better defining at-risk patients.  Hypotension, when prolonged or in conjunction with metabolic acidosis, hypoxia, hypo- or hypercapnia and/or impaired cerebral autoregulation, is more likely to be associated with poor outcome.  Pathophysiology-based and individualized management of cardiovascular compromise is likely helpful in selecting a treatment option that is more likely to revert the circulatory derangement and exert fewer side-effects.  TnEcho is valuable in defining the underlying pathophysiology of circulatory compromise.  Monitoring techniques such as NIRS can be helpful in management of shock. However, further information is needed before the widespread, routine application of NIRS in clinical practice.

Research directions  Define the gestational and postnatal age-dependent threshold for treating hypotension with consideration of the individual patient's ability to compensate for the decreased perfusion pressure.  Define the role of NIRS and non-invasive cardiac output monitoring in management of neonatal circulatory compromise.  Study the underlying mechanisms and pathophysiology in neonatal shock.  Study the impact of cardiovascular supportive care on circulatory function and outcome.  Develop and study the utility of comprehensive, real-time hemodynamic monitoring and data acquisition systems.

Conflict of interest statement None declared. Funding sources None declared. References [1] Watkins AM, West CR, Cooke RW. Blood pressure and cerebral haemorrhage and ischaemia in very low birthweight infants. Early Hum Dev 1989;19: 103e10. [2] Munro MJ, Walker AM, Barfield CP. Hypotensive extremely low birth weight infants have reduced cerebral blood flow. Pediatrics 2004;114:1591e6. [3] Børch K, Lou HC, Greisen G. Cerebral white matter blood flow and arterial blood pressure in preterm infants. Acta Paediatr 2010;99:1489e92.

7

[4] Stranak 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;173:793e8. [5] Logan JW, O’Shea TM, Allred EN, Laughon MM, Bose CL, Dammann O, et al. Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns. Archs Dis Childh Fetal Neonatal Ed 2011;96:F321e8. [6] Batton B, Li L, Newman NS, Das A, Watterberg KL, Yoder BA, et al. Use of antihypotensive therapies in extremely preterm infants. Pediatrics 2013;131: e1865e73. [7] Alderliesten T, Lemmers PMA, van Haastert IC, de Vries LS, Bonestroo HJC, Baerts W, et al. Hypotension in preterm neonates: low blood pressure alone does not affect neurodevelopmental outcome. J Pediatr 2014;164:986e91. [8] Low JA, Froese AB, Galbraith RS, Smith JT, Sauerbrei EE, Derrick EJ. The association between preterm newborn hypotension and hypoxemia and outcome during the first year. Acta Paediatr 1993;82:433e7. [9] Goldstein RF, Thompson Jr RJ, Oehler JM, Brazy JE. Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics 1995;95:238e43. [10] Martens SE, Rijken M, Stoelhorst GMSJ, van Zwieten PHT, Zwinderman AH, Wit JM, et al. Is hypotension a major risk factor for neurological morbidity at term age in very preterm infants? Early Hum Dev 2003;75(1‒2):79e89. [11] Hunt RW, Evans N, Rieger I, Kluckow M. Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. J Pediatr 2004;145: 588e92. [12] Fanaroff JM, Wilson-Costello DE, Newman NS, Montpetite MM, Fanaroff AA. Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants. Pediatrics 2006;117:1131e5. [13] Batton B, Batton D, Riggs T. Blood pressure during the first 7 days in premature infants born at postmenstrual age 23 to 25 weeks. Am J Perinatol 2007;24:107e15. [14] Kuint J, Barak M, Morag I, Maayan-Metzger A. Early treated hypotension and outcome in very low birth weight infants. Neonatology 2009;95:311e6. [15] Batton B, Zhu X, Fanaroff J, Kirchner HL, Berlin S, Wilson-Costello D, et al. Blood pressure, anti-hypotensive therapy, and neurodevelopment in extremely preterm infants. J Pediatr 2009;154:351e7. 357.e1. ~ as F. Early systemic [16] Pellicer A, Bravo M del C, Madero R, Salas S, Quero J, Caban hypotension and vasopressor support in low birth weight infants: impact on neurodevelopment. Pediatrics 2009;123:1369e76. [17] Noori S, Seri I. Neonatal blood pressure support: the use of inotropes, lusitropes, and other vasopressor agents. Clin Perinatol 2012;39:221e38. [18] Soleymani S, Borzage M, Seri I. Hemodynamic monitoring in neonates: advances and challenges. J Perinatol 2010;30(Suppl.):S38e45. [19] De Boode W-P. Clinical monitoring of systemic hemodynamics in critically ill newborns. Early Hum Dev 2010;86:137e41. [20] Batton BJ, Li L, Newman NS, Das A, Watterberg KL, Yoder BA, et al. Feasibility study of early blood pressure management in extremely preterm infants. J Pediatr 2012;161. 65e9.e1. [21] Dempsey EM, Al Hazzani F, Barrington KJ. Permissive hypotension in the extremely low birthweight infant with signs of good perfusion. Archs Dis Childh Fetal Neonatal Ed 2009;94:F241e4. [22] Wiswell TE, Graziani LJ, Kornhauser MS, Stanley C, Merton DA, McKee L, et al. Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high-frequency jet ventilation. Pediatrics 1996;98:918e24. [23] McKee LA, Fabres J, Howard G, Peralta-Carcelen M, Carlo WA, Ambalavanan N. PaCO2 and neurodevelopment in extremely low birth weight infants. J Pediatr 2009;155. 217e21.e1. [24] Kaiser JR, Gauss CH, Pont MM, Williams DK. Hypercapnia during the first 3 days of life is associated with severe intraventricular hemorrhage in very low birth weight infants. J Perinatol 2006;26:279e85. [25] Fabres J, Carlo WA, Phillips V, Howard G, Ambalavanan N. Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants. Pediatrics 2007;119:299e305. [26] De Waal K, Evans N. Hemodynamics in preterm infants with late-onset sepsis. J Pediatr 2010;156. 918e22, 922.e1. [27] Raj S, Killinger JS, Gonzalez JA, Lopez L. Myocardial dysfunction in pediatric septic shock. J Pediatr 2014;164. 72e7.e2. [28] Brierley J, Peters MJ. Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 2008;122:752e9. [29] Saini SS, Kumar P, Kumar RM. Hemodynamic changes in preterm neonates with septic shock: a prospective observational study. Pediatr Crit Care Med 2014;15:443e50. [30] Fairchild KD, Schelonka RL, Kaufman DA, Carlo WA, Kattwinkel J, Porcelli PJ, et al. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013;74:570e5. [31] Seri I, Tan R, Evans J. Cardiovascular effects of hydrocortisone in preterm infants with pressor-resistant hypotension. Pediatrics 2001;107:1070e4. [32] Noori S, Friedlich P, Wong P, Ebrahimi M, Siassi B, Seri I. Hemodynamic changes after low-dosage hydrocortisone administration in vasopressortreated preterm and term neonates. Pediatrics 2006;118:1456e66. [33] Armstrong K, Franklin O, Sweetman D, Molloy EJ. Cardiovascular dysfunction in infants with neonatal encephalopathy. Archs Dis Childh 2012;97:372e5.

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

8

S. Noori, I. Seri / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e8

 F, Caban ~ as F, Burgueros M, Quero J. Multiple [34] Martín-Ancel A, García-Alix A, Gaya organ involvement in perinatal asphyxia. J Pediatr 1995;127:786e93. [35] Kanik E, Ozer EA, Bakiler AR, Aydinlioglu H, Dorak C, Dogrusoz B, et al. Assessment of myocardial dysfunction in neonates with hypoxic‒ischemic encephalopathy: is it a significant predictor of mortality? J Matern Fetal Neonatal Med 2009;22:239e42.  MP, Cordaro S, Gitto E, Sottile A, Prudente D, et al. [36] Barberi I, Calabro Myocardial ischaemia in neonates with perinatal asphyxia. Electrocardiographic, echocardiographic and enzymatic correlations. Eur J Pediatr 1999;158:742e7. [37] Szymankiewicz M, Matuszczak-Wleklak M, Hodgman JE, Gadzinowski J. Usefulness of cardiac troponin T and echocardiography in the diagnosis of hypoxic myocardial injury of full-term neonates. Biol Neonate 2005;88: 19e23. [38] Costa S, Zecca E, De Rosa G, De Luca D, Barbato G, Pardeo M, et al. Is serum troponin T a useful marker of myocardial damage in newborn infants with perinatal asphyxia? Acta Paediatr 2007;96:181e4. [39] Liu J, Li J, Gu M. The correlation between myocardial function and cerebral hemodynamics in term infants with hypoxic‒ischemic encephalopathy. J Trop Pediatr 2007;53:44e8. [40] Nestaas E, Støylen A, Brunvand L, Fugelseth D. Longitudinal strain and strain rate by tissue Doppler are more sensitive indices than fractional shortening for assessing the reduced myocardial function in asphyxiated neonates. Cardiol Young 2011;21:1e7. [41] Wei Y, Xu J, Xu T, Fan J, Tao S. Left ventricular systolic function of newborns with asphyxia evaluated by tissue Doppler imaging. Pediatr Cardiol 2009;30: 741e6. [42] Van Bel F, van de Bor M, Stijnen T, Baan J, Ruys JH. Cerebral blood flow velocity pattern in healthy and asphyxiated newborns: a controlled study. Eur J Pediatr 1987;146:461e7. [43] Levene MI, Fenton AC, Evans DH, Archer LN, Shortland DB, Gibson NA. Severe birth asphyxia and abnormal cerebral blood-flow velocity. Dev Med Child Neurol 1989;31:427e34. [44] Ilves P, Talvik R, Talvik T. Changes in Doppler ultrasonography in asphyxiated term infants with hypoxic‒ischaemic encephalopathy. Acta Paediatr 1998;87: 680e4. [45] Pryds O, Greisen G, Lou H, Friis-Hansen B. Vasoparalysis associated with brain damage in asphyxiated term infants. J Pediatr 1990;117(1 Pt 1):119e25. [46] Toet MC, Lemmers PMA, van Schelven LJ, van Bel F. Cerebral oxygenation and electrical activity after birth asphyxia: their relation to outcome. Pediatrics 2006;117:333e9. [47] Ancora G, Maranella E, Grandi S, Sbravati F, Coccolini E, Savini S, et al. Early predictors of short term neurodevelopmental outcome in asphyxiated cooled infants. A combined brain amplitude integrated electroencephalography and near infrared spectroscopy study. Brain Dev 2013;35:26e31.

[48] Kluckow M. Functional echocardiography in assessment of the cardiovascular system in asphyxiated neonates. J Pediatr 2011;158(Suppl. 2):e13e8. [49] Moin F, Kennedy KA, Moya FR. Risk factors predicting vasopressor use after patent ductus arteriosus ligation. Am J Perinatol 2003;20:313e20. [50] Clyman RI, Wickremasinghe A, Merritt TA, Solomon T, McNamara P, Jain A, et al. Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones. J Pediatr 2014;164. 1449e55.e1. [51] Noori S, Friedlich P, Seri I, Wong P. Changes in myocardial function and hemodynamics after ligation of the ductus arteriosus in preterm infants. J Pediatr 2007;150:597e602. [52] McNamara PJ, Stewart L, Shivananda SP, Stephens D, Sehgal A. Patent ductus arteriosus ligation is associated with impaired left ventricular systolic performance in premature infants weighing less than 1000 g. J Thorac Cardiovasc Surg 2010;140:150e7. [53] Noori S, McNamara P, Jain A, Lavoie PM, Wickremasinghe A, Merritt TA, et al. Catecholamine-resistant hypotension and myocardial performance following patent ductus arteriosus ligation. J Perinatol 2015;35:123e7. [54] Jain A, Sahni M, El-Khuffash A, Khadawardi E, Sehgal A, McNamara PJ. Use of targeted neonatal echocardiography to prevent postoperative cardiorespiratory instability after patent ductus arteriosus ligation. J Pediatr 2012;160. 584e9.e1. [55] Ullmo S, Vial Y, Di Bernardo S, Roth-Kleiner M, Mivelaz Y, Sekarski N, et al. Pathologic ventricular hypertrophy in the offspring of diabetic mothers: a retrospective study. Eur Heart J 2007;28:1319e25. [56] Osborn D, Evans N, Kluckow M. Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow. J Pediatr 2002;140:183e91. [57] Paradisis M, Evans N, Kluckow M, Osborn D. Randomized trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants. J Pediatr 2009;154:189e95. [58] Mertens L, Seri I, Marek J, Arlettaz R, Barker P, McNamara P, et al. Targeted Neonatal Echocardiography in the Neonatal Intensive Care Unit: practice guidelines and recommendations for training. Writing Group of the American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC). J Am Soc Echocardiogr 2011;24:1057e78. [59] Noori S, Drabu B, Soleymani S, Seri I. Continuous non-invasive cardiac output measurements in the neonate by electrical velocimetry: a comparison with echocardiography. Archs Dis Childh Fetal Neonatal Ed 2012;97:F340e3. [60] Noori S, Drabu B, McCoy M, Sekar K. Non-invasive measurement of local tissue perfusion and its correlation with hemodynamic indices during the early postnatal period in term neonates. J Perinatol 2011;31:785e8. [61] Van Bel F, Lemmers P, Naulaers G. Monitoring neonatal regional cerebral oxygen saturation in clinical practice: value and pitfalls. Neonatology 2008; 94:237e44.

Please cite this article in press as: Noori S, Seri I, Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.005

Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise.

With the advances in biomedical research and neonatal intensive care, our understanding of cardiovascular developmental physiology and pathophysiology...
433KB Sizes 5 Downloads 13 Views