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Management of Neonatal Hypotension and Shock

  • Christoph E. Schwarz
    Affiliations
    Department of Paediatrics & Child Health, University College Cork, Cork, Ireland

    INFANT Irish Centre for Maternal and Child Health Research, Cork, Ireland

    Department of Neonatology, University Children's Hospital, Tübingen, Germany
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  • Eugene M. Dempsey
    Correspondence
    Corresponding author. Dept. of Neonatology, Cork University Maternity Hospital, Wilton, Cork, Ireland.
    Affiliations
    Department of Paediatrics & Child Health, University College Cork, Cork, Ireland

    INFANT Irish Centre for Maternal and Child Health Research, Cork, Ireland
    Search for articles by this author
Open AccessPublished:May 20, 2020DOI:https://doi.org/10.1016/j.siny.2020.101121

      Abstract

      The current standard approach to manage circulatory insufficiency is inappropriately simple and clear: respond to low blood pressure to achieve higher values. However, the evidence for this is limited affecting all steps within the process: assessment, decision making, therapeutic options, and treatment effects. We have to overcome the ‘one size fits all’ approach and respect the dynamic physiologic transition from fetal to neonatal life in the context of complex underlying conditions. Caregivers need to individualize their approaches to individual circumstances. This paper will review various clinical scenarios, including managing transitional low blood pressure, to circulatory impairment involving different pathologies such as hypoxia-ischemia and sepsis. We will highlight the current evidence and set potential goals for future development in these areas. We hope to encourage caregivers to question the current standards and to support urgently needed research in this overlooked but crucial field of neonatal intensive care.

      Keywords

      Abbreviations

      BAPM
      British Association Perinatal Medicine
      CrCP
      Critical Closing Pressure
      DA
      Dopamine
      DOB
      Dobutamine
      EPI
      Epinephrine
      GNN
      German Neonatal Network
      LCOS
      Low cardiac output syndrome
      LEV
      Levosimendan
      LOS
      Late onset Sepsis
      MIL
      Milrinone
      NE
      Norepinephrine
      ni/i
      non-invasive/invasive
      TH
      Therapeutic Hypothermia
      PVR
      Pulmonary Vascular Resistance
      RDS
      Respiratory Distress Syndrome
      SVR
      Systemic Vascular Resisitance

      1. Introduction

      Over preceding years there has been a growing realization that our current approach to the management of babies with cardiovascular instability is limited: limited in our assessment, limited in our understanding of the pathophysiology, and limited in our choice of therapeutic interventions. The current ‘standard approach’ to circulatory impairment continues to lack any supporting evidence base: intervention with volume followed by dopamine (DA), and observation of the response in mean blood pressure (BPmean) values [
      • 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.
      ]. This prescriptive approach provides the clinician with great clarity: intervene below a certain BP value, titrate inotropic support to achieve certain BP values, and achieve that value safe in the knowledge that one has addressed the problem. However, while in many situations this approach may result in a positive outcome for the infant, it often fails to address the complexity of the underlying problem, and, in some circumstances may result in undue harm [
      • Fanaroff J.M.
      • Wilson-Costello D.E.
      • Newman N.S.
      • Montpetite M.M.
      • Fanaroff A.A.
      Treated hypotension is associated with neonatal morbidity and hearing loss in extremely low birth weight infants.
      ].
      Deciding on when it is necessary to intervene, or not, is the crucial first step in the management pathway. Enhanced recognition of the underlying condition should allow improved choice of therapeutic strategies, which may range from careful ongoing observation to immediate intervention with volume and/or inotrope. Clinical evaluation, notwithstanding its limitations, in conjunction with readily available continuous bedside monitoring parameters such as heart rate (HR) and BP, intermittent measures such as urine output and point of care lactate values, should provide greater understanding of the underlying circulatory status. Recent objective assessment tools (discussed in other chapters of this series) including echocardiography, near infrared spectroscopy, and non-invasive cardiac output (CO) monitoring may provide an enhanced picture of the underlying pathophysiology. It is important that clinicians understand the specific limitations of each of these assessment tools. Application and utilization of these devices in the most immature infants present their own unique technical challenges. With an increased number of monitoring devices providing increased markers of circulatory status, decision-making becomes more complex but offers the hope that a much more informed rational decision can be made.
      One of the major challenges in cardiovascular management is deciding when a numerically low BP value (hypotension) is something that warrants intervention and/or whether an infant with or without low BP is in a clinical state of hypoperfusion (shock). In this chapter, we set out to differentiate between hypotension and shock in the newborn infant and address the various therapeutic options available for the more commonly encountered causes of circulatory insufficiency.

      2. Definitions

      2.1 Normal blood pressure and hypotension

      Determining normality in a relatively heterogeneous population is challenging. Numerous normative reference ranges exist, which is a relatively unique phenomenon compared to other areas of neonatal care. The method of assessment is critical, especially for the most immature preterm infant where non-invasive (NI) measurements often overestimate the true invasive (I) BPmean value. Lower gestational age (GA), postnatal age, birthweight, and gender all impact BP – thus a “one size fits all” approach defining certain absolute BP intervention values is rather limited. BP progressively increases in both term and preterm populations, especially during the first hours and days of life [
      • Zubrow A.B.
      • Hulman S.
      • Kushner H.
      • Falkner B.
      Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group.
      ,
      • Batton B.
      • Li L.
      • Newman N.S.
      • Das A.
      • Watterberg K.L.
      • Yoder B.A.
      • et al.
      Evolving blood pressure dynamics for extremely preterm infants.
      ,
      • Vesoulis Z.A.
      • Flower A.A.
      • Zanelli S.
      • Rambhia A.
      • Abubakar M.
      • Whitehead H.V.
      • et al.
      Blood pressure extremes and severe IVH in preterm infants.
      ]. These dynamic changes are often neglected, especially in the most commonly used definitions of low BP.
      One of the most commonly used definitions is a BPmean < GA in weeks - the so called British Association Perinatal Medicine (BAPM) rule [
      Development of audit measures and guidelines for good practice in the management of neonatal respiratory distress syndrome. Report of a joint working group of the British association of perinatal medicine and the research unit of the royal college of physicians.
      ]. While there is little evidence to support this definition, it seems to be embedded in clinical practice. This definition is somewhat similar numerically to a recent large German Neonatal Network (GNN) cohort study [
      • Faust K.
      • Hartel C.
      • Preuss M.
      • Rabe H.
      • Roll C.
      • Emeis M.
      • et al.
      Short-term outcome of very-low-birthweight infants with arterial hypotension in the first 24 h of life.
      ]. The GNN data suggest that the BAPM rule may be an overestimate in extremely low gestational age newborns (ELGANs) on the first day. Infants born <29 weeks were found to have at least one median minimal BPmean 1–2 mmHg below their equivalent GA in completed weeks [
      • Faust K.
      • Hartel C.
      • Preuss M.
      • Rabe H.
      • Roll C.
      • Emeis M.
      • et al.
      Short-term outcome of very-low-birthweight infants with arterial hypotension in the first 24 h of life.
      ] on the first day of life. Alternative single BPmean values have been suggested. Vesoulis identified iBPmean of approximately 33 mmHg at birth to be “normal” in 35 preterm infants <28 weeks’ GA [
      • Vesoulis Z.A.
      • El Ters N.M.
      • Wallendorf M.
      • Mathur A.M.
      Empirical estimation of the normative blood pressure in infants <28 weeks gestation using a massive data approach.
      ]. However, they excluded high risk infants: those who received inotropic support, those who died within first 14 days, or those who developed severe intraventricular hemorrhage (IVH grade III/IV). The BPmean<30 mm Hg is based on physiologic aspects regarding cerebral perfusion and impaired autoregulation in low BP states – the so called cerebral critical closing pressure (CrCP). An older study by Miall-Allen identified an increased incidence of significant IVH, ischemic lesions, or death in 33 preterm newborns (GA ranged from 26 to 30 weeks) whose BPmean was less than 30 mmHg for at least 1 h on the first day of life [
      • Miall-Allen V.M.
      • de Vries L.S.
      • Whitelaw A.G.
      Mean arterial blood pressure and neonatal cerebral lesions.
      ]. No severe lesions developed with a BPmean greater than or equal to 30 mmHg. However, this study was conducted some 30 years ago and a number of confounders including pethidine use and inotrope administration were not factored into the analysis. It seems physiologically unlikely that a single BPmean value should exist for a relatively wide gestational age cohort. Recently published measured and calculated cerebral CrCP in ELGANs (GA range 23–26 weeks) indicate lower median (interquartile range) values: measured 20 mmHg (18–25 mmHg) and calculated 19 mmHg (17–22 mmHg) [
      • Elizondo L.I.
      • Rios D.R.
      • Vu E.
      • Kibler K.
      • Easley R.B.
      • Andropoulos D.B.
      • et al.
      Observed and calculated cerebral critical closing pressure are highly correlated in preterm infants.
      ].
      Some of these definitions have been associated with adverse outcome, but in many instances no association was identified. Much of this variability probably relates to differing definitions, differing assessment methods, different populations, different statistical methods, and the inability to account for potential known (or unknown) confounders. We believe we have to accept the current limitations in definitions and stop searching for simple solutions to more complex issues. Big data analysis may provide an enhanced approach to better define low BP but will also be challenged with associations instead of clear causality [
      • Batton B.
      Alternative facts? Using big data to identify high and low blood pressure values.
      ]. Thus, we need definitions that at least consider the method of assessment, and both the gestational and postnatal age, to guide us. Perhaps the best way to think of BP during transition is to think of an evaluation pressure and a trigger pressure. The initial evaluation pressure should be based around gestational age equivalent values on day one. The trigger pressure is the value upon which one decides to intervene and is more complicated. This should not be a single value alone, but rather considered as an important value in the setting of other equally important elements, whether they be clinical, biochemical, or other objective assessment criteria.

      2.2 Shock

      Shock can be summarized descriptively as circulatory impairment leading to a state of impaired oxygen delivery to tissues. Normal cellular or tissue oxygenation depends on blood flow, oxygen saturation, transport capacity of the blood, and tissue oxygen demand. If this deficiency is for a short time period, cellular metabolism could be impaired but reversible; however, if prolonged, it may become irreversible. Currently, there is no single direct bedside measure of shock. Various technical and clinical surrogates or biomarkers are used to estimate tissue oxygenation and perfusion in neonates and are discussed elsewhere in more detail in this issue. The challenge is that in the early stages of newborn shock many subtle compensatory mechanisms occur that may mask the degree of circulatory impairment. It may be difficult to appreciate these subtle changes, such that by the time shock becomes clinically obvious, the infant is often in an uncompensated state. Relying solely on BP to determine whether or not an infant is in shock is problematic: when the BP is genuinely low, the patient may be in the uncompensated or even irreversible state, but a normal BP does not necessarily imply a normal flow state, and equally, a low BP can be present in the absence of shock. Each of these factors makes management such a complicated area. Fig. 1 provides a schematic overview of the complexity in this decision-making process.
      Fig. 1
      Fig. 1Complexity of Decision making in Circulatory Management.

      3. Individual scenarios

      Low BP and shock can occur in many settings in the neonatal period. It is often helpful to consider the timing of such events, as they provide an insight into the underlying pathophysiology: early, within the first few days of life, and late, beyond this time period. It is equally important to acknowledge the structural, metabolic, and developmental aspects of the cardiovascular system and the changes that occur over the first weeks of life. Table 1 provides a summary of different factors potentially affecting the circulatory status. This may aid with the choice and dose of therapeutic interventions used. Also, it needs to factor in the natural postnatal increase in blood pressure over this time period.
      Table 1Factors contributing to early cardiovascular insufficiency.
      ProblemPotential Hemodynamic Disturbances
      Immature MyocardiumReduced contractility, altered filling, reduced cardiac output, reduced effect of endogenous and exogenous catecholamine
      Immature Vasomotor ToneDecreased SVR, Increased SVR, altered effect of catecholamine
      Patent ductus arteriosusShunting direction, dependent on SVR and PVR,

      Altered cardiac output
      Sepsis (Inflammation)Affects SVR and PVR, impaired contractility, reduced intravascular volume due to capillary leak
      HypoxiaAltered SVR, PVR, impaired contractility
      Therapeutic HypothermiaIncreased SVR, reduced heart rate and cardiac output
      Respiratory Conditions eg RDS, PPHNHigh PVR, Right to left shunt, hypoxia
      Mechanical Ventilation/PneumothoraxImpact on cardiac filling and cardiac output
      Blood Loss/early cord clampingReduced blood volume and oxygen transport capacity, decreased cardiac output

      3.1 Early hypotension/circulatory insufficiency

      3.1.1 Permissive hypotension

      Much has been written about the management of low BP in the extremely preterm infant during the first days of life, but unfortunately there is very little evidence to support or refute these various approaches. We previously described an approach termed ‘permissive hypotension’ that advocated a global assessment of the infant including various clinical and biochemical parameters in addition to BP values prior to intervening, and not based solely on BPmean values [
      • Dempsey E.M.
      • Al Hazzani F.
      • Barrington K.J.
      Permissive hypotension in the extremely low birthweight infant with signs of good perfusion.
      ]. More recent data from the Epipage 2 nested matched-control cohort study showed a higher incidence of significant brain injury in the low BP group who did not receive any antihypotensive treatment (fluid bolus, inotropes, or corticosteroids) compared to those who did for treatment of isolated hypotension defined by BAPM rule [
      • Durrmeyer X.
      • Marchand-Martin L.
      • Porcher R.
      • Gascoin G.
      • Roze J.C.
      • Storme L.
      • et al.
      Abstention or intervention for isolated hypotension in the first 3 days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study.
      ]. This suggests a worse short-term outcome when an approach of limiting inotropic therapy was advocated. Interestingly, in the subgroup of infants with a minimal BPmean ≤ GA-5, survival without severe morbidity was higher for the treated group (Odds Ratio, 3.15; 95% Confidence Interval 1.28 to 7.74). However, there were a number of potential confounders not factored into this analysis. A recent prospective randomized trial attempted to address the problem of intervening or not when the mean BP falls below a certain numeric threshold (BAPM rule). The HIP trial compared a restrictive versus a more conventional approach (volume and DA when BPmean < GA) in preterm infants <28 weeks' gestation. Recruitment stopped after only 58 patients were included, primarily because of the challenges with enrolment. Approximately one in four infants <28 weeks had a BPmean less than their GA in the first three days of life which lasted for at least a 15 min period, and this occurred predominantly on day 1. There was no difference in the primary outcome of survival free of significant brain injury at 36 weeks' corrected gestational age in the restrictive compared to the conventional approach (69% versus 62%). This would suggest that a ‘wait and see approach’ is not unreasonable in this group of extreme preterm infants. The overall incidence of gastrointestinal complications was approximately 20%, suggesting that low BP may be associated with later gastrointestinal complications. However, it should be acknowledged that the sample size was very small, and no long-term outcome data are available. The inclusion of echocardiography as an assessment tool may help better classify patients with low BP who may benefit from targeted intervention. However, trials of low flow states identified on echocardiography have not shown any difference between DA and dobutamine (DOB) use [
      • Osborn D.
      • Evans N.
      • Kluckow M.
      Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow.
      ], and the only trial aimed at reducing the incidence of low blood flow utilized milrinone (MIL) and found no improvement in outcome [
      • 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.
      ]. Targeting end organ blood flow, as is occurring with the SafeBoosC-III trial, may provide an alternative physiology-based approach. This trial represents a paradigm shift in the care of preterm infants in the first few days of life. It focuses on maintaining cerebral oxygenation above a certain threshold value. If it falls below this threshold, an assessment occurs, which incorporates cardiovascular, respiratory, and metabolic variables prior to deciding to intervene. Low BP values and/or the presence of a patent ductus arteriosus represent potential cardiovascular factors that may warrant therapy. This trial is currently ongoing (ClinicalTrials.gov NCT03770741).

      3.1.2 Hypoxia- ischemia

      Circulatory impairment in hypoxic-ischemic encephalopathy is common and its pathophysiologic background and specific treatment options were recently summarized [
      • Giesinger R.E.
      • Bailey L.J.
      • Deshpande P.
      • McNamara P.J.
      Hypoxic-ischemic encephalopathy and therapeutic hypothermia: the hemodynamic perspective.
      ]. Whereas the initial period following injury is often characterized by a global multiorgan insult, prolonged circulatory insufficiency can lead to further organ dysfunction. Despite the introduction of therapeutic hypothermia (TH) and its documented benefits, there remains a significant risk for mortality and long-term neuro-disability. When circulatory compromise exceeds the limited cerebral autoregulatory capacity, further brain injury may occur [
      • Burton V.J.
      • Gerner G.
      • Cristofalo E.
      • Chung S.E.
      • Jennings J.M.
      • Parkinson C.
      • et al.
      A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia.
      ]. Thus, hemodynamic management provides the clinician with an opportunity to potentially improve short- and long-term outcomes [
      • Lee J.K.
      • Poretti A.
      • Perin J.
      • Huisman T.
      • Parkinson C.
      • Chavez-Valdez R.
      • et al.
      Optimizing cerebral autoregulation may decrease neonatal regional hypoxic-ischemic brain injury.
      ]. The severity of right ventricular dysfunction is associated with adverse outcome [
      • Giesinger R.E.
      • El Shahed A.I.
      • Castaldo M.P.
      • Breatnach C.R.
      • Chau V.
      • Whyte H.E.
      • et al.
      Impaired right ventricular performance is associated with adverse outcome after hypoxic ischemic encephalopathy.
      ]. Pulmonary hypertension often exacerbates the degree of circulatory compromise, and its presence is associated with abnormal brain imaging on MRI [
      • More K.S.
      • Sakhuja P.
      • Giesinger R.E.
      • Ting J.Y.
      • Keyzers M.
      • Sheth J.N.
      • et al.
      Cardiovascular associations with abnormal brain magnetic resonance imaging in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia and rewarming.
      ]. Management involves primarily reducing pulmonary vascular resistance with a view to enhancing right ventricular performance and ultimately biventricular performance.
      TH may effect hemodynamic parameters such as BP, HR, HR variability, and CO [
      • Yoon J.H.
      • Lee E.J.
      • Yum S.K.
      • Moon C.J.
      • Youn Y.A.
      • Kwun Y.J.
      • et al.
      Impacts of therapeutic hypothermia on cardiovascular hemodynamics in newborns with hypoxic-ischemic encephalopathy: a case control study using echocardiography.
      ]. Bradycardia is perhaps the most common feature, and is associated with decreased CO. However, studies evaluating the prognostic value of lower HR or low CO are controversial. As TH reduces tissue oxygen demand, high CO is potentially associated with reperfusion injury [
      • Hochwald O.
      • Jabr M.
      • Osiovich H.
      • Miller S.P.
      • McNamara P.J.
      • Lavoie P.M.
      Preferential cephalic redistribution of left ventricular cardiac output during therapeutic hypothermia for perinatal hypoxic-ischemic encephalopathy.
      ], and low HR seems to be an appropriate response to decreased oxygen demand [
      • Montaldo P.
      • Cuccaro P.
      • Caredda E.
      • Pugliese U.
      • De Vivo M.
      • Orbinato F.
      • et al.
      Electrocardiographic and echocardiographic changes during therapeutic hypothermia in encephalopathic infants with long-term adverse outcome.
      ]. Clinical features of shock, such as skin color, capillary refill time, or urine output, may be difficult to appreciate during hypothermia treatment [
      • Giesinger R.E.
      • Bailey L.J.
      • Deshpande P.
      • McNamara P.J.
      Hypoxic-ischemic encephalopathy and therapeutic hypothermia: the hemodynamic perspective.
      ]. This underlines the urgent need for objective assessment of cardiovascular stability in this patient group. Non-invasive CO monitoring and cerebral perfusion monitoring is feasible in the setting of neonatal encephalopathy [
      • Forman E.
      • Breatnach C.R.
      • Ryan S.
      • Semberova J.
      • Miletin J.
      • Foran A.
      • et al.
      Noninvasive continuous cardiac output and cerebral perfusion monitoring in term infants with neonatal encephalopathy: assessment of feasibility and reliability.
      ], but further investigation is needed prior to its routine use at the bedside.
      Joynt and Cheung recently summarized specific circulatory management options in neonatal encephalopathy [
      • Joynt C.
      • Cheung P.Y.
      Cardiovascular supportive therapies for neonates with Asphyxia - a literature review of pre-clinical and clinical studies.
      ]. Data from pre-cooling RCTs must be interpreted cautiously. Excessive use of fluid boluses risk overload, and may potentially exacerbate the risk of cerebral edema. DA, DOB, Epinephrine (EPI), Norepinephrine (NE), MIL, and vasopressin, as well as respiratory strategies [oxygen, nitric oxide (NO)] all may have an important role in this setting, especially with associated pulmonary hypertension [
      • Joynt C.
      • Cheung P.Y.
      Cardiovascular supportive therapies for neonates with Asphyxia - a literature review of pre-clinical and clinical studies.
      ]. The evidence relating the choice of agent is limited to predominantly pre-clinical studies, with the majority of clinical studies mainly observational in design and limited to small numbers. Individualization of therapy is required, as there may be different degrees of myocardial dysfunction, vasomotor dysfunction, and pulmonary hypertension present. Incorporation of echocardiography and non-invasive cardiac output monitoring may assist in individualizing the agent/s used. MIL was associated with greater BPmean deviation below autoregulation-derived values, and this deviation was shown to be associated with brain injury [
      • Carrasco M.
      • Perin J.
      • Jennings J.M.
      • Parkinson C.
      • Gilmore M.M.
      • Chavez-Valdez R.
      • et al.
      Cerebral autoregulation and conventional and diffusion tensor imaging magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy.
      ]. Hydrocortisone may play a specific role in neonatal encephalopathy, as physiologic responses to stress may be impaired. A recent RCT compared effects of low dose hydrocortisone to placebo on BP in addition to DA in term infants undergoing TH with low BP (defined by BAPM rule) not responding to a fluid bolus [
      • Kovacs K.
      • Szakmar E.
      • Meder U.
      • Szakacs L.
      • Cseko A.
      • Vatai B.
      • et al.
      A randomized controlled study of low-dose hydrocortisone versus placebo in dopamine-treated hypotensive neonates undergoing hypothermia treatment for hypoxic-ischemic encephalopathy.
      ]. They found increased BP within 2 h comparable to the effects of a DA dose of 15 μg/kg/min accompanied by decreased peak and cumulative dose and decreased duration of cardiovascular support. However, short-term clinically relevant outcomes were unaffected. For the neonate with severe circulatory compromise and persistent pulmonary hypertension (PPHN) resistant to standard treatment, additional options that may be considered including discontinuation of TH and/or the initiation of extracorporeal membrane oxygenation. If these options are to be considered they must be balanced against the realization that TH is thus far the only therapy proven to reduce brain injury in some patients.
      Another important aspect to consider is the potential effect of TH on drug metabolism. At the moment, there is no evidence for adapted dosing strategy for cardiovascular active therapy during TH in neonates. However, TH is known to affect pharmacokinetics of certain drugs, including sedatives, which may have a negative impact on cardiovascular status [
      • Zanelli S.
      • Buck M.
      • Fairchild K.
      Physiologic and pharmacologic considerations for hypothermia therapy in neonates.
      ]. Animal studies suggest that TH alters the efficacy of inotropic agents, with a decreasing efficacy as the temperature is lowered [
      • Dietrichs E.S.
      • Sager G.
      • Tveita T.
      Altered pharmacological effects of adrenergic agonists during hypothermia.
      ]. It should also be noted that the original insult often has multiorgan involvement with a degree of renal insufficiency which may affect drug clearance and this may need to be considered in treatment and dosing decisions, something particularly relevant for MIL use. Thus, there remains a paucity of data to guide therapy in the setting of therapeutic hypothermia and studies, including pharmacokinetic/pharmacodynamic studies, are urgently warranted in this area.

      3.1.3 Septic shock

      The clinical presentation of early onset sepsis in the newborn is variable. Typically, cold shock is characterized by peripheral vasoconstriction, cool peripheries, and tachycardia; hypotension is often a pre-terminal event. Warm shock is characterized by peripheral vasodilation and hypotension secondary to endotoxin release. These clinically different presentations may benefit from different therapeutic interventions. The most up to date recommendations for treatment in pediatric sepsis include volume expansion up to 40–60 mL/kg in boluses (10–20 mL/kg per bolus), titrated to clinical markers of CO, and EPI or NE, rather than DA as the first choice vasoactive agents, followed by vasopressin in non-responders [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ]. All these recommendations were classified as “weak,“ based on low or very low quality evidence in pediatric studies.
      In a recent retrospective study in older children, moderate fluid administration, compared to larger volumes, was found to be associated with improved survival [
      • Barboza C.L.
      • Valete C.O.
      • da Silva A.R.
      Bundle adherence of intravenous antibiotic fluid resuscitation and vasopressor in children with severe sepsis or septic shock.
      ]. The Fluid Expansion as Supportive Therapy (FEAST) study showed increased mortality in pediatric participants in receipt of 40 mL/kg of volume (either saline or albumin) compared to those who did not receive a bolus [
      • Maitland K.
      • Kiguli S.
      • Opoka R.O.
      • Engoru C.
      • Olupot-Olupot P.
      • Akech S.O.
      • et al.
      Mortality after fluid bolus in African children with severe infection.
      ]. Another study compared the effects of more intravenous fluid intake (i.e., liberal fluid therapy, defined as 40 mL/kg of fluid over 15 min) versus less intravenous fluid intake (i.e., conservative fluid therapy defined as 20 mL/kg over 20 min) for children with septic shock. There was no difference identified between the two groups, other than increased hepatomegaly in the group in receipt of the larger bolus volume [
      • Santhanam I.
      • Sangareddi S.
      • Venkataraman S.
      • Kissoon N.
      • Thiruvengadamudayan V.
      • Kasthuri R.K.
      A prospective randomized controlled study of two fluid regimens in the initial management of septic shock in the emergency department.
      ].
      There is a paucity of data pertaining to volume resuscitation and inotrope administration in septic shock in the newborn infant. Rapid volume administration has been associated with an increased risk of coagulopathy in animal models. In the preterm neonate, volume has been associated with an increased risk of IVH and mortality [
      • Ewer A.K.
      • Tyler W.
      • Francis A.
      • Drinkall D.
      • Gardosi J.O.
      Excessive volume expansion and neonatal death in preterm infants born at 27-28 weeks gestation.
      ]. Higher versus lower fluid intake regimens have been associated with an increased risk of patent ductus arteriosus (PDA) and chronic lung disease in preterm neonates. These data suggest that volume should be used judiciously, particularly in the preterm infant. There are no newborn trials that allow us to draw any firm conclusions about the agent, the amount, and rate of administration of volume in the setting of neonatal sepsis. However, given the current lack of evidence, it would seem reasonable to use normal saline rather than albumin as a general rule, but balanced/buffered crystalloids could be an alternative to saline based on very low quality evidence [
      • Weiss S.L.
      • Peters M.J.
      • Alhazzani W.
      • Agus M.S.D.
      • Flori H.R.
      • Inwald D.P.
      • et al.
      Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.
      ].
      Data pertaining to inotrope use in neonatal sepsis are also limited because of a paucity of clinical trials. Unlike the pediatric and adult world, DA remains the first line agent used in neonatal care. Epidemiologic information from large databases confirms this finding. Most of the randomized trials of cardiovascular support in the newborn have included DA (18 of 21 studies) as the primary inotrope. DA will increase BP compared to volume, placebo, and DOB, and has similar efficacy to EPI and NE. However, its effect on CO is variable (inotrope/vasopressor imbalance) and there are little data suggesting improved clinically relevant endpoints. However, it continues to be used presumably because in a significant percentage of patients it increases BPmean, clinicians are familiar with its use and there is no compelling evidence to suggest an alternative agent. Baske et al. found comparable efficacy of EPI vs. DA in a randomized trial of neonatal septic shock fluid non-responders [
      • Baske K.
      • Saini S.S.
      • Dutta S.
      • Sundaram V.
      Epinephrine versus dopamine in neonatal septic shock: a double-blind randomized controlled trial.
      ]. However, five neonates in the EPI group and no neonates in the DA group had reversal of shock after the initial 45 min, and the overall mortality was very high (70/80%) between both groups. EPI is thought to have variable effects depending on the dose administered, with predominantly beta-mediated effects at lower doses and alpha-mediated effects at higher doses. One potential adverse effect of EPI is an increase in serum lactate and metabolic acidosis. NE infusion might be beneficial, especially when there is loss of vascular tone as can occur in warm shock. Rizk et al. found improved BP, urine output, and oxygen dependency in a retrospective study of preterm infants treated with NE for septic shock [
      • Rizk M.Y.
      • Lapointe A.
      • Lefebvre F.
      • Barrington K.J.
      Norepinephrine infusion improves haemodynamics in the preterm infants during septic shock.
      ]. It may be considered that a single inotrope may not as effective as a combination of agents. A recent meta-analysis of adult studies suggests that a combination of cardiovascular agents improves outcome [
      • Chen C.
      • Pang L.
      • Wang Y.
      • Wen T.
      • Yu W.
      • Yue X.
      • et al.
      Combination era, using combined vasopressors showed benefits in treating septic shock patients: a network meta-analysis of randomized controlled trials.
      ]. It remains to be seen whether single therapeutic agents or a combination of agents improves outcome in neonates with early onset sepsis.

      3.1.4 Cardiogenic shock secondary to congenital heart disease (CHD)

      CHD is a rare cause of shock and/or hypotension. However, it is an important and specific contributor to neonatal mortality. Despite its rarity, CHD is the major underlying cause of cardiogenic shock in neonates [
      • Hsu D.T.
      • Pearson G.D.
      Heart failure in children: part I: history, etiology, and pathophysiology.
      ]. Early recognition of cardiac defects results in an enhanced outcome for the infant, as delayed presentations often present with cardiogenic shock and impaired cerebral blood flow.
      Historically, DA and EPI were the primary agents used. More recent trials have focused on the role of MIL and levosimendan (LEV), both peri- or post-operatively. Low cardiac output syndrome (LCOS) is a common condition occurring following coronary artery bypass in neonates and is multifactorial in origin. The PRIMACORP study found that high dose MIL resulted in a significant reduction in the incidence of LCOS in the 36 h following cardiac surgery [
      • Hoffman T.M.
      • Wernovsky G.
      • Atz A.M.
      • Kulik T.J.
      • Nelson D.P.
      • Chang A.C.
      • et al.
      Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease.
      ]. MIL is now the most common agent used following cardiac surgery. LEV has recently been evaluated for its use post-cardiac surgery, but data on long term safety are lacking [
      • Hummel J.
      • Rucker G.
      • Stiller B.
      Prophylactic levosimendan for the prevention of low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease.
      ]. It might improve cerebral oxygenation and systemic perfusion [
      • Bravo M.C.
      • Lopez P.
      • Cabanas F.
      • Perez-Rodriguez J.
      • Perez-Fernandez E.
      • Quero J.
      • et al.
      Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study.
      ] in post-surgical LCOS – comparable to MIL – without an incremental increase in myocardial oxygen demand [
      • Pellicer A.
      • Riera J.
      • Lopez-Ortego P.
      • Bravo M.C.
      • Madero R.
      • Perez-Rodriguez J.
      • et al.
      Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery.
      ]. However, in a recent double blind RCT by Wang et al. of 187 infants undergoing cardiac surgery, the primary outcome of LCOS did not differ significantly between prophylactic postoperative LEV and placebo (10.6% vs 19.4%). An alternate study by Lechner and colleagues compared the effect of prophylactically administered LEV and MIL on cardiac index in neonates and infants after corrective open-heart surgery [
      • Lechner E.
      • Hofer A.
      • Leitner-Peneder G.
      • Freynschlag R.
      • Mair R.
      • Weinzettel R.
      • et al.
      Levosimendan versus milrinone in neonates and infants after corrective open-heart surgery: a pilot study.
      ]. They found no difference between the groups over time.

      3.1.5 Rarer causes

      Typically, acute shock from blood loss occurs in the delivery room secondary to a substantial fetal antepartum hemorrhage, vasa praevia, feto-maternal transfusion, or a subgaleal hemorrhage. The infant may present relatively well in appearance but pale, or may be significantly distressed, either bradycardic or tachycardic. The clinical situation will often determine the rate at which intervention is required. A well appearing infant may require a blood transfusion administered slowly in the neonatal unit, or the unwell infant may require volume and whole blood transfusion immediately in the delivery suite [
      • Finn D.
      • Roehr C.C.
      • Ryan C.A.
      • Dempsey E.M.
      Optimising intravenous volume resuscitation of the newborn in the delivery room: practical considerations and gaps in knowledge.
      ]. The potential role of delayed cord clamping for the depressed term infant is currently being evaluated. Obstructive shock in the setting of a tension pneumothorax is another rare cause of shock typically occurring in the first days of life. Initial management involves treating the air leak, either with needle aspiration or thoracostomy tube insertion, prior to dealing with any underlying cardiac compromise.

      3.2 Late onset hypotension/circulatory insufficiency

      3.2.1 PDA

      A moderate to large PDA can negatively impact the overall circulatory status, and may result in reduced CO, hypotension, and decreased organ perfusion later in life, but also as early as the first days of life [
      • Hsu K.H.
      • Nguyen J.
      • Dekom S.
      • Ramanathan R.
      • Noori S.
      Effects of patent ductus arteriosus on organ blood flow in infants born very preterm: a prospective study with serial echocardiography.
      ,
      • Rios D.R.
      • Bhattacharya S.
      • Levy P.T.
      • McNamara P.J.
      Circulatory insufficiency and hypotension related to the ductus arteriosus in neonates.
      ]. PDA-associated hypotension can be difficult to treat, with retrospective data demonstrating that hypotension may be resistant to both volume and inotropes [
      • Sarkar S.
      • Dechert R.
      • Schumacher R.E.
      • Donn S.M.
      Is refractory hypotension in preterm infants a manifestation of early ductal shunting?.
      ]. Early treatment of PDA does result in a lower incidence of hypotension requiring inotropes within the first week [
      • Clyman R.I.
      • Liebowitz M.
      • Kaempf J.
      • Erdeve O.
      • Bulbul A.
      • Hakansson S.
      • et al.
      PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 Week of age.
      ]. Surgical treatment of PDA may result in severe hemodynamic effects in the immediate post-surgical time period [
      • Noori S.
      • Friedlich P.
      • Seri I.
      • Wong P.
      Changes in myocardial function and hemodynamics after ligation of the ductus arteriosus in preterm infants.
      ]. This post-ligation cardiac syndrome is associated with increased morbidity [
      • Ulrich T.J.B.
      • Hansen T.P.
      • Reid K.J.
      • Bingler M.A.
      • Olsen S.L.
      Post-ligation cardiac syndrome is associated with increased morbidity in preterm infants.
      ] and potentially increased risk of long-term neuro-developmental impairment [
      • Bravo M.C.
      • Ybarra M.
      • Madero R.
      • Pellicer A.
      Childhood neurodevelopmental outcome in low birth weight infants with post-ligation cardiac syndrome after ductus arteriosus closure.
      ]. Therefore, close peri- and post-operative monitoring is mandatory [
      • Rios D.R.
      • Bhattacharya S.
      • Levy P.T.
      • McNamara P.J.
      Circulatory insufficiency and hypotension related to the ductus arteriosus in neonates.
      ]. Hydrocortisone might be particularly beneficial in catecholamine-resistant hypotension [
      • Noori S.
      • McNamara P.
      • Jain A.
      • Lavoie P.M.
      • Wickremasinghe A.
      • Merritt T.A.
      • et al.
      Catecholamine-resistant hypotension and myocardial performance following patent ductus arteriosus ligation.
      ]. Echocardiography in the immediate post-operative period may help to identify infants who may benefit from targeted therapy. However, in a retrospective study of infants following PDA surgical closure, treatment with MIL was not associated with improved outcome, but prospective clinical trials are lacking [
      • Halliday M.
      • Kavarana M.
      • Ebeling M.
      • Kiger J.
      Milrinone use for hemodynamic instability in patent ductus arteriosus ligation.
      ].

      3.2.2 Late onset sepsis (LOS)

      LOS occurs in up to 25% of extremely preterm infants and can result in significant short-term morbidity and adverse long-term neurodevelopmental outcomes. Abnormalities of heart rate characteristics have been associated with the development of sepsis and may play an important role in the early detection and management of the at-risk infant. However, circulatory instability may occur early and complex continuous analysis of vital signs might further improve diagnosis of both LOS and necrotizing enterocolitis (NEC) [
      • Fairchild K.D.
      • Lake D.E.
      • Kattwinkel J.
      • Moorman J.R.
      • Bateman D.A.
      • Grieve P.G.
      • et al.
      Vital signs and their cross-correlation in sepsis and NEC: a study of 1,065 very-low-birth-weight infants in two NICUs.
      ]. It must be remembered that reliance on BP values needs to take into consideration the significant postnatal changes that occur in BP over the first weeks of life. Also, in the majority of circumstances the BP values available will typically be non-invasive and may be falsely reassuring. In circumstances where there is uncertainty, placement of a peripheral arterial catheter should be considered. Postnatal age reference ranges may serve as a useful guide, but the evaluation pressure here is substantially higher than the GA-based rule. As an example, an infant delivered at 24 weeks who develops sepsis at 4 weeks of age, a BPmean in the high 20's should be very concerning and certainly warrant intervention. This is on contrast to a day 1 BPmean in a newborn delivered at 28 weeks. In a retrospective study of NE use in preterm infants less than 32 weeks, in almost two-thirds of cases the primary underlying diagnosis was sepsis. De Waal and Evans described the hemodynamic changes and their evolution over time in preterm infants with late onset clinical sepsis. The mean (SD) values for right ventricular, left ventricular CO, and Superior Vena Cava flow were high at 555 (133), 441 (164), and 104 (39) mL/kg/min, respectively, at the first assessment [
      • de Waal K.
      • Evans N.
      Hemodynamics in preterm infants with late-onset sepsis.
      ]. All infants received volume and inotrope(s). COs were found to decrease, and systemic vascular resistance increase in non-surviving infants, whereas there was no change in these parameters in the survivors. Echocardiography may have an important role in the individualization of care in this setting. The choice of optimal agent is guided somewhat by the clinical presentation, and in some circumstances may warrant a combination of agents such as NE and MIL, but again there is no evidence to support such therapeutic choices.

      3.2.3 NEC

      NEC is multifactorial in origin. Hypotension in the first days of life has been associated with NEC [
      • Murdoch E.M.
      • Sinha A.K.
      • Shanmugalingam S.T.
      • Smith G.C.
      • Kempley S.T.
      Doppler flow velocimetry in the superior mesenteric artery on the first day of life in preterm infants and the risk of neonatal necrotizing enterocolitis.
      ]. Hypovolemia and impaired cardiac contractility can occur in the setting of NEC. The first line intervention is typically volume replacement. Vasoconstrictive effects of catecholamine are mediated via alpha adrenergic receptors. In an animal model reduction of perfusion in newborn swine intestine enhanced efficacy of NE via decreased NO production [
      • Nowicki P.T.
      Effects of sustained low-flow perfusion on the response to vasoconstrictor agents in postnatal intestine.
      ]. As vasopressin uses a different receptor to catecholamine, it might be preferable, but further investigations are needed. NEC itself might cause further hemodynamic changes: intestinal vascular resistance, and microcirculatory and increased abdominal pressure cause reduced inferior vena cava flow. The increased intraabdominal pressure often results in increased ventilatory support, which may have negative connotations on preload and resultant cardiac output. In an animal study myocardial dysfunction was found to be associated with endotoxin release mediated by decreased adrenergic responsiveness [
      • Shepherd R.E.
      • McDonough K.H.
      • Burns A.H.
      Mechanism of cardiac dysfunction in hearts from endotoxin-treated rats.
      ].

      3.2.4 Other causes

      Blood loss is a rare cause of hypovolemic shock but can be devastating when it occurs. A catastrophic hemorrhage can occur if an umbilical venous catheter is malpositioned and infiltrates a portal vein. The infant can present with signs of acute blood loss, and despite fluid, red blood cells, and additional blood products, the situation may not be retrievable. Early recognition and prompt intervention may result in an improved outcome. Likewise, an obstructive form of shock can occur in the setting of cardiac tamponade secondary to infiltration of a peripherally inserted catheter resulting in a large pericardial effusion. Prompt recognition and drainage can be lifesaving. In both situations meticulous central line management procedures should significantly reduce the risk of either of these events.

      4. Conclusion

      Each section above highlighs one consistent factor: limited data upon which to guide intervention. Conducting trials in this area of care has been challenging. This lack of evidence should not result in an inappropriate simplification that leads to an automatic response to low BP values. However, low BP should trigger evaluation of the infant's status, including a spectrum physiologic parameters, clinical status, and more objective assessments of the hemodynamic status. This brings complexity to the bedside decision-making process but should result in a more individualized approach. Despite the importance of hemodynamic management to further improve outcome, there have been no large randomized controlled trials evaluating particular inotropes for specific conditions. The opposite can be said for other trials of cardiovascular intervention such as PDA management. It is difficult to pinpoint exactly why this is the case, but a number of recent trials have highlighted a few important points: the incidence of some of the conditions has improved (e.g., PPHN, transitional low BP), the problem often occurs in the first hours of life, physician willingness to depart from firmly held (though unsupported) beliefs, and finally challenges with obtaining timely informed consent. We will continue to make strides in reducing the prevalence of each of the conditions listed above, but we need to work harder at convincing physicians of the importance of conducting trials in this area, and perhaps consider alternative consent pathways. Otherwise, we will continue to treat patients inappropriately, potentially subjecting them to more harm than good.

      Funding

      This review was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project number 420536451 .

      Financial disclosure

      The authors have indicated they have no financial relationships relevant to this article to disclose.

      Contributor's statement

      Chrsitoph E. Schwarz received the research support and wrote the initial manuscript; Eugene M. Dempsey led the review process, revised the draft of the manuscript. Both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

      Declaration of Competing Interest

      The authors Competing Interest: None declared.

      Acknowledgements

      We thank Brian H. Walsh, Department of Neonatology, Cork University Maternity Hospital, Cork, Ireland for critically reviewing the manuscript and we acknowledge the support by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project number 420536451 .

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