Assessment of neonatal perfusion

  • Samir Gupta
    Correspondence
    Corresponding author. Lead for Neonatal Hemodynamics & Transitional Physiology Program, Sidra Medicine, Doha, Qatar.
    Affiliations
    School of Medical Physics & Engineering, Durham University, United Kingdom

    Division of Neonatology, Sidra Medicine, Doha, Qatar
    Search for articles by this author
  • Steven M. Donn
    Affiliations
    Department of Pediatrics, Division of Neonatal-Perinatal Medicine, C.S. Mott Children's Hospital, Michigan Medicine, Ann Arbor, MI, USA
    Search for articles by this author
Open AccessPublished:July 31, 2020DOI:https://doi.org/10.1016/j.siny.2020.101144

      Abstract

      Disorders of perfusion in newborn infants are frequently observed in neonatal intensive care units. The current assessment practices are primarily based on clinical signs. Significant technologic advances have opened new avenues for continuous assessment at the bedside. Combining these devices with functional echocardiography provides an in-depth understanding of perfusion and allows targeting therapy to the pathophysiology rather than monitoring and targeting blood pressure. This change in approach is guided by the fact that perfusion disorders can result from a number of causes and a single management approach might do more harm than good. This approach has the potential to improve long term outcomes but needs to be tested in well-designed trials.

      Keywords

      1. Introduction

      Assessment and management of neonatal perfusion is an integral part of neonatal intensive care. The routinely used clinical signs have a limitation because of low sensitivity during early periods of impaired perfusion and are deranged only when the newborn has progressed to a state of uncompensated or irreversible shock [
      • Weindling M.
      • Paize F.
      Peripheral haemodynamics in newborns: best practice guidelines.
      ]. Over the years there have been key technologic advances that help complement the clinical examination with bedside assessment tools. There is now a potential for early diagnosis of neonatal perfusion impairment, which if timely managed, could reduce morbidity and mortality. There are, however, concerns that overzealous treatment could do more harm than good. The selection of assessment tools is governed by striking a balance between tests with high sensitivity but limited availability (such as functional echocardiography, MRI) with tests enabling continuous assessment but with only borderline sensitivity [such as near-infrared spectroscopy (NIRS)].
      With better understanding of transitional circulation and the heterogeneity of neonatal hemodynamic problems, it is now clear that one size does not fit all. Clinicians have to understand the pathophysiology of the hemodynamic problems to objectively match the therapy to the cause rather than be guided by the traditional approaches to management using volume, inotropes and vasopressors. This requires an understanding of the physiologic concepts of hemodynamics and the pharmacodynamic properties of the pharmaceutical agents used for management.
      Over the years we have been treating hypotension rather than impaired perfusion. Hypotension is a numerical or statistical value connoting a blood pressure that is more than two standard deviations from the mean. This may or may not represent a pathological state of shock, which is derangement of perfusion. It is a condition connoting circulatory failure, where tissues cannot be provided with adequate oxygen or nutrients. This change in concept is pivotal for appropriate management of hemodynamic disturbance and hence assessment of neonatal perfusion is important in day to day practice.

      2. What is perfusion and why is it important?

      Perfusion is the delivery of blood to the tissue capillary bed. This facilitates oxygen transport to the tissues (DO2), which in turn is utilized for aerobic metabolism. In hypoxic or ischemic states, when the oxygen delivery falls below the critical level,anaerobic metabolism commences resulting in the production of lactic acid. To maintain oxygen delivery, the cardio-pulmonary system has to function effectively and the systemic vascular resistance should be maintained. The DO2 is dependent upon the lungs, heart, vascular bed, and hemoglobin. Ventilation and diffusion of gases are often affected in respiratory disorders and could affect transitional circulation leading to pulmonary hypertension. The heart is a pump and systolic or diastolic dysfunction can lead to pump failure and states of shock. The vascular system is comprised of venous and arterial sides. The venous bed accounts for preload, and the arterioles maintain the systemic vascular resistance within the capillary bed affecting end organ perfusion of tissues. The oxygen carrying capacity is dependent upon hemoglobin as the majority of oxygen is bound to hemoglobin and only a small percentage is dissolved in the blood. Thus, evaluation of perfusion should incorporate a global assessment of its various components to diagnose perfusion problems.

      2.1 Oxygen delivery (DO2) and cellular metabolism

      The oxygen delivery is the product of cardiac output and oxygen content (Fig. 1).
      DO2 = Cardiac output (CO) x Arterial oxygen content (CaO2)


      Fig. 1
      Fig. 1Oxygen delivery and Determinants of myocardial function.
      The blood oxygen content is dependent on the hemoglobin concentration of blood and the oxygen saturation, which in turn affects cellular metabolism. The oxygen saturation is dependent on airway, breathing and the fraction of inspired oxygen (FiO2). The common lung problems in newborn babies can range from surfactant-deficient lung disease, parenchymal disorders of the lung, congenital malformations (such as diaphragmatic hernia) and intra-pleural collections of air or fluid. The airway problems encompass obstruction by secretions or debris, congenital abnormalities of the airway and chronic conditions, such as bronchopulmonary dysplasia. These airway and lung problems should be recognized and treated early to facilitate a smooth transition from fetal to neonatal circulation; otherwise, if persistent, they can adversely impact perfusion. Further discussion on monitoring and assessment of lung disorders is beyond the scope of this article.
      In ventilated infants, increasing airway pressure decreases the alveolar/capillary transmural pressure gradient, squeezing blood out of the intra-alveolar capillaries, resulting in an increase in pulmonary vascular resistance (PVR) and a decrease in pulmonary blood flow (PBF). It is important to ventilate infants at functional residual capacity (FRC), where the total PVR and alveolar PVR are minimum for the given lung volume. Additionally, the extra-alveolar PVR is also coincidently low at FRC. Thus, it allows successful perfusion of the lungs at the minimum achievable PVR to optimize ventilation-perfusion matching [
      • Polglase G.R.
      • Miller S.L.
      • Barton S.K.
      • Kluckow M.
      • Gill A.W.
      • Hooper S.B.
      • et al.
      Respiratory support for premature neonates in the delivery room: effects on cardiovascular function and the development of brain injury.
      ].
      The other determinant of cellular metabolism is the target blood flow. The target blood flow is dependent upon cardiac output. The cardiac output is the product of heart rate and stroke volume. Disorders of heart rate can be caused by sepsis, arrhythmias, and pain, and could affect cardiac output even if the stroke volume is maintained. To the contrary, stroke volume is dependent upon myocardial performance. The determinants of myocardial performance are preload, afterload, and myocardial contractility. Different conditions, such as hypovolemia, ischemia and elevated viscosity could thus affect myocardial performance by affecting preload, contractility, and afterload, respectively.
      Blood pressure is another important factor. Perfusion pressure is reflected by mean blood pressure and is derived from systemic vascular resistance and cardiac output. However, the systolic pressure can be utilized to assess cardiac contractility and cardiac output, and the diastolic pressure reflects the systemic vascular resistance, which can be affected by inflammatory states, fetal shunts, and other conditions.
      Once ventilation and hemoglobin are optimized, one should concentrate on the hemodynamic assessment of perfusion using bedside tools and clinical examination to prevent progression to uncompensated and irreversible states of shock. It is important to understand and treat the cause(s) of poor perfusion and direct therapy selectively rather than blindly following a regimented approach with the potential for harm.

      3. Clinical assessment of perfusion and its limitations

      The clinical bedside assessment of perfusion in newborn infants has been used routinely to direct decision making. The commonly advocated signs include capillary refill time, urine output, heart rate, peripheral color, base excess, lactate concentration, and blood pressure. The acceptable limits for each measurement are embedded in practice, but all of them reflect end organ perfusion. The derangement of end organ perfusion reflects states of uncompensated or irreversible shock requiring prompt intervention and treatment. However, early disorders of perfusion are difficult to detect using clinical signs alone. Used in conjunction with other monitoring could be more critical to decision making.
      A survey of neonatal intensive care units by Stranak et al. [
      • 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.
      ] reported enormous variation in diagnosis, management, and clinical practice. The diagnosis of hypotension in extremely low gestational age infants continues to utilize mean blood pressure less than the gestational age as the criterion by 73% of units across the 38 countries surveyed. The use of mean blood pressure in clinical practice is related to the ease of measurement rather than the objectivity. It is derived from systolic and diastolic pressures and reflects the perfusion pressure, but it does not provide any information on the cause of an abnormal reading. Widely practiced mean BP values less than the gestational age stem from the recommendations of an expert working group of the British Association of Perinatal Medicine on audit measures and guidelines for management of respiratory distress syndrome in preterm infants [
      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.
      ] but is without sufficient evidence. Clearly, the practices over the last 30 years have changed, with more extremely preterm infants surviving, but the extrapolation to practice from this old recommendation still continues to be used for lower gestational age groups. Another report of mean blood pressure <30 mm of Hg for 1 h in infants <31 weeks’ gestation was reported to be associated with severe hemorrhage, ischemic cerebral lesions, or death within 48 h [
      • Miall-Allen V.M.
      • de Vries L.S.
      • Whitelaw A.G.
      Mean arterial blood pressure and neonatal cerebral lesions.
      ]. Comprehensive assessment of perfusion is more informative than relying solely on mean blood pressure. The use of specific systolic and diastolic blood pressure measurements is more important to guide therapy, as they reflect cardiac function and systemic vascular resistance.
      The other bedside signs used to assess perfusion have been reported to have poor sensitivity, specificity, and predictive values. Superior vena caval flow reflects the systemic venous return from the brain and upper body and was reported to be poorly correlated with clinical signs, such as capillary refill time (CRT), core-peripheral temperature difference, and mean blood pressure. The sensitivity improved to 78% after combining a mean BP < 30 mm Hg with a CRT >3 s. The authors suggested that low upper body blood flow is common on the first postnatal day and is associated with intraventricular hemorrhage, but clinical signs such as BP and CRT have limitations in detecting low blood flow in the first day of life [
      • Osborn D.A.
      • Evans N.
      • Kluckow M.
      Clinical detection of low upper body blood flow in very premature infants using blood pressure, capillary refill time, and central-peripheral temperature difference.
      ]. Thus, clinicians should be cautious in using only these clinical signs for decision making in infants with perfusion disorders.
      Base excess reflects acid-base hemostasis and chronic conditions affected by renal compensatory mechanisms. However, in acute states a negative base excess reflects metabolic acidosis and anaerobic metabolism. It is a marker to be used with other parameters to assess hypoxic states such as asphyxia, but on its own is a poor predictor for outcome. Blood lactate concentrations reflect the perfusion state but are deranged only if anaerobic metabolism is persistent. High lactate concentrations can also be observed in poorly perfused peripheral tissues when a capillary sample is taken for analysis. Rather than using a singular lactate concentration, serial measurements are more helpful to predict outcomes. It has been reported that in ventilated infants elevated lactate concentrations, which do not decrease over 24 h, are associated with high mortality [
      • Deshpande S.A.
      • Platt M.P.
      Association between blood lactate and acid-base status and mortality in ventilated babies.
      ].

      4. Bedside monitoring

      The determination of adequate circulation and perfusion should be made based on the composite appraisal of hemodynamic variables [
      • Gupta S.
      • Donn S.M.
      Neonatal hypotension: dopamine or dobutamine?.
      ]. For systematic assessment of the hemodynamic apparatus, bedside monitoring can utilize various assessment tools, which can be grouped based on level of assessment (Fig. 2). Broadly, this can be divided into five assessments:
      • 1.
        Preload
      • 2.
        Contractility
      • 3.
        Afterload
      • 4.
        Capillary perfusion
      • 5.
        End organ perfusion

      4.1 Assessment of preload

      Preload is dependent on cardiac compliance, circulating blood volume, and venous capacitance. The cardiac compliance is well described by the relation between preload and stroke volume by Frank-Starling curve. The ability of the heart to change its force of contraction- and thus the stroke volume-is proportional to the blood present in the ventricle at the end of diastole. The diastolic function of the heart is thus important to allow filling of the ventricles and thus effective cardiac output. In addition to cardiac compliance, a reduction in circulating blood volume will lead to decreased preload and ventricular dysfunction. The reduction in circulating blood volume can be seen in acute or chronic blood loss and third space losses seen in necrotizing enterocolitis and systemic inflammatory response syndrome. In contrast, (abundant) fluid administration might also impair ventricular function and cardiac output. The venous capacitance and mean systemic filling pressure is controlled by veins, as they hold 65% of the blood volume and are sensitive to α1 and α2 adrenergic stimulation. This allow modulation of the pressure from the arterial to the venous side.
      Unlike pediatric and adult patients, the assessment of preload in newborn infants is difficult, as the jugular venous pressure cannot be reliably assessed. Echocardiography can be used to assess preload – visualizing the heart, assessing inferior vena cava and superior vena cava (SVC) flows. The “eye-balling” of the heart in the 4-chamber view provides information about end-diastolic volume. The inferior vena cava can be sampled using 2D echo. The SVC flow measurement was first described by Kluckow et al. and has been widely used in clinical practice albeit with some limitations [
      • Kluckow M.
      • Evans N.
      Superior vena cava flow in newborn infants: a novel marker of systemic blood flow.
      ]. Please refer to the article by deWaal and Kluckow in this issue for a comprehensive review of SVC flow.
      Indirect assessment of preload has been reported using Electric velocimetry ICON®. An increase in stroke volume variation (SVV) and thoracic fluid content (TFC) has been utilized in pediatric populations as a marker for preload, but there is paucity of data in the newborn population [
      • Voss F.
      • Becker R.
      • Hauck M.
      • Katus H.A.
      • Bauer A.
      The basic pacing rate in CRT patients: the higher the better?.
      ]. Similarly, the Pleth-variability index (PVi) using the Masimo® pulse oximeter has been described in adults as a marker to assess preload status [
      • Liu T.
      • Xu C.
      • Wang M.
      • Niu Z.
      • Qi D.
      Reliability of pleth variability index in predicting preload responsiveness of mechanically ventilated patients under various conditions: a systematic review and meta-analysis.
      ]. It is calculated from (Pimax – Pimin) x 100/Pimax. The bedside assessment of blood pressure gives reliable qualitative information on preload in hypovolemic states, but this can be a late sign when compensatory mechanisms fail.

      4.2 Assessment of contractility (pump)

      The cardiac output is dependent upon preload, afterload, and contractility, the heart function. The assessment of cardiac function can be done invasively using catheterization, but that is reserved for the catheterization laboratory for cardiac intervention and pre-surgical planning. For bedside assessment, the systolic and diastolic function can be assessed to direct therapy. However, this requires expertise in functional echocardiography. The indirect measures of cardiac function utilize measurement of cardiac output. Echocardiography can assess cardiac output for both the left and right ventricles, but the limitation is that it only provides point-of-care assessment.
      There are various non-invasive cardiac output (CO) assessment devices available that have been reported to measure the CO continuously. The ‘Thoracic electrical bio-impedance’ (TEB) device is a non-invasive, easily applicable (four disposable surface electrodes), and continuous CO measurement method for newborns. TEB is based on impedance cardiographic technology and uses changes in thoracic electrical impedance caused by the cardiac cycle: the difference in measured voltage—produced by a small electrical current—caused by the change in alignment of red blood cells in the aorta during systole respective to diastole is used to calculate SV and CO. Examples of TEB are Electrical Cardiometry (EC; ICON®, Ausculon®, Osypka Medical GmbH, Berlin, Germany) and the bioreactance method (Starlin®, NICOM®; Cheetah Medical Inc., Vancouver, WA, USA). The first method analyzes the changes in signal amplitude and the latter method measures changes in phase shift of thoracic impedance during the cardiac cycle. The measurements obtained by these devices indirectly measure cardiac output and are thus affected by loading conditions, such as fetal shunts and congenital heart defects [
      • Narula J.
      • Chauhan S.
      • Ramakrishnan S.
      • Gupta S.K.
      Electrical Cardiometry: a reliable solution to cardiac output estimation in children with structural heart disease.
      ]. We longitudinally assessed ICON® and observed that assessments done using ICON® correlated with assessments using functional echocardiography for LVO but not for RVO. The ease of its use and bedside continuous display of data are helpful in the early diagnosis of perfusion disorders and also to assess the response to interventions [
      • Noori S.
      • Drabu B.
      • Soleymani S.
      • Seri I.
      Continuous non-invasive cardiac output measurements in the neonate by electrical velocimetry: a comparison with echocardiography.
      ,
      • Grollmuss O.
      • Gonzalez P.
      Non-invasive cardiac output measurement in low and very low birth weight infants: a method comparison.
      ,
      • Torigoe T.
      • Sato S.
      • Nagayama Y.
      • Sato T.
      • Yamazaki H.
      Influence of patent ductus arteriosus and ventilators on electrical velocimetry for measuring cardiac output in very-low/low birth weight infants.
      ]. Another non-invasive cardiac output assessment utilizes transcutaneous Doppler technique. It is used in the ultrasonic CO monitor (USCOM®, Sydney, NSW, Australia), continuous wave Doppler device. USCOM® is designed for rapid, non-invasive measurement of CO located at either the sternal notch (aortic valve; LVO) or parasternal view (pulmonary valve; RVO). The cardiac output is calculated from the measured blood flow velocity profile across the aortic or pulmonary valves. The limitations of this method results from the use of a nomogram based on the patient's height, weight, and age for estimation of the valve cross-sectional area. The measurements done by USCOM are not inter-changeable with echocardiographic assessments [
      • Fraga M.V.
      • Dysart K.C.
      • Rintoul N.
      • Chaudhary A.S.
      • Ratcliffe S.J.
      • Fedec A.
      • et al.
      Cardiac output measurement using the ultrasonic cardiac output monitor: a validation study in newborn infants.
      ].

      4.2.1 Role of functional echocardiography

      The echocardiographic assessment of cardiac function incorporates 2D, spectral Doppler, M-mode, tissue Doppler, and more recently speckle tracking for strain analysis. Using these modalities, the systolic and diastolic functions of the heart, cardiac output of left and right ventricle, contractility of the left ventricle, ejection fraction, and segmental dysmotility of the myocardium can be assessed [
      • de Boode W.P.
      • Roehr C.C.
      • El-Khuffash A.
      Comprehensive state-of-the-art overview of neonatologist performed echocardiography: steps towards standardization of the use of echocardiography in neonatal intensive care.
      ,
      • Singh Y.
      • Roehr C.C.
      • Tissot C.
      • Rogerson S.
      • Gupta S.
      • Bohlin K.
      • et al.
      Education, training, and accreditation of neonatologist performed echocardiography in europe-framework for practice.
      ,
      • de Boode W.P.
      • van der Lee R.
      • Horsberg Eriksen B.
      • Nestaas E.
      • Dempsey E.
      • Singh Y.
      • et al.
      The role of Neonatologist Performed Echocardiography in the assessment and management of neonatal shock.
      ,
      • Nestaas E.
      • Schubert U.
      • de Boode W.P.
      • El-Khuffash A.
      European Special Interest Group 'Neonatologist Performed E. Tissue Doppler velocity imaging and event timings in neonates: a guide to image acquisition, measurement, interpretation, and reference values.
      ,
      • El-Khuffash A.
      • Schubert U.
      • Levy P.T.
      • Nestaas E.
      • de Boode W.P.
      European Special Interest Group 'Neonatologist Performed E. Deformation imaging and rotational mechanics in neonates: a guide to image acquisition, measurement, interpretation, and reference values.
      ,
      • Levy P.T.
      • Tissot C.
      • Horsberg Eriksen B.
      • Nestaas E.
      • Rogerson S.
      • McNamara P.J.
      • et al.
      Application of neonatologist performed echocardiography in the assessment and management of neonatal heart failure unrelated to congenital heart disease.
      ]. This also helps in assessing the right heart pressures and function and evidence of pulmonary hypertension commonly associated in babies with hypoxemia and poor cardiac function. The point-of-care assessments using bedside functional echocardiography combined with continuous assessment using non-invasive cardiac output monitoring seems a good approach for continuous assessment of cardiac function to assess perfusion.
      The use of functional echocardiography in neonatal intensive care units is increasing. There are concerns that if the measurements and assessments are not performed by trained personnel, the risk of misdiagnosis could potentially delay intervention or result in inappropriate treatment. In trained hands, therapy can be directed to the specific cause to improve short and long-term outcomes [
      • Singh Y.
      • Roehr C.C.
      • Tissot C.
      • Rogerson S.
      • Gupta S.
      • Bohlin K.
      • et al.
      Education, training, and accreditation of neonatologist performed echocardiography in europe-framework for practice.
      ,
      • Groves A.M.
      • Singh Y.
      • Dempsey E.
      • Molnar Z.
      • Austin T.
      • El-Khuffash A.
      • et al.
      Introduction to neonatologist-performed echocardiography.
      ,
      • van Laere D.
      • van Overmeire B.
      • Gupta S.
      • El-Khuffash A.
      • Savoia M.
      • McNamara P.J.
      • et al.
      Application of NPE in the assessment of a patent ductus arteriosus.
      ,
      • de Boode W.P.
      • Kluckow M.
      • McNamara P.J.
      • Gupta S.
      Role of neonatologist-performed echocardiography in the assessment and management of patent ductus arteriosus physiology in the newborn.
      ,
      • de Boode W.P.
      • Singh Y.
      • Gupta S.
      • Austin T.
      • Bohlin K.
      • Dempsey E.
      • et al.
      Recommendations for neonatologist performed echocardiography in europe: consensus statement endorsed by European society for paediatric research (ESPR) and European society for Neonatology (ESN).
      ,
      • Singh Y.
      • Gupta S.
      • Groves A.M.
      • Gandhi A.
      • Thomson J.
      • Qureshi S.
      • et al.
      Expert consensus statement 'Neonatologist-performed echocardiography (NoPE)'-training and accreditation in UK.
      ].

      4.3 Assessment of afterload

      Afterload is defined as the force against which the heart must act in order to pump the SV and largely depends on ventricular dimensions, blood pressure, (systemic) vascular resistance, and vascular compliance. With increasing afterload, the ventricular wall stress increases and the echocardiography derived velocity of circumferential fiber shortening decreases, resulting in a decrease in stroke volume. Echocardiographic studies have reported an age-dependent relationship, suggesting that newborn infants with an immature heart and a higher basal contractile state, the myocardial performance is more sensitive to afterload [
      • Rowland D.G.
      • Gutgesell H.P.
      Noninvasive assessment of myocardial contractility, preload, and afterload in healthy newborn infants.
      ,
      • Toyono M.
      • Harada K.
      • Takahashi Y.
      • Takada G.
      Maturational changes in left ventricular contractile state.
      ]. High afterload can be observed in infants shortly after transition, following ductal ligation, and in the presence of “cold” shock (low CO and high SVR). Low afterload as a result of low vascular tone/SVR is a cause of circulatory failure in neonates with “warm” shock (high CO and low SVR). It is important to differentiate between these different presentations of shock, as they require other therapeutic approaches (inotropes versus vasopressors) [
      • de Waal K.
      • Evans N.
      Hemodynamics in preterm infants with late-onset sepsis.
      ,
      • Saini S.S.
      • Kumar P.
      • Kumar R.M.
      Hemodynamic changes in preterm neonates with septic shock: a prospective observational study∗.
      ].

      4.4 Assessment of capillary perfusion

      The assessment of capillary perfusion at the bedside can be done clinically using CRT. A CRT > 3 s is abnormally prolonged. The CRT should be assessed centrally after applying pressure for 3–5 s and timing the return of color. It is not possible to do it in babies undergoing therapeutic hypothermia. The Masimo® pulse oximeter displays the pulse wave contour, which has been used to assess capillary perfusion using the perfusion index (Pi). Pi reflects the amplitude of the pulse oximeter waveform and is calculated as the pulsatile infrared signal (AC or variable component), indexed against the non-pulsatile infrared signal (DC or constant component). Pi is expressed as a percentage (0.02–20%). In the neonatal acute care setting, a low PI has been shown to be an objective and accurate measure of acute illness. The determination of Pi is unambiguous and independent compared to subjective means of assessing the health status of neonates. When combined with the heart rate and pulse oximetry value, it can be an objective predictor of illness severity in newborn infants [
      • De Felice C.
      • Latini G.
      • Vacca P.
      • Kopotic R.J.
      The pulse oximeter perfusion index as a predictor for high illness severity in neonates.
      ]. In healthy term infants, a cutoff value of 0.75 (10th centile) and 0.54 (3rd centile) was reported from a study cohort of 1073 infants [
      • Van Laere D.
      • O'Toole J.M.
      • Voeten M.
      • McKiernan J.
      • Boylan G.B.
      • Dempsey E.
      Decreased variability and low values of perfusion index on day one are associated with adverse outcome in extremely preterm infants.
      ].
      Mixed venous oxygen saturation (SvO2) represents the oxygen reserve after tissue oxygen extraction. Under normal conditions, the body extracts approximately 25–30% of oxygen from the arterial blood resulting in an SvO2 of 70–75%. A decrease in SvO2 is either the result of an increase in oxygen consumption or a decrease in CO. SvO2 can only be measured from blood sampled from the main pulmonary artery, which is not feasible in neonates. An alternative is to sample venous blood from the right atrium or the caval veins (ScO2). While decreasing values of SvO2 mostly reflect inadequate oxygen delivery or increased consumption, normal or high values cannot be interpreted as normal tissue oxygenation. A number of factors affect its measurement – sampling site, intra-cardiac shunts, redistribution of blood during shock, level of consciousness, and myocardial oxygen consumption [
      • de Boode W.P.
      Clinical monitoring of systemic hemodynamics in critically ill newborns.
      ].

      4.5 Assessment of end-organ perfusion

      The assessment of end-organ perfusion has historically utilized clinical signs as described above. The various states of shock influence end-organ perfusion, but the clinical signs are predictive only in advanced or late stages of shock when it is either uncompensated or irreversible. It is postulated that early intervention, if possible, could improve outcome by preserving reasonable hemodynamics.
      Near-infrared spectroscopy (NIRS) estimates regional blood flow, regional tissue oxygenation, and—when simultaneously measured with arterial oxygen saturation—also fractional tissue oxygenation extraction. End-organ perfusion can be assessed using NIRS in newborn infants. So far, it is regarded as a research tool, but in the last decade there is renewed interest with improving technology. Observational studies in neonates evaluated the use of NIRS in the NICU to monitor cerebral/splanchnic/renal circulation and in the delivery room with promising results. Interventional trials evaluating the use of NIRS are in progress [
      • Kenosi M.
      • Naulaers G.
      • Ryan C.A.
      • Dempsey E.M.
      Current research suggests that the future looks brighter for cerebral oxygenation monitoring in preterm infants.
      ]. Studies such as the SafeBoosC trial reported that episodes of cerebral hypoxemia and hyperoxemia were significantly reduced in preterm infants monitored by NIRS. However, there was no difference in the short-term outcome. A full overview of this topic is covered separately in this issue [
      • Hyttel-Sorensen S.
      • Pellicer A.
      • Alderliesten T.
      • Austin T.
      • van Bel F.
      • Benders M.
      • et al.
      Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial.
      ].

      5. Functional cardiac magnetic resonance imaging (fCMRI)

      Cardiac MRI techniques can be used to assess ventricular function and systemic perfusion in preterm and term newborns. The fast heart rate, sedation, and transport to the MR scanner has limited the usefulness of this modality on the NICU. Because of the shape of the ventricles, CMRI provides the highest sensitivity and specificity of cardiac function measurement compared to other modalities, including echocardiography. Groves et al. reported the feasibility of using CMRI in preterm infants and demonstrated that CMRI provides additional value over echocardiography [
      • Groves A.M.
      • Chiesa G.
      • Durighel G.
      • Goldring S.T.
      • Fitzpatrick J.A.
      • Uribe S.
      • et al.
      Functional cardiac MRI in preterm and term newborns.
      ].

      6. Decision making in different types of shock

      Neonatal hemodynamic perfusion disorders can be broadly grouped into four types of shock:
      • a.
        Hypovolemic shock
      • b.
        Cardiogenic shock
      • c.
        Distributive shock
      • d.
        Obstructive shock
      In hypovolemic shock, there is decreased intravascular blood volume. This could result from a hemorrhagic disorder with acute or chronic blood loss, or from non-haemorrhagic disorders, such as diabetes insipidus, dehydration, or iatrogenic fluid imbalance. In these situations, the preload is reduced and the cardiac function is initially preserved. If persistent, the decreased end-diastolic volume leads to diastolic dysfunction of the heart with resultant decreased systolic BP and reduced end-organ perfusion. Appropriate history, detection, and prompt treatment of hypovolemia can prevent acute kidney injury and other systemic ischemic problems common with other causes of shock as late events with a potential for long term complications.
      Cardiogenic shock can be caused by prematurity, myocardial hypoxemia-ischemia, myocarditis, cardiomyopathy, and arrhythmias. It can also be associated with congenital heart defects pre- and post-intervention. In these situations, the preload and afterload is normal for gestational age. However, the myocardium can be poorly organized (as in premature infants), subject to hypoxemia/ischemia, or with myocardial dysfunction, as in myocarditis and cardiomyopathy. In these situations, the blood pressure is initially compensated by compensatory response mechanisms and/or iatrogenically by injudicious use of vasopressors such as dopamine. The cardiac dysfunction and reduced cardiac output can be detected by invasive and non-invasive assessment tools, but echocardiography is important to assess the degree and extent of cardiac dysfunction, and also to assess systolic/diastolic dysfunction. Afterload reducing agents with positive ionotropic effects, such as dobutamine, milrinone, or low dose epinephrine are drugs of choice in the initial states. The arrhythmias are associated with reduced cardiac output, and the treatment of the primary cause and conversion to a normal sinus rhythm is required to maintain perfusion.
      In distributive shock there can be loss of fluid into the third space with reduced systemic vascular resistance (low diastolic BP as in warm shock) with normal or high cardiac output as seen in sepsis and severe systemic inflammatory response syndromes. In cold shock, to the contrary, the blood pressure is maintained but the cardiac output is low with or without low intravascular volume. In these situations, careful and judicious use of fluid boluses and vasopressors to improve SVR (in warm shock) and inotropes to improve cardiac contractility (in cold shock) is advocated. Patients should be closely followed with functional echocardiography and non-invasive continuous monitoring of perfusion to manage further.
      In obstructive shock, the baby can present with signs of decreased preload, afterload, and cardiac function depending on the duration of exposure and delay in treatment of the primary cause. Tension pneumothorax, and cardiac tamponade (pneumo- or hemo-pericardium) require prompt decompression. These are usually neonatal emergencies that require prompt recognition and intervention. Clinical management of different types of shock is covered in the article by Dempsey et al. in this issue.
      Shock can also be classified as:
      • 1.
        Compensated shock
      • 2.
        Uncompensated shock
      • 3.
        Irreversible shock
      By measurement of cardiac output and blood pressure, the state of shock can be assessed at bedside. If the cardiac output is low and the blood pressure is normal or high, the baby is in compensated shock. If both cardiac output and blood pressure are low then the baby is already in uncompensated shock. If the uncompensated state persists and affects the end- organ perfusion with derangement of cellular metabolism, the baby has entered into irreversible shock (Fig. 3).
      Fig. 3
      Fig. 3Stage of shock by cardiac output and blood pressure [Adapted from deBoode et al. [
      • de Boode W.P.
      • van der Lee R.
      • Horsberg Eriksen B.
      • Nestaas E.
      • Dempsey E.
      • Singh Y.
      • et al.
      The role of Neonatologist Performed Echocardiography in the assessment and management of neonatal shock.
      ]].
      Based on the assessment, the clinician should make an informed decision on the state of perfusion and take decisive steps for management:
      • Adequate perfusion – No action
      • Borderline perfusion – Monitor and review frequently
      • Inadequate perfusion – Commence first line management and request functional echocardiogram
      • Grossly inadequate perfusion – Emergency management and urgent functional echocardiogram
      • No perfusion – “Crash” call

      7. Conclusion

      Management of perfusion has evolved over the last decade with improvement in technology and the availability of bedside functional echocardiography. Bedside continuous monitoring techniques are rapidly evolving to complement clinical assessment and diagnose inadequate perfusion states sooner rather than later. Basing decisions on blood pressure alone is a questionable practice, and an extended assessment beyond blood pressure seems the way forward. This understanding allows treating the cause of impaired perfusion rather than following the heretofore regimented approach to management of hypotension. Although the long term data on the utility of new biomarkers for perfusion assessment are lacking, a physiology-based approach seems logical and a step towards precision medicine. It is equally important to recognize the limitations of the monitoring systems used, and above all monitoring itself will not improve outcome unless a rational physiologic approach is used.
      • 1.
        Assessment of perfusion should take into account preload, afterload, and cardiac function.
      • 2.
        Clinical signs of perfusion assess end organ perfusion and thus are not deranged until late into perfusion disorders.
      • 3.
        Functional echocardiography is increasingly utilized for perfusion and hemodynamic assessment of infants presenting with impending shock.
      • 4.
        Non-invasive bedside tools and techniques are increasingly utilized for longitudinal continuous assessment and trend analysis.
      • 1.
        Monitoring and trend analysis to diagnose infants during compensated shock.
      • 2.
        Clinical short and long term outcomes of the physiologic approach to perfusion management requires investigation through well-designed trials.
      • 3.
        Methods to diagnose preload and assess fluid responsiveness in hypotensive newborn infants.

      Financial disclosure

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

      Declaration of Competing Interest

      The authors Competing Interest: None declared.

      References

        • Weindling M.
        • Paize F.
        Peripheral haemodynamics in newborns: best practice guidelines.
        Early Hum Dev. 2010; 86: 159-165
        • Polglase G.R.
        • Miller S.L.
        • Barton S.K.
        • Kluckow M.
        • Gill A.W.
        • Hooper S.B.
        • et al.
        Respiratory support for premature neonates in the delivery room: effects on cardiovascular function and the development of brain injury.
        Pediatr Res. 2014; 75: 682-688
        • 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: 793-798
      1. 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.
        Arch Dis Child. 1992; 67: 1221-1227
        • Miall-Allen V.M.
        • de Vries L.S.
        • Whitelaw A.G.
        Mean arterial blood pressure and neonatal cerebral lesions.
        Arch Dis Child. 1987; 62: 1068-1069
        • Osborn D.A.
        • Evans N.
        • Kluckow M.
        Clinical detection of low upper body blood flow in very premature infants using blood pressure, capillary refill time, and central-peripheral temperature difference.
        Arch Dis Child Fetal Neonatal Ed. 2004; 89: F168-F173
        • Deshpande S.A.
        • Platt M.P.
        Association between blood lactate and acid-base status and mortality in ventilated babies.
        Arch Dis Child Fetal Neonatal Ed. 1997; 76: F15-F20
        • Gupta S.
        • Donn S.M.
        Neonatal hypotension: dopamine or dobutamine?.
        Semin Fetal Neonatal Med. 2014; 19: 54-59
        • Kluckow M.
        • Evans N.
        Superior vena cava flow in newborn infants: a novel marker of systemic blood flow.
        Arch Dis Child Fetal Neonatal Ed. 2000; 82: F182-F187
        • Voss F.
        • Becker R.
        • Hauck M.
        • Katus H.A.
        • Bauer A.
        The basic pacing rate in CRT patients: the higher the better?.
        Clin Res Cardiol. 2009; 98: 219-223
        • Liu T.
        • Xu C.
        • Wang M.
        • Niu Z.
        • Qi D.
        Reliability of pleth variability index in predicting preload responsiveness of mechanically ventilated patients under various conditions: a systematic review and meta-analysis.
        BMC Anesthesiol. 2019; 19: 67
        • Narula J.
        • Chauhan S.
        • Ramakrishnan S.
        • Gupta S.K.
        Electrical Cardiometry: a reliable solution to cardiac output estimation in children with structural heart disease.
        J Cardiothorac Vasc Anesth. 2017; 31: 912-917
        • Noori S.
        • Drabu B.
        • Soleymani S.
        • Seri I.
        Continuous non-invasive cardiac output measurements in the neonate by electrical velocimetry: a comparison with echocardiography.
        Arch Dis Child Fetal Neonatal Ed. 2012; 97: F340-F343
        • Grollmuss O.
        • Gonzalez P.
        Non-invasive cardiac output measurement in low and very low birth weight infants: a method comparison.
        Front Pediatr. 2014; 2: 16
        • Torigoe T.
        • Sato S.
        • Nagayama Y.
        • Sato T.
        • Yamazaki H.
        Influence of patent ductus arteriosus and ventilators on electrical velocimetry for measuring cardiac output in very-low/low birth weight infants.
        J Perinatol. 2015; 35: 485-489
        • Fraga M.V.
        • Dysart K.C.
        • Rintoul N.
        • Chaudhary A.S.
        • Ratcliffe S.J.
        • Fedec A.
        • et al.
        Cardiac output measurement using the ultrasonic cardiac output monitor: a validation study in newborn infants.
        Neonatology. 2019; 116: 260-268
        • de Boode W.P.
        • Roehr C.C.
        • El-Khuffash A.
        Comprehensive state-of-the-art overview of neonatologist performed echocardiography: steps towards standardization of the use of echocardiography in neonatal intensive care.
        Pediatr Res. 2018; 84: 472-473
        • Singh Y.
        • Roehr C.C.
        • Tissot C.
        • Rogerson S.
        • Gupta S.
        • Bohlin K.
        • et al.
        Education, training, and accreditation of neonatologist performed echocardiography in europe-framework for practice.
        Pediatr Res. 2018; 84: 13-17
        • de Boode W.P.
        • van der Lee R.
        • Horsberg Eriksen B.
        • Nestaas E.
        • Dempsey E.
        • Singh Y.
        • et al.
        The role of Neonatologist Performed Echocardiography in the assessment and management of neonatal shock.
        Pediatr Res. 2018; 84: 57-67
        • Nestaas E.
        • Schubert U.
        • de Boode W.P.
        • El-Khuffash A.
        European Special Interest Group 'Neonatologist Performed E. Tissue Doppler velocity imaging and event timings in neonates: a guide to image acquisition, measurement, interpretation, and reference values.
        Pediatr Res. 2018; 84: 18-29
        • El-Khuffash A.
        • Schubert U.
        • Levy P.T.
        • Nestaas E.
        • de Boode W.P.
        European Special Interest Group 'Neonatologist Performed E. Deformation imaging and rotational mechanics in neonates: a guide to image acquisition, measurement, interpretation, and reference values.
        Pediatr Res. 2018; 84: 30-45
        • Levy P.T.
        • Tissot C.
        • Horsberg Eriksen B.
        • Nestaas E.
        • Rogerson S.
        • McNamara P.J.
        • et al.
        Application of neonatologist performed echocardiography in the assessment and management of neonatal heart failure unrelated to congenital heart disease.
        Pediatr Res. 2018; 84: 78-88
        • Groves A.M.
        • Singh Y.
        • Dempsey E.
        • Molnar Z.
        • Austin T.
        • El-Khuffash A.
        • et al.
        Introduction to neonatologist-performed echocardiography.
        Pediatr Res. 2018; 84: 1-12
        • van Laere D.
        • van Overmeire B.
        • Gupta S.
        • El-Khuffash A.
        • Savoia M.
        • McNamara P.J.
        • et al.
        Application of NPE in the assessment of a patent ductus arteriosus.
        Pediatr Res. 2018; 84: 46-56
        • de Boode W.P.
        • Kluckow M.
        • McNamara P.J.
        • Gupta S.
        Role of neonatologist-performed echocardiography in the assessment and management of patent ductus arteriosus physiology in the newborn.
        Semin Fetal Neonatal Med. 2018; 23: 292-297
        • de Boode W.P.
        • Singh Y.
        • Gupta S.
        • Austin T.
        • Bohlin K.
        • Dempsey E.
        • et al.
        Recommendations for neonatologist performed echocardiography in europe: consensus statement endorsed by European society for paediatric research (ESPR) and European society for Neonatology (ESN).
        Pediatr Res. 2016; 80: 465-471
        • Singh Y.
        • Gupta S.
        • Groves A.M.
        • Gandhi A.
        • Thomson J.
        • Qureshi S.
        • et al.
        Expert consensus statement 'Neonatologist-performed echocardiography (NoPE)'-training and accreditation in UK.
        Eur J Pediatr. 2016; 175: 281-287
        • Rowland D.G.
        • Gutgesell H.P.
        Noninvasive assessment of myocardial contractility, preload, and afterload in healthy newborn infants.
        Am J Cardiol. 1995; 75: 818-821
        • Toyono M.
        • Harada K.
        • Takahashi Y.
        • Takada G.
        Maturational changes in left ventricular contractile state.
        Int J Cardiol. 1998; 64: 247-252
        • de Waal K.
        • Evans N.
        Hemodynamics in preterm infants with late-onset sepsis.
        J Pediatr. 2010; 156: 918-922 e1
        • Saini S.S.
        • Kumar P.
        • Kumar R.M.
        Hemodynamic changes in preterm neonates with septic shock: a prospective observational study∗.
        Pediatr Crit Care Med. 2014; 15: 443-450
        • De Felice C.
        • Latini G.
        • Vacca P.
        • Kopotic R.J.
        The pulse oximeter perfusion index as a predictor for high illness severity in neonates.
        Eur J Pediatr. 2002; 161: 561-562
        • Van Laere D.
        • O'Toole J.M.
        • Voeten M.
        • McKiernan J.
        • Boylan G.B.
        • Dempsey E.
        Decreased variability and low values of perfusion index on day one are associated with adverse outcome in extremely preterm infants.
        J Pediatr. 2016; 178: 119-124 e1
        • de Boode W.P.
        Clinical monitoring of systemic hemodynamics in critically ill newborns.
        Early Hum Dev. 2010; 86: 137-141
        • Kenosi M.
        • Naulaers G.
        • Ryan C.A.
        • Dempsey E.M.
        Current research suggests that the future looks brighter for cerebral oxygenation monitoring in preterm infants.
        Acta Paediatr. 2015; 104: 225-231
        • Hyttel-Sorensen S.
        • Pellicer A.
        • Alderliesten T.
        • Austin T.
        • van Bel F.
        • Benders M.
        • et al.
        Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial.
        BMJ. 2015; 350: g7635
        • Groves A.M.
        • Chiesa G.
        • Durighel G.
        • Goldring S.T.
        • Fitzpatrick J.A.
        • Uribe S.
        • et al.
        Functional cardiac MRI in preterm and term newborns.
        Arch Dis Child Fetal Neonatal Ed. 2011; 96: F86-F91