Early priorities in cardiovascular support in premature infants

Current Paediatrics (2001) 11, 181d186 ^ 2001 Harcourt Publishers Ltd doi:10.1054/cupe.2000.0170, available online at http://www.idealibrary.com on

Early priorities in cardiovascular support in premature infants M. Sellwood and J. Wyatt Neonatal Unit, Obstetric Hospital, University College London Hospital, Huntley Street, London WC1E 6AU, UK KEYWORDS prematurity, blood pressure, patent ductus arteriosus, inotropes

Summary Haemodynamic dysfunction in the first days of life is common in premature infants. They are prone to hypovolaemia and retain fetal circulatory connections that potentially impair cardiac output and tissue perfusion. Immature organs are vulnerable to the effects of hypoperfusion with potentially debilitating or life-threatening consequences. Recognizing infants at risk, seeking to maintain an adequate circulating volume and providing them with appropriate inotropic support are crucial to optimizing their care. There is evidence that early treatment to close the ductus arteriosus mitigates some of the malignant effects of ductal shunting. Clinical assessment of cardiovascular function is not always straightforward. The increasing use of echocardiography by neonatologists means that more informed decisions about cardiovascular management can be made. ^ 2001 Harcourt Publishers Ltd

PRACTICE POINTS E Hypovolaemia is common; relatively substantial reductions in circulating volume may occur due to perinatal events or due to blood taken for investigations in preterm infants E Clinical evidence of hypovolaemia may be scant and hard to interpret E Inappropriate ventilation may significantly compromise cardiovascular function E Blood pressure correlates poorly with systemic blood flow and circulating volume E It is important to ensure that there is adequate circulating volume. Faced with a haemodynamically compromised infant, in the absence of echocardiographic assessment, it is reasonable to increase preload and vascular filling with a fluid bolus before starting inotropes E If this is unsuccessful, inotropic support should be given recognizing the differing effects of available inotropes E Dopamine causes a rise in systemic resistance; this tends to increase blood pressure, but it has

Correspondence to: MS. E-mail: [email protected]

E

E

E E

E

a variable impact on cardiac output. Its greatest efficacy is usually in infants who are vasodilated with good cardiac output. At low doses, it increases renal perfusion and urine production in normotensive infants Dobutamine causes a reduction in systemic resistance but increases myocardial contractility. It is the logical choice in infants who have poor cardiac contractility, particularly if they are vasoconstricted The ductus arteriosus frequently remains patent. Left to right shunting may reduce systemic blood flow, particularly during diastole. During the first few days of life, this may contribute to the development of intraventricular haemorrhage (IVH) and later to pulmonary hyperaemia and prolonged oxygen requirement Early prophylactic indomethacin has been shown to decrease the risk of severe grades of IVH The foramen ovale may remain open for some weeks following delivery allowing left to right shunting at atrial level, increasing pulmonary blood flow and reducing left ventricular filling Echocardiography adds considerably to the amount of haemodynamic information available at the cotside. To what extent we should regard it as a standard part of neonatal intensive care is still under debate

182

INTRODUCTION Post-natal circulatory adaptation tends to be prolonged in very preterm infants when compared with term infants. In infants with respiratory distress, the fall in pulmonary vascular resistance is often delayed,1 the ductus arteriosus and foramen ovale tend to close later, and ventricular function may be relatively inadequate in the face of high systemic resistance. In addition to this, hypovolaemia is a common phenomenon, and shunting into the pulmonary circulation at atrial or ductal level may result in pulmonary hyperaemia and systemic hypoperfusion. Failure of circulatory adaptation after birth may have serious consequences because of the vulnerability of immature organs, especially brain, kidneys and gut, to ischaemic injury. This paper is intended to review the current knowledge on circulatory adaptation of the very preterm infant, in order to aid clinical management in the critical first hours and days of life.

INTRAVASCULAR BLOOD VOLUME The mean total blood volume of a newborn infant is typically about 85 ml/kg but a wide range of values is found in preterm infants.2 Acute changes in circulating blood volume can occur at birth due to feto-maternal haemorrhage, bruising, accidental haemorrhages from the cord, twin-to-twin transfusion or placental abruption. The speed of cord clamping and the management of delivery can also have an effect on total blood volume. By contrast, chronic fetal blood loss or haemolysis usually leads to a normal blood volume with reduced haemoglobin concentration. As the blood volume of extremely low birthweight infants is so small, apparently trivial losses from the circulation can have significant consequences. The haematocrit and haemoglobin concentration at or shortly after birth are both unreliable guides to the circulating blood volume. If these measurements are repeated after a few hours, they may reveal evidence that blood loss had occurred around birth. In infants in whom this can be predicted, for instance, those with extensive bruising, it is advisable to transfuse early, before the haematocrit falls. A low circulating volume characteristically results in poor tissue perfusion, both because of inadequate vascular filling peripherally and because of low cardiac preload compromising ventricular output. However, clinical assessment of intravascular volume is often difficult. A history of intrapartum blood loss or significant blood taken for investigations might raise the probability of an inadequate circulating volume. Guttering of the veins may suggest venous underfilling and venous access may prove very difficult until the intravascular volume is

CURRENT PAEDIATRICS improved. Slow capillary refill, low urine output or metabolic acidosis may suggest inadequate vascular filling, but there are other causes of these findings, especially poor myocardial function. Arterial blood pressure (BP) correlates poorly with blood volume in premature infants2 and cannot be used as a reliable clinical indicator. Central venous pressure measurements are useful and can be obtained from an umbilical venous catheter provided that the tip is accurately situated within the right atrium. However, the potential complications from umbilical venous catheterization cannot be ignored and many neonatologists are reluctant to use this route routinely. Echocardiography allows the adequacy of the circulating volume to be determined from the ventricular filling and function. In an infant with evidence of poor tissue perfusion, it seems reasonable to try increasing the preload of the heart by transfusion. The most rational agent for restoring the circulating blood volume is whole blood. If urgent volume replacement is required, crystalloid or albumin solution are acceptable and some neonatologists would advocate the use of these as initial treatment for hypotension. Repeated attempts to improve BP or perfusion using crystalloid or albumin fluid boluses should be undertaken with caution, risking sodium and water overload. Overfilling of the ventricles may compromise cardiac function, particularly in the face of an open ductus arteriosus which may add significantly to left ventricular preload. For very small infants undergoing intensive care, routine blood sampling leads to losses which rapidly amount to a significant proportion of the circulating volume. It is our practice to keep a detailed blood log to accurately document the volume of blood taken each time investigations are performed within the first week of life; when the losses reach 10% of the estimated blood volume, an equivalent volume is transfused using whole blood or packed cells. Since both haemoglobin concentration and haematocrit are unreliable guides to blood volume, it is preferable not to withhold transfusion until clinical signs of hypovolaemia are seen, but to anticipate the need for maintenance of the circulating volume.

EFFECT OF VENTILATION ON CARDIAC FUNCTION Ventilation strategy may have a significant effect on cardiac function and tissue perfusion. If the lungs are underexpanded, there may be regions of ventilation} perfusion mismatch leading to hypoxaemia. In addition, the pulmonary vascular resistance is likely to remain high. As a result, deoxygenated blood is shunted from right to left through the ductus arteriosus, and left ventricular filling is compromised. Right to left ductal shunting will

EARLY PRIORITIES IN CV SUPPORT only happen during periods of the cardiac cycle in which the pulmonary artery pressure exceeds that of the descending aorta. It leads to a reduction in the saturation of the lower half of the body relative to the upper, and may be detected by measuring the simultaneous difference in saturation between two pulse oximetry probes, one on the right hand and the other on a foot. The solution to this problem lies in recruiting collapsed alveoli with more appropriate ventilation and, if the problem persists, reducing pulmonary vascular resistance has been attempted using prostacyclin; the use of inhaled nitric oxide remains the subject of research. Overexpansion of the lungs leads to a reduction in venous return to the thorax and direct mechanical compression of the ventricles. Both these phenomena have the effect of compromising ventricular output. This complication is a particular risk during highfrequency oscillatory ventilation in which a constant distending pressure is applied to the lungs. The same problem may be observed in infants with conventional ventilation with excessive or inadvertent positive end expiratory pressure. If the mean airway pressure is above that necessary to achieve normal lung expansion, direct compression of the pulmonary microvasculature occurs, leading to elevation of the pulmonary vascular resistance. The chest radiograph shows a compressed heart and mediastinum with hyperexpanded lung fields and flat diaphragms. This situation may be rectified by reducing the mean airway pressure or end expiratory pressure.

CARDIAC FUNCTION AND BLOOD PRESSURE Arterial blood pressure is determined by the product of cardiac output and systemic vascular resistance. Hence, it is possible to maintain BP, in the face of low cardiac output, by increasing vascular resistance. Various adverse outcomes in preterm infants have been found to be statistically associated with low arterial BP. Particularly worrying are the reported association between IVH3 and adverse neurological outcome.4 However, it seems unlikely that a universally applicable lower limit for systemic BP can be defined in extremely preterm infants. What is important is whether oxygen and metabolic substrate delivery is meeting tissue demands, and in particular that vital organs receive sufficient oxygen and substrate to avoid permanent injury. Attempts have been made to use Doppler ultrasound to derive information about organ perfusion. Doppler ultrasound is capable of providing the velocity profile of blood within a vessel, but in order to obtain absolute quantification of the blood flow, the diameter of the insonated vessel must be measured and the cross-

183 sectional area calculated. As a result, any inaccuracy in the measurement of vessel diameter will lead to large errors in the calculation of flow, and the method is therefore only useful when large vessels such as the aorta are insonated. The diastolic flow velocity tends to fall with increasing downstream vascular resistance. Several indices, such as the resistance index [(systolic flow velocity!diastolic flow velocity)9(systolic flow velocity)], have been developed in order to provide a semi-quantitative assessment of vascular resistance (in the mesenteric vessels, for instance). Quantitative techniques for measuring organ flow such as nearinfrared spectroscopy or the intravenous xenon clearance are not easily applied in routine clinical practice. In clinical practice, attempts to ensure adequate arterial BP have tended to rely on rather arbitrary ‘rules of thumb,’ such as, keeping the value of the mean BP above the tenth centile for the gestational age or keeping mean BP (in mm Hg) above the numerical gestational age (in weeks). Normative BP centile values have been derived from healthy preterm infants.5 Accurate measurement of BP requires intra-arterial monitoring which may be central or peripheral. Automated cuff measurements tend to be least accurate in those infants that are most at risk of ischaemic organ injury, in other words the smallest infants with the lowest BP.6

INOTROPIC AGENTS If the hypotensive infant’s arterial BP does not respond to a significant increase in the intravascular volume, there is either a very low peripheral vascular resistance as a result of generalized vasodilatation or the intrinsic cardiac function is inadequate. Cardiac output can be improved by increasing the stroke volume or by increasing the heart rate or both. Preterm infants have less capacity to increase their cardiac output by increasing their heart rate when compared with older children and adults. If intrinsic cardiac function is poor or there is peripheral vasodilatation, tissue perfusion may be improved with the use of appropriate inotropic agents. Dopamine has various cardiovascular effects. b-adrenoceptor stimulation has an inotropic effect on the myocardium which may increase cardiac output in newborn infants. Alternatively, it may decrease cardiac output because a-adrenoceptor stimulation produces peripheral vasoconstriction which increases afterload.7 However, dopaminergic stimulation may cause peripheral vasodilatation in certain organ beds. Low-dose dopamine infusion (2 lg/kg/min) has been shown to increase urine output and sodium excretion in normotensive preterm infants;8 it may be useful in selectively improving renal

184 perfusion. Higher dose infusions of 5}20 lg/kg/min are likely to increase arterial blood pressure, although it cannot be simply assumed that tissue perfusion will be improved as a result. Doppler studies in preterm infants imply that dopamine has vasodilator action on the renal arteries but does not affect cerebral vascular resistance.9 Dobutamine is a synthetic adrenoceptor agonist that produces b1-adrenergic inotropic effects. It also has a1-adrenergic properties that produce vasoconstriction at low doses, and b2 effects that produce vasodilatation at higher doses.12 Comparative studies suggest that it is not as effective at increasing arterial blood pressure as dopamine in preterm infants.10 However, the effect on blood pressure may not be of critical importance. Ideally, before commencing an inotrope infusion, one should ascertain what circulatory changes are required and then select an agent that is most likely to achieve the desired effect. If there is low cardiac output and peripheral vasoconstriction, infusing dopamine may lead to an increase in BP at the expense of reducing left ventricular output even further, leading to worsening of tissue perfusion. In contrast, dobutamine tends to increase cardiac output but decrease peripheral vascular resistance. Other inotropes are used more infrequently but should be considered as a last resort. Noradrenaline acts principally as an a-agonist and has intense vasoconstrictor effects. Hence, it will usually raise the BP but may not improve and can reduce cardiac output. Adrenaline has a- and b-agonist effects. It increases heart rate and also increases myocardial contractility, condution and output. It produces mixed effects on peripheral vascular beds, tending to produce vasoconstriction in the skin, for instance.

STEROIDS Steroids can be an effective treatment to raise BP in hypotensive preterm infants. Dexamethasone has been shown to be effective in refractory hypotension11 and hydrocortisone treatment has also been demonstrated to lead to a sustained rise in blood pressure in hypotensive preterm infants.12 We have used a dose of hydrocortisone 2 mg/kg every 8 hours to treat refractory hypotension in preterm infants. The mechanisms by which steroids cause a rise in blood pressure are disputed. Some critically ill preterm infants appear to have reduced adrenocorticoid function leading to a relative deficiency in circulating cortisol.13 Steroids may also impair catecholamine breakdown in both vascular tissue and myocardium, and may also increase b-adrenergic receptor numbers.12 Thus steroid administration may bring about an increase in BP by a combination of increased cardiac contractility and increased vascular resistance.

CURRENT PAEDIATRICS

EFFECT OF PERSISTENT FETAL CIRCULATORY CONNECTIONS Patent ductus arteriosus Flow in the ductus arteriosus is frequently bidirectional after birth, becoming more predominantly left to right over the first few days. The pulmonary vascular resistance falls over this period and the pressure difference between the aorta and pulmonary artery increases. Ductal shunting may cause reversed diastolic flow in the descending aorta, the mesenteric artery and in the cerebral arteries. It has been suggested that left to right ductal shunting may lead to reduced cerebral perfusion, and this might explain the observation that left to right ductal shunting in the early postnatal period appears to be a risk factor for the subsequent development of IVH.14 Hypotension and fluctuations in BP are more common on the day of or the day preceding the development of IVH.5 More severe forms of IVH have been associated with low cerebral blood flow on the first day15 and low right ventricular output associated with a large ductal shunt.14 Patency of the ductus arteriosus has also been shown to be associated with necrotizing enterocolitis, hypotension and pulmonary hyperperfusion. It may cause difficulty in weaning ventilation and may contribute to the development of chronic lung disease. The classical clinical signs of a patent ductus arteriosus (systolic cardiac murmur, bounding pulses, active praecordium and low arterial BP) tend to emerge when the infant is a few days old. In the first days of life no murmur may be audible despite clear echocardiographic evidence of a substantial shunt. The ductus arteriosus closes in two phases: the initial closure caused by muscular constriction, which is reversible; the ductus arteriosus frequently re-opens before final anatomical closure. This occurs whether indomethacin is given as early prophylaxis or following the development of clinical signs. However, final anatomical closure is more likely to occur if indomethacin is given early.16 Indomethacin leads to a temporary reduction in cerebral blood flow,17 probably because of a direct vasoconstrictor action on the cerebral vasculature. It has been suggested that this might contribute to its protective effect on intraventricular haemorrhage by stabilizing the cerebral circulation.18 It also appears to have an effect on the composition of blood vessel walls within the germinal matrix.19 Ibuprofen seems to have similar efficacy with respect to ductal closure but has less marked effects on cerebral blood flow.20 There have been concerns that the widespread use of indomethacin might lead to an increase in the incidence of periventricular leukomalacia. This has not been borne out by a large randomized controlled trial of early, prophylactic indomethacin in infants of birthweights

EARLY PRIORITIES IN CV SUPPORT between 600 and 1250 g. The treated children showed no evidence of delayed development at 54 months of age compared with controls.21 The major drawbacks to the use of indomethacin are its side-effects, particularly in sick, preterm infants. The principal problems are impaired renal function and haemorrhage or perforation of the gut; it also affects platelet function.

Intra-atrial shunting The foramen ovale frequently fails to completely close in premature infants, providing a further means of left to right vascular shunting. As with ductal shunting, this produces an elevated pulmonary blood flow, reducing the proportion of the cardiac output that perfuses the body.22 Blood returning to the left atrium crosses to the right atrium and recirculates through the pulmonary circulation. This wastes right ventricular work, reduces left ventricular output, causes pulmonary hyperaemia and may lead to a prolonged need for ventilatory support. There may be little clinical evidence of a patent foramen ovale and it usually can only be confirmed echocardiographically. Postnatally, the foramen ovale may remain patent for several weeks.

The use of echocardiography Routine echocardiographic assessment undertaken by neonatologists has a number of potential benefits in the clinical care of preterm infants. An estimation of ventricular filling can be obtained, ventricular output can be quantified, appropriate inotrope medication can be selected and their impact on cardiovascular function measured. The size and flow characteristics of the ductus arteriosus and its impact on the circulation can be determined,23 and the presence of atrial shunting also detected. In some infants, it is possible to estimate pulmonary artery pressure echocardiographically.24 Finally, major abnormalities of cardiac structure may be detected. If congenital heart disease is suspected, a detailed assessment by a paediatric cardiologist is mandatory. Even with detailed haemodynamic information acquired using echocardiography, it is not always possible to determine perfusion at a tissue level. However, in difficult clinical situations, the more information that one can accumulate about the state of the circulation, the more likely one is to make appropriate management decisions. It is increasingly clear that echocardiographic skills are valuable for the practising neonatologist. Unfortunately, colour doppler apparatus is very expensive and the development and maintenance of the necessary technique requires considerable training and frequent practice at the cotside. It is a matter of debate

185 whether or not echocardiographic training should be undertaken by all neonatologists who undertake the care of critically ill preterm infants.

REFERENCES 1. Skinner J R, Boys R J, Hunter S, Hey E N. Pulmonary and systemic arterial pressure in hyaline membrane disease. Arch Dis Child 1992; 67: 366}373. 2. Bauer K, Linderkamp O, Versmold H T. Systolic blood pressure and blood volume in preterm infants. Arch Dis Child Fetal Neonatal Ed 1993; 69: F521}522. 3. Miall-Allen V M, De Vries L S, Whitelaw A G L. Mean arterial blood pressure and neonatal cerebral lesions. Arch Dis Child 1987; 62: 1068}1069. 4. Goldstein R F, Thompson R J Jr, Oehler J M et al. Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics 1995; 95: 238}243. 5. Cunningham S, Symon A G, Elton R A, Zhu C, McIntosh N. Intra-arterial blood pressure reference ranges, death and morbidity in very low birthweight infants during the first seven days of life. Early Hum Dev 1999; 56: 151}165. 6. Diprose G K, Evans D H, Archer L N J, Levene M I. Dinamap fails to detect hypotension in very low birthweight infants. Arch Dis Child 1986; 61: 771}773. 7. Zhang J, Penny D J, Kim N S, Yu V Y H, Smolich J J. Mechanisms of blood pressure increase induced by dopamine in hypotensive preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999; 81: F99}104. 8. Seri I, Rudas G, Bors Z, Kayicska B, Tulassay T. Effects of low-dose dopamine infusion on cardiovascular and renal functions, cerebral blood flow and plasma catacholamine levels in sick preterm neonates. Pediatr Research 1993; 34: 742}749. 9. Seri I, Abbasi S, Wood D C, Gerdes J S. Regional hemodynamic effects of dopamine in the sick preterm neonate. J Pediatr 1998; 133: 728}734. 10. Greenough A, Emery E F. Randomized trial comparing dopamine and dobutamine in preterm infants. Eur J Pediatr 1993; 152: 925}927. 11. Gaissmaier R E, Pohlandt F. Single-dose dexamethasone treatment of hypotension in preterm infants. J Pediatr 1999; 134: 701}705. 12. Bourchier D, Weston P J. Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 1997; 76: F174}178. 13. Ng P C. The fetal and neonatal hypothalamic-pituitaryadrenal axis. Arch Dis Child Fetal Neonatal Ed 2000; 82: F250}254. 14. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed. 1996; 75: F183}186. 15. Meek J H, Tyszczuk L, Elwell C E, Wyatt J S. Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Arch Dis Child Fetal Neonatal Ed 1999; 81(1): F15}18. 16. Narayanan M, Cooper B, Weiss H, Clyman RI. Prophylactic indomethacin: factors determining permanent ductus arteriosus closure. J Pediatr 2000; 136(3): 330}337. 17. Edwards A D, Wyatt J S, Richardson C, Potter A, Cope M, Delpy D T, Reynolds E O. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990; 23; 335(8704): 1491}1495. 18. Yanowitz T D, Yao A C, Werner J C, Pettigrew K D, Oh W, Stonestreet B S. Effects of prophylactic low-dose indomethacin on

186

hemodynamics in very low birth weight infants. J Pediatr 1998; 132(1): 28}34. 19. Ment L R, Stewart W B, Ardito T A, Huang E, Madri J A. Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup. Stroke 1992; 23: 132}137. 20. Ohlsson A. Back to the drawing board. Pediatr Res 2000; 47: 4}5. 21. Ment L R, Vohr B, Allan W et al. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2000; 105: 485}491.

CURRENT PAEDIATRICS

22. Evans N, Iyer P. Incompetence of the foramen ovale in preterm infants supported by mechanical ventilation. J Pediatr 1994; 125: 786}792. 23. Evans N, Iyer P. Assessment of ductus arteriosus shunt in preterm infants supported by mechanical ventilation: effects of interatrial shunting. J Pediatr 1994; 125: 778}785. 24. Evans N. Echocardiographic assessment of the newborn infant with suspected persistent pulmonary hypertension. Semin Neonatol 1997; 2: 37}48.