Seminars in Fetal & Neonatal Medicine (2008) 13, 16e23

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Hypotension and shock in the preterm infant

Keith J. Barrington*
al, Que bec H3A 1A1, Canada McGill University, NICU, Royal Victoria Hospital, 687 Pine Ave W, Montre

KEYWORDS
Hypotension; Inotrope; Preterm infant; Shock

Summary Between 16% and 98% of extremely preterm infants receive treatment for hypotension in the rst few days of life. This enormous variation has arisen because of a lack of reliable information to create an evidence base for intervention. This review article provides the unique characteristics of the neonatal cardiovascular system, and addresses the denitions of hypotension and shock in the preterm infant, the indications for treatment and appropriate therapies in individual cases. The treatment of shock and hypotension in the preterm infant may be the area of neonatology where there is the greatest intervention/data imbalance; more babies receive more treatments with less supportive evidence than in virtually any other domain. Treatment of hypotension in infants with good perfusion is probably unnecessary and may be harmful, but the assessment of adequate perfusion remains problematic. Infants with inadequate oxygen delivery to the tissues may benet from treatment, but which treatments are effective are unknown. It is essential that better evidence be available to create a rational basis for intervention. 2007 Elsevier Ltd. All rights reserved.

Introduction
Large numbers of very premature infants receive cardiovascular support in the rst few days of life. The proportion receiving such support varies dramatically between institutions,1 with a maximum of 98% receiving therapy for hypotension in some neonatal intensive care units (NICUs). The variations between NICUs are not accounted for by variations in patient characteristics, but seem to result entirely from patterns of practice.1 Many neonatologists treat premature infants solely on the basis of the numerical blood pressure (BP) value,2 while others require additional clinical signs before intervening. Why are there such discrepancies? What do we really know about the diagnosis,
* Tel.: 1 514 934 1934x34876; fax: 1 514 843 1741. E-mail address: keith.barrington@mcgill.ca

management and outcomes of hypotension in the preterm infant? The preterm infant is a unique patient, born during development of the cardiovascular system, which makes it essential to have a basic understanding of some of the major aspects of developmental cardiovascular physiology.

The unique characteristics of the neonatal cardiovascular system

At the subcellular level, the newborn myocardium differs substantially from the mature myocardium, particularly in the lack of sarcoplasmic reticulum3 and a poorly formed or absent t-tubule system. The myobrils are shorter and more rounded, with a much higher number of mitochondria, and are relatively disorganised.4 The myocardium contains much more brous non-contractile tissue and has reduced sympathetic innervation.5 Despite these limitations, the

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Hypotension and shock in the preterm infant neonatal myocardium operates at a very high functional level, with a much higher cardiac output than older individuals, and is therefore working at near maximal capacity with very little contractile reserve.6 There is a very limited ability to increase cardiac output in response to drugs or changes in loading conditions,6 and an elevated sensitivity to increased afterload,7 which commonly leads to decreases in cardiac output.8 Many of the drugs used for cardiac support increase afterload; this effect may lessen the cardiac output responses to any positive inotropic effect. If afterload is increased sufciently, cardiac output may fall despite a positive inotropic intervention, the so-called inotropic/afterload imbalance.

17 compared to older subjects. Similar to the responses to aadrenergic agents, b-receptor stimulation in the newborn has a limited effect on myocardial contractility.11 In the developing peripheral vasculature, there appears to be fewer b2-receptors12 but many active a1-receptors. Thus, vasoconstriction from a1-adrenoceptor stimulation can cause marked increases in systemic vascular resistance. The increases in vascular resistance and BP evident from controlled and uncontrolled experience with inotropes demonstrate that these receptors must be active in the preterm human infant. Administering the selective a1-agonist phenylephrine causes major increases in vascular resistance; despite a-adrenergic stimulation of the myocardium, the increase in afterload leads to a decrease in cardiac output and there results a minor increase in BP.13 The development of the dopaminergic receptor appears to be more complex in that the d1-receptors are present in the renal circulation of the newborn mammal, but selectively stimulating these receptors appears to have no effect.9,14 This is probably because the dopaminergic receptor is not linked to post-receptor events,9 even though the post-receptor mechanisms are intact, in what appears to be a lack of linkage of the d1-receptor to the stimulatory G-protein. In the bowel, however, a decrease in mesenteric vascular resistance is detectable with high doses of the selective d1-agonist, fenoldopam.14 The pattern of maturation of these receptors in other regional circulations, such as the coronary or cerebral circulations, is not known.

Responses to catecholamine agents

Most inotropic medications used in the newborn are catecholamines; responses to these drugs are receptor-mediated. The receptors were initially divided into a- and b-receptors, and more recently into a1-, a2-, b1- and b2-receptors, and their subtypes. The a1-receptors are post-synaptic and linked to phospholipase C through a stimulatory G-protein; they are found both in the myocardium and in the vasculature. Stimulation of a1-receptors causes an increase in the inotropic state of the heart, as well as an increase in vascular tone, leading to increases in BP and increases in afterload. The a2-receptor is a pre-synaptic receptor involved in the regulation of norepinephrine release and mediates an increase in vascular tone. b1-receptors are present mostly in the heart, increase cyclic AMP levels through a G-proteindependent pathway and increase both heart rate and the inotropic state of the myocardium. b2-receptors largely cause vasodilation and bronchodilation; they may mediate an increased heart rate, partly through reex action and partly through a minor direct action. Specic dopaminergic receptors consist of ve genetically different receptors, which fall into two groups, the d1-like (consisting of the d1 and d5 receptor), and the d2like (consisting of the d2, d3 and d4 receptors). The d1-like receptors are largely post-synaptic and G-protein-dependent, coupled to adenyl cyclase and phospholipase C. They mediate vasodilation in the circulations of the kidneys, bowel, myocardium and brain.9 The d2-like receptors are both pre- and post-synaptic and inhibit adenyl cyclase activity. Limited physiological effects on tubular function of the kidney have been described.

Catecholamines
Dopamine
Dopamine stimulates a1-receptors, a2-receptors, b1receptors and specic dopaminergic receptors. The myth that low-dose dopamine in the newborn causes selective renal vasodilation, medium-dose dopamine causes general vasodilation and inotropy, and high-dose dopamine causes vasoconstriction must be dismissed. This information was derived from studies in healthy adult dogs and is clearly not generalisable to critically ill newborn infants.15 Dopamine has little or no b2 activity16 and has not been demonstrated to cause b2-mediated vasodilation.16 At the b1-receptor, dopamine is 30e40 times less potent than either epinephrine or norepinephrine. Thus, dopamine primarily has a1 effects, some a2 effects and dopaminergic effects. Dopamine pharmacokinetics is very variable in the newborn; the same administered dose may produce serum concentrations varying by as much as 100-fold.17 This results from variable clearance, probably because of variable activity of the three different enzyme systems metabolising dopamine. There are also variations in receptor density and afnity, which lead to marked inter-individual variations in actions of dopamine and of all of these drugs, for that matter. The same pharmacokinetic variability probably applies to the other inotropic agents, which have, however, been studied much less. Toxicities Dopamine is an important neurotransmitter. Although systemically administered dopamine does not cross the

Adrenergic receptor ontogeny

At birth, there are limited a-receptors and little sympathetic innervation of the myocardium. However, those that are present may exhibit so-called denervation hypersensitivity, whereby they are maximally stimulated by small concentrations of catecholamines.5 The haemodynamic effects, which result from stimulation of these receptors, are minor, because of the aforementioned limited capacity of neonatal myocardium to increase its inotropic state. In contrast, the density of b-adrenoceptors, which is low at ages equivalent to extreme preterm delivery, appears to increase during the later part of gestation10 and the density of the b-receptors at term gestational age is actually increased

18 bloodebrain barrier in large quantity, the anterior medium eminence of the hypothalamus and the pituitary are outside of this barrier. The d2-receptors are important in endocrine regulation; systemically administered dopamine, even at very low doses, has profound endocrine effects. Thus, during dopamine therapy, prolactin production completely stops, growth hormone pulses disappear and thyrotropin-releasing hormone production is inhibited, leading to a reduction in thyroxine and triiodothyronine (T3).18 Low levels of thyroxine and T3 are associated with poor neurodevelopmental outcome of preterm infants. Dopamine is sometimes administered over many days in this critical phase of brain development. It seems unlikely that the suppression of thyroid function, which is a consequence, is benecial to the infant (although it has not been proven to be harmful). Other catecholamines in therapeutic use have no action at the dopamine receptor. Dopamine also stimulates the same receptors in the carotid body leading to a decrease in ventilation and respiratory drive.19 Dopamine may also impair T-cell function20 and increase energy expenditure and lipolysis.21

K.J. Barrington metabolism, leading to increased serum lactate concentrations.26 At higher doses, there may be an impairment of bowel blood ow and oxygen delivery to the gut, as seen in some studies of septic adults and in acutely instrumented piglets at a dose of 3.2 mg/kg/min.26 This is presumably an a-mediated effect and does not seem to be occur at lower doses.

Norepinephrine
Norepinephrine has not been studied much in neonatal models, presumably because of its lower afnity for the b2 receptor. Norephinephrine is therefore more likely to cause vasoconstriction compared to epinephrine. For this reason, it has been widely used in adults for gram-negative sepsis and warm shock, in whom improvements in tissue oxygen delivery and urine output may result.27 Since vasodilated septic shock is not commonly seen in the newborn, norepinephrine probably has a limited place.

Non-catechol inotrope/pressor agents

Agents that block the action of phosphodiesterase III have been used in adults and older children with some effect. The drugs increase intracellular cAMP, which leads to both inotropic effects and vasodilation. However, in neonatal mammalian models, class III phosphodiesterase (PDE) inhibitors have minimal effects, no effect, or even negative inotropic effects, perhaps because of a developmental imbalance between class III and class IV PDE in neonatal sarcoplasmic reticulum. The effects on the preterm human myocardium are unknown and clearly cannot be predicted from animal studies. In contrast, vasodilation has been noted in limited neonatal studies.28 Milrinone may have other adverse effects. In dogs, milrinone at 1 mg/kg produced lesions in the left ventricle and the right atrium. Similar lesions have been noted with other inotropes or pressors; they may occur whenever myocardial workload is increased, as this may exceed any increases in myocardial oxygen and substrate supply. Other agents undergoing extensive evaluation in older subjects, such as levosimendan, are completely unstudied in the newborn. Given the brief review of developmental cardiovascular physiology above, it is clear that very careful evaluation of any agent is required before using it in the newborn infant.

Dobutamine
Dobutamine was synthesised with the intention of creating a selective b1-agonist. However, its functions are actually quite complex, with the two stereoisomers of dobutamine, both present in the clinical product, having various degrees of action at both a- and b-receptors. Overall, dobutamine is an effective inotropic agent, which also causes vasodilation and causes mild tachycardia. At very high doses of dobutamine, BP may sometimes increase22 and there may also be an increase in systemic vascular resistance, probably because of the stimulation of the a-receptor by the () enantiomer. Toxicities Few toxic effects have been associated with dobutamine; infants may become excessively tachycardic during dobutamine therapy, but a reduction in dose is usually all that is required. Dobutamine also appears to have metabolic effects. A study in lambs suggested that any potential benet of increased oxygen delivery to the tissues was offset by an increase in tissue metabolic rate.23 There appear to be no studies that have examined the relative increases in oxygen delivery and oxygen consumption during inotrope therapy in the human newborn.

Epinephrine
Epinephrine stimulates a1-, a2-, b1- and b2-receptors and causes vasodilation at very low doses, an inotropic action that appears to increase as the dose increases, and begins to cause signicant vasoconstriction at high doses.24 At very high doses, the vasoconstriction is sufcient to overcome the inotropic benets and cardiac output may begin to fall.25 Thus, epinephrine at low doses will probably increase cardiac output and at moderate doses will likely increase BP as well, but studies in humans are limited. Toxicities Epinephrine directly impacts lactate metabolism, causing an increase in lactate production and a decrease in lactate

The denition of hypotension and shock

Hypotension
Blood pressures are normally lower in more immature infants. Normal BP is also lower immediately after birth, progressively increasing thereafter.29 Hypotension could be dened statistically by taking the mean minus two standard deviations at each postnatal and postmenstrual age. Hypotension, as dened statistically, in the majority of infants is still associated with normal systemic blood ow30 and low systemic vascular resistance. Hypotension could also be dened as an unsafe BP, i.e. a BP below which outcomes are worse. More valuable still would be an operational

Hypotension and shock in the preterm infant denition, i.e. a threshold pressure, below which intervention has been shown to improve outcomes. We recently performed a systematic review to look for evidence that a particular BP threshold was associated with an increase in poor outcomes.31 There does appear to be a broad association between lower BP and an increase in ultrasound-diagnosed brain injury. However, it is not possible to determine at what BP threshold this occurs, or whether the effect is independent of treatment. In many studies, the normal values were constructed after excluding infants who received treatment for hypotension, while the infants who received treatment were then included when ascertaining the risk of hypotension. In some studies, the same BP threshold was applied for infants of all gestational ages, but the most immature infants, at greatest risk of poor outcomes, have the lowest BP; therefore, this kind of analysis will show an artefactual association between hypotension and brain injury. In numerous studies, the same BP threshold was applied at all postnatal ages; as BP normally increases spontaneously in the rst week of life, infants who have a BP below a threshold on, for example, day 7, are much more severely hypotensive than those whose BP is below the same threshold on day 1. Such methods of data analysis generate biases that cannot be overcome by multivariate statistical manipulation of the data. The denition of hypotension, therefore, remains elusive.

19 pH as determined by gastric tonometry, currently being investigated in the newborn. Clinical signs The relative sensitivity of any of these clinical or laboratory ndings for detecting shock as dened above is unknown. Capillary lling has been correlated with systemic blood ows in preterm infants33; there is a statistically signicant correlation, but a great deal of scatter. Urine output is normally low on the rst day of life and the use of oliguria as an estimate of renal perfusion is therefore problematic. It is likely that no single clinical sign of decreased perfusion is important by itself, but the overall assessment of the infant by an experienced individual does appear to identify infants with poor outcomes.34 Serum lactate concentrations and outcomes The relationship between absolute serum lactate concentrations and an increasing trend in concentrations are both associated with adverse outcomes.32 In term and preterm infants, these factors can be used for prediction of mortality and there is an association between neurological outcomes and peak serum lactate concentration.35 However, routinely measuring serum lactate, which in order to be accurate should be obtained from a freely running blood sample, sent on ice and analysed immediately, has not been demonstrated to improve outcomes. Intracellular pH by gastric tonometry In many studies in adults and older children, intracellular pH as estimated by gastric tonometry has been shown to be associated with short-term outcomes. As yet, human neonatal data are limited,36 but the data suggest that this may become a useful tool in the future. Randomised studies to demonstrate whether outcomes are improved are warranted. Flow measurements Oxygen demand is different among categories of patients; hypoxia suppresses oxygen demand in the newborn,37 whereas oxygen demand may be increased in sepsis.38 Oxygen extraction at the tissue level may also be impaired in certain pathological states. For these reasons, low systemic blood ow, as an isolated variable in preterm infants, does not e by itself e dene shock. However, this may be irrelevant if it could be shown that outcomes are improved by measurement of ows and treatment according to low ow states. Direct measurements of systemic blood ow, championed by the group in Sydney, have been used to show that low ows correlate with outcomes.39 However, does knowledge of ows allow more appropriate therapy and therefore improve outcomes? Although a reasonable hypothesis, this has not been proven and is amenable to clinical studies.

Shock
Shock is a pathological state in which tissue oxygen delivery is inadequate to meet demand. Thus, the occurrence of shock depends on systemic blood ow, the oxygen content of the blood and oxygen demand. The balance between oxygen delivery and oxygen demand is difcult to assess in the clinical situation. Measurements of ow are only one part of this equation. In animal models, the mixed venous partial pressure of oxygen (PO2) is the single best measurement to indicate the adequacy of oxygen delivery to satisfy demands. However, this measurement is almost never available in the premature infant. Right atrial PO2 or oxygen (O2) saturation, which is limited even in the absence of shunts because of incomplete mixing, may be contaminated in the newborn by inter-atrial shunting. Evaluation of shock in the newborn infant The diagnosis of shock is suggested by the appearance of prolonged capillary lling, reduced strength of peripheral pulses, cool skin, lethargy, oliguria, increasing lactate concentrations and a progressive anion-gap acidosis. Direct measurement of systemic blood ow must take into account the common occurrence of shunts in the newborn. Left ventricular output, for example, equals pulmonary blood ow (plus or minus any net foraminal shunting), unless the ductus arteriosus is shown to be closed. Either pulmonary artery ow (if net foraminal shunting is minimal) as a measure of total systemic blood ow, or selective measurement of the ow in the superior vena cava, can give valuable information about systemic perfusion.30 Measurements which take into account the balance between supply and demand include serum lactate concentration,26,32 and decreased intracellular

Hypotension without shock: treatment worse than the disease?

It is unclear whether infants who are hypotensive, but have adequate tissue oxygen delivery, require any treatment.

20 Our systematic review mentioned above also addressed a second question: are there any reliable data to demonstrate that routine treatment of infants with statistically low BP improves outcomes? We were unable to nd any reliable evidence that treatment of low BP decreases brain injury or improves any other clinically important outcome. In many NICUs, preterm infants with numerically low BP are routinely treated, and in fact are easily the largest group of preterm infants who receive cardiovascular support. Such infants will frequently receive one or several boluses of uid followed by dopamine (or occasionally additional catecholamines) followed by glucocorticoids if they do not respond. One common approach is to attempt to maintain the BP of all infants above a mean of 30 mmHg,40 intervening with albumin, dopamine, dobutamine and then glucocorticoids when this threshold is not reached. A mean BP of 30 mmHg is above the 50th percentile for infants of 25 weeks gestation at 3 h of age, and thus the majority of infants in such units must receive intervention, despite no evidence of benet and substantial risk of harm. Presumably such infants are treated because of data from a prospective observational study,41 which demonstrated a statistical association between a mean BP below 30 mmHg and brain injury in preterm infants (n Z 9 with major intraventricular haemorrhage (IVH) or periventricular leukomalacia). However, using the same threshold for infants at different gestational ages will artefactually show an association, as the more immature infants (who are at greater risk of severe IVH) are more likely to be deemed hypotensive. The commonest approach is to maintain the BP above the gestational age in weeks.2 This ignores the usual spontaneous increase in BP over the rst few postnatal days and there are no published data to support this denition of hypotension. Data from the Canadian Neonatal Network show substantial and statistically signicant variations in IVH frequency among NICUs.42 These variations remained after correction for multiple demographic factors and severity of illness. After further correction for the use of pressor agents and bicarbonate, all differences between NICUs disappeared. Another analysis of this dataset,43 which took the lowest recorded BP into account, showed that infants who had a BP below their gestational age, or had a BP below the 10th percentile, had a slightly increased chance of having a severe IVH, but this risk also disappeared after correction for the use of pressors. Furthermore, the infants in the database who had treatment with pressors, despite a BP that was never hypotensive according to these two criteria, had a higher frequency of severe IVH than hypotensive infants who were not treated. One potential explanation for this nding is that it is the treatment of hypotension rather than hypotension, itself, which is harmful.

K.J. Barrington transfusion or following external haemorrhage; concealed haemorrhage from feto-matenal bleeding is very uncommon at early gestational ages. Fluid boluses in non-hypovolemic infants may not be benign. In an observational study, Goldberg et al.45 found an increase in the incidence of IVH in preterm infants receiving rapid volume expansion. Adverse neurological outcomes have also been reported in preterm infants receiving colloid infusion.46 Multiple uid boluses are associated with increased mortality in the preterm infant.47 Furthermore, the amount of sodium contained in a single uid bolus is within the range shown in two randomised trials to increase bronchopulmonary dysplasia when given in the rst days of life.48,49 There is, therefore, no physiological justication to give uid boluses to hypotensive preterm infants and no empirical evidence to support the practice, with observational data showing an association with worse outcomes.

Inotrope/pressor agents
Despite the treatment of many thousands of preterm infants with dopamine, the haemodynamic responses to this agent, the clinical risk/benet ratio and the long-term consequences of its use are uncertain. Randomised trials have shown that the increase in BP with dopamine is usually accompanied by a decrease in left ventricular output, a decrease or no change in right ventricular output and superior vena caval ows,50e53 and no improvement in contractility54 or cerebral perfusion.55 Thus, the main mechanism of the action of dopamine on BP appears to be vasoconstriction.56 Dobutamine in clinical studies is more effective at increasing systemic perfusion, but does not reliably increase BP.53,57 Epinephrine has also been studied very little in prospective trials,52,58 and, although BP and systemic ow appear to be increased, clinical outcomes have not been shown to be superior to other treatments.

Glucocorticoids
Glucocorticoids are now prescribed to almost 10% of very low birthweight infants for the management of hypotension, as shown in a recent prospective evaluation of postnatal glucocorticoid use.59 This has occurred despite potential short-term adverse effects and the lack of any data on long-term follow-up. A randomised controlled trial (RCT) of dexamethasone versus placebo60 (n Z 17) found that, in both groups, there was a signicant increase in BP at 4 h following infusion and that the duration of epinephrine use was signicantly shorter with dexamethasone. However, no improvements in clinical outcomes were shown. Ng et al.61 randomised preterm infants with a mean arterial pressure below their gestational age (despite receiving at least 30 mL/kg of normal saline and at least 10 mg/kg/min of dopamine) to 3 mg/kg/d of hydrocortisone for 5 days. The babies receiving hydrocortisone had a slightly faster increase in their BP, but no clinical difference in outcomes was found. The use of glucocorticoids for prevention or treatment of hypotension cannot be recommended unless prospective RCTs demonstrate that clinical outcomes are improved.

Fluid boluses
Fluid boluses are the usual rst intervention in infants with a low BP;2 they are presumably given in the belief that such infants are hypovolemic. However, in most hypotensive infants, circulating blood volumes are normal and there is little or no response to volume administration.44 Hypovolemia rarely occurs, for example as a result of twinetwin

Hypotension and shock in the preterm infant

21 increase cardiac output while attempting to decrease systemic and pulmonary vascular resistance. This would suggest a preference for dobutamine, with low-dose epinephrine possibly being a reasonable alternative. Possibly other vasodilators may have a role. Some infants with this haemodynamic prole have persistent pulmonary hypertension of the newborn; decreasing pulmonary vascular resistance with inhaled nitric oxide may improve right ventricular function, and therefore aid in the treatment of shock, even when the infant is not hypoxic.64 If sepsis is thought likely, uid boluses could be considered, perhaps after institution of dobutamine or low-dose epinephrine. Adults with septic shock have improved outcomes when physiological stress doses of corticosteroids are added to their therapy. In contrast, outcomes with high-dose glucocorticoids are substantially worse. In some studies, both glucocorticoids and mineralocorticoids have been used. Whether glucocorticoids have a role in septic shock or other forms of shock in the newborn are unknown, and what dose should be used is also unknown.

Permissive hypotension
Many infants who are hypotensive have normal systemic blood ows, are clinically well perfused and can have a good short-term outcome without intervention.62 There appears to be no justication from the literature for the common practice of routinely intervening with potent and potentially harmful therapies because a baby has a BP less than the gestational age. Such an approach leads to a very high proportion of extremely preterm infants receiving these interventions, up to 98% in some NICUs.1 For years in our NICU, we have only intervened for hypotension when infants showed clinical signs of poor perfusion. With such an approach, about 16% of extremely low birth weight infants receive treatment. Infants who are clinically well perfused, but with lower than average BPs, have good short-34 and long-term outcomes without therapy. Is there any risk to permissive hypotension? When cerebral vasodilation is maximal, at low BP, it is possible that uctuations in BP could put the cerebral circulation at risk. This possibility makes it essential that prospective RCTs are performed to determine the appropriateness of intervention for hypotension.

Hypotension with shock

Infants who are both hypotensive and in shock will probably have very high morbidity and mortality. Pathophysiologically appropriate therapy should be directed at increasing systemic perfusion, while attempting to avoid the adverse effects of increased afterload on myocardial function. This suggests that epinephrine may be the optimal single therapy and that close monitoring of cardiac function and blood ows may help in determining the appropriate manipulations. Infants who are in shock and hypotensive are likely to require higher doses of epinephrine, and possibly norepinephrine could be considered, but the effects on afterload and potential decrease in systemic perfusion must be closely monitored. Direct measurements of systemic blood ow can help to make the therapy more rational and aid in ensuring that increases in therapy actually improve ows. Consideration of uid boluses and stress-dose glucocorticoids may be reasonable, especially if sepsis is likely, but have as yet not been denitively studied.

Shock without hypotension

When cardiac output is low, peripheral vasoconstriction will maintain BP up to a certain limit; thus, shock can occur without hypotension. One common cause for shock is sepsis, but the haemodynamic features of sepsis in the human neonate have not been well described. In newborn infants, the pathophysiology, bacteriology, haemodynamic responses, effects of manipulation of cardiac-loading conditions, toxicities of medications, and potential complications are different than in adults. The haemodynamics of sepsis in adults may be quite different and better models may be neonatal animals infected with the same organisms.63 In experimental newborn piglets with sepsis induced by the Group B streptococcus, the early changes consist of a rapid fall in cardiac output accompanying an early and progressive pulmonary hypertension and normal systemic BP, which is maintained by vigorous peripheral vasoconstriction.64 As cardiac output falls further, there is hypotension in the pre-terminal phase. These changes are in contrast to those in adults with gram-negative sepsis, who frequently have increased cardiac output and are vasodilated and hypotensive, so-called warm shock. The vasodilation is largely a result of overproduction of nitric oxide in the peripheral circulation. Adults with septic shock have improved outcomes with early goal-directed therapy.65 Optimising therapy with the goal of achieving a mixed venous oxygen saturation target of 70% required more inotropes, more transfusions and earlier uid boluses. Studies of goal-directed therapy in newborn infants with suspected septic shock are warranted. In view of the difculty of obtaining mixed venous blood in a newborn, different goals will have to be used. Treatments that may be appropriate for the septic adult may be completely inappropriate for newborn infants, who usually exhibit cold shock. For infants who are shocked but normotensive, pathophysiologically appropriate therapy would be directed to

Summary
Interventions for different categories of patients should be individualised. There is little reliable information on an appropriate response to infants with hypotension or different categories of shock. Although there are data suggesting that some commonly used interventions increase BP, there is little information about the effects on systemic ows and tissue oxygen delivery, little information about effects on oxygen demand, and almost no reliable information on the effects of intervention on clinically important outcomes. Infants who are hypotensive without shock probably require no treatment, but only close observation and reassessment at frequent intervals. There is no reasonable rationale for the administration of uid boluses to such infants, and dopamine and other vasoactive drugs may do more harm than good. Glucocorticoids are poorly studied and carry substantial risks. Permissive hypotension should be studied prospectively.

22 Studies investigating appropriate goals and goal-directed therapy in neonates with shock are required in order to make evidence-based recommendations. Meanwhile, pathophysiology-based recommendations have been made, with the understanding that such recommendations may be proven incorrect when evidence based on clinical outcomes becomes available.66 It is essential that prospective controlled evaluations of cardiovascular interventions for all of these categories of patients be performed, with the focus on clinically important outcomes.67 Measuring BP or ows or any other surrogate outcomes is inadequate; effects on survival, brain injury and developmental sequelae are essential in future investigations of these potent and toxic therapies. Only in this way can we ensure that future cohorts of preterm infants will receive treatment that is safe, effective and benecial.

K.J. Barrington
4. Walker AM. Developmental aspects of cardiac physiology and morphology. In: Lipshitz J, Maloney J, Nimrod C, Nimrold G, editors. Perinatal development of the heart & lung. Perinatology Press; 1987. p. 73e82. 5. Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 1972;15:87e111. 6. Teitel DF, Sidi D. Developmental changes in myocardial contractile reserve in the lamb. Pediatr Res 1985;119:948e55. 7. Van Hare GF, Hawkins JA, Schmidt KG, Rudolph MA. The effects of increasing mean arterial pressure on left ventricular output in newborn lambs. Circ Res 1990;67:78e83. 8. Belik J, Light RB. Effect of increased afterload on right ventricular function in newborn pigs. J Appl Physiol 1989;66:863e9. 9. Cheung PY, Barrington KJ. Renal dopamine receptors: mechanisms of action and developmental aspects. Cardiovasc Res 1996;31:2e6. 10. Kojima M, Ishima T, Taniguchi N, Kimura K, Sada H, Sperelakis N. Developmental changes in beta adrenoceptors, muscarinic cholinoceptors and Ca2 channels in rat ventricular muscles. Br J Pharmacol 1990;99:334e9. 11. Inayatulla A, Li D-Y, Chemtob S, Varma DR. Ontogeny of positive inotropic responses to sympathomimetic agents and of myocardial adrenoceptors in rats. Can J Physiol Pharmacol 1994;72:361e7. 12. Chemtob S, Guest I. Ontogeny of responses of rabbit aorta to atrial natriuretic factor and isoproterenol. Dev Pharmacol Ther 1991;16:108e15. 13. Meadow WL, Rudinsky BF, Strates E. Effects of phenylephrine on systemic and pulmonary artery pressure during sepsis-induced pulmonary hypertension in piglets. Dev Pharmacol Ther 1986;9:249e59. 14. Pearson RJ, Barrington KJ, Jirsch DW, Cheung PY. Dopaminergic receptor-mediated effects in the mesenteric vasculature and renal vasculature of the chronically instrumented newborn piglet. Crit Care Med 1996;24:1706e12. 15. Barrington KJ. Circulatory effects of dopamine in neonates [letter]. J Pediatr 1995;127:843e4. 16. Goldberg LI, Toda N. Dopamine induced relaxation of isolated canine renal, mesenteric, and femoral arteries contracted with prostaglandin F2-alpha. Circ Res 1975;36(6 Suppl. 1):97e102. 17. Padbury JF, Agata Y. Pharmacokinetics of dopamine in critically ill newborn infants. J Pediatr 1990;117:472e6. 18. Filippi L, Cecchi A, Tronchin M, et al. Dopamine infusion and hypothyroxinaemia in very low birth weight preterm infants. Eur J Pediatr 2004;163:7e13. 19. Boetger CL, Ward DS. Effect of dopamine on transient ventilatory response to exercise. J Appl Physiol 1986;61:2102e7. 20. Panajotova V. The effect of dopaminergic agents on cellmediated immune response in mice. Physiol Res 1997;46: 113e8. 21. Regan CJ, Duckworth R, Fairhurst JA, Maycock PF, Frayn KN, Campbell IT. Metabolic effects of low-dose dopamine infusion in normal volunteers. Clin Sci (Lond) 1990;79:605e11. 22. Cheung PY, Barrington KJ, Bigam D. The hemodynamic effects of dobutamine infusion in the chronically instrumented newborn piglet. Crit Care Med 1999;27:558e64. 23. Penny DJ, Sano T, Smolich JJ. Increased systemic oxygen consumption offsets improved oxygen delivery during dobutamine infusion in newborn lambs. Intensive Care Med 2001;27:1518e25. 24. Barrington KJ, Chan WKY. The circulatory effects of epinephrine infusion in the anesthesised piglet. Pediatr Res 1993;33: 190e4. 25. Barrington KJ, Finer NN, Chan WK. A blind, randomized comparison of the circulatory effects of dopamine and epinephrine infusions in the newborn piglet during normoxia and hypoxia. Crit Care Med 1995;23:740e8. 26. Cheung PY, Barrington KJ, Pearson RJ, Bigam DL, Finer NN, Van Aerde JE. Systemic, pulmonary and mesenteric perfusion and

Practice points
 Cardiovascular physiology in the neonate is so different that responses to interventions cannot be extrapolated from adults.  Many infants who are hypotensive by statistical denitions have normal tissue oxygen delivery.  Infants who are hypotensive by statistical denitions and well perfused may not require any intervention.  Infants who are in shock require individualised assessment and intervention.

Research directions
 Prospective studies to evaluate appropriate criteria for intervention in extremely preterm infants are required.  If appropriate criteria for intervention can be dened, then comparative studies randomly examining uid boluses versus no boluses, and various inotrope/vasopressor agents are required.  The role, benets and toxicities of the use of glucocorticoids for treatment of hypotension must be dened by adequate prospective controlled trials.

References
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