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Assessment and support of the preterm circulation
Early Human Development (2006) 82, 803–810
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Assessment and support of the preterm circulation Nick Evans ⁎ Department of Neonatal Medicine, RPA Women and Babies, Royal Prince Alfred Hospital and University of Sydney, Missenden Rd, Camperdown, Sydney, NSW 2050 Australia
KEYWORDS Infant-premature; Shock; Echocardiography; Low systemic blood flow; Inotropes
Abstract There are no clinical outcome data on which to base recommendations on how to assess and support the preterm circulation. Current standards are derived from an assumed proportionality between systemic and organ blood flow and mean blood pressure. Our study of central measures of systemic blood flow suggests preterm haemodynamics are more complex than this. Low systemic blood flow is common in the first 24 h after birth in very preterm babies and is not necessarily reflected by low blood pressure. The causes of this low systemic blood flow are complex but may relate to maladaptation to high extrauterine systemic (and sometimes pulmonary) vascular resistance. After day 1, hypotensive babies are more likely to have normal or high SBF reflecting vasodilatation. Empirically, inotropes that reduce afterload (such as dobutamine) may be more appropriate in the transitional period, while those with more vasoconstrictor actions (such as dopamine) may be more appropriate later on. Defining the haemodynamic in an individual baby needs both blood pressure and echocardiographic measures of systemic blood flow. Research in this area needs to move beyond just demonstrating changes in physiological variables to showing improvements in important clinical outcomes. Crown Copyright © 2006 Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence based circulatory support . . . . . . . . . . . . . . . . History of preterm circulatory support . . . . . . . . . . . . . . Systemic blood flow in the preterm infant . . . . . . . . . . . . Circulatory support of the preterm infant: what do we know? . 5.1. Volume: what's the evidence? . . . . . . . . . . . . . . . 5.2. Inotropes: what's the evidence? . . . . . . . . . . . . . . 5.3. Hydrocortisone: what's the evidence? . . . . . . . . . . . 6. Circulatory support in the very preterm infant: what should we 7. Assessment of systemic blood flow . . . . . . . . . . . . . . . . . 8. Preterm circulatory support: where to now? . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Tel.: +61 2 9515 8760; fax: +61 2 9550 4375. E-mail address: [email protected]. 0378-3782/$ - see front matter. Crown Copyright © 2006 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2006.09.020
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804 Key guidelines: • Maintaining systemic and organ blood flow in preterm babies is probably more complex than just maintaining blood pressure. • Preterm babies have a hypoperfusion reperfusion cycle over the first 24-48 h. The hypoperfusion seems to relate to maladaptation to high vascular resistance while the reperfusion relates to loss of vascular resistance. • To define the haemodynamic in an individual infant needs measures of blood pressure and flow. • The empirical treatment choice will depend on this widely varying haemodynamic, so ‘one size fits all’ recommendations may not be possible. Key research directions: • To establish methods to allow continuous monitoring of systemic blood flow. • To establish ways of preventing low systemic blood flow in preterm infants. • To establish effects of circulatory support strategies on important clinical outcomes, specifically whether preventing early low systemic blood flow improves outcomes for very preterm babies.
1. Introduction It has been hypothesised for some years that many complications of prematurity have an ischaemic origin, particularly those relating to adverse neurological outcome [1-7]. It is therefore perhaps surprising that the evidence base, that we use to define standards in assessment and support the preterm circulation, is really wafer thin. The clinical assessment of the preterm circulation has relied heavily on invasive blood pressure monitoring and, to a lesser extent, poorly validated clinical markers such as capillary refill and acidosis. The study of circulatory support has almost entirely used change in a physiological variable (usually blood pressure) in response to an intervention as the primary outcome variable. I hope the reader will see during the course of this review that this is an area of neonatology that is defined by how much we don't know rather than what we do know.
N. Evans mental outcomes. This is unusual in that if one asked a group of neonatologists why they give inotropes to preterm babies, the answer from many would be bto protect the immature brainQ. So how did we get to a point where a therapy that has been a standard of care for many years, and where the goal is to protect the brain, has absolutely zero evidence that this benefit is achieved?
3. History of preterm circulatory support Current standards in preterm circulatory support were arrived at through a constellation of two themes. The first theme was the absent autoregulation hypothesis of preterm brain injury in which a linear relationship between cerebral blood flow and blood pressure is assumed with a limited autoregulatory plateau [12]. The latter, the range of blood pressure over which cerebral blood flow will be maintained constant by the peripheral vascular responses, is a feature of a mature intact circulation (see Fig. 1). This relationship suggests that there is a blood pressure below which cerebral blood flow will fall and brain injury may be sustained. The second theme followed on from the introduction of continuous intra-arterial blood pressure monitoring in the late 1970s/early 1980s. After this, several papers appeared associating lower measures of blood pressure with ultrasound evidence brain injury, intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL) [2,3]. The study of Miall Allen et al [2] suggested that a mean blood pressure below 30 mmHg was associated with increased risk of ultrasound evidence of brain injury, while the study of Watkins et al [3] defined normal ranges of blood pressure for babies of different birth weight and demonstrated similar associations in babies whose blood pressure dropped below these ranges. From this the hypothesis developed that if MBP could be kept above a somewhat arbitrary number (usually 30 mmHg or the baby's gestation) then risk of brain injury could be reduced. The leap that was made in the development of an evidence base in this area was that this hypothesis was never tested. The focus became the numbers and these numbers became in themselves the clinical outcome. There still seems to be a tendency to ignore what they are, namely intermediate physiological variables.
2. Evidence based circulatory support All good reviews should start with the highest level of available evidence, the Cochrane Database of Systematic Reviews. The only one of these that relates to preterm circulatory support and contains any long term outcome data is that looking at routine use of early volume expansion [8]. The Northern Neonatal Nursing Initiative trial [9] demonstrated that this strategy makes no difference to short or long term outcomes for premature babies. Reviews also inform us that dopamine is better than dobutamine at increasing blood pressure [10]. Dopamine is also better than volume expansion at increasing blood pressure but none of the studies or reviews have been able to demonstrate any effect on any other outcome [11]. Specifically none of the studies or reviews has any information on neurodevelop-
Figure 1 Shows the hypothesised direct relationship between cerebral blood flow (CBF) and mean blood pressure (MBP) with the limited dautoregulatory plateauT with a cut point below which CBF may fall with lower MBP.
Assessment and support of the preterm circulation The data supporting the absent autoregulation hypothesis in the preterm baby is conflicting. Much of the recent data on this comes from the measurement of cerebral blood flow (CBF) using near infra-red spectroscopy (NIRS). These data are not consistent. Some studies have shown the suggested correlation between MBP and CBF. Tsuji et al [13] showed a dynamic longitudinal correlation between MBP and cerebral oxygenation (a relative rather than absolute measure of CBF) but only in a subgroup of preterm babies. In turn this subgroup was more likely to develop ultrasound evidence of brain injury. Munro et al [14] measured absolute cerebral blood flow in two small groups of preterm babies, 12 babies who had an MBP <30 mmHg who were to receive inotropes and 5 whose MBP was >30 mmHg. They found a correlation between MBP and CBF in the babies with low MBP whereas there was no correlation in those with MBP above 30 mmHg. The regression lines through the two groups met at 29 mmHg and the authors hypothesised that this reflected the autoregulatory cut point. An alternative interpretation of this would be that when a cohort is separated by an arbitrary cut point, it becomes statistically quite likely that regression lines between the two groups will meet near that cut point. In a very similarly designed but larger study to that of Munro et al, Tyszczuk et al [15] showed no cross-sectional relationship between MBP and CBF. Kissack et al [16] studied cerebral oxygen extraction as a measure of CBF, as CBF falls so cerebral oxygen extraction will rise to compensate. They found no relationship between cerebral oxygen extraction and MBP but did find significant relationships with lower LV output and pCO2. So the data supporting the absent cerebral autoregulation theory on which we base much of our current therapeutic rationale is conflicting. The studies of Munro and Tsuji do suggest that there is a subgroup of preterm babies in whom cerebral autoregulation is compromised. The design of these studies did not allow interpretation of whether this is a primary or intermediate factor on the causal pathway to cerebral injury or even whether it is a secondary phenomenon. Logic would dictate that there must be a blood pressure below which CBF will fall and potentially compromise cerebral well being. There is little in the literature to guide as to what that number is or that it is necessarily the same in all babies. There is a seductive simplicity about the cerebral autoregulation hypothesis. All we have to do is chase up a number on the monitor, by whatever means, and everything will be fine. The results of our work suggest to us that preterm haemodynamics are much more complicated than this. We have focused more on central measures of systemic blood flow rather than peripheral measures of organ blood flow. Blood pressure must be important but our concern relates less to the possibly unnecessary treatment of babies with low blood pressure but more the amount of haemodynamic pathology that lies masqueraded behind normal blood pressures.
805 Before explaining the way in which we studied systemic blood flow (SBF) in preterm infants, I need to bust two very tenacious neonatal myths. The first myth is that early shunting through the duct is not haemodynamically significant. In fact early preterm ductal constriction is characterized by great variability but the dominant direction of shunting is left to right [17] so, in those where constriction fails, significant volumes of blood can be moving from the systemic back to the pulmonary circulation even from the early hours after birth. The second myth is that left ventricular output (LVO) is a measure of systemic blood flow. While this is true in the mature circulation, in a scenario where there is a significant left to right ductal shunt, LVO becomes the product of SBF and the ductal shunt and so overestimates SBF. In fact, in this haemodynamic, LVO is more a measure of pulmonary blood flow. RV output is a better measure of systemic blood flow but that can also be confounded by left to right shunting across the foramen ovale [18,19]. Because of this, we developed the measure of Superior Vena Cava (SVC) Flow as a way of avoiding the confounding effect of these intracardiac shunts and also studying the part of the systemic circulation that supplies the upper body and brain [20]. In prospective serial studies, we have shown that low SVC flow occurs in about 35% of babies born before 30 weeks [21]. The nadir in flow occurs in a predictable time frame within the first 12 h after birth and is followed by a recovery of flow to normal values by 24 to 48 h. This low SVC flow is significantly associated with a range of adverse outcomes, particularly IVH, which occurs as or after the SVC flow improves, and neurodevelopmental outcomes. Low SVC flow is associated with lower gestational age, higher mean airway pressures on the ventilator and larger ductal shunts draining blood out of the systemic circulation. There is only a weak relationship between SVC and MBP, Fig. 2, with many babies with low BP having normal SVC flow and some babies with normal MBP having quite low SVC flow. It is the latter group who is probably of most concern as they will be treated late if one was being guided by blood pressure alone. Fig. 3 shows the very low Doppler velocities in the main pulmonary artery in a baby at 8 h of age who had normal MBP (between 30 and 35 mmHg) but very low SBF (RV output was 75 mls/kg/min [NR 150-300]). This weak
4. Systemic blood flow in the preterm infant Our serial observations of systemic blood flow in preterm babies suggest there is a hypoperfusion reperfusion cycle that is occurring over the first 24 to 48 h of life. To a certain extent this cycle occurs in all babies, but there is a group in whom SBF drops to very low levels and these babies seem at particular risk for a range of adverse outcomes.
Figure 2 Plots mean blood pressure against SVC flow in 110 babies born before 30 weeks at a mean of 5 h of age. The dotted lines represent possible lower limits of normal, for blood pressure this has been plotted at the mean gestation of the cohort, 27 weeks.
806 relationship between SVC flow and MBP means there is a close inverse relationship between SVC flow and calculated vascular resistance. While this could be compensatory, it could also be causative. There is consistent evidence that the preterm myocardium has a limited ability to respond to an increase in afterload [22,23] and we hypothesise that the transition from the low resistance intra-uterine state to the high resistance exutero state is the primary problem during the first 24 h. When this is compounded by large ductal shunts out of the systemic circulation (which are not uncommon in the early postnatal hours) and positive pressure ventilation then critically low blood flow to all organs of the body (not just the brain) results. The above relates to the first 24 h, after this time and with very few exceptions, babies who are hypotensive will have normal or high SBF suggesting vasodilation. This period has been less systematically studied but this would be our observation in a range of hypotensive situations including inotrope resistant hypotension and septic shock. Fig. 4 shows an example of a baby at 7 days of age with a closed duct, who had an MBP ranging between 18-20 mmHg despite full and poly-pharmacological inotropic support but whose LV output was 600 mls/kg/min (NR 150-300). Also despite such low blood pressure appeared to be maintaining very generous CBF as estimated by cerebral artery Doppler. So herein lies the problem with making global recommendations about circulatory support in the preterm neonate. There is a changing perfusion cycle which goes from low flow/high resistance in the first 24 h to normal/high flow low resistance after this time. To complicate things further, there are some babies who are exceptions to the rules in both time frames. The logically correct treatment in one situation will be diametrically the wrong treatment in the other. To even further complicate this issue, there are other important causes of hypotension to exclude such as
N. Evans hypovolaemia in the transitional postnatal period (rare but it happens) [24] and patent ductus arteriosus during and after the transitional period. The latter has a negative effect on all parameters of blood pressure not just diastolic pressure as is often perceived [25].
5. Circulatory support of the preterm infant: what do we know? Volume expansion, dopamine, dobutamine, adrenaline and, in some settings, hydrocortisone are the mainstays of neonatal circulatory support. Volume will restore normovolaemia in a hypovolaemic infant and will increase pre-load and hence cardiac output in a normovolaemic infant. Dobutamine is a synthetic catecholamine with beta-adrenergic effects, which tend to vasodilate, and cardiac alphaadrenergic effects, which stimulate cardiac contractility and increase heart rate. Dopamine is a naturally occurring precursor to adrenaline and noradrenaline. It has dopaminergic, beta and alpha effects with each of these (in the order shown) more likely to be stimulated as the dose increases. At a dose of over 10 mcg/kg/min the alpha vasoconstrictive effects on BP predominate, but particularly in the very immature baby, these alpha effects may be apparent at lower doses. Adrenaline is naturally occurring and has broad alpha and beta-adrenergic effects and, like dopamine, will vasoconstrict as higher doses. Hydrocortisone puts up BP but data are only just beginning to emerge on how it does this.
5.1. Volume: what's the evidence? We know from systematic review that routine early volume expansion in preterm babies does not improve outcomes [8].
Figure 3 Shows Doppler velocity in the pulmonary artery in two babies. (A) shows the low maximum velocity (Vmax) in an 8-hour old 26 week baby whose mean blood pressure was above 30 mmHg. This translated to a very low RV output of 75 mls/kg/min (NR 150-300) representing low systemic blood flow. This is compared with (B) which shows a normal Vmax representing a normal RV output.
Assessment and support of the preterm circulation
807
Figure 4 Shows Doppler velocity in the ascending aorta (A) and middle cerebral artery (B) in a 7 day old, 27 week baby with pseudomonas sepsis and a closed ductus arteriosus. The MBP was 18 mmHg on maximum inotrope support. Normal mean Vmax in aorta would be 0.8 m/s and (A) represents an LV output of approx 600 mls/kg/min (normal 150-300). The Vmax of 0.9 m/s shown in (B) also suggests high CBF, normal mean Vmax in the MCA would be 0.34 m/s.
There is probably no advantage in using a colloid compared to a crystalloid and we know that volume is not as good as dopamine at increasing BP [11]. We know less about the effect of volume on organ blood flows. Studies have shown increases in LV output [26,27] or SVC flow [28] with volume, however in the study of Lunstrom et al, [26] this did not translate to an increase in cerebral blood flow. In all these studies, measures were taken immediately after the volume, so it is not known if these increases are maintained. There is some evidence that the fluid used in volume expansion redistributes quite quickly out of the vascular compartment. There is a need to study whether the positive effects of volume on SBF are sustained.
5.2. Inotropes: what's the evidence? We know that dopamine is better than dobutamine at increasing BP though there is no evidence that this translates into better short term outcomes [10]. In a double blind RCT, Pellicer et al [29] showed that adrenaline and dopamine have similar efficacy in increasing BP. None of the studies to date have been powered or designed to look at clinical outcomes. In most of these studies, babies were enrolled on the basis of BP below a cut off and change in BP was main central haemodynamic outcome. Roze et al [30] did measure LV output and showed an increase in babies with dobutamine while LV output decreased with dopamine. In a small randomised study of babies <1750 g, Phillipos and Robertson [31] reported that dopamine and adrenaline titrated to the BP response, have similar effects in increasing heart rate and BP but that dopamine caused a significant 10% fall in LV output
while adrenaline resulted in an insignificant 14% increase. This study has only been published as an abstract so should be interpreted with caution. Our group has done the only randomised study of dopamine and dobutamine that enrolled babies on the basis of low blood flow [28]. For each drug, there were two dosage steps (10 and 20 mcg/kg/min) depending on the SBF response. In view of the possible role of high afterload, we hypothesised that dobutamine which will reduce afterload, would increase flow more than dopamine, which can increase afterload. At the highest dose reached, dobutamine produced significantly better increases in SVC flow than dopamine while dopamine produced better increases in MBP. At 10 mcg/kg/min, there was no difference between the two drugs but in those that needed to be increased to 20 mcg/kg/min, dobutamine produced more benefit in SBF, which was not seen in those on dopamine, even though MBP continued to increase. Babies who did not increase flow adequately on 20 mcg/kg/min crossed over to the other drug and probably the most important observation from this study was that 40% of the babies enrolled, failed to increase or maintain SBF after either drug. SVC flow will incorporate CBF but it is not the same thing, so what do we know about the effect of inotropes on cerebral blood flow? The effect of dobutamine on cerebral blood flow in preterm babies has not been studied. Using Xe clearance, Lundstrom et al [26] showed that dopamine, while increasing LVO and MBP, did not increase CBF. Seri et al [32] showed no effect on middle cerebral artery pulsatility index after dopamine in a group of preterm babies with normal blood pressure but clinical evidence of poor perfusion. In an open label observational study, Munro et al [14] used NIRS to show
808 an increase in mean CBF after dopamine was given to a cohort of 12 preterm babies with an MBP <30 mmHg. In a double blind RCT, Pellicer et al [29] also using NIRS, showed both dopamine (at doses up to 10 mcg/kg/min) and adrenaline (at doses up to 0.5 mcg/kg/min) produced similar increases in cerebral intravascular oxygenation which in turn was correlated with increases in MAP.
5.3. Hydrocortisone: what's the evidence? Much of the data on hydrocortisone is observational and relates to its use in inotrope resistant hypotension. In this situation, hydrocortisone seems to increase BP and allow weaning of other inotropic support [33]. Noori et al [34] have shown increases in BP, LV output and systemic vascular resistance after 2 mg/kg of hydrocortisone in 14 babies with inotrope resistant hypotension. One RCT showed hydrocortisone at 2.5 mg/kg had similar efficacy to dopamine in improving BP in hypotensive preterm babies [35]. There was no difference in other clinical outcomes. To my knowledge there are no data on the effects of hydrocortisone on CBF.
6. Circulatory support in the very preterm infant: what should we do? There is no clinical outcome based evidence on which to base therapeutic recommendations. No study, including those from our group, has shown any improvement in any meaningful clinical outcome, short, intermediate or long term, in response to a specific inotrope. Until such evidence is available, we will have to rely on an empirical approach to therapy. If it is your bias that the problems of the preterm circulation relate to absent cerebral autoregulation then it makes sense to use the
N. Evans agent that is most likely to improve blood pressure. I do not have evidence that this is the wrong thing to do but it is our bias that preterm haemodynamics are considerably more complex than this. If we consider the circulation as a set of scales in precarious balance, Fig. 5. At one end is vasoconstriction and with the scales tipped too far that way there is the potential for afterload compromise and, at the other end, too much vasodilation will lead to hypotension, CBF could be compromised in either scenario. In the middle is the rather inadequate immature heart and all the complexities of the transitional circulation. To know where one is on this continuum, there is a need for measures of both pressure and flow. If the measures suggest high afterload, then it probably makes sense to use an inotrope with vasodilating properties such as dobutamine. If the measures point to vasodilation, then it makes sense to use one with pressor properties such as dopamine or adrenaline. If you can't measure flow then it probably makes sense to guess on the basis of time frame and use dobutamine during the first 24 h and dopamine after that time. The reader is pointed to another recent review for more details of our empirical approach to circulatory support based on our physiological observations [36]. The principle that more BP may not necessarily be better was highlighted by both Pellicer [29] and Munro, [14] whose studies both showed some babies with quite dramatic rises in CBF in response to an increase in BP. Hyperperfusion after hypoperfusion seems important in the pathogenesis of IVH [21] so is probably best avoided. These risks together with the risk of afterload compromise, can probably be minimised by starting at a low dose (5 μg/kg/min for dopamine or 0.1 μg/ kg/min for adrenaline) and titrating in careful steps to a minimally acceptable BP. I would suggest aiming to have MBP within 5 mmHg of your therapeutic threshold and being
Figure 5 Above, represents the circulation as a set of scales balancing vasoconstriction and vasodilation. Having scales tipped too far either way is probably not good. Below, represents the common haemodynamic changes in the early postnatal time frame when the common milieu changes from afterload compromise to vasodilation. The suggested logical choice of inotrope in each haemodynamic milieu is shown.
Assessment and support of the preterm circulation prepared to wean the infusion rate quickly in babies whose BP overshoots above this. We rarely use hydrocortisone but, if you do, the data of Noori et al [34] suggests that to avoid the risk of afterload compromise then you need to be ready to wean other pressor inotropes quickly as the blood pressure responds.
7. Assessment of systemic blood flow What evidence there is suggests that the common clinical examination criteria for examining circulatory well-being (such as capillary refill) are of limited accuracy [37]. Full assessment of SBF and an individual baby's haemodynamic needs good echocardiographic skills. There is no reason why a neonatologist cannot develop these skills but it does take time and some commitment. Flow in a vessel is the product of the mean velocity of blood and the cross-sectional area of the vessel. The velocity can be measured with Doppler and the cross-sectional area is derived from the diameter measured by 2D or M-mode imaging. SVC flow is a useful research tool but is determined equally by changes in diameter and velocity, so is a fiddle to derive and I would not recommend it as a clinical screening tool for low SBF. However velocity in the main pulmonary artery is the dominant determinant of RV output and so measuring the maximum velocity in the pulmonary artery (PA Vmax) provides a simple way to screen for low SBF, Fig. 2. Large atrial shunts are not common in the first 48 h, so, for clinical purposes, RV output is a reasonably accurate marker of low SBF [36]. In the first 48 h after birth, if the PA Vmax is over 0.45 m/s, low SBF is unlikely (in 381 studies, 99% had RV output over 120 mls/kg/min and 88% over 150 mls/kg/min). If the PA Vmax is less than 0.35 m/s, most babies have low SBF (in 37 studies, 87% had RV output less than 150 mls/kg/min and 75% less than 120 mls/kg/min). Between 0.35 and 0.45 m/s, is a grey zone where discriminatory accuracy is less good, Fig. 6. In practice, I would recommend screening with PA Vmax and then doing full RV output and/or SVC flow measures in those with a PA Vmax less than 0.45 m/s. The highest pick up of low systemic blood flow will occur if you screen very preterm babies between 3 and 9 h of age.
809 blood pressure. As discussed above this may not mean necessarily that it is less effective on clinical outcomes. Another model would be to take a cohort of at risk babies and then randomise them to treatment at different blood pressure thresholds, possibly including a factorial design so at each threshold, babies are also randomised to different inotropes. This design would tell us more about where we should target blood pressure and this may be a more clinically relevant question than which agent we should use to do it. The model we are currently exploring is a preventative approach. Extremely preterm infants during the transitional period are a population at very high risk of circulatory compromise and there is consistent evidence linking this to adverse outcomes. Our observations have caused us to question the accuracy of clinical diagnosis of low SBF [36] and the reliability of the response to inotropes [29]. In turn, this has led us to question whether a reactive therapeutic strategy is going to be the best way to improve outcomes. We are exploring a preventative strategy using Milrinone, an inodilator that has been successfully used to prevent the low SBF state seen after cardiac bypass surgery [38]. We have some encouraging preliminary data [39,40] and are currently close to completion of a pilot randomised trial in which babies are randomised milrinone or placebo from 3 until 18 h of age with the aim of tiding them over the nadir of SBF. It is too early to make any recommendations on the basis of these findings but similar trial model could be used to explore whether the traditional inotropes discussed in this review would be more effective if used preventatively on the basis of risk factors rather than therapeutically on the basis of clinical signs.
9. Conclusion
8. Preterm circulatory support: where to now?
Overall I hope the reader, by appreciating how much we do not understand, will be encouraged to develop skills that allow a better understanding of the circulation. There is a pressing need to move the research beyond simply showing change in a physiological variable in response to a treatment. While it is important to understand the physiological effect of these treatments, unless we can show that these effects improve clinical outcome, such research is just phenomenology. These
There is a pressing need for some outcome evidence on which to base our practice. The introduction of inotropes in preterm babies resulted from a hypothesis that was never tested and it could be argued that we now need to do the trials that will test that hypothesis. But in doing this, we need to go beyond just showing a change in a physiological parameter (whether it be pressure or flow) and design the studies to explore meaningful clinical outcomes. This will not be easy as this is an area in which strong views (biases) are held and achieving the level of equipoise necessary to run a big trial will be a challenge. How should such studies be designed? One model would involve taking a cohort of at risk babies, defining a threshold blood pressure and then randomising to different inotropes (e.g. dopamine and dobutamine). The problem with this approach is that depending on where the threshold blood pressure is set, there will inevitably be more short term failure in the inotrope that has less effect on
Figure 6 Shows box and whisker plot of RV output against low, intermediate and normal PA Vmax. The dotted line denotes 150 mls/kg/min.
810 are therapies that have been in routine clinical practice for many years, yet we have no idea whether they achieve our intended goal, which is to reduce neurological morbidity. Correcting this knowledge gap is the challenge for the future.
References [1] Lou HC, Skov H, Pedersen H. Low cerebral blood flow: a risk factor in the neonate. J Pediatr 1979;95:606–9. [2] Miall-Allen VM, de Vries LS, Whitelaw AG. Mean arterial blood pressure and neonatal cerebral lesions. Arch Dis Child 1987;62:1068–9. [3] Watkins AM, West CR, Cooke RW. Blood pressure and cerebral haemorrhage and ischaemia in very low birthweight infants. Early Hum Dev 1989;19:103–10. [4] Goldstein RF, Thomson RJ, Oehler JM, Brazy JE. Influence of acidosis, hypoxia and hypotension on neurodevelopmental outcome in very low birth weight babies. Pediatrics 1995;95:238–43. [5] Meek JH, Tyszczuk L, Elwell CE, Wyatt JS. Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Arch Dis Child 1999;81:F15–8. [6] Osborn DA, Evans N, Kluckow M. Hemodynamic and antecedent risk factors of early and late periventricular/intraventricular hemorrhage in premature infants. Pediatrics 2003;112:33. [7] Hunt R, Kluckow M, Reiger I, Evans N. Low superior vena cava flow and neurodevelopmental outcome at 3 years in very preterm babies. J Pediatr 2004;145:588–92. [8] Osborn DA, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev Rev 2004;2. [9] Northern Neonatal Nursing Initiative Trial Group. Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. Lancet 1996;348(9022):229–32. [10] Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive preterm infants. Cochrane Database Syst Rev Rev 2003;3. [11] Osborn DA, Evans N. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev Rev 2001;2. [12] Lou HC. The blost autoregulation hypothesisQ and brain lesions in the newborn-an update. Brain Develop 1988;10:143–6. [13] Tsuji M, Saul JP, du Plessis A, Eichenwald E, Sobh J, Crocker R, et al. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 2000;106:625–32. [14] Munro MJ, Walker AM, Barfield CP. Hypotensive extremely low birth weight infants have reduced cerebral blood flow. Pediatrics 2004;114:1591–6. [15] Tyszczuk L, Meek J, Elwell C, Wyatt JS. Cerebral blood flow is independent of mean arterial blood pressure in preterm infants undergoing intensive care. Pediatrics 1998;102:337–41. [16] Kissack CM, Garr R, Wardle SP, Weindling AM. Cerebral fractional oxygen extraction in very low birth weight infants is high when there is low left ventricular output and hypocarbia but is unaffected by hypotension. Pediatr Res 2004;55:400–5. [17] Evans N, Kluckow M, Osborn DA. Diagnosis of patent ductus arteriosus. Neoreviews 2004;5:86–97. [18] Evans NJ, Iyer P. Incompetence of the foramen ovale in preterm infants requiring ventilation. J Pediatr 1994;125:786–92. [19] Evans NJ, Iyer P. Assessment of ductus arteriosus shunting in preterm infants requiring ventilation: effect of inter-atrial shunting. J Pediatr 1994;125:778–85. [20] Kluckow M, Evans NJ. Superior vena cava flow. A novel marker of systemic blood flow. Arch Dis Child 2000;82:F182–7.
N. Evans [21] Kluckow M, Evans NJ. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child 2000;82:F188–94. [22] Takahashi Y, Harada K, Kishkurno S, Ishida A, Takada G. Postnatal left ventricular contractility in very low birth weight infants. Pediatr Cardiol 1997;18:112–7. [23] Osborn D, Evans N, Kluckow M. Left ventricular contractility and wall stress in very preterm infants in the first day of life. Pediatr Res 2002;51:386A [abstr]. [24] Vanhaesebrouck P, Vanneste K, de Praeter C, Van Trappen Y, Thiery M. Tight nuchal cord and neonatal hypovolaemic shock. Arch Dis Child 1987;62:1276–7. [25] Evans N, Moorcraft J. Effect of patency of the ductus arteriosus on blood pressure in very preterm infants. Arch Dis Child 1992;67:1169–73. [26] Lundstrom K, Pryds O, Greisen G. The haemodynamic effects of dopamine and volume expansion in sick preterm infants. Early Hum Dev 2000;57:157–63. [27] Pladys P, Wodey E, Betremieux P, Beuchee A, Ecofey C. Effects of volume expansion on cardiac output in the preterm infant. Acta Paediatr 1997;86:1241–5. [28] Osborn DA, Kluckow M, Evans N. Randomised trial of dobutamine vs dopamine in preterm infants with low systemic blood flow. J Pediatr 2002;140:183–91. [29] Pellicer A, Valverde E, Elorza MD, Madero R, Gayá F, Quero J, et al. Cardiovascular support for low birth weight infants and cerebral hemodynamics: a randomized, blinded, clinical trial. Pediatrics 2005;115:1501–12. [30] Roze JC, Tohier C, Maingueneau C, Lefevre M, Mouzard A. Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child 1993;69:59–63. [31] Phillipos EZ, Robertson MA. A randomized double blinded controlled trial of dopamine vs epinephrine for inotropic support in premature infants <1750 g. Pediatr Res 2000;47:425A [abstr]. [32] Seri I, Abbasi S, Wood DC, Gerdes JS. Regional hemodynamic effects of dopamine in the sick preterm neonate. J Pediatr 1998;133(6):728–34. [33] Seri I, Tan R, Evans J. Cardiovascular effects of hydrocortisone in preterm infants with pressor resistant hypotension. Pediatrics 2001;107:1070–4. [34] Noori S, Friedlich P, Ebrahimi M, Wong P, Siassi B, Seri I. Haemodynamic changes in response to hydrocortisone in pressor treated neonates. Pediatric Academic Societies Meeting 2005; abstract no 581. [35] Bouchier D, Weston PJ. Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birth weight infants. Arch Dis Child 1997;76:F174–8. [36] Evans N. Which inotrope for which baby? Arch Dis Child Fetal Neonatal Ed 2006;91:F213–20. [37] Osborn DA, Kluckow M, Evans N. Blood pressure, capillary refill and central-peripheral temperature difference. Clinical detection of low upper body blood flow in very premature infants. Arch Dis Child 2004;89:F168–73. [38] Hoffman TM, Wernovsky G, Atz AM, Bailey JM, Akbary A, Kocsis JF, et al. Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study. Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics. Am Heart J 2002;143:15–21. [39] Paradisis M, Evans N, Kluckow M, Osborn D, McLachlan AJ. Pilot study of milrinone for low systemic blood flow in very preterm infants. J Pediatr 2006;148(3):306–13. [40] Paradisis M, Jiang X, McLachlan A, Evans N, Kluckow M, Osborn DA. Population pharmacokinetics and dosing regimen design of milrinone in preterm infants. Arch Dis Child Fetal Neonatal Ed. Published Online First: 11 May 2006. doi:10.1136/adc.2005.092817. _________________________
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Assessment and support of the preterm circulation Nick Evans ⁎ Department of Neonatal Medicine, RPA Women and Babies, Royal Prince Alfred Hospital and University of Sydney, Missenden Rd, Camperdown, Sydney, NSW 2050 Australia
KEYWORDS Infant-premature; Shock; Echocardiography; Low systemic blood flow; Inotropes
Abstract There are no clinical outcome data on which to base recommendations on how to assess and support the preterm circulation. Current standards are derived from an assumed proportionality between systemic and organ blood flow and mean blood pressure. Our study of central measures of systemic blood flow suggests preterm haemodynamics are more complex than this. Low systemic blood flow is common in the first 24 h after birth in very preterm babies and is not necessarily reflected by low blood pressure. The causes of this low systemic blood flow are complex but may relate to maladaptation to high extrauterine systemic (and sometimes pulmonary) vascular resistance. After day 1, hypotensive babies are more likely to have normal or high SBF reflecting vasodilatation. Empirically, inotropes that reduce afterload (such as dobutamine) may be more appropriate in the transitional period, while those with more vasoconstrictor actions (such as dopamine) may be more appropriate later on. Defining the haemodynamic in an individual baby needs both blood pressure and echocardiographic measures of systemic blood flow. Research in this area needs to move beyond just demonstrating changes in physiological variables to showing improvements in important clinical outcomes. Crown Copyright © 2006 Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence based circulatory support . . . . . . . . . . . . . . . . History of preterm circulatory support . . . . . . . . . . . . . . Systemic blood flow in the preterm infant . . . . . . . . . . . . Circulatory support of the preterm infant: what do we know? . 5.1. Volume: what's the evidence? . . . . . . . . . . . . . . . 5.2. Inotropes: what's the evidence? . . . . . . . . . . . . . . 5.3. Hydrocortisone: what's the evidence? . . . . . . . . . . . 6. Circulatory support in the very preterm infant: what should we 7. Assessment of systemic blood flow . . . . . . . . . . . . . . . . . 8. Preterm circulatory support: where to now? . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Tel.: +61 2 9515 8760; fax: +61 2 9550 4375. E-mail address: [email protected]. 0378-3782/$ - see front matter. Crown Copyright © 2006 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2006.09.020
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804 Key guidelines: • Maintaining systemic and organ blood flow in preterm babies is probably more complex than just maintaining blood pressure. • Preterm babies have a hypoperfusion reperfusion cycle over the first 24-48 h. The hypoperfusion seems to relate to maladaptation to high vascular resistance while the reperfusion relates to loss of vascular resistance. • To define the haemodynamic in an individual infant needs measures of blood pressure and flow. • The empirical treatment choice will depend on this widely varying haemodynamic, so ‘one size fits all’ recommendations may not be possible. Key research directions: • To establish methods to allow continuous monitoring of systemic blood flow. • To establish ways of preventing low systemic blood flow in preterm infants. • To establish effects of circulatory support strategies on important clinical outcomes, specifically whether preventing early low systemic blood flow improves outcomes for very preterm babies.
1. Introduction It has been hypothesised for some years that many complications of prematurity have an ischaemic origin, particularly those relating to adverse neurological outcome [1-7]. It is therefore perhaps surprising that the evidence base, that we use to define standards in assessment and support the preterm circulation, is really wafer thin. The clinical assessment of the preterm circulation has relied heavily on invasive blood pressure monitoring and, to a lesser extent, poorly validated clinical markers such as capillary refill and acidosis. The study of circulatory support has almost entirely used change in a physiological variable (usually blood pressure) in response to an intervention as the primary outcome variable. I hope the reader will see during the course of this review that this is an area of neonatology that is defined by how much we don't know rather than what we do know.
N. Evans mental outcomes. This is unusual in that if one asked a group of neonatologists why they give inotropes to preterm babies, the answer from many would be bto protect the immature brainQ. So how did we get to a point where a therapy that has been a standard of care for many years, and where the goal is to protect the brain, has absolutely zero evidence that this benefit is achieved?
3. History of preterm circulatory support Current standards in preterm circulatory support were arrived at through a constellation of two themes. The first theme was the absent autoregulation hypothesis of preterm brain injury in which a linear relationship between cerebral blood flow and blood pressure is assumed with a limited autoregulatory plateau [12]. The latter, the range of blood pressure over which cerebral blood flow will be maintained constant by the peripheral vascular responses, is a feature of a mature intact circulation (see Fig. 1). This relationship suggests that there is a blood pressure below which cerebral blood flow will fall and brain injury may be sustained. The second theme followed on from the introduction of continuous intra-arterial blood pressure monitoring in the late 1970s/early 1980s. After this, several papers appeared associating lower measures of blood pressure with ultrasound evidence brain injury, intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL) [2,3]. The study of Miall Allen et al [2] suggested that a mean blood pressure below 30 mmHg was associated with increased risk of ultrasound evidence of brain injury, while the study of Watkins et al [3] defined normal ranges of blood pressure for babies of different birth weight and demonstrated similar associations in babies whose blood pressure dropped below these ranges. From this the hypothesis developed that if MBP could be kept above a somewhat arbitrary number (usually 30 mmHg or the baby's gestation) then risk of brain injury could be reduced. The leap that was made in the development of an evidence base in this area was that this hypothesis was never tested. The focus became the numbers and these numbers became in themselves the clinical outcome. There still seems to be a tendency to ignore what they are, namely intermediate physiological variables.
2. Evidence based circulatory support All good reviews should start with the highest level of available evidence, the Cochrane Database of Systematic Reviews. The only one of these that relates to preterm circulatory support and contains any long term outcome data is that looking at routine use of early volume expansion [8]. The Northern Neonatal Nursing Initiative trial [9] demonstrated that this strategy makes no difference to short or long term outcomes for premature babies. Reviews also inform us that dopamine is better than dobutamine at increasing blood pressure [10]. Dopamine is also better than volume expansion at increasing blood pressure but none of the studies or reviews have been able to demonstrate any effect on any other outcome [11]. Specifically none of the studies or reviews has any information on neurodevelop-
Figure 1 Shows the hypothesised direct relationship between cerebral blood flow (CBF) and mean blood pressure (MBP) with the limited dautoregulatory plateauT with a cut point below which CBF may fall with lower MBP.
Assessment and support of the preterm circulation The data supporting the absent autoregulation hypothesis in the preterm baby is conflicting. Much of the recent data on this comes from the measurement of cerebral blood flow (CBF) using near infra-red spectroscopy (NIRS). These data are not consistent. Some studies have shown the suggested correlation between MBP and CBF. Tsuji et al [13] showed a dynamic longitudinal correlation between MBP and cerebral oxygenation (a relative rather than absolute measure of CBF) but only in a subgroup of preterm babies. In turn this subgroup was more likely to develop ultrasound evidence of brain injury. Munro et al [14] measured absolute cerebral blood flow in two small groups of preterm babies, 12 babies who had an MBP <30 mmHg who were to receive inotropes and 5 whose MBP was >30 mmHg. They found a correlation between MBP and CBF in the babies with low MBP whereas there was no correlation in those with MBP above 30 mmHg. The regression lines through the two groups met at 29 mmHg and the authors hypothesised that this reflected the autoregulatory cut point. An alternative interpretation of this would be that when a cohort is separated by an arbitrary cut point, it becomes statistically quite likely that regression lines between the two groups will meet near that cut point. In a very similarly designed but larger study to that of Munro et al, Tyszczuk et al [15] showed no cross-sectional relationship between MBP and CBF. Kissack et al [16] studied cerebral oxygen extraction as a measure of CBF, as CBF falls so cerebral oxygen extraction will rise to compensate. They found no relationship between cerebral oxygen extraction and MBP but did find significant relationships with lower LV output and pCO2. So the data supporting the absent cerebral autoregulation theory on which we base much of our current therapeutic rationale is conflicting. The studies of Munro and Tsuji do suggest that there is a subgroup of preterm babies in whom cerebral autoregulation is compromised. The design of these studies did not allow interpretation of whether this is a primary or intermediate factor on the causal pathway to cerebral injury or even whether it is a secondary phenomenon. Logic would dictate that there must be a blood pressure below which CBF will fall and potentially compromise cerebral well being. There is little in the literature to guide as to what that number is or that it is necessarily the same in all babies. There is a seductive simplicity about the cerebral autoregulation hypothesis. All we have to do is chase up a number on the monitor, by whatever means, and everything will be fine. The results of our work suggest to us that preterm haemodynamics are much more complicated than this. We have focused more on central measures of systemic blood flow rather than peripheral measures of organ blood flow. Blood pressure must be important but our concern relates less to the possibly unnecessary treatment of babies with low blood pressure but more the amount of haemodynamic pathology that lies masqueraded behind normal blood pressures.
805 Before explaining the way in which we studied systemic blood flow (SBF) in preterm infants, I need to bust two very tenacious neonatal myths. The first myth is that early shunting through the duct is not haemodynamically significant. In fact early preterm ductal constriction is characterized by great variability but the dominant direction of shunting is left to right [17] so, in those where constriction fails, significant volumes of blood can be moving from the systemic back to the pulmonary circulation even from the early hours after birth. The second myth is that left ventricular output (LVO) is a measure of systemic blood flow. While this is true in the mature circulation, in a scenario where there is a significant left to right ductal shunt, LVO becomes the product of SBF and the ductal shunt and so overestimates SBF. In fact, in this haemodynamic, LVO is more a measure of pulmonary blood flow. RV output is a better measure of systemic blood flow but that can also be confounded by left to right shunting across the foramen ovale [18,19]. Because of this, we developed the measure of Superior Vena Cava (SVC) Flow as a way of avoiding the confounding effect of these intracardiac shunts and also studying the part of the systemic circulation that supplies the upper body and brain [20]. In prospective serial studies, we have shown that low SVC flow occurs in about 35% of babies born before 30 weeks [21]. The nadir in flow occurs in a predictable time frame within the first 12 h after birth and is followed by a recovery of flow to normal values by 24 to 48 h. This low SVC flow is significantly associated with a range of adverse outcomes, particularly IVH, which occurs as or after the SVC flow improves, and neurodevelopmental outcomes. Low SVC flow is associated with lower gestational age, higher mean airway pressures on the ventilator and larger ductal shunts draining blood out of the systemic circulation. There is only a weak relationship between SVC and MBP, Fig. 2, with many babies with low BP having normal SVC flow and some babies with normal MBP having quite low SVC flow. It is the latter group who is probably of most concern as they will be treated late if one was being guided by blood pressure alone. Fig. 3 shows the very low Doppler velocities in the main pulmonary artery in a baby at 8 h of age who had normal MBP (between 30 and 35 mmHg) but very low SBF (RV output was 75 mls/kg/min [NR 150-300]). This weak
4. Systemic blood flow in the preterm infant Our serial observations of systemic blood flow in preterm babies suggest there is a hypoperfusion reperfusion cycle that is occurring over the first 24 to 48 h of life. To a certain extent this cycle occurs in all babies, but there is a group in whom SBF drops to very low levels and these babies seem at particular risk for a range of adverse outcomes.
Figure 2 Plots mean blood pressure against SVC flow in 110 babies born before 30 weeks at a mean of 5 h of age. The dotted lines represent possible lower limits of normal, for blood pressure this has been plotted at the mean gestation of the cohort, 27 weeks.
806 relationship between SVC flow and MBP means there is a close inverse relationship between SVC flow and calculated vascular resistance. While this could be compensatory, it could also be causative. There is consistent evidence that the preterm myocardium has a limited ability to respond to an increase in afterload [22,23] and we hypothesise that the transition from the low resistance intra-uterine state to the high resistance exutero state is the primary problem during the first 24 h. When this is compounded by large ductal shunts out of the systemic circulation (which are not uncommon in the early postnatal hours) and positive pressure ventilation then critically low blood flow to all organs of the body (not just the brain) results. The above relates to the first 24 h, after this time and with very few exceptions, babies who are hypotensive will have normal or high SBF suggesting vasodilation. This period has been less systematically studied but this would be our observation in a range of hypotensive situations including inotrope resistant hypotension and septic shock. Fig. 4 shows an example of a baby at 7 days of age with a closed duct, who had an MBP ranging between 18-20 mmHg despite full and poly-pharmacological inotropic support but whose LV output was 600 mls/kg/min (NR 150-300). Also despite such low blood pressure appeared to be maintaining very generous CBF as estimated by cerebral artery Doppler. So herein lies the problem with making global recommendations about circulatory support in the preterm neonate. There is a changing perfusion cycle which goes from low flow/high resistance in the first 24 h to normal/high flow low resistance after this time. To complicate things further, there are some babies who are exceptions to the rules in both time frames. The logically correct treatment in one situation will be diametrically the wrong treatment in the other. To even further complicate this issue, there are other important causes of hypotension to exclude such as
N. Evans hypovolaemia in the transitional postnatal period (rare but it happens) [24] and patent ductus arteriosus during and after the transitional period. The latter has a negative effect on all parameters of blood pressure not just diastolic pressure as is often perceived [25].
5. Circulatory support of the preterm infant: what do we know? Volume expansion, dopamine, dobutamine, adrenaline and, in some settings, hydrocortisone are the mainstays of neonatal circulatory support. Volume will restore normovolaemia in a hypovolaemic infant and will increase pre-load and hence cardiac output in a normovolaemic infant. Dobutamine is a synthetic catecholamine with beta-adrenergic effects, which tend to vasodilate, and cardiac alphaadrenergic effects, which stimulate cardiac contractility and increase heart rate. Dopamine is a naturally occurring precursor to adrenaline and noradrenaline. It has dopaminergic, beta and alpha effects with each of these (in the order shown) more likely to be stimulated as the dose increases. At a dose of over 10 mcg/kg/min the alpha vasoconstrictive effects on BP predominate, but particularly in the very immature baby, these alpha effects may be apparent at lower doses. Adrenaline is naturally occurring and has broad alpha and beta-adrenergic effects and, like dopamine, will vasoconstrict as higher doses. Hydrocortisone puts up BP but data are only just beginning to emerge on how it does this.
5.1. Volume: what's the evidence? We know from systematic review that routine early volume expansion in preterm babies does not improve outcomes [8].
Figure 3 Shows Doppler velocity in the pulmonary artery in two babies. (A) shows the low maximum velocity (Vmax) in an 8-hour old 26 week baby whose mean blood pressure was above 30 mmHg. This translated to a very low RV output of 75 mls/kg/min (NR 150-300) representing low systemic blood flow. This is compared with (B) which shows a normal Vmax representing a normal RV output.
Assessment and support of the preterm circulation
807
Figure 4 Shows Doppler velocity in the ascending aorta (A) and middle cerebral artery (B) in a 7 day old, 27 week baby with pseudomonas sepsis and a closed ductus arteriosus. The MBP was 18 mmHg on maximum inotrope support. Normal mean Vmax in aorta would be 0.8 m/s and (A) represents an LV output of approx 600 mls/kg/min (normal 150-300). The Vmax of 0.9 m/s shown in (B) also suggests high CBF, normal mean Vmax in the MCA would be 0.34 m/s.
There is probably no advantage in using a colloid compared to a crystalloid and we know that volume is not as good as dopamine at increasing BP [11]. We know less about the effect of volume on organ blood flows. Studies have shown increases in LV output [26,27] or SVC flow [28] with volume, however in the study of Lunstrom et al, [26] this did not translate to an increase in cerebral blood flow. In all these studies, measures were taken immediately after the volume, so it is not known if these increases are maintained. There is some evidence that the fluid used in volume expansion redistributes quite quickly out of the vascular compartment. There is a need to study whether the positive effects of volume on SBF are sustained.
5.2. Inotropes: what's the evidence? We know that dopamine is better than dobutamine at increasing BP though there is no evidence that this translates into better short term outcomes [10]. In a double blind RCT, Pellicer et al [29] showed that adrenaline and dopamine have similar efficacy in increasing BP. None of the studies to date have been powered or designed to look at clinical outcomes. In most of these studies, babies were enrolled on the basis of BP below a cut off and change in BP was main central haemodynamic outcome. Roze et al [30] did measure LV output and showed an increase in babies with dobutamine while LV output decreased with dopamine. In a small randomised study of babies <1750 g, Phillipos and Robertson [31] reported that dopamine and adrenaline titrated to the BP response, have similar effects in increasing heart rate and BP but that dopamine caused a significant 10% fall in LV output
while adrenaline resulted in an insignificant 14% increase. This study has only been published as an abstract so should be interpreted with caution. Our group has done the only randomised study of dopamine and dobutamine that enrolled babies on the basis of low blood flow [28]. For each drug, there were two dosage steps (10 and 20 mcg/kg/min) depending on the SBF response. In view of the possible role of high afterload, we hypothesised that dobutamine which will reduce afterload, would increase flow more than dopamine, which can increase afterload. At the highest dose reached, dobutamine produced significantly better increases in SVC flow than dopamine while dopamine produced better increases in MBP. At 10 mcg/kg/min, there was no difference between the two drugs but in those that needed to be increased to 20 mcg/kg/min, dobutamine produced more benefit in SBF, which was not seen in those on dopamine, even though MBP continued to increase. Babies who did not increase flow adequately on 20 mcg/kg/min crossed over to the other drug and probably the most important observation from this study was that 40% of the babies enrolled, failed to increase or maintain SBF after either drug. SVC flow will incorporate CBF but it is not the same thing, so what do we know about the effect of inotropes on cerebral blood flow? The effect of dobutamine on cerebral blood flow in preterm babies has not been studied. Using Xe clearance, Lundstrom et al [26] showed that dopamine, while increasing LVO and MBP, did not increase CBF. Seri et al [32] showed no effect on middle cerebral artery pulsatility index after dopamine in a group of preterm babies with normal blood pressure but clinical evidence of poor perfusion. In an open label observational study, Munro et al [14] used NIRS to show
808 an increase in mean CBF after dopamine was given to a cohort of 12 preterm babies with an MBP <30 mmHg. In a double blind RCT, Pellicer et al [29] also using NIRS, showed both dopamine (at doses up to 10 mcg/kg/min) and adrenaline (at doses up to 0.5 mcg/kg/min) produced similar increases in cerebral intravascular oxygenation which in turn was correlated with increases in MAP.
5.3. Hydrocortisone: what's the evidence? Much of the data on hydrocortisone is observational and relates to its use in inotrope resistant hypotension. In this situation, hydrocortisone seems to increase BP and allow weaning of other inotropic support [33]. Noori et al [34] have shown increases in BP, LV output and systemic vascular resistance after 2 mg/kg of hydrocortisone in 14 babies with inotrope resistant hypotension. One RCT showed hydrocortisone at 2.5 mg/kg had similar efficacy to dopamine in improving BP in hypotensive preterm babies [35]. There was no difference in other clinical outcomes. To my knowledge there are no data on the effects of hydrocortisone on CBF.
6. Circulatory support in the very preterm infant: what should we do? There is no clinical outcome based evidence on which to base therapeutic recommendations. No study, including those from our group, has shown any improvement in any meaningful clinical outcome, short, intermediate or long term, in response to a specific inotrope. Until such evidence is available, we will have to rely on an empirical approach to therapy. If it is your bias that the problems of the preterm circulation relate to absent cerebral autoregulation then it makes sense to use the
N. Evans agent that is most likely to improve blood pressure. I do not have evidence that this is the wrong thing to do but it is our bias that preterm haemodynamics are considerably more complex than this. If we consider the circulation as a set of scales in precarious balance, Fig. 5. At one end is vasoconstriction and with the scales tipped too far that way there is the potential for afterload compromise and, at the other end, too much vasodilation will lead to hypotension, CBF could be compromised in either scenario. In the middle is the rather inadequate immature heart and all the complexities of the transitional circulation. To know where one is on this continuum, there is a need for measures of both pressure and flow. If the measures suggest high afterload, then it probably makes sense to use an inotrope with vasodilating properties such as dobutamine. If the measures point to vasodilation, then it makes sense to use one with pressor properties such as dopamine or adrenaline. If you can't measure flow then it probably makes sense to guess on the basis of time frame and use dobutamine during the first 24 h and dopamine after that time. The reader is pointed to another recent review for more details of our empirical approach to circulatory support based on our physiological observations [36]. The principle that more BP may not necessarily be better was highlighted by both Pellicer [29] and Munro, [14] whose studies both showed some babies with quite dramatic rises in CBF in response to an increase in BP. Hyperperfusion after hypoperfusion seems important in the pathogenesis of IVH [21] so is probably best avoided. These risks together with the risk of afterload compromise, can probably be minimised by starting at a low dose (5 μg/kg/min for dopamine or 0.1 μg/ kg/min for adrenaline) and titrating in careful steps to a minimally acceptable BP. I would suggest aiming to have MBP within 5 mmHg of your therapeutic threshold and being
Figure 5 Above, represents the circulation as a set of scales balancing vasoconstriction and vasodilation. Having scales tipped too far either way is probably not good. Below, represents the common haemodynamic changes in the early postnatal time frame when the common milieu changes from afterload compromise to vasodilation. The suggested logical choice of inotrope in each haemodynamic milieu is shown.
Assessment and support of the preterm circulation prepared to wean the infusion rate quickly in babies whose BP overshoots above this. We rarely use hydrocortisone but, if you do, the data of Noori et al [34] suggests that to avoid the risk of afterload compromise then you need to be ready to wean other pressor inotropes quickly as the blood pressure responds.
7. Assessment of systemic blood flow What evidence there is suggests that the common clinical examination criteria for examining circulatory well-being (such as capillary refill) are of limited accuracy [37]. Full assessment of SBF and an individual baby's haemodynamic needs good echocardiographic skills. There is no reason why a neonatologist cannot develop these skills but it does take time and some commitment. Flow in a vessel is the product of the mean velocity of blood and the cross-sectional area of the vessel. The velocity can be measured with Doppler and the cross-sectional area is derived from the diameter measured by 2D or M-mode imaging. SVC flow is a useful research tool but is determined equally by changes in diameter and velocity, so is a fiddle to derive and I would not recommend it as a clinical screening tool for low SBF. However velocity in the main pulmonary artery is the dominant determinant of RV output and so measuring the maximum velocity in the pulmonary artery (PA Vmax) provides a simple way to screen for low SBF, Fig. 2. Large atrial shunts are not common in the first 48 h, so, for clinical purposes, RV output is a reasonably accurate marker of low SBF [36]. In the first 48 h after birth, if the PA Vmax is over 0.45 m/s, low SBF is unlikely (in 381 studies, 99% had RV output over 120 mls/kg/min and 88% over 150 mls/kg/min). If the PA Vmax is less than 0.35 m/s, most babies have low SBF (in 37 studies, 87% had RV output less than 150 mls/kg/min and 75% less than 120 mls/kg/min). Between 0.35 and 0.45 m/s, is a grey zone where discriminatory accuracy is less good, Fig. 6. In practice, I would recommend screening with PA Vmax and then doing full RV output and/or SVC flow measures in those with a PA Vmax less than 0.45 m/s. The highest pick up of low systemic blood flow will occur if you screen very preterm babies between 3 and 9 h of age.
809 blood pressure. As discussed above this may not mean necessarily that it is less effective on clinical outcomes. Another model would be to take a cohort of at risk babies and then randomise them to treatment at different blood pressure thresholds, possibly including a factorial design so at each threshold, babies are also randomised to different inotropes. This design would tell us more about where we should target blood pressure and this may be a more clinically relevant question than which agent we should use to do it. The model we are currently exploring is a preventative approach. Extremely preterm infants during the transitional period are a population at very high risk of circulatory compromise and there is consistent evidence linking this to adverse outcomes. Our observations have caused us to question the accuracy of clinical diagnosis of low SBF [36] and the reliability of the response to inotropes [29]. In turn, this has led us to question whether a reactive therapeutic strategy is going to be the best way to improve outcomes. We are exploring a preventative strategy using Milrinone, an inodilator that has been successfully used to prevent the low SBF state seen after cardiac bypass surgery [38]. We have some encouraging preliminary data [39,40] and are currently close to completion of a pilot randomised trial in which babies are randomised milrinone or placebo from 3 until 18 h of age with the aim of tiding them over the nadir of SBF. It is too early to make any recommendations on the basis of these findings but similar trial model could be used to explore whether the traditional inotropes discussed in this review would be more effective if used preventatively on the basis of risk factors rather than therapeutically on the basis of clinical signs.
9. Conclusion
8. Preterm circulatory support: where to now?
Overall I hope the reader, by appreciating how much we do not understand, will be encouraged to develop skills that allow a better understanding of the circulation. There is a pressing need to move the research beyond simply showing change in a physiological variable in response to a treatment. While it is important to understand the physiological effect of these treatments, unless we can show that these effects improve clinical outcome, such research is just phenomenology. These
There is a pressing need for some outcome evidence on which to base our practice. The introduction of inotropes in preterm babies resulted from a hypothesis that was never tested and it could be argued that we now need to do the trials that will test that hypothesis. But in doing this, we need to go beyond just showing a change in a physiological parameter (whether it be pressure or flow) and design the studies to explore meaningful clinical outcomes. This will not be easy as this is an area in which strong views (biases) are held and achieving the level of equipoise necessary to run a big trial will be a challenge. How should such studies be designed? One model would involve taking a cohort of at risk babies, defining a threshold blood pressure and then randomising to different inotropes (e.g. dopamine and dobutamine). The problem with this approach is that depending on where the threshold blood pressure is set, there will inevitably be more short term failure in the inotrope that has less effect on
Figure 6 Shows box and whisker plot of RV output against low, intermediate and normal PA Vmax. The dotted line denotes 150 mls/kg/min.
810 are therapies that have been in routine clinical practice for many years, yet we have no idea whether they achieve our intended goal, which is to reduce neurological morbidity. Correcting this knowledge gap is the challenge for the future.
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