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Volume expansion during neonatal intensive care: do we know what we are doing?
Seminars in Neonatology (2003) 8, 315–323
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Volume expansion during neonatal intensive care: do we know what we are doing? Nick Evans * Department of Neonatal Medicine, RPA Centre for Newborn Care, Royal Prince Alfred Hospital and University of Sydney, Sydney, New South Wales 2050, Australia Received 1 December 2002; accepted 1 January 2003
KEYWORDS Infant newborn; Blood volume; Plasma substitutes; Circulatory support; Hypotension; Hypovolemia; Echocardiography
Summary Although volume expansion is liberally used in newborn intensive care, we know little about its effects on hemodynamics or outcomes. Given appropriately to a truly hypovolemic baby, it can be life-saving, but the clinical diagnosis of hypovolemia is probably very inaccurate. We know that volume expansion has less effect on blood pressure than dopamine, and although it seems to produce immediate increases in systemic blood flow, we do not know for how long these increases are sustained. There is evidence to show that the routine use of volume expansion in preterm babies has no effect on outcome, and there is little evidence to support its routine use during resuscitation or the treatment of metabolic acidosis. Whether crystalloids or colloids are preferable is also unclear in newborns. In situations of concern related to circulatory compromise, if possible, define the hemodynamics echocardiographically. Otherwise, if in doubt, some volume should be given, although it is probably unwise to keep expanding the volume if this is not improving physiologic (blood pressure and heart rate) or echocardiographic systemic blood flow parameters. © 2003 Elsevier Ltd. All rights reserved.
Introduction Volume expansion must be one of the most widely used non-evidence-based therapies in newborn intensive care. If given appropriately to a truly hypovolemic infant, it is life-saving. On the other hand, volume pushed into an already fluidoverloaded sick infant may well be deleterious.1 The problem and challenge here is separating these two extremes on the basis of clinical signs and knowing when, how much and what type of volume expansion to give the baby. In the sick preterm or term infant, the challenge is to know whether volume expansion has a role as a circulatory support measure. This article will review the current evidence in each of these areas and, because good
* Tel.: +612-9515-8760; fax: +612-9550-4375 E-mail address: [email protected] (N. Evans).
evidence is rather sparse, combine it with some anecdotal experience from the author.
Pathophysiology of hypovolemia Hypovolemia can be absolute, when there is loss of volume from the intravascular compartment, or relative, when there is vasodilatation (such as in septic shock) and inadequate volume to fill the expanded intravascular compartment. The result in both situations is inadequate filling pressure (or preload) on the heart. If the condition is severe enough, cardiac output will fall, and inadequate tissue perfusion and oxygenation will result. In pure volume loss, the body will respond with corticosteroid, adrenaline and noradrenaline excretion, which will contract the vascular compartment to maintain blood and filling pressure, and increase the heart rate and contractility to maintain systemic blood flow (SBF). This response may be limited in the sick and or immature newborn.2
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Diagnosis of hypovolemia
decompensation may result. An exchange transfusion is the correct approach in this situation.
Clinical history
Clinical signs
The clinical diagnosis of hypovolemia is difficult and often relies on a high degree of clinical suspicion on the basis of the perinatal history or clinical scenario. With postnatal hypovolemia, there is usually a history of blood loss or an illness that might be associated with loss of volume from the vascular space, such as necrotizing enterocolitis or severe sepsis. In most case of significant neonatal hypovolemia, however, the blood loss occurs in the intrapartum period so may not be apparent clinically. There are four main routes of intrapartum blood loss that should be considered in situations of suspected antepartum hemorrhage, uterine pain or tenderness, evidence of fetal compromise or a monochorionic twin pregnancy. The first route is via an open bleed from the fetal side of the placenta, which will usually manifest as an antepartum hemorrhage; the possibility of fetal blood loss should be considered when there is a significant antepartum hemorrhage late in labor. Second is fetomaternal hemorrhage. Diagnosis here depends on a high degree of suspicion and the demonstration of a significant number of fetal red cells in the maternal bloodstream. Reduced or absent fetal movements and a sinusoidal fetal heart rate trace seem to be non-specific and late antenatal signs that are associated with fetomaternal hemorrhage.3 The third route, fetoplacental hemorrhage, occurs in situations in which there is external pressure on the umbilical cord and the cord is separated early. This is classically seen in babies whose cord is around their neck but may occur in breech deliveries. As pressure on the cord increases, the vein will obstruct before the artery, and blood will continue to be pumped into the placenta. If the cord is separated early, this blood will be trapped in the placenta. This probably happens to some extent in many cases of nuchal cords, babies in this group having significantly lower hemoglobins levels.4 It occasionally results in a baby being born with severe hypovolemia.5 Finally, twin–twin transfusion is often chronic so the donor twin is born anemic but normovolemic. In acute or acute-on-chronic cases, however, the donor is hypovolemic. Seng and Rajadurai6 described 18 twin–twin transfusion pairs, 56% of whom were assessed as chronic and 44% as acute. Accurate diagnosis is critical here because if volume replacement is poured into a normovolemic, chronically anemic baby, cardiovascular
The classic clinical picture of hypovolemia is that of a baby who is pale, shut down, hypotensive and tachycardic with very slow capillary refill when the skin is blanched. Although it will be clear there is something wrong with this baby, each of these clinical signs is non-specific for circulatory compromise and could reflect anything from sepsis to congenital heart disease: none of these signs provides a definitive diagnosis of hypovolemia. In the immediate postnatal period, this clinical picture is common in babies with mild-to-moderate degrees of perinatal asphyxia. Most of these infants are not hypovolemic, the clinical signs probably reflecting the peripheral vascular effects of the hormonal stress response and acidosis.7 What is the evidence for the diagnostic accuracy of each of these signs when compared against measures of SBF?
Measures of peripheral perfusion Capillary refill time and core–peripheral temperature difference are widely used as the basis for volume expansion in acute care situations. The evidence suggests that both are tests of limited accuracy in the newborn. A capillary refill time of less than 3 s is traditionally accepted as normal. Tibby et al.,8 showed there was little relationship between capillary refill and measures of SBF in more mature babies in a pediatric intensive care setting, finding a positive predictive value only when the refill time was over 6 s. We have found a similar lack of relationship for low SBF in babies born before 30 weeks: only when the capillary refill time exceeded 5 s did the test have any degree of specificity.9 When the refill time is this long, the clinician generally does not need to press the skin to know that something is wrong. Both studies found no significant relationship between core peripheral temperature difference and measures of SBF.
Blood pressure Although blood pressure is commonly used as a gold standard of hemodynamic well-being in neonatology, there are now several studies that have shown only a weak relationship between measures of blood pressure and blood flow.9–14 This reflects the fact that pressure is also determined by resistance. As outlined above, resistance is increased as a compensatory response to hypovolemia, so a fall
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in blood pressure may be a relatively late sign. This is highlighted by the observation that small, acute changes in blood volume (8.5 ml/kg) produce little change in blood pressure.15 There are also consistent data from three studies in preterm babies that there is no relationship between blood pressure and blood volume.1,16,17
Heart rate There is no literature on the accuracy of a persistently increased heart rate as a marker of hypovolemia. Anecdotally, persistent tachycardia has been a feature of most cases of true hypovolemia the author has seen, particularly in more mature babies. In the preterm babies that we studied, heart rate had no relationship to low SBF.13
Investigations Hemoglobin/hematocrit Babies quickly redistribute extracellular fluid back into the vascular space, so spinning a blood sample for a hematocrit can be a useful adjunct to clinical assessment for a fetal bleed. The mean hematocrit in a term baby is 50% (±4.5%)18 so a fetal bleed should be considered in a shocked-looking baby with a hematocrit of less than 40%.
Central venous pressure monitoring In a mature circulation, central venous pressure (CVP) is accepted as a measure of blood volume, but whether this is also true in the transitional circulation is unclear. Differences in pulmonary vascular resistance in the transitional circulation may also influence CVP. CVP can be measured in babies via an umbilical venous line, and normal values have been established.19 Whether a low CVP accurately diagnoses hypovolemia in the newborn is, however, not known.
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that is not corrupted by intracardiac shunts.22 Flow is derived from blood velocity and vessel crosssectional area, the latter being calculated from vessel diameter. The velocity in the SVC can be measured using Doppler ultrasound from a low subcostal window, and the diameter can be measured from the low parasternal window (Fig. 1). Normal SVC flow in preterm babies is between 50 and 110 ml/kg/min.22 About 35% of babies born before 30 weeks have a period of SVC flow less than 40 ml/kg/min during the first 12 hours, the flow improving after this time. A strong association has been shown between this low flow and subsequent intraventricular hemorrhage.13,23 The reasons for this low flow state are complex, and the extent to which hypovolemia contributes to this is unclear. Volume expansion given to preterm babies with a low SVC flow improved flow by on average 55%, but the researchers did not study whether this was sustained (see subsequently).23 The other potential echocardiographic assessment of hypovolemia is ventricular filling, which can be assessed by left ventricular end-diastolic diameter (LVEDD). This is usually measured with m-mode echocardiography from the parasternal long axis view of the heart with the m-mode line transecting the ventricle at the tips of the mitral valve (Fig. 2). LVEDD is measured at the point of maximal ventricular filling. Normal mean LVEDD increases from 12 mm at 26–28 weeks to 17 mm at term.24,25 LVEDD as a test for hypovolemia has not been systematically examined in the newborn, but given that, at all gestations, the normal range for LVEDD is wide (e.g. 7.5–16.3 in 26–28 week fetus), and that there are many other factors that can affect left ventricular load conditions in the transitional circulation, it is unlikely this would be a reliable test. In cases of severe hypovolemia, however, dramatically poor ventricular filling may be apparent on echocardiography and can help to clarify the diagnosis, as demonstrated in the following case history.
Echocardiography
Case report
Ventricular outputs can be assessed using Doppler echocardiography. In a mature circulation, these outputs will reflect SBF. Again, however, this is not true in the transitional circulation, particularly in very preterm babies, in whom shunts through the ductus arteriosus and foramen ovale may cause ventricular output to overestimate SBF on the first day of life.20,21 Because of this, we developed the measure of superior vena cava (SVC) flow as a measure of part of the SBF (upper body and brain)
A term baby was born in poor condition. A tight nuchal cord had been clamped prior to delivery of the shoulders. The Apgar scores were 1 at 1 min and 2 at 5 min, the cord arterial pH 7.23 and the base excess −8.0. The baby was ventilated but remained pale with a tachycardia of 170 bpm. Echocardiography showed poor ventricular filling (Fig. 3), and the mean blood pressure was 35 mmHg. She was given 20 ml/kg normal saline, with immediate improvement. When the clamp was removed from the
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Fig. 1 Shows the parasternal saggital view of the SVC used for diameter measurement (left) and the Doppler velocity time integral (VTI) measurement from the subcostal position. The VTI is 0.137 m in this normal baby.
Evidence-based treatment with volume expansion Where volume is given to a truly hypovolemic baby, the physiological response is to normalize the pathological state as long as volume replacement is given before hypoxic organ injury results. Most babies given volume expansion in newborn intensive care are not, however, hypovolemic, so what are the appropriate clinical indications and what are the physiological responses to and outcome resulting from volume expansion in these babies?
What is the effect of volume expansion on blood pressure?
Fig. 2 Shows the left ventricular end-diastolic diameter (LVEDD) measurement taken from the m-mode echocardiogram. LVEDD is 16.1 mm in this term baby.
placental cord after delivery, blood under high pressure in the placenta was reported. The presumed diagnosis was acute fetoplacental transfusion with a nuchal cord.5
It is not surprising, considering that most hypotensive babies are not hypovolemic, that the blood pressure response to volume expansion is inconsistent. In observational studies, Bignall et al.26 showed, in infants with suspected hypovolemia, no overall change in blood pressure after 6 ml/kg 20% albumin, although four out of 12 babies demonstrated an increase in blood pressure. Rennie,27 studying infants on the first postnatal day, the majority of whom were hypotensive, reported no change in systolic blood pressure after 10 ml/kg plasma. Osborn et al.23 showed no significant
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Fig. 3 Contrasts the poor end-diastolic volumes of both ventricles in a severely hypovolemic baby (A) with the normal appearance in this parasternal long axis view (B).
Fig. 4 Percentage change in superior vena cava (SVC) flow and mean blood pressure after 10 ml/kg normal saline in 44 preterm babies with low systemic blood flow.
change in blood pressure after 10 ml/kg saline in 43 babies with low SVC flow, although there was again a wide range of response (Fig. 4). In randomized studies, Emery et al.28 recorded a median 20% increase in systolic blood pressure in hypotensive infants after 15 ml/kg 4.5% albumin or fresh frozen plasma (FFP) but little change after 5 ml 20% albumin. There was a wide variation in response. Lundstrom et al.29 found no difference in the change in mean blood pressure in normotensive infants between infants who received 15 ml/kg 20% albumin and controls. Volume expansion is not as good as dopamine at improving blood pressure. Gill and Weindling30 randomized hypotensive babies to 20 ml/kg volume or dopamine, dopamine increasing blood pressure into
the normal range in 89% of babies compared with only 45% of those given volume expansion. Lundstrom et al.29 also showed that dopamine was better than 15 ml/kg 20% albumin at improving blood pressure in a group of normotensive preterm babies. A systematic review of these randomized studies concluded that, because there were only limited data on the effect on blood flow, there was insufficient evidence to make firm recommendations.31
What is the effect of volume on systemic blood flow? Blood pressure and blood flow are not the same thing, and it cannot be assumed that an increase in
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one reflects an increase in the other. Three studies have examined changes in measures of SBF in response to volume, all showing a short-term increase in SBF after volume addition in the presence of only a limited response in blood pressure. In observational studies, Pladys et al.32 showed that left ventricular output increased from 193 to 272 ml/kg/min after 20 ml/kg of volume expansion. Osborn et al.23 showed a 55% increase in SVC flow after 10 ml/kg saline, but with little overall change in blood pressure. In randomized studies, Lundstrom et al.29 showed a mean increase in left ventricular output of 19% after 15 ml/kg but only a 6% increase in blood pressure. What none of these studies has resolved is whether these increases are sustained. Of note, Bignall et al.26 showed that blood volume had returned to baseline by 4 hours after 6 ml/kg 20% albumin.
What is the effect of volume on metabolic acidosis? This is perhaps the least evidence-based of all the indications for volume. There is little evidence that pH and base excess are good markers of circulatory compromise. They correlate very poorly with lactic acid levels,33 and, in our studies, neither pH nor base excess showed any correlation with measures of SBF.34 Not surprisingly, therefore, the few data that exist suggests that volume expansion is not a good way to correct a metabolic acidosis. Dixon et al.35 showed a small change in base excess after 10 ml/kg albumin, which was only about half the improvement achieved with sodium bicarbonate. Dimitriou et al.36 showed a small reduction in base deficit but no significant change in pH after albumin infusion. In the baby with clear-cut circulatory compromise and acidosis, volume may well be an appropriate response, but there is little support for its use as a first-line treatment for metabolic acidosis.
What is the effect of routine early volume expansion in preterm babies? Interest in this approach was triggered in 1985 by the trial of Beverley et al.37 In this study, 80 preterm babies were randomized to 10 ml/kg FFP on admission and again 24 hours later, or to a control treatment. The results suggested a reduction in intraventricular hemorrhage (IVH) in the treatment arm. However, analysis on an ‘intention-to-treat’ basis converted this to a statistically insignificant difference for severe grades of IVH.38 The issue was resolved by the much larger Northern Neonatal
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Nursing Initiative (NNNI) trial in 1996.39,40 A total of 776 babies were randomized to three groups who were given 10 ml/kg of a gelatin-based colloid or FFP, or to a control group. The volumeexpanded groups received volume on admission, a further 10 ml/kg being given 24 hours later. There were no significant differences in any important clinical outcomes, including neurodevelopmental outcomes at 2 years. A recent systematic review found four randomized trials including those already mentioned that compared routine early volume expansion with no treatment in a total of 940 very preterm infants.41 Meta-analysis of these studies showed no significant difference in mortality relative risk [RR] (1.11, 95% confidence interval [CI] 0.88–1.40). The 1996 NNNI study reported no significant difference in severe disability (RR 0.80, 95% CI 0.52–1.23), cerebral palsy (RR 0.76, 95% CI 0.48–1.20) and combined death or severe disability (RR 1.00, 95% CI 0.80–1.24). No significant difference was reported in grade 3–4 IVH and combined death or grade 3–4 IVH. One study (NNNI 1996) reported no significant difference in the incidence of hypotension. The conclusion of this review was that there was no evidence from randomized trials to support the routine use of early volume expansion in very preterm infants without cardiovascular compromise. There are, however, no trials that address the issue of the effect of volume on clinical outcome for infants with evidence of cardiovascular compromise, including hypotensive infants, infants with low blood flow or infants with clinically suspected hypovolemia.
What is the role of volume expansion in resuscitation? This is another area in which volume is used somewhat liberally. The clinical trigger here is usually the baby who remains pale after resuscitation. Most such babies are not hypovolemic but have varying degrees of acidosis and, if kept well oxygenated, will ‘pink up’ nicely by themselves. The circulatory compromise in the severely asphyxiated baby will usually result from the myocardial effects of hypoxia and acidosis.42,43 As the problem is cardiogenic, volume-loading an already compromised myocardium may not be the most appropriate response. The difficulty here is that a few of these babies are truly hypovolemic. In some, the diagnosis and action needed is obvious but, as discussed above, many of these can be very difficult to diagnose clinically. I would suggest that if, having explored the diagnostic strategies above, there is
Volume expansion during neonatal intensive care
any doubt about the volume status of a baby, it is reasonable to give 10 ml/kg volume expansion. If possible, however, it should be given when the physiologic response can be monitored. If heart rate falls and blood pressure rises, more volume can be given if needed. If there is no physiologic response to volume addition, further volume expansion should be approached with caution.
What is the role of volume expansion in the sick term baby? Sick term babies tend to be a more heterogeneous group than preterm babies. Apart from resuscitation, the situations in which volume is commonly considered in term babies are severe respiratory failure/pulmonary hypertension of the newborn and septic shock. Again, despite widespread clinical use in term babies, there are almost no data in the literature that document the physiologic responses to volume expansion in these situations. There are also no data on clinical outcomes. The reasons for circulatory compromise in both these clinical scenarios are complex. Relative hypovolemia can occur in septic shock as a result of vasodilatation and capillary leakage. Our anecdotal observations in such babies suggest that although they are vasodilated, they tend to have a normal or high cardiac output, particularly early in the course of the illness. There are no formal hemodynamic studies of neonatal sepsis, so whether a large amount of volume expansion is useful in this vasodilated situation remains uncertain. We studied a cohort of term babies with high oxygen requirements using serial echocardiography and found very variable hemodynamics that were not easily predictable from the clinical situation.44 In these situations, it is worth trying accurately to define the hemodynamics with echocardiography. If there is any doubt, some volume expansion (10–20 ml/kg) might be helpful but should be abandoned if it is obviously not proving beneficial.
What type of fluid should be used for volume expansion? The issue of whether to use crystalloid or colloid was thrown into the limelight by the systematic review of Alderson et al.45 This review included all studies over a 30 year period, for all clinical indications, in all age groups, that had compared crystalloid with colloid infusion in sick patients. The meta-analysis suggested an increased mortality in the colloid group, with a combined odds ratio of 1.52 (95% CI 1.17–1.99). This review has been
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criticized for the heterogeny of inclusion criteria. Of the 35 trials included, five were neonatal, and, of these, only two compared crystalloid with colloid volume expansion given for circulatory support reasons. Only one of these two trials has so far been published in a peer-reviewed journal. This is the study of So et al.,46 which compared volume expansion with 10 ml/kg 5% albumin vs 0.9% saline in 63 hypotensive preterm babies. The researchers found that normal saline was as effective as 5% albumin for treating hypotension, as well as causing less fluid retention. There were no differences in any other clinical outcomes, although the trial was not powered to look at long-term outcome. Two other trials have so far appeared only in abstract form. That of Oca et al.47 compared the short-term effects on blood pressure and found no significant difference in a small group of 24 babies. There was a trend towards a more successful resolution of hypotension with albumin (82 vs 54%), but the response was only measured over 30 min. In the larger trial of Lynch et al.,48 102 hypotensive babies were similarly randomized to albumin or normal saline. Babies given albumin had a better immediate blood pressure response and were less likely to need inotropes afterwards. No details of other clinical outcomes were given in the abstract. The jury remains out on this issue in newborns. Because there are no comparative data on the effects on blood flow or important clinical outcomes, there is insufficient evidence to make firm recommendations. Our approach has been to use normal saline for circulatory support on the basis that it is cheaper, it is not a blood product and there is no evidence of any advantage form using colloid.
Conclusion We all use volume expansion, even though we cannot accurately diagnose when babies need it and we do not know much about what it does when we give it. The only definite conclusion is that there is no evidence to support the routine early use of volume expansion in preterm babies. In situations of circulatory concern, the goal should if possible be to define the hemodynamic situation echocardiographically. It is probably wise to use at least 10 ml/kg for volume expansion because hypovolemia can be very difficult to diagnose and there is some evidence of short-term circulatory benefit. Whether more should be given should be judged by monitoring the effects of this bolus on physiologic and, ideally, echocardiographic parameters of circulatory well-being. The benefits of giving more
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than 20 ml/kg in any but the most obvious hypovolemic situations must be questioned: the ‘Michelin Man’ appearance of many of these babies the day after repeated volume infusions would suggest that the fluid is not staying long in the vascular compartment. Future research in this area needs to focus on more accurate ways to diagnose hypovolemia and on whether volume expansion used for circulatory support produces sustained hemodynamic improvement (not just improved blood pressure) and whether it improves clinical outcomes.
Acknowledgements I would like to thank Dr David Osborn for his comments and help with this paper.
References 1. Barr PA, Bailey PE, Sumners J et al. Relation between arterial blood pressure and blood volume and effect of infused albumin in sick preterm infants. Pediatrics 1977; 60:282–90. 2. Ng PC, Lam CW, Fok TF et al. Refractory hypotension in preterm infants with adrenocortical insufficiency. Arch Dis Child Fetal Neonatal Ed 2001;84:F122–4. 3. Giacoia P. Severe fetomaternal haemorrhage: a review. Obstet Gynecolog Survey 1997;56:372–80. 4. Shepherd AJ, Richardson CJ, Brown JP. Nuchal cord as a cause of neonatal anemia. Am J Dis Child 1985;139:71–3. 5. Vanhaesebrouck P, Vanneste K, de Praeter C et al. Tight nuchal cord and neonatal hypovolaemic shock. Arch Dis Child 1987;62:1276–7. 6. Seng YC, Rajadurai VS. Twin–twin transfusion syndrome: a five year review. Arch Dis Child Fetal Neonatal Ed 2000; 83:F168–70. 7. Greenough A, Lagercrantz H, Pool J et al. Plasma catecholamine levels in preterm infants. Effect of birth asphyxia and Apgar score. Acta Paediatr Scand 1987;76(1):54–9. 8. Tibby SM, Hatherill M, Murdoch IA. Capillary refill and core– peripheral temperature gap as indicators of haemodynamic status in paediatric intensive care patients. Arch Dis Child 1999;80(2):163–6. 9. Osborn D, Evans N, Kluckow M. Accuracy of capillary refill time and blood pressure for detecting low systemic blood flow in preterm infants. Pediatr Res 2001;49:376A. 10. Pladys P, Wodey E, Beuchee A et al. Left ventricle output and mean arterial blood pressure in preterm infants during the 1st day of life. Eur J Pediatr 1999;158:817–24. 11. Tyszczuk L, Meek J, Elwell C et al. Cerebral blood flow is independent of mean arterial blood pressure in preterm infants undergoing intensive care. Pediatrics 1998;102: 337–41. 12. Lopez SL, Leighton JO, Walther FJ. Supranormal cardiac output in dopamine and dobutamine dependent preterm infants. Pediatr Cardiol 1997;18:292–6. 13. Kluckow M, Evans N. Low superior vena flow and intraventricular haemorrhage in preterm infants. Arch Dis Child 2000;82:F188–94. 14. Kluckow M, Evans N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. J Pediatr 1996;129:506–12.
N. Evans 15. Lundell BP, Lagercrantz H. Left ventricular systolic time intervals and plasma noradrenaline concentrations during acute hypovolaemia and newborn infants. J Dev Physiol 1983;5:23–9. 16. Wright IMR, Goodhall SR. Blood pressure and blood volume in preterm infants. Arch Dis Child 1994;70:F230–2. 17. Bauer K, Linderkamp O, Versmold HT. Systolic blood pressure and blood volume in preterm infants. Arch Dis Child 1994;69:521–2. 18. Forestier F, Daffos F, Catherine N et al. Developmental hematopoesis in normal human fetal blood. Blood 1991; 77:2260–3. 19. Skinner JR, Milligan DW, Hunter S et al. Central venous pressure in the ventilated neonate. Arch Dis Child 1992; 67:374–7. 20. Evans N, Iyer P. Assessment of ductus arteriosus shunt in preterm infants supported by mechanical ventilation: effects of interatrial shunting. J Pediatr 1994;125:778–85. 21. Evans N, Iyer P. Incompetence of the foramen ovale in preterm infants supported by mechanical ventilation. J Pediatr 1994;125:786–92. 22. Kluckow M, Evans N. Superior vena flow in preterm infants: a novel marker of systemic blood flow. Arch Dis Child 2000; 82:F182–7. 23. 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. 24. Skelton R, Gill AB, Parsons JM. Reference ranges for cardiac dimensions and blood flow velocity in preterm infants. Heart 1998;80:281–5. 25. Harada K, Siota T, Takahashi Y et al. Changes in the volume and performance of the left ventricle in the early neonatal period. Early Hum Dev 1994;34:201–9. 26. Bignall S, Bailey PC, Bass CA et al. The cardiovascular and oncotic effects of albumin infusion in premature infants. Early Hum Dev 1989;20:191–201. 27. Rennie JM. Cerebral blood flow velocity variability after cardiovascular support in premature babies. Arch Dis Child 1989;64:897–901. 28. Emery EF, Greenough A, Gamsu HR. Randomised controlled trial of colloid infusions in hypotensive preterm infants. Arch Dis Child 1992;67:1185–8. 29. 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. 30. Gill AB, Weindling AM. Randomised controlled trial of plasma protein fraction versus dopamine in hypotensive very low birth weight infants. Arch Dis Child 1993;69:284–7. 31. Osborn DA, Evans N. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants Cochrane Review. The Cochrane Library, Issue 2, 2002. Oxford: Update Software. 32. Pladys P, Wodey E, Betremieux P et al. Effects of volume expansion on cardiac output in the preterm infant. Acta Paediatr 1997;86:1241–5. 33. Deshpande SA, Platt MP. Association between blood lactate and acid base status and mortality in ventilated babies. Arch Dis Child 1997;76:F15–20. 34. Kluckow M, Evans N. Hypoperfusion, hyperkalaemia and serum lactate levels in the preterm infant. Pediatr Res 1998;43:179A. 35. Dixon H, Hawkins K, Stephensen T. Comparison of albumin vs bicarbonate treatment for neonatal metabolic acidosis. Eur J Pediatr 1999;158:414–5. 36. Dimitriou G, Greenough A, Mantagos J et al. Metabolic acidosis, core peripheral temperature difference and blood
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pressure response to albumin infusion in hypotensive, very preterm infants. J Perinat Med 2001;29:442–5. Beverley DW, Pitts-Tucker TJ, Congdon PJ et al. Prevention of intraventricular haemorrhage by fresh frozen plasma. Arch Dis Child 1985;60:710–3. Hope P. Pump up the volume? The routine early use of colloid in very preterm infants. Arch Dis Child 1998; 78:F163–5. Northern Neonatal Nursing Initiative (NNNI) Trial Group. A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma, gelatin or glucose on early mortality and morbidity in preterm babies. Eur J Pediatr 1996;155:580–8. Northern Neonatal Nursing Initiative (NNNI) Trial Group. Randomized trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. Lancet 1996;348:229–32. Osborn DA, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants Cochrane Review. The Cochrane Library, Issue 2, 2002. Oxford: Update Software Primhak RA, Jedeikin R, Ellis G et al. Myocardial ischaemia in asphyxia neonatorum. Electrocardiographic, enzymatic
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and histological correlations. Acta Paediatr Scand 1985; 74:595–600. Tapia-Rombo CA, Carpio-Hernandez JC, Salazar-Acuan AH et al. Detection of transitory myocardial ischaemia secondary to perinatal asphyxia. Arch Med Res 2000;31: 377–83. Evans NJ, Kluckow M, Currie A. The range of echocardiographic findings in term and near term babies with high oxygen requirements. Arch Dis Child 1998;78:105–11. Alderson P, Bunn F, Lefebvre C et al. The Albumin Reviewers Human albumin solution for resuscitation and volume expansion in critically ill patients Cochrane Review. The Cochrane Library, Issue 2, 2002. Oxford: Update Software So KW, Fok TF, Ng PC et al. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child 1997;76:F43–6. Oca MJ, Nelson M, Donn SM. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. Pediatr Res 1999;45 abstract 1265. Lynch SK, Stone CS, Graeber J et al. Colloid vs crystalloid fluid therapy for hypotension in neonates. Pediatr Res 2002; 51:348A.
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Volume expansion during neonatal intensive care: do we know what we are doing? Nick Evans * Department of Neonatal Medicine, RPA Centre for Newborn Care, Royal Prince Alfred Hospital and University of Sydney, Sydney, New South Wales 2050, Australia Received 1 December 2002; accepted 1 January 2003
KEYWORDS Infant newborn; Blood volume; Plasma substitutes; Circulatory support; Hypotension; Hypovolemia; Echocardiography
Summary Although volume expansion is liberally used in newborn intensive care, we know little about its effects on hemodynamics or outcomes. Given appropriately to a truly hypovolemic baby, it can be life-saving, but the clinical diagnosis of hypovolemia is probably very inaccurate. We know that volume expansion has less effect on blood pressure than dopamine, and although it seems to produce immediate increases in systemic blood flow, we do not know for how long these increases are sustained. There is evidence to show that the routine use of volume expansion in preterm babies has no effect on outcome, and there is little evidence to support its routine use during resuscitation or the treatment of metabolic acidosis. Whether crystalloids or colloids are preferable is also unclear in newborns. In situations of concern related to circulatory compromise, if possible, define the hemodynamics echocardiographically. Otherwise, if in doubt, some volume should be given, although it is probably unwise to keep expanding the volume if this is not improving physiologic (blood pressure and heart rate) or echocardiographic systemic blood flow parameters. © 2003 Elsevier Ltd. All rights reserved.
Introduction Volume expansion must be one of the most widely used non-evidence-based therapies in newborn intensive care. If given appropriately to a truly hypovolemic infant, it is life-saving. On the other hand, volume pushed into an already fluidoverloaded sick infant may well be deleterious.1 The problem and challenge here is separating these two extremes on the basis of clinical signs and knowing when, how much and what type of volume expansion to give the baby. In the sick preterm or term infant, the challenge is to know whether volume expansion has a role as a circulatory support measure. This article will review the current evidence in each of these areas and, because good
* Tel.: +612-9515-8760; fax: +612-9550-4375 E-mail address: [email protected] (N. Evans).
evidence is rather sparse, combine it with some anecdotal experience from the author.
Pathophysiology of hypovolemia Hypovolemia can be absolute, when there is loss of volume from the intravascular compartment, or relative, when there is vasodilatation (such as in septic shock) and inadequate volume to fill the expanded intravascular compartment. The result in both situations is inadequate filling pressure (or preload) on the heart. If the condition is severe enough, cardiac output will fall, and inadequate tissue perfusion and oxygenation will result. In pure volume loss, the body will respond with corticosteroid, adrenaline and noradrenaline excretion, which will contract the vascular compartment to maintain blood and filling pressure, and increase the heart rate and contractility to maintain systemic blood flow (SBF). This response may be limited in the sick and or immature newborn.2
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Diagnosis of hypovolemia
decompensation may result. An exchange transfusion is the correct approach in this situation.
Clinical history
Clinical signs
The clinical diagnosis of hypovolemia is difficult and often relies on a high degree of clinical suspicion on the basis of the perinatal history or clinical scenario. With postnatal hypovolemia, there is usually a history of blood loss or an illness that might be associated with loss of volume from the vascular space, such as necrotizing enterocolitis or severe sepsis. In most case of significant neonatal hypovolemia, however, the blood loss occurs in the intrapartum period so may not be apparent clinically. There are four main routes of intrapartum blood loss that should be considered in situations of suspected antepartum hemorrhage, uterine pain or tenderness, evidence of fetal compromise or a monochorionic twin pregnancy. The first route is via an open bleed from the fetal side of the placenta, which will usually manifest as an antepartum hemorrhage; the possibility of fetal blood loss should be considered when there is a significant antepartum hemorrhage late in labor. Second is fetomaternal hemorrhage. Diagnosis here depends on a high degree of suspicion and the demonstration of a significant number of fetal red cells in the maternal bloodstream. Reduced or absent fetal movements and a sinusoidal fetal heart rate trace seem to be non-specific and late antenatal signs that are associated with fetomaternal hemorrhage.3 The third route, fetoplacental hemorrhage, occurs in situations in which there is external pressure on the umbilical cord and the cord is separated early. This is classically seen in babies whose cord is around their neck but may occur in breech deliveries. As pressure on the cord increases, the vein will obstruct before the artery, and blood will continue to be pumped into the placenta. If the cord is separated early, this blood will be trapped in the placenta. This probably happens to some extent in many cases of nuchal cords, babies in this group having significantly lower hemoglobins levels.4 It occasionally results in a baby being born with severe hypovolemia.5 Finally, twin–twin transfusion is often chronic so the donor twin is born anemic but normovolemic. In acute or acute-on-chronic cases, however, the donor is hypovolemic. Seng and Rajadurai6 described 18 twin–twin transfusion pairs, 56% of whom were assessed as chronic and 44% as acute. Accurate diagnosis is critical here because if volume replacement is poured into a normovolemic, chronically anemic baby, cardiovascular
The classic clinical picture of hypovolemia is that of a baby who is pale, shut down, hypotensive and tachycardic with very slow capillary refill when the skin is blanched. Although it will be clear there is something wrong with this baby, each of these clinical signs is non-specific for circulatory compromise and could reflect anything from sepsis to congenital heart disease: none of these signs provides a definitive diagnosis of hypovolemia. In the immediate postnatal period, this clinical picture is common in babies with mild-to-moderate degrees of perinatal asphyxia. Most of these infants are not hypovolemic, the clinical signs probably reflecting the peripheral vascular effects of the hormonal stress response and acidosis.7 What is the evidence for the diagnostic accuracy of each of these signs when compared against measures of SBF?
Measures of peripheral perfusion Capillary refill time and core–peripheral temperature difference are widely used as the basis for volume expansion in acute care situations. The evidence suggests that both are tests of limited accuracy in the newborn. A capillary refill time of less than 3 s is traditionally accepted as normal. Tibby et al.,8 showed there was little relationship between capillary refill and measures of SBF in more mature babies in a pediatric intensive care setting, finding a positive predictive value only when the refill time was over 6 s. We have found a similar lack of relationship for low SBF in babies born before 30 weeks: only when the capillary refill time exceeded 5 s did the test have any degree of specificity.9 When the refill time is this long, the clinician generally does not need to press the skin to know that something is wrong. Both studies found no significant relationship between core peripheral temperature difference and measures of SBF.
Blood pressure Although blood pressure is commonly used as a gold standard of hemodynamic well-being in neonatology, there are now several studies that have shown only a weak relationship between measures of blood pressure and blood flow.9–14 This reflects the fact that pressure is also determined by resistance. As outlined above, resistance is increased as a compensatory response to hypovolemia, so a fall
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in blood pressure may be a relatively late sign. This is highlighted by the observation that small, acute changes in blood volume (8.5 ml/kg) produce little change in blood pressure.15 There are also consistent data from three studies in preterm babies that there is no relationship between blood pressure and blood volume.1,16,17
Heart rate There is no literature on the accuracy of a persistently increased heart rate as a marker of hypovolemia. Anecdotally, persistent tachycardia has been a feature of most cases of true hypovolemia the author has seen, particularly in more mature babies. In the preterm babies that we studied, heart rate had no relationship to low SBF.13
Investigations Hemoglobin/hematocrit Babies quickly redistribute extracellular fluid back into the vascular space, so spinning a blood sample for a hematocrit can be a useful adjunct to clinical assessment for a fetal bleed. The mean hematocrit in a term baby is 50% (±4.5%)18 so a fetal bleed should be considered in a shocked-looking baby with a hematocrit of less than 40%.
Central venous pressure monitoring In a mature circulation, central venous pressure (CVP) is accepted as a measure of blood volume, but whether this is also true in the transitional circulation is unclear. Differences in pulmonary vascular resistance in the transitional circulation may also influence CVP. CVP can be measured in babies via an umbilical venous line, and normal values have been established.19 Whether a low CVP accurately diagnoses hypovolemia in the newborn is, however, not known.
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that is not corrupted by intracardiac shunts.22 Flow is derived from blood velocity and vessel crosssectional area, the latter being calculated from vessel diameter. The velocity in the SVC can be measured using Doppler ultrasound from a low subcostal window, and the diameter can be measured from the low parasternal window (Fig. 1). Normal SVC flow in preterm babies is between 50 and 110 ml/kg/min.22 About 35% of babies born before 30 weeks have a period of SVC flow less than 40 ml/kg/min during the first 12 hours, the flow improving after this time. A strong association has been shown between this low flow and subsequent intraventricular hemorrhage.13,23 The reasons for this low flow state are complex, and the extent to which hypovolemia contributes to this is unclear. Volume expansion given to preterm babies with a low SVC flow improved flow by on average 55%, but the researchers did not study whether this was sustained (see subsequently).23 The other potential echocardiographic assessment of hypovolemia is ventricular filling, which can be assessed by left ventricular end-diastolic diameter (LVEDD). This is usually measured with m-mode echocardiography from the parasternal long axis view of the heart with the m-mode line transecting the ventricle at the tips of the mitral valve (Fig. 2). LVEDD is measured at the point of maximal ventricular filling. Normal mean LVEDD increases from 12 mm at 26–28 weeks to 17 mm at term.24,25 LVEDD as a test for hypovolemia has not been systematically examined in the newborn, but given that, at all gestations, the normal range for LVEDD is wide (e.g. 7.5–16.3 in 26–28 week fetus), and that there are many other factors that can affect left ventricular load conditions in the transitional circulation, it is unlikely this would be a reliable test. In cases of severe hypovolemia, however, dramatically poor ventricular filling may be apparent on echocardiography and can help to clarify the diagnosis, as demonstrated in the following case history.
Echocardiography
Case report
Ventricular outputs can be assessed using Doppler echocardiography. In a mature circulation, these outputs will reflect SBF. Again, however, this is not true in the transitional circulation, particularly in very preterm babies, in whom shunts through the ductus arteriosus and foramen ovale may cause ventricular output to overestimate SBF on the first day of life.20,21 Because of this, we developed the measure of superior vena cava (SVC) flow as a measure of part of the SBF (upper body and brain)
A term baby was born in poor condition. A tight nuchal cord had been clamped prior to delivery of the shoulders. The Apgar scores were 1 at 1 min and 2 at 5 min, the cord arterial pH 7.23 and the base excess −8.0. The baby was ventilated but remained pale with a tachycardia of 170 bpm. Echocardiography showed poor ventricular filling (Fig. 3), and the mean blood pressure was 35 mmHg. She was given 20 ml/kg normal saline, with immediate improvement. When the clamp was removed from the
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Fig. 1 Shows the parasternal saggital view of the SVC used for diameter measurement (left) and the Doppler velocity time integral (VTI) measurement from the subcostal position. The VTI is 0.137 m in this normal baby.
Evidence-based treatment with volume expansion Where volume is given to a truly hypovolemic baby, the physiological response is to normalize the pathological state as long as volume replacement is given before hypoxic organ injury results. Most babies given volume expansion in newborn intensive care are not, however, hypovolemic, so what are the appropriate clinical indications and what are the physiological responses to and outcome resulting from volume expansion in these babies?
What is the effect of volume expansion on blood pressure?
Fig. 2 Shows the left ventricular end-diastolic diameter (LVEDD) measurement taken from the m-mode echocardiogram. LVEDD is 16.1 mm in this term baby.
placental cord after delivery, blood under high pressure in the placenta was reported. The presumed diagnosis was acute fetoplacental transfusion with a nuchal cord.5
It is not surprising, considering that most hypotensive babies are not hypovolemic, that the blood pressure response to volume expansion is inconsistent. In observational studies, Bignall et al.26 showed, in infants with suspected hypovolemia, no overall change in blood pressure after 6 ml/kg 20% albumin, although four out of 12 babies demonstrated an increase in blood pressure. Rennie,27 studying infants on the first postnatal day, the majority of whom were hypotensive, reported no change in systolic blood pressure after 10 ml/kg plasma. Osborn et al.23 showed no significant
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Fig. 3 Contrasts the poor end-diastolic volumes of both ventricles in a severely hypovolemic baby (A) with the normal appearance in this parasternal long axis view (B).
Fig. 4 Percentage change in superior vena cava (SVC) flow and mean blood pressure after 10 ml/kg normal saline in 44 preterm babies with low systemic blood flow.
change in blood pressure after 10 ml/kg saline in 43 babies with low SVC flow, although there was again a wide range of response (Fig. 4). In randomized studies, Emery et al.28 recorded a median 20% increase in systolic blood pressure in hypotensive infants after 15 ml/kg 4.5% albumin or fresh frozen plasma (FFP) but little change after 5 ml 20% albumin. There was a wide variation in response. Lundstrom et al.29 found no difference in the change in mean blood pressure in normotensive infants between infants who received 15 ml/kg 20% albumin and controls. Volume expansion is not as good as dopamine at improving blood pressure. Gill and Weindling30 randomized hypotensive babies to 20 ml/kg volume or dopamine, dopamine increasing blood pressure into
the normal range in 89% of babies compared with only 45% of those given volume expansion. Lundstrom et al.29 also showed that dopamine was better than 15 ml/kg 20% albumin at improving blood pressure in a group of normotensive preterm babies. A systematic review of these randomized studies concluded that, because there were only limited data on the effect on blood flow, there was insufficient evidence to make firm recommendations.31
What is the effect of volume on systemic blood flow? Blood pressure and blood flow are not the same thing, and it cannot be assumed that an increase in
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one reflects an increase in the other. Three studies have examined changes in measures of SBF in response to volume, all showing a short-term increase in SBF after volume addition in the presence of only a limited response in blood pressure. In observational studies, Pladys et al.32 showed that left ventricular output increased from 193 to 272 ml/kg/min after 20 ml/kg of volume expansion. Osborn et al.23 showed a 55% increase in SVC flow after 10 ml/kg saline, but with little overall change in blood pressure. In randomized studies, Lundstrom et al.29 showed a mean increase in left ventricular output of 19% after 15 ml/kg but only a 6% increase in blood pressure. What none of these studies has resolved is whether these increases are sustained. Of note, Bignall et al.26 showed that blood volume had returned to baseline by 4 hours after 6 ml/kg 20% albumin.
What is the effect of volume on metabolic acidosis? This is perhaps the least evidence-based of all the indications for volume. There is little evidence that pH and base excess are good markers of circulatory compromise. They correlate very poorly with lactic acid levels,33 and, in our studies, neither pH nor base excess showed any correlation with measures of SBF.34 Not surprisingly, therefore, the few data that exist suggests that volume expansion is not a good way to correct a metabolic acidosis. Dixon et al.35 showed a small change in base excess after 10 ml/kg albumin, which was only about half the improvement achieved with sodium bicarbonate. Dimitriou et al.36 showed a small reduction in base deficit but no significant change in pH after albumin infusion. In the baby with clear-cut circulatory compromise and acidosis, volume may well be an appropriate response, but there is little support for its use as a first-line treatment for metabolic acidosis.
What is the effect of routine early volume expansion in preterm babies? Interest in this approach was triggered in 1985 by the trial of Beverley et al.37 In this study, 80 preterm babies were randomized to 10 ml/kg FFP on admission and again 24 hours later, or to a control treatment. The results suggested a reduction in intraventricular hemorrhage (IVH) in the treatment arm. However, analysis on an ‘intention-to-treat’ basis converted this to a statistically insignificant difference for severe grades of IVH.38 The issue was resolved by the much larger Northern Neonatal
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Nursing Initiative (NNNI) trial in 1996.39,40 A total of 776 babies were randomized to three groups who were given 10 ml/kg of a gelatin-based colloid or FFP, or to a control group. The volumeexpanded groups received volume on admission, a further 10 ml/kg being given 24 hours later. There were no significant differences in any important clinical outcomes, including neurodevelopmental outcomes at 2 years. A recent systematic review found four randomized trials including those already mentioned that compared routine early volume expansion with no treatment in a total of 940 very preterm infants.41 Meta-analysis of these studies showed no significant difference in mortality relative risk [RR] (1.11, 95% confidence interval [CI] 0.88–1.40). The 1996 NNNI study reported no significant difference in severe disability (RR 0.80, 95% CI 0.52–1.23), cerebral palsy (RR 0.76, 95% CI 0.48–1.20) and combined death or severe disability (RR 1.00, 95% CI 0.80–1.24). No significant difference was reported in grade 3–4 IVH and combined death or grade 3–4 IVH. One study (NNNI 1996) reported no significant difference in the incidence of hypotension. The conclusion of this review was that there was no evidence from randomized trials to support the routine use of early volume expansion in very preterm infants without cardiovascular compromise. There are, however, no trials that address the issue of the effect of volume on clinical outcome for infants with evidence of cardiovascular compromise, including hypotensive infants, infants with low blood flow or infants with clinically suspected hypovolemia.
What is the role of volume expansion in resuscitation? This is another area in which volume is used somewhat liberally. The clinical trigger here is usually the baby who remains pale after resuscitation. Most such babies are not hypovolemic but have varying degrees of acidosis and, if kept well oxygenated, will ‘pink up’ nicely by themselves. The circulatory compromise in the severely asphyxiated baby will usually result from the myocardial effects of hypoxia and acidosis.42,43 As the problem is cardiogenic, volume-loading an already compromised myocardium may not be the most appropriate response. The difficulty here is that a few of these babies are truly hypovolemic. In some, the diagnosis and action needed is obvious but, as discussed above, many of these can be very difficult to diagnose clinically. I would suggest that if, having explored the diagnostic strategies above, there is
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any doubt about the volume status of a baby, it is reasonable to give 10 ml/kg volume expansion. If possible, however, it should be given when the physiologic response can be monitored. If heart rate falls and blood pressure rises, more volume can be given if needed. If there is no physiologic response to volume addition, further volume expansion should be approached with caution.
What is the role of volume expansion in the sick term baby? Sick term babies tend to be a more heterogeneous group than preterm babies. Apart from resuscitation, the situations in which volume is commonly considered in term babies are severe respiratory failure/pulmonary hypertension of the newborn and septic shock. Again, despite widespread clinical use in term babies, there are almost no data in the literature that document the physiologic responses to volume expansion in these situations. There are also no data on clinical outcomes. The reasons for circulatory compromise in both these clinical scenarios are complex. Relative hypovolemia can occur in septic shock as a result of vasodilatation and capillary leakage. Our anecdotal observations in such babies suggest that although they are vasodilated, they tend to have a normal or high cardiac output, particularly early in the course of the illness. There are no formal hemodynamic studies of neonatal sepsis, so whether a large amount of volume expansion is useful in this vasodilated situation remains uncertain. We studied a cohort of term babies with high oxygen requirements using serial echocardiography and found very variable hemodynamics that were not easily predictable from the clinical situation.44 In these situations, it is worth trying accurately to define the hemodynamics with echocardiography. If there is any doubt, some volume expansion (10–20 ml/kg) might be helpful but should be abandoned if it is obviously not proving beneficial.
What type of fluid should be used for volume expansion? The issue of whether to use crystalloid or colloid was thrown into the limelight by the systematic review of Alderson et al.45 This review included all studies over a 30 year period, for all clinical indications, in all age groups, that had compared crystalloid with colloid infusion in sick patients. The meta-analysis suggested an increased mortality in the colloid group, with a combined odds ratio of 1.52 (95% CI 1.17–1.99). This review has been
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criticized for the heterogeny of inclusion criteria. Of the 35 trials included, five were neonatal, and, of these, only two compared crystalloid with colloid volume expansion given for circulatory support reasons. Only one of these two trials has so far been published in a peer-reviewed journal. This is the study of So et al.,46 which compared volume expansion with 10 ml/kg 5% albumin vs 0.9% saline in 63 hypotensive preterm babies. The researchers found that normal saline was as effective as 5% albumin for treating hypotension, as well as causing less fluid retention. There were no differences in any other clinical outcomes, although the trial was not powered to look at long-term outcome. Two other trials have so far appeared only in abstract form. That of Oca et al.47 compared the short-term effects on blood pressure and found no significant difference in a small group of 24 babies. There was a trend towards a more successful resolution of hypotension with albumin (82 vs 54%), but the response was only measured over 30 min. In the larger trial of Lynch et al.,48 102 hypotensive babies were similarly randomized to albumin or normal saline. Babies given albumin had a better immediate blood pressure response and were less likely to need inotropes afterwards. No details of other clinical outcomes were given in the abstract. The jury remains out on this issue in newborns. Because there are no comparative data on the effects on blood flow or important clinical outcomes, there is insufficient evidence to make firm recommendations. Our approach has been to use normal saline for circulatory support on the basis that it is cheaper, it is not a blood product and there is no evidence of any advantage form using colloid.
Conclusion We all use volume expansion, even though we cannot accurately diagnose when babies need it and we do not know much about what it does when we give it. The only definite conclusion is that there is no evidence to support the routine early use of volume expansion in preterm babies. In situations of circulatory concern, the goal should if possible be to define the hemodynamic situation echocardiographically. It is probably wise to use at least 10 ml/kg for volume expansion because hypovolemia can be very difficult to diagnose and there is some evidence of short-term circulatory benefit. Whether more should be given should be judged by monitoring the effects of this bolus on physiologic and, ideally, echocardiographic parameters of circulatory well-being. The benefits of giving more
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than 20 ml/kg in any but the most obvious hypovolemic situations must be questioned: the ‘Michelin Man’ appearance of many of these babies the day after repeated volume infusions would suggest that the fluid is not staying long in the vascular compartment. Future research in this area needs to focus on more accurate ways to diagnose hypovolemia and on whether volume expansion used for circulatory support produces sustained hemodynamic improvement (not just improved blood pressure) and whether it improves clinical outcomes.
Acknowledgements I would like to thank Dr David Osborn for his comments and help with this paper.
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