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Keywords:

  • asphyxia;
  • cardiovascular;
  • fetal sheep;
  • organ perfusion;
  • prematurity

SUMMARY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES
  • 1
    Poor perfusion of the kidneys and gut, and associated functional impairment, are major problems in the first days of life in very preterm infants. These complications can be associated with a substantial mortality and further problems such as reduced kidney growth and chronic renal problems in later childhood.
  • 2
    There is very little information, and consequently considerable debate, about how or even whether to improve perfusion of the vital organs of this most vulnerable group of babies. Current treatments simply do not consistently improve babies’ perfusion generally or kidney and gut perfusion and function in particular.
  • 3
    In this review we critically examine clinical and experimental evidence that suggests that exposure to low oxygen levels before and during birth may be a significant contributor to impaired systemic perfusion, and highlight areas requiring further research.
  • 4
    This knowledge is essential to develop and refine ways of improving perfusion of the kidneys and other vital organs in premature babies.

INTRODUCTION

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

Five to 10 percent of all births in the Western world occur before term (37 weeks gestation).1,2 Such prematurely born infants represent about 75% of neonatal morbidity, with most complications occurring in the most premature infants.3 Advances in neonatal care have seen the survival of the most vulnerable low birth weight babies improve significantly over the last two decades. Unfortunately, there has not been a proportionate improvement in age-specific morbidity. Indeed, there is some evidence that the increasing success of newborn intensive care has actually been associated with a moderate rise in the childhood prevalence of cerebral palsy.4 In the USA, the direct costs of caring for premature infants were estimated in 1992 to be 7.4 billion USD/year, double the direct costs of AIDS,5 and acute and chronic costs remain substantial.6,7

COMPLICATIONS OF PREMATURITY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

Although most recent research has been focused on neurodevelopmental disability, the immediate issues that confront premature infants and their carers after birth are primarily related to systemic complications, which, as well as respiratory distress, include frequent early gastrointestinal dysfunction, with an increased risk of later severe complications such as necrotizing enterocolitis (NEC) and renal impairment, including acute renal failure.8 In turn, adverse neurodevelopmental outcomes are highly associated with systemic complications including NEC.9 Acute renal failure (ARF) is estimated to occur in 8–24% of neonates that spend time in neonatal intensive care units (NICU).10,11 Early gastrointestinal dysfunction is nearly universal among extremely low birth weight infants and later NEC occurs in 1–5% of NICU admissions.12

The premature infant is undoubtedly more vulnerable to these complications in part simply because of immature organ structural and functional development. However, there is increasing evidence that impaired perfusion is a key factor that may link many perinatal events, such as exposure to hypoxia (low oxygen levels) around the time of birth, growth retardation, exposure to prostaglandin inhibitors and postnatal surgery, with early gastrointestinal and renal dysfunction in prematurely born infants.13–18

This review will dissect recent clinical data implicating hypoperfusion in the pathogenesis of some of the systemic complications in premature newborns, examine recent evidence suggesting that hypoperfusion may be actively mediated, and finally highlight avenues for future research.

GUT DYSFUNCTION AFTER PREMATURE BIRTH

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

Premature birth is associated with a high rate of impaired postnatal intestinal adaptation during the first days of life; for example, delayed meconium passage, abdominal distension, bilious vomiting and a delay in tolerating enteral feeding and later NEC.19 The aetiology of ultimate NEC is much more complex than that of the earlier symptoms and involves a triad of hypoperfusion, enteral feeding and bacterial invasion.20,21 Hypoperfusion is the earliest stage and seems to link a wide variety of disparate clinical associations with early gastrointestinal dysfunction.13,14,17,18 Currently, there is little information on the specific mechanisms that control gut perfusion in the perinatal period.

Hypoperfusion and gut dysfunction

The histopathologic changes that occur in NEC such as mucosa oedema, haemorrhage and necrosis, are most often found in the watershed areas between the superior and inferior mesenteric artery, the ileum and proximal colon, strongly suggesting ischaemic injury. The timing of this injury has been the subject of considerable debate.22 Both epidemiological and clinical evidence point toward at least some cases being triggered by prenatal and perinatal hypoxic events. Epidemiologically, NEC is closely associated with prematurity or low birth weight,23 but also with a number of other factors including exposure to antenatal glucocorticoids, vaginal delivery, need for mechanical ventilator support, treatment for patent ductus arteriosus with indomethacin, treatment for hypotension and low Apgar score at 5 min.3,24–26 In turn, most of these factors imply an association with either hypoxia or with hypoperfusion, or both.

Clinically, several studies have shown a close association between absent or reverse end diastolic flow (A/R EDF, i.e. reduced utero-placental perfusion leading to fetal hypoxia) before birth in low birth weight infants and subsequent necrotizing enterocolitis. For example, Bhatt and colleagues found in a case control study of infants born weighing less than 2 000 g that A/R EDF had a positive predictive value for NEC of 52.6% (RR 30.2; OR 264),27 with a subsequent mortality from NEC of 50%. Conversely, when umbilical artery velocimetry was not reduced, there were no cases of NEC or mortality. This was a highly selected, retrospective analysis; however, others have also found an increased risk of perinatal complications including NEC and non-specific feeding problems, such as delayed meconium passage, abdominal distension, bilious vomiting and a delay in tolerating enteral feeding in growth-restricted infants with impaired uteroplacental blood flow.17,28–33 This association appears to be independent of other variables such as degree of growth retardation and prematurity.17 Strikingly, fetuses with A/R EDF also have abnormal mesenteric artery pulsatility on Doppler, which was in turn associated with later NEC.33

These prenatal events affect postnatal gut perfusion, with evidence that low birth weight infants have a reduced rise in preprandial gut blood flow and further, that those who failed to show this preprandial increase had a very high rate of feeding intolerance.34,35 Reduced intestinal blood flow after birth is also highly associated with an increased risk for subsequent NEC.14 This hypoperfusion precedes the development of NEC. However, once NEC is established several groups have reported that mesenteric (gut) blood flow velocity is consistently increased.16,36 Interestingly, in three infants, in whom previous serial monitoring studies had been performed, gut perfusion had been decreased or were non-responsive to feeding in the days before the onset of NEC.16 Thus, these data suggest that NEC is linked to preceding impairment of gut perfusion in the preterm infant.

RENAL DYSFUNCTION IN THE PRETERM INFANT

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

Renal dysfunction and overt acute renal failure are also extremely common in prematurely born infants. These problems are most frequent and severe in the more premature infants. Nearly all extremely premature infants (< 30 weeks gestation) will develop an early phase of intense polyuria with salt wasting after birth, which resolves over the first week.37,38 Acute renal failure, a rapid and sustained reduction in renal function which results in accumulation of waste products in the body, such as urea, and a critical inability to control fluid and ion balance,39 occurs in 8–24% of all preterm infants.10 Acute renal failure may be polyuric (increased urine output) or oliguric (reduced urine output). The mortality of oliguric neonatal renal failure may be as high as 60%. In survivors, there is now evidence of reduced glomerulogenesis and thus reduced numbers of nephrons in the long term,40,41 and they are at high risk of chronic deterioration of renal function in later childhood.42 As discussed in depth below, recent clinical studies have highlighted reduced renal blood flow in the first 3–24 h after premature birth as a major predisposing factor for renal impairment, but the underlying mechanisms are not fully understood. Consequently, we know much more about what potential clinical interventions do not help than about which ones might.

In broad terms, there are three general causes of ARF; prerenal, intrinsic and postrenal.39 Pre-renal implies that reduced glomerular filtration rate (GFR) is a consequence of low renal blood flow, which in turn is due to low mean arterial blood pressure.39 Intrinsic ARF describes injury in the renal tissue itself, such as acute tubular necrosis and postrenal denotes significant restriction of the downstream collecting system.39 The aetiology of preterm ARF remains unclear. Chevalier et al. suggested that the majority of neonatal ARF is accompanied by renal ischaemia (i.e. hypoperfusion).43

Based primarily on this observation and the high incidence of ‘hypotension’ in preterm infants, it has been strongly argued that 85% of cases of ARF in premature newborns are due to prerenal mechanisms.11 Supporting this concept, basal renal blood flow and GFR in preterm infants are of a very similar magnitude, implying that even a very small reduction in renal perfusion should impair GFR. However, there is surprisingly little direct evidence for this assertion. Indeed, Doppler flow measurements suggest that renal vascular resistance is initially elevated shortly after birth and progressively falls with time.44,45 These studies found only a weak relationship between renal blood flow velocity and urine output,46 and suggested that oliguria is typically seen only with the most marked reductions in renal blood flow velocity. Limited studies involving a mixture of term and preterm infants have suggested that the majority of neonatal renal failure is associated with perinatal hypoxia/asphyxia.18,47 Thus, the role of poor perfusion in determining preterm renal function remains unclear.

MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

Blood pressure is not a good marker of organ perfusion

Blood flow to organs, organ perfusion, is dependent on two main factors: net perfusion pressure across the organ and peripheral vascular resistance. The equation is simply ‘Blood flow = arterio-venous blood pressure difference/vascular resistance’. In most cases absolute venous pressure is low and therefore arterial blood pressure is a good surrogate for the pressure gradient. Not surprising, traditionally, blood pressure, which is easily measured and readily available, has been the major or indeed only measure of the adequacy of circulation in the newborn. Current clinical management is almost entirely orientated around preventing or treating hypotension. However, there is no evidence that this is an effective strategy for the majority of babies. Although there are some very limited data showing an association between very low blood pressure and adverse outcomes (such as abnormal cranial ultrasound changes),48,49 as recently reviewed, there is no evidence that treating blood pressure with volume or inotropic agents generally improves outcome.50 Thus there is a great need to better understand the physiological mechanisms underpinning hypoperfusion.

Peripheral vascular resistance is the key to perfusion

Given that blood pressure is not a primary determinant of reduced peripheral blood flow, the key to understanding preterm organ perfusion is the other half of the equation: peripheral resistance. If vascular resistance is elevated, then perfusion of organs such as the kidney will be impaired despite normal blood pressure. Measurement of cardiac output is more complex in the preterm newborn than in later life, because the fetal shunts, such as the ductus arteriosus which transfers blood from the pulmonary circulation to the aorta before birth, are still open and thus direct measurements of ventricular output potentially can be misleading. Instead, measurement of blood flow in the superior vena cava (SVC) corrected for bodyweight is now used as an accurate measure of total systemic perfusion, that allows rational comparison between babies across gestations.51 Doppler velocity in the large arteries supplying particular organs can be used to supplement this information.

These studies have shown that pathologically low systemic blood flow occurs in one-third of infants born before 30 weeks gestation. In 80% of cases it was lowest at 5–12 h of age and progressively resolved with time; less than 5% of infants had low flows by 48 h. This hypoperfusion was strongly and independently associated with oliguria and hyperkalaemia,52 and mortality and adverse neurodevelopmental outcome.53 In contrast, there were no such associations with mean blood pressure in the first 24 h of life.53 Consistent with this, mean arterial blood pressure is poorly correlated with systemic perfusion as measured by SVC flow or with left ventricular output.54,55

Evidence of increased renal vascular resistance after preterm birth

The studies discussed above have shown that impaired total systemic perfusion is associated with evidence of renal impairment, with a transient increase in plasma potassium and oliguria. Consistent with this overall evidence for increased systemic vascular resistance, there is direct evidence in the kidney, from Doppler flow measurements, that renal vascular resistance is maximally elevated shortly after birth in preterm infants and progressively falls with time.44,45 Such studies suggest that oliguria is closely correlated with marked reductions in renal blood flow.46

The very weak relationship between systemic or organ perfusion and arterial blood pressure denotes a correspondingly close, inverse, relationship between perfusion and vascular resistance.54,55 Clearly, elevated resistance may be a compensatory response to a primary impairment of cardiac output. There is evidence supporting this in some babies, who show impaired contractility in the first day of life, which resolves by day 5.56 However, elevated resistance can also be the cause of poor perfusion.57 The specific mechanisms of this increase are unknown. Potentially, as suggested mainly by indirect information in adult species, it could be due to local endothelial injury or dysfunction,58–61 or it could be actively mediated, reflecting at least in part reduced metabolic requirements.62,63

Hypoxia and increased vascular resistance

The other major factor associated with impaired renal (and gut) function in preterm infants is evidence of perinatal hypoxia. The majority of cases of severe ARF in preterm infants have multisystem evidence of severe hypoxic injury.18,43,47,64 More generally, although it is not often appreciated, perinatal hypoxia is much more common in infants born prematurely than at term,65 and frequently occurs before the onset of labour.66 Further evidence comes from early serial electroencephalographic (EEG) and imaging studies, which suggest that preterm neural injury occurs in the immediate perinatal period in approximately two-thirds of cases, while up to a third of cases may occur antenatally and cases in the chronic postnatal period are the least common.67–69 Further, worse outcomes are strongly associated with exposure to perinatal hypoxia, active labour, abnormal heart rate traces in labour and subsequent low Apgar scores.69–72 Thus, antenatal and perinatal hypoxia is a common adverse event in premature birth.

It is very important to appreciate that immature animals are much more resistant to hypoxia than adults.73 Further, preterm animals are able to survive remarkable periods of profound hypoxia without injury, as previously reviewed.74 Nevertheless, the adaptations that the fetus makes to hypoxia can include prolonged secondary hypoperfusion and reduced metabolism, even after insults that do not cause immediate damage. During this secondary phase, the prematurely born newborn may be vulnerable to secondary insults. For example, the newborn gut is both required to be more active than in fetal life, and is exposed almost from the first few hours to significant bacterial colonization. Similarly, before birth the placenta is the primary organ responsible for clearing waste products and fluid management, whereas after birth, the kidney must assume this role. Thus fetal adaptations after hypoxia may have deleterious consequences for the newborn.

Metabolic acidosis at birth (denoting acute exposure to hypoxia), active labour, abnormal heart rate traces in labour and subsequent low Apgar scores are all highly associated with perinatal complications such as ARF and with adverse outcomes in the long-run.69–72 The relationship between renal dysfunction and hypoxia suggests that, in these cases at least, increased renal vascular resistance may be triggered by the hypoxic exposure.

Sympathetic nervous system activity during severe hypoxia

As shown in Fig. 1, exposure to severe hypoxia, induced by complete occlusion of the umbilical cord is associated with a very rapid and intense, but transient, fall in renal blood flow and a corresponding increase in vascular resistance. The rapidity and pattern of changes in renal blood strongly suggest a neural mechanism rather than local endothelial injury.

image

Figure 1. The impact of asphyxia on mean arterial blood pressure (MAP), fetal heart rate (FHR), renal blood flow (RBF) and renal vascular resistance (mmHg/mL per min) in preterm fetal sheep. Note the partial failure of renal vasoconstriction after 4 min of asphyxia leading to renal vasodilatation and a fall in blood pressure. Data are 1 min averages (mean±SEM). Data are derived from Quaedackers et al.103

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Although there is no specific information in the preterm fetus, there is considerable evidence, from older fetuses and postnatally, that alpha-adrenergic sympathetic nervous system (SNS) activity plays a central role in regulating renal and gut perfusion during severe hypoxia/asphyxia. The fetal gut is innervated by the autonomic nervous system from very early in development,75 and the autonomic nervous system is an important regulator of intestinal blood flow under a variety of physiological and pathological conditions.76–81 Similarly, the kidney receives a dense innervation of sympathetic fibres to the afferent and efferent arterioles, juxtaglomerular apparatus and the proximal tubules. In the adult animal, changes in renal sympathetic nerve activity (RSNA) have been shown to influence renal blood flow, glomerular filtration rate, renin release and sodium excretion.82

Strong evidence indicates that the central nervous system produces a highly differentiated pattern of sympathetic drive to different target organs to redistribute blood flow in response to different challenges.83–85 In particular, redistribution of blood flow away from the peripheral organs such as the gut and kidney during hypoxia and asphyxia in near-term animals in utero is largely mediated by alpha-adrenergic receptors,77,86,87 and sympathectomy in the sheep fetus results in increased meconium passage.88 Importantly it appears that the longer-term control of blood pressure is specifically dependent on the level of RSNA and its associated effects on renal function.89–91 In the adult rat, increased RSNA is involved in cardiovascular compensation for primary cardiac failure.92 Although resting sympathoadrenal activity is thought to be low in the fetus,93 there is good evidence in the term-equivalent fetus that SNS activation is essential for survival during hypoxic stress.94 During severe hypoxia there is a dramatic reduction in blood flow to peripheral organs, such as the gut and kidney, that is largely mediated by sympathetic activity and which helps support blood flow to the brain and heart.95–97

PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

In the near-term sheep fetus studies using microsphere blood flow measurements reported that gut blood flow is maintained or increased during moderate hypoxia or asphyxia, whereas during severe hypoxia there is a redistribution of blood flow away from peripheral organs such as the gut in favour of central organs.98–100 In contrast, in the near mid-gestation sheep fetus partial compression of the umbilical cord did not decrease intestinal blood flow.101 However, this may reflect the greater anaerobic capacity of the preterm fetus. Consistent with this interpretation, we have demonstrated that even the very preterm fetus can mount an effective cardiovascular defence, with initial vasoconstriction and hypoperfusion in the kidney (as well as the limbs and the gut).102–105 Strikingly, we found that this initial peripheral vasoconstriction was maximal after just 4 min of hypoxia (Fig. 1), then failed, with a corresponding increase in renal perfusion.103 This failure of vasoconstriction corresponded with a rapid fall in blood pressure, strongly suggesting that fetal systemic adaptation was compromised by this failure. A nearly identical pattern of change was seen in femoral and gut blood flow, demonstrating that it does not represent a unique vulnerability of the kidney.102–106

The mechanisms mediating this critical loss of redistribution are unknown. We have previously speculated that it was essentially a passive phenomenon, mediated by profound local peripheral acidosis causing vasoparesis.103 Alternatively, it could reflect a reduction in SNS activity. However, it seems improbable that there could be a loss of circulating sympathetic tone, since catecholamine levels increase logarithmically during prolonged periods of severe hypoxia.107 Future studies using continuous recordings of RSNA in the unanaesthetized preterm fetus will be required to resolve this question.

HYPOPERFUSION AFTER SEVERE HYPOXIA

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

As mentioned above, secondary hypoperfusion is known to develop in many vascular beds after hypoxic or ischaemic insults both pre- and postnatally, typically in the first few days after an insult.108 Further, studies in the newborn piglet intestine have shown that sustained reduction of intestinal blood flow caused a decrease in production of the vasodilator nitric oxide and an increased response to vasoconstrictors in the 3-day-old but not the 35-day-old piglet, suggesting the immature intestine is more vulnerable to secondary hypoperfusion.109,110 However, it is critical to appreciate that this represents a mature, term-equivalent model. In the preterm fetal sheep model there is strong experimental evidence of hypoperfusion after asphyxia in multiple vascular beds.103–106

Thus, for example, we found that a marked, delayed (secondary) renal hypoperfusion developed during recovery from severe hypoxia (Fig. 2).103 This hypoperfusion was associated with increased vascular resistance. Fetal blood pressure was mildly increased during this time. This suggested the possibility that in part, this increased vascular resistance may help support supraphysiological perfusion pressures for the heart and brain. The evidence discussed in the mesenteric circulation below supports this hypothesis.

image

Figure 2. This figure demonstrates the mean arterial (MAP) and renal blood flow (RBF) responses of preterm fetal sheep for 4 h before and for 12 h after an asphyxial insult (dashed arrow, see Fig. 1 for these data). Note the secondary fall in RBF during the early hours of recovery which occurs despite blood pressure being elevated. Data are 1 min averages (mean±SEM). Data are derived from Quaedackers et al.103

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MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

The pattern of blood flow changes after severe hypoxia in the mesenteric bed is much more complex than in the femoral/renal beds, but highly consistent.104,106 As shown in Fig. 3, the delayed fall in superior mesenteric artery (SMA) blood flow after hypoxia was reversed transiently between 2 and 5 h, suggesting that hypoperfusion can be overridden. This rise in SMA blood flow between distinct periods of postasphyxial gut hypoperfusion was not related to a rise in blood pressure, but was associated with a significant fall in SMA vascular resistance. It is of interest that this increase in SMA blood flow was associated with a delayed period of sustained tonic nuchal EMG activity. When this muscle activity subsided, SMA blood flow once again fell. The aetiology of this increased nuchal EMG activity is not known. Mean EEG amplitude remained depressed at this time, however, it is notable that there was an evolving increase in epileptiform transient activity at this time,105 suggesting a centrally mediated mechanism, leading to a loss of central sympathetic tone. This was associated with a rise in FHR and thus an increase in combined ventricular output. The secondary gut hypoperfusion was prevented by a short post-hypoxic infusion of an α-adrenoceptor antagonist.104 Normalization of blood flow to the gut was associated with mild hypotension. This study did not examine perfusion in other vascular beds such as the kidney, and of course could not distinguish between sympathetic neural activity and an effect of circulating catecholamines released by the adrenal gland. There is no other evidence on the role of sympathetic neural activity in secondary hypoperfusion.

image

Figure 3. This figure shows changes in superior mesenteric artery blood flow (SMABF) of preterm fetal sheep for 4 h before and for 10 h after an asphyxial insult (data not shown). Note the biphasic secondary fall in SMABF during the early hours of recovery which occurs despite blood pressure being elevated as shown in Fig. 2. An infusion of the α-adrenoceptor antagonist phentolamine after asphyxia (infusion period) completely abolished the fall in SMABF. Data are 1 min averages (mean±SEM). Data are derived from Quaedackers et al.104

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The physiological significance of this apparently active and relatively prolonged period of hypoperfusion of the gut during the latent phase of recovery after asphyxia is unknown. In large part, it is likely that it reflects a reduction in local metabolism. However, in addition we hypothesize that its ‘purpose’ is in part to maintain systemic perfusion pressure. In the adult under conditions of decreased cardiac output caused by cardiogenic or hypovolaemic shock, selective vasoconstriction of the afferent mesenteric arterioles is reported to be crucial in sustaining total systemic vascular resistance, thereby maintaining systemic arterial pressure.111,112 Under these conditions, while there is some degree of vasoconstriction in other peripheral systems, it is disproportionately greater within the mesenteric circulation and thus perfusion of non-mesenteric organs is maintained at the expense of the gut.111,112 Similarly, in the fetal sheep marked constriction of the mesenteric bed occurs during acute asphyxia to facilitate redistribution of combined ventricular output in favour of central organs,99,106,113 but its role during postasphyxial recovery has not been evaluated.

There is considerable clinical and experimental evidence to show that reversible myocardial injury and associated cardiac dysfunction are common during recovery from exposure to perinatal asphyxia.114–116 Consistent with the hypothesis of early myocardial dysfunction, an infusion of the α-adrenoceptor antagonist phentolamine led to a reduction in blood pressure for 3–4 hours despite normalization of SMA blood flow for most of this period (Fig. 3).104 This is in contrast with the significant elevation seen in the asphyxia vehicle group, which was associated with an increase in SMA vascular resistance. This hypothesis is further supported by a fall in blood pressure observed in the asphyxia vehicle group during the period of spontaneous gastrointestinal vasodilatation around 4 hours postasphyxia, which was followed by a modest increase in pressure during the second period of hypoperfusion between 5–7 hours. Currently it is unclear what is mediating this transient rise in blood flow. It may be related to a reduction in sympathetic tone; however, other factors are likely to play a role in mediating both the vasoconstriction and vasodilatation. Nitric oxide (NO), for example, is known to be an important modulator of perfusion in the preterm gut,60,117 and is also known to modulate sympathetic activity.118 Additionally, NO can also alter vascular reactivity at the sympathetic neuroeffector junction in the rat mesenteric bed by deactivating noradrenaline.119 There may also be similar roles for other neurotransmitters and peptides such as NPY.119,120

CONCLUSIONS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

In summary, the preterm fetus and newborn are critically susceptible to functional renal and gut impairment in the first days after birth. In many cases this appears to be closely and potentially causally associated with hypoperfusion brought about by an increase in underlying renal and mesenteric vascular resistance. This review has examined data demonstrating that hypoperfusion following exposure to severe hypoxia is not a result of some vague ‘endothelial dysfunction’ but rather is actively mediated. Further, activation of the sympathetic nervous system was a key mediator of hypoperfusion. We speculate that this is due to a selective increase in sympathetic nerve activity, which needs to be tested in the future by direct nerve measurement and cardiovascular parameters in the preterm fetus before, during and after a period of severe hypoxia.

These findings are consistent with the recent clinical finding that severe systemic hypoperfusion can occur in a subset of preterm infants, despite normal blood pressure. Further studies are needed to fully understand the significance of these changes in different settings. In part, it may simply reflect a posthypoxic reduction in tissue metabolism. However, in part increased vascular resistance in the gut in particular seems to play a vital role in supporting cardiovascular function after hypoxia, as shown by the significant fall in blood pressure when perfusion was normalized by α-adrenoceptor blockade. These findings are consistent with the highly equivocal effects of many clinical interventions, such as a volume expansion, administration of inotropes and closure of the ductus arteriosus after birth. Focused, physiolologically orientated studies are required in the future to evaluate when (if ever) and how promotion of blood flow should be considered and to dissect the role of specific mechanisms such as increased activity of the sympathetic nervous system.

ACKNOWLEDGEMENTS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES

The authors’ studies in the present review were supported by grants from the Health Research Council of New Zealand, USPHS grant RO1 HD-32752, the Auckland Medical Research Foundation and the Lottery Grants Board of New Zealand. JD was supported by a Bright Futures scholarship from the National Foundation for Research, Science & Technology.

REFERENCES

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. COMPLICATIONS OF PREMATURITY
  5. GUT DYSFUNCTION AFTER PREMATURE BIRTH
  6. RENAL DYSFUNCTION IN THE PRETERM INFANT
  7. MECHANISMS OF HYPOPERFUSION: THEORETICAL AND PRACTICAL CONSIDERATIONS
  8. PERIPHERAL BLOOD FLOW DURING SEVERE HYPOXIA
  9. HYPOPERFUSION AFTER SEVERE HYPOXIA
  10. MESENTERIC HYPOPERFUSION IS ESSENTIAL FOR CARDIOVASCULAR SUPPORT
  11. CONCLUSIONS
  12. ACKNOWLEDGEMENTS
  13. REFERENCES
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