ischaemia and necrotizing enterocolitis

Semin Neonato11997; 2:245--254

Enteral hypoxia/ischaemia and necrotizing enterocolitis H. R. Gamsu a and S. T. Kempley b

"King's College &hool of Medicine and Dentistry, Bessemer Road, London, UK bRoyal London Hospital, Whitechapel, London, UK

Key words: mesenteric artery, superior, necrotizing enterocolitis, blood flow velocity

The intestinal circulation normally meets the bowel's metabolic needs, but adaptive responses may sacrifice flow to the intestine to preserve the oxygenation of other organs. Severe or prolonged hypoxia associated with birth asphyxia or intrauterine growth restriction may predispose to necrotizing enterocolitis (NEC) by repeated or persistent redistribution of blood flow away from the bowel. Immature autoregulation of gut blood flow in the face of such challenges may explain the susceptibility of neonates to gut ischaemia. Other factors reducing intestinal blood flow may interact with the increased metabolic demands imposed by enteral feeding to contribute to the development of NEC.

Anatomy and physiology of the neonatal intestinal circulation The intestinal blood supply is unusual in a number of respects which are relevant to the pathogenesis of necrotizing enterocolitis (NEC). Intestinal blood flow transports the products of digestion and meets the metabolic needs of the intestine which change with the demands of secretion, absorption and motor activity. Substantial increases in gut blood flow follow enteral feeding, but in other circumstances the needs of the intestine are sacrificed to maintain an adequate blood supply to organs less able to tolerate ischaemia, such as the brain. The intestine derives its arterial blood supply from three branches of the abdominal aorta. The coeliac axis (arising at T12 L1) supplies the stomach and duodenum; the superior mesenteric artery (SMA, arising at L1) supplies the rest of the small intestine, and the ascending and transverse colon; the inferior mesenteric artery (arising at L3) supplies the transverse, descending and sigmoid colon and the rectum. Post mortem studies indicate that NEC is most likely to occur in the regions supplied by the SMA [1]. Anastomotic networks between the ileal arcades protect against thromboCorrespondence: It. R. Gamsu. King's College School of Medicine and Dentistry, BessemerRoad, LondonSE5. UK. 1084-2756/97/040245 + 10 $12.00/0

embolism. Venous drainage via the portal vein and the liver means that the intestine functions with a higher venous pressure than other parts of the neonatal circulation. Reduction in gut blood flow may follow hypoxia, haemorrhage, and hypotension, and it was initially suggested that NEC was the result of such redistributive mechanisms [2]. In the case of hypoxia, increased vascular resistance results from the stimulation of alpha-adrenergic receptors via sympathetic nerves [3]. The adult intestine is protected from ischaemia by myogenic and metabolic autoregulation, but this may be impaired in immature animals [4, 5] so that hypotension and hypoxia could cause bowel injury more easily in neonates. Myogenic autoregulation occurs as increased intravascular pressure stretches vascular smooth muscle inducing vasoconstriction. Conversely, decreased arterial pressure leads to dilatation of resistance vessels and recruitment of capillaries, preserving blood flow in the face of lowered perfusion pressure. This pressure-flow autoregulation is absent in three day old piglets, whereas in 35 day old piglets, intestinal oxygen uptake is independent of arterial pressure. However, the response to acute elevations of venous pressure in piglets under a day old suggests that in this age-group this autoregulatory constricting response may be better than in older animals [6]. © 1997 W.B. Saunders Company Ltd

246

Metabolic autoregulation increases blood flow when oxygen delivery fails to meet metabolic needs. In response to an infusion of hypoxic blood there is a fall in intestinal vascular resistance of up to 50% in the older piglet but only a small fall (less than 20%) in piglets aged tess than 7 days. After perfusion of hypoxic blood this failure of metabolic autoregulation results in reduction in oxygen delivery (blood flow x oxygen content) to the intestine of the newborn piglet of more than 50% [7]. Decreased blood flow does not necessarily result in tissue hypoxia, since increased oxygen uptake can compensate for reduced oxygen delivery. Intestinal oxygen uptake falls, however, when blood flow is reduced by 30% below resting levels [8] and mucosal injury occurs when oxygen uptake is reduced by 50% [9], with blood flow reductions of 50-60% from resting levels. Because oxygen consumption is higher in the newborn intestine [6] smaller reductions in blood flow could have a greater effect on tissue oxygenation. These intrinsic mechanisms are crucial in maintaining the viability of the gut when oxygen supply is diminished in the presence of arterial hypotension or hypoxia. If they are ineffective in immature neonates, then vasodilatation and capillary recruitment will not occur and intestinal integrity will be jeopardized.

The diving seal response and acute asphyxia In diving aquatic animals, redistribution of blood flow occurs during a dive. This was first extensively studied by Scholander et al in the seal [10], though the diving response has been demonstrated in animals as diverse as the duck, the porpoise [11], the whale, hippopotamus [12] and paradoxically in the flying fish when it is air-borne. In the seal, upon immersion, the heart rate falls dramatically. While blood flow to the brain and heart increases, flow to the flippers, kidneys and intestine is markedly reduced. A similar diving response has been described in the pearl divers of Australia who are trained in childhood to dive deeply. They develop bradycardia and show evidence of peripheral vasoconstriction, with increased blood lactate levels after the dive on reperfusion of previously ischaemic organs [I3]. What is the relevance of these studies to NEC in the human infant? A bradycardic response to

H.R. Gamsu and S. T,

Kempley

hypoxia is seen in the fetus during labour, and in the premature neonate who develops apnoea with bradycardia. However, intestinal vasoconstriction from efferent sympathetic nervous stimulation is not sustained. Within 3-5 minutes there is autoregulatory escape and rapid restoration of intestinal oxygen uptake [14, 15] so that vasoconstriction from neural adrenergic stimulation is unlikely to result in sufficiently prolonged ischaemia to cause intestinal necrosis. If a diving type response has occurred before birth, the interval between the stimulus and the onset of NEC is usually much longer than that shown in the experimental studies cited--sometimes weeks rather than hours after the event. It is, however, postulated that repeated hypoxic episodes causing reduced intestinal blood flow, with subsequent reperfusion injury, may damage the bowel sufficiently to predispose to other factors which then lead to NEC [16]. Birth asphyxia alters intestinal motility in term neonates [17] leading to intolerance of enteral feeds in the first week of life. Other studies have shown an association of NEC with hypoxia due to perinatal asphyxia [18-20] although Palmer et al [20] found that in the very low birth weight baby recurrent or prolonged post-partum hypoxia was a more likely antecedent than asphyxia noted at birth, which was a predisposing factor only in heavier babies. We have observed extensive intestinal mucosal loss only hours after severe birth asphyxia and Kosloske [21] gives a similar example. Asphyxia has been shown in newborn piglets to result in intestinal vasoconstriction and ischaemia [22] and a similar reduction in intestinal blood flow has been found in lambs exposed to hypoxia [23]. This response is modified by intestinal denervation [3]. Hypoxia needed to last longer than 90 minutes to cause a reduction in intestinal blood flow and intestinal damage in studies on the newborn piglet [24]. In preterm babies, who as a group are those most prone to the development of NEC, it seems that if hypoxia plays a role in the development of this disease, that it would need to be prolonged, repeated or accompanied by other factors that would predispose to the disorder.

Chronically reduced mesenteric blood flow in the fetus Growth restricted fetuses are at an increased risk of intra-uterine death or asphyxia at birth. If growth

Enteral hypoxia/ischaemia

247

Table 1. Incidence of necrotizing enterocolitis according to fetal Doppler ultrasound findings of absent or forward end-diastolic flow in the umbilical artery. NEC and absent or reversed end-diastolic flow velocity in u.a: 25 high risk pregnancies with AREDF; 19 morphologically normal; 4 perinatal deaths

Gest. age B. wt NEC Proven Suspect Total

High risk AREDF n = 15

Matched controls n = 15

30.5 4- 3.0 1059 4- 343

30.4 4- 2.9 1079 4- 353

5 3 8

1 0 1 p<0.01

From G. Malcolm et al [27] Arch Dis Child 1991; 66: 805-807, with permission.

retardation is due to uteroplacental insufficiency, the fetus may be hypoxaemic. Doppler ultrasound measurements of blood flow velocity in the umbilical artery demonstrating absence of end-diastolic frequencies have been shown to relate to decreased pH and PO 2 in fetal blood taken from the umbilical vein [25]. Hackett et al [26], using Doppler techniques to study end-diastolic blood flow velocity in the fetal aorta in fetuses with growth restriction, found in 26 fetuses of <2000 g, significant associations between reduced or absent end-diastolic blood flow velocity with NEC, perinatal mortality and haemorrhage. Both duration and severity of the absent end-diastolic flow velocity were associated with neonatal death, NEC and a complicated course. Subsequently a number of other reports have found a similar relationship between absent or reversed end-diastolic flow velocity (AREDV) and neonatal problems including NEC (Table 1) [27-29]. The association with NEC was not found in every series as Pattinson et al [30, 31] show. In their first study though neonates with AREDV had reduced platelet counts, were more likely to be growth retarded and anaemic, there was no increased incidence of NEC, and in the second study none of the most severely preterm and low birth weight babies survived for very long, important in a group who would tend to develop NEC at a later age. Most series have found an association between poor perinatal outcome and reversed enddiastolic flow velocity in the umbilical artery or fetal aorta. Eronen et al [28] point out that AREDV

in the fetal umbilical arteries is a normal finding at less than 18 weeks gestation but that after 20 weeks it is associated with high perinatal morbidity and mortality. As can be seen later in this chapter, babies who as fetuses are noted to have absent end-diastolic flow are likely to have persistent reduction in superior mesenteric and coeliac artery flow in the neonatal period, and this finding has persuaded us to exercise particular caution when introducing feeds in premature babies.

Cocaine A different cause of reduced intra-uterine blood flow is that of the fetus exposed to cocaine taken by the addicted mother. The fetus is at risk of the effects of reduction in uterine and placental blood flow [32, 33]. Bowel infarction and colitis have been reported in adults who have taken this drug. Cocaine blocks the presynaptic re-uptake of neurotransmitters norepinephrine and dopamine, and produces an excess of transmitter at the postsynaptic receptor site. Sympathetic over-activity produces vasoconstriction, and ischaemic lesions have been reported in the heart, brain and kidney. There are a number of reports of necrotizing enterocolitis in babies of mothers who have habitually taken cocaine or derivatives in pregnancy [32, 34, 35].

Factors affecting intestinal blood flow in the human newborn Case-control studies have identified a number of clinical factors which are statistically associated with NEC, and which could cause intestinal ischaemia either directly, or through the action of extrinsic control mechanisms activated by hypoxia. Such associations have been taken to imply an ischaemic aetiology for NEC, but they cannot prove a causal link between each factor and the disease, and they cannot incriminate ischaemia as part of the pathogenic mechanism leading to NEC. Animal studies have demonstrated the effect of various factors on intestinal blood flow, but are difficult to generalize to the human newborn. Many premature infants at greatest risk of NEC are far more functionally immature than the animals used in physiological studies. Furthermore, in many animal

248

models intestinal ischaemia results in patterns of injury which are pathologically distinct from NEC. In the past it was not possible to measure intestinal perfusion in the human newborn, but recently a number of investigators have used Doppler ultrasound to study the effects of various clinical factors on the velocity of blood flow in the human SMA. This technique measures the Doppler shift in the frequency of ultrasound reflected from moving blood cells within the lumen of the SMA, and uses this to calculate the velocity of blood flow within the artery. In the adult it is possible to measure the diameter of the artery and thereby compute volume flow, yielding values close to those obtained using other techniques [36]. In the newborn, the arterial diameter cannot be accurately measured, so that it is only possible to measure velocity, and indices of velocity waveform pulsatility which reflect downstream vascular resistance. If arterial diameter remains constant, then velocity will be proportional to volume flow, but if vessel diameter decreases then velocity may increase, even if there is no change in volume flow.

Enteral feeding Using Doppler ultrasound Leidig [37] has shown that the velocity of SMA blood flow increases following feeds, and Gladman et al [38] have shown that this occurs in response to as little as I ml of milk given as the first feed to premature infants. Fang and Gamsu (unpublished data) have found that in very low birthweight babies, the response of the superior mesenteric velocity to a small volume of feed will predict whether the baby will tolerate the early introduction of enterat feeds. An increase in gut blood flow and oxygen extraction is necessary to meet the increased oxygen requirements of the bowel during digestion [39]. The mechanism responsible for this increase in blood flow is uncertain. Gut hormones have powerful effects on mesenteric blood flow and could mediate the vascular response seen in adults. However, premature infants do not produce a normal dynamic hormonal response to feeding during the first week of postnatal life [40]. Increases in gut hormone concentrations were noted in preterm infants when they had received considerably greater volumes of milk than those used by Gladman [41]. The increase in blood flow seen in premature infants could be due to an intrinsic

H.R. Gamsu and S. 1". Kempley

regulatory response to the increased oxygen requirement during feeding. However, if blood flow is not directly coupled to the oxygen requirements of the bowel, small reductions in blood flow during feeding could lead to inadequate oxygen delivery in the presence of an increased oxygen demand. Reduced superior mesenteric and coeliac arterial flow may also lead to interference with the blood supply to organs such as the pancreas. It could be postulated that reduced pancreatic exocrine secretion might result in reduced intraluminal protein digestion. Pig-bel, a disorder found in New Guinea after a large protein meal, predisposes to severe and often fatal colitis in children and adults. The analogy with necrotizing enterocolitis is quite close, though Pig-bel is known to be a consequence of infection with clostridia. Reduced intestinal blood flow, reduced pancreatic enzyme production, the protein load imposed by-enteral feeding and bacterial replication might predispose to the development of NEC. The frequency, quantity and composition of milk feeds may influence the vascular response of the intestine. Coombs et al [42] have shown in term infants a smaller increase in SMA velocity after breast compared with formula milk. With 3-hourly bolus feeding there is a pulsatile increase in blood flow velocity with a return to baseline after 100 minutes, but with hourly feeding there is a constant hyperaemia [43].

Intrauterine growth restriction Most case control studies did not identify intrauterine growth restriction (IUGR) as a risk factor for NEC, perhaps due to the matching of controls on the basis of birthweight rather than gestational age. Recent data indicate that IUGR is a clinical risk factor for NEC [44], primarily because of a greatly increased risk in those poorly grown infants who had absent end-diastolic flow in the aorta in fetal life. This predisposition to NEC could result from hypoxic-ischaemic tissue damage occurring in utero or from persisting abnormalities of perfusion after delivery. We have used Doppler ultrasound to study severely growth-restricted infants weighing less than 1500g at birth [45]. On the first day of postnatal life both SMA and coeliac axis blood flow velocity were reduced in growth-retarded infants, when compared with appropriately grown

Enteral hypoxla/ischaemla

249

40

60 50

30~ 4o c.l v

"~ 2 0 -

30

-

•

~

2o

-

"

=

Q

~" 0r~

f

.?

1010 0

Day i

Day 3

Day 7

Figure 1. Blood flow velocity (means and 95% confidence intervals) in the superior mesenteric artery of small-forgestational age infants and their weight-matched and gestation-matched controls, on the first, third and seventh days of postnatal life. Small-for-gestational age infants have lower velocity blood flow than either control group throughout the first week of life [45]. O SGA, A Wt controls; [] GA controls.

weight-matched and gestation-matched control infants (Fig. I). This change was specific to the visceral circulation, with normal or increased cerebral artery velocities in the growth retarded infants. Reduced SMA blood flow velocity was only found in those growth-retarded infants who had Doppler evidence of fetal hypoxia, indicated by absence of end-diastolic flow in the fetal aorta (Fig. 2). The differences could not be explained by differences in blood pressure or oxygen tension at the time of measurement, and the finding of an increased SMA velocity waveform pulsatility index suggests that the differences were due to a persisting elevation of intestinal vascular resistance, 'programmed' during fetal life. The difference in SMA velocity persisted for at least the first week of postnatal life, but by one week of age SMA velocity was the same in the IUGR infants as that found in appropriately grown babies on the first day of life. However, there is some evidence that the increase in blood flow velocity normally seen after the introduction of enteral feeding was still reduced in the IUGR infants. These data provide direct evidence that abnormalities of gastrointestinal perfusion are present during postnatal life in a group of infants at greatly increased risk of developing NEC. Care should be taken when introducing enteral feeds to the severely growth-restricted infant who had abnormal Doppler findings in utero.

SGA-EDF absent

Wt GA Controls

SGA-EDF present

Wt GA Controls

Figure 2. Blood flow velocity on the first day of life in the superior mesenteric artery of small-for-gestational age infants with and without absent fetal aortic end-diastolic flow (EDF). Individual data for the SGA infants and their weight-matched (Wt) and their gestation-matched (GA) controls. SMA blood flow velocity is only reduced in the small-for-gestational age infants who had absent end-diastolic flow (absent EDF) in the fetal aorta [45].

Umbilical vessel catheterization Black et al [46], in a randomized controlled trial, have shown that partial plasma exchange transfusion for polycythemia (mostly carried out using umbilical venous catheters) increases the risk of subsequent NEC. In the case of umbilical arterial catheters (UACs), there is conflicting evidence. Although five retrospective case-control studies have shown an association between the use of UACs and NEC, a greater number have failed to show any association [47]. Some studies may have failed to shown any effect of catheterization because of the selected populations they studied: Lehmiller and Kanto [1] only looked at infants who died of NEC, and Han et al [48] looked at epidemic cases. In these populations other factors may have been operating which obscured the effects of UACs. Even when these studies are excluded however, there are a number which show no effect of catheterization in unselected neonatal unit populations, whereas Smith et al [49] found an association with UACs during an outbreak. It has been suggested that UACs may have a role in the aetiology of NEC only in certain birthweight groups [20]. An alternative explanation is that UACs do not directly cause NEC, but that they are a marker for the types of illness and physiological instability which do lead to NEC.

H.R. Gamsu and S, T. Kempley

250

Table 2. Rates of various complications in a prospective randomized trial of umbilical arterial catheter position. The numbers with each complication are shown, with the relative risk of a baby with a high UAC developing the condition [47] Relative risk for high UACs

UAC position High

It

Duration of catheterization Emergency removal Blockage Lower limb cyanosis Suspected NEC Confirmed NEC

162 105 h 32 2 28 8 11

Low

146 79 h 64 12 51 6 9

(95% CI)

0.5 0.2 0.5 1.2 1.1

---** (0.3-0.7)*** (0.3-0.7)* (0.3-0.7)*** (0.4-3.4) (0.5-2.6)

*P 0.05; *'P 0.0I; *"P 0.00I.

If UACs do have a role in the aetiology of NEC it is most likely to be that of compromising blood flow in the mesenteric arteries, although it is also possible that release of bacterial or chemical toxins into blood flowing into these arteries might contribute [50]. On this basis it would be expected that only those catheters with their tip above the origin of the rnesenteric arteries (the 'high' position) would increase the incidence of NEC. Two small studies, and a large prospective randomized trial carried out in our unit did not substantiate this (Table 2) [47, 51, 52]. However, it is possible that UACs could compromise intestinal blood flow without causing NEC. We used Doppler ultrasound to measure SMA blood flow velocity in infants randomized to receive a high or a low umbilical arterial catheter [53]. No differences were found in those whose catheter remained in place for less than a week. High catheters were associated with an elevation of blood flow velocity if they stayed in place for more than a week, suggesting the presence of either intestinal hyperaemia or catheter-associated thrombosis or embolism. High catheters staying in place for more than a week were associated with an excess of non-specific abdominal symptoms (Table 3). This suggests that abnormal intestinal blood flow can injure the bowel without causing true NEC.

Table 3. Numbers of infants developing episodes marked by abdominal distension, tenderness or rigidity, according to whether they were randomized to receive a high or a low umbilical catheter, and according to the duration of catheterization. The relative risk of abdominal symptoms that prolonged catheterization carries is shown for high and low catheter groups [53] UAC position High Catheter in 0-7 days Catheter in >7 days Relative risk (95% CI)

8147 10/22 2.7 (1.3-5.3)

Low

7147 3/I5 1.3 (0.4-4.5)

the US National Collaborative Study on PDA did not find any such association [55]. Using Doppler ultrasound, Coombs et al [56] found that PDA is associated with absent or reversed blood flow in the SMA during diastole, although systolic blood flow velocity may be increased. Increased blood flow during systole could possibly compensate for reduced blood flow in diastole. They found that the rapid administration of indomethacin resulted in profound reductions in SMA blood flow velocity, which was attenuated if the drug was infused slowly.

Patent ductus arteriosus and indomethacin

Other factors

A case control study has identified patent ductus arteriosus (PDA) as a risk factor for NEC [54], but

In addition to patent ductus arteriosus there are congenital cardiac problems which predispose to NEC [57]. The use of hypertonic contrast media,

Enteral hypoxia/ischaemia

induced hypothermia, apnoea and hypotension following the use of prostaglandin E2 have all been incriminated. Rapid administration of prostaglandins should be avoided. Hypoplastic left heart syndrome is especially associated with mesenteric ischaemia though Hebra et al [58] feel that this entity should be distinguished from NEC, since it occurs later and in full term infants. Reduced intestinal perfusion is also seen with polycythaemia [46, 59], intraluminal tension and acidemia [60]. In the older neonatal piglet, after haemorrhage was induced, Crissinger and Granger [5] were able to demonstrate that compensatory increased oxygen extraction by the intestine maintained oxygen uptake in spite of a reduction in intestinal blood flow. However, the young piglet of up to one week of age was unable to do this and oxygen uptake by the intestine was reduced. Hypothermia has been found to interfere with intestinal blood supply. Alexander [61] showed that in lambs exposed to severe cold there was a striking redistribution of cardiac output with the blood supply to abdominal organs being reduced by more than half. Congestive cardiac failure, cardiac arrhythmia, digitalis toxicity and low flow states associated with shock all predispose the bowel to ischaemia. Robinson et al [62] have proposed a relationship between administration of xanthines to the newborn and NEC and the subject has been reviewed by Nowicki and Oh [63]. Xanthines antagonize adenosine binding at receptor sites which could impair the ability to regulate vascular oxygen uptake. In the dog, theophylline decreases the vascular response to arterial hypotension [64]. In the lamb, oxygen utilization of the intestine of the neonatal animal is twice that of older animals, and this is markedly increased after theophylline administration [65]. If there is coexisting hypotension or hypoxaemia then the increased oxygen demand produced by xanthines will add to the tissue hypoxia. Grosfeld et al [66] propose that aminophylline serving as a substrate for xanthine oxidase can generate more toxic flee-radicals after reperfusion. Decreased gastro-intestinal motility after xanthines may lead to increased bacterial proliferation. Intestinal hypertonicity induced by neostigmine administration in dogs [67] resulted in intestinal mucosal necrosis. Beta blockers administered to the mother in the treatment of hypertension may compromise intestinal blood supply and function in the fetus and newborn.

251

70 60 "~ 50 ~ 40

o

.~,

• e

ee

(~

8

o

•

0

~ 3o rn 20 10

O

•

0-~

o

Confirmed Unconfirmed Other abdo NEC path

8

Feeds IV fluids Controls

Figure 3. Blood flow velocity in the SMA for infants with confirmed NEC, suspected NEC, and other abdominal pathology. Control infants were matched with the confirmed cases, and were either receiving enteral feeds or intravenous fluids. At the time of symptoms, infants with confirmed NEC have significantly higher SMA velocity than controls receiving IV fluids, or infants with suspected by unconfirmed NEC [68]. S enterally fed; O no enteral feeds.

Doppler ultrasound findings in NEC It has generally been assumed that the infant with established NEC would have reduced intestinal blood flow, but recent data have cast doubt on this view [68]. We used Doppler ultrasound to measure blood flow velocity in the SMA of 17 infants soon after the onset of symptoms suggestive of NEC. These infants were subsequently classified as 'confirmed' or 'suspected, but unconfirmed' cases using the classification of the British Association of Perinatal Medicine. For the confirmed cases, findings were compared with those from infants matched for birthweight, gestation, degree of growth restriction and postnatal age. For each index case we selected one control who received enteral feeds and one who was given only intravenous fluids. Blood flow velocity in the SMA of the confirmed cases was significantly higher than in suspected, but unconfirmed cases, and was also significantly higher than in the controls receiving IV fluids. The mean SMA velocity was slightly higher than in the controls receiving enteral feeds (Fig. 3). There were no differences between the groups in cerebral artery or coeliac axis blood flow velocity.

252

H.R. Gamsu and S. Z Kempley

Case 2 10

7O 6O -

-8

NEC

so -6 4o -

"~ 30

/

--4

~..-/

20 -

..~

(3" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10

I

{

5

10

t 15

2

0"

I 20

I 25

I

3O

0

Case 3 10

~NEC

70 60

8

A ~eds/ I

~ 40

Feeds I

6

"~ 30

N

4

2o

2

10 I

I

I

I

I

I

5

10

15

20

25

3O

0

What does this increased SMA blood flow velocity in infants with NEC represent? There was no thrombus visible in the aorta or SMA of any of the infants studied, and the fact that measurements were obtained from near the origin of the SMA makes active changes in vessel diameter unlikely. These findings probably represent an increased total gut blood flow, as a result of the inflammatory reaction in remaining viable bowel, or possibly as a result of a post-ischaemic hyperaemia, similar to the changes found in inflammatory bowel disease in adults [69]. This suggests that an overall reduction in intestinal blood flow is not responsible for the progression of the disease, although localized factors may affect discrete areas of bowel. However, low total gut blood flow may have a causative role early in the pathogenesis of the disease, and ultrasound measurements of SMA blood flow velocity might help to delineate those infants at increased risk of NEC, at the-time period during which abnormalities of intestinal perfusion are present.

Case 7

60 50

10

NEC~

References -8

"~ 4 0 -

-6

U

30-

N

-4

2o

lOkj / 0

-..°

I 5

•

2 I 10

(

I

15 20 Age in days

f

I

25

30

0

Figure 4. Blood flow velocity and pulsatility index in the SMA of three infants with confirmed NEC who had data collected before the onset of symptoms. One infant had very low blood flow velocity on Day 1, but all three had relatively high velocities at the time they developed their NEC [681.

Because of the unpredictable and sporadic nature of NEC, prospective pre-morbid data of any sort are difficult to collect. We have obtained Doppler ultrasound data from before the onset of symptoms from three inhnts (Fig. 4). One infant (Case 2) had a single normal reading on the third day of postnatal life, another (Case 3) had a normal blood flow velocity which did not increase with the introduction of enteral feeds, and a third infant (Case 7) was a growth retarded infant who had the lowest SMA blood flow velocity that we have recorded on the first day of life. All had much higher velocities at the time that symptoms developed.

I Lehmiller DJ, Kanto WP. Relationships of mesenteric thromboembolism, oral feeding and necrotizing enterocolitis. ] Pediatr 1978; 92: 96--I00. 2 Lloyd JR. The etiology of gastrointestinal perforations in the newborn. ] Ped Surg 1969; 4: 77-84. 3 Nowicki PT, Caniano DA, Szaniszlo K. Effect of intestinal denervation on intestinal vascular response to severe arterial hypoxia in newborn swine. Am ] Physiol 1987; 253: G201-5. 4 Nowicki PT, Miller CE. Autoregulation in the developing postnatal intestinal circulation. Am ] Physiol 1988; 254: G189-93. 5 Crissinger KD, Granger DN. Intestinal blood flow and oxygen consumption responses to hemorrhage in the developing piglet. Pedfatr Res 1989, 26: 102-5. 6 Crissinger KD, Kvietys PR, Granger DN. Developmental intestinal vascular responses to venous pressure elevation. Ain ] Physiol 1988; 254: G658--63. 7 Nowicki P. Intestinal ischaemia and necrotising enterocolitis. ] Pedhtr 1990; 117: 514. 8 Kvietys PR, Granger DN. Relation between intestinal blood flow and oxygen uptake. Am ] Physiol 1982; 242: G202-8. 9 Bulkley GB, Kvietys PR, Parks DA, Perry MA, Granger DN. Relationship of blood flow and oxygen consumption to ischemie injury in the canine small intestine. Gastroenterology 1985; 89: 852-7. 10 Irving L, Scholander PF, Grennell SW. The regulation of arterial blood pressure in the seal during diving. Am ] Physiol 1942; 135: 557-66. 11 Eisner R, Kenney DW, Burgess K. Diving bradycardia in the trained dolphin. Nature 1966; 212: 407.

Enteral hypoxia/ischaemia

12 Eisner R. Diving bradycardia in the unrestrained hippopotamus. Nature 1966; 212: 408. 13 Scholander PF, Hammel HT, Le Mesurier H. Circulatory adjustment in pearl divers. ]Appl Physio11962; 17: 184-91. 14 Nowicki PT, Miller CE. Effects of sustained mesenteric nerve stimulation on postnatal intestinal haemodynamics. Pediatr Res 1990; 27: 236A. 15 Ross G. Escape of mesenteric vessels from adrenergic and noradrenergic vasoconstriction. Am J Physiol 1971; 2 2 1 : G217-22. 16 Touloukian R]'. Etiologic role of the circulation in neonatal necrotising enterocolitis. In: Brown EG, Sweet AY, Eds. Neo-natat Necrotizing Enterocolitis. Grune & Stratton, 1980: 41-56. 17 Berseth CL, McCoy HH. Birth asphyxia alters neonatal intestinal motility in term neonates. Pediatrics 1992; 90: 669-73. 18 Wiswell TE, Robertson CF, Jones TA, Tuttle DJ. Necrotising enterocolitis in full-term infants. Am J Dis Child 1988; 142: 532-5. 19 Wilson R, Delportillo M, Schmidt E, Feldman RA, Kanto WP. Risk factors for necrotising enterocolitis in infants weighing more than 2000 grams at birth: a case control study. Pediatrics 1983; 71: 19-22. 20 Palmer SR, Thomas SJ, Cooke RWI, Low WJ, Fysh WJ, Murphy JF, Gandy GM, Gamsu H. Birthweight specific risk factors for necrotising enterocolitis. ] Epidemiol Community Health 1987; 41: 210-4. 21 Kosloske AM. ~ unifying hypothesis for pathogenesis and prevention of necrotising enterocolitis. J Pediatr 1990; 1 1 7 : $68-$74. 22 Touloukian RJ, Posch JN, Spencer RP. The pathogenesis of ischemic gastroenterocolitis of the neonate; selective gut mucosal ischemia in asphyxiated neonatal piglets. Pediatr Surg 1972; 7: 194-205. 23 Eddlestone DI, Lattanzi DR, Paulone ME, Holzman IR. Neonatal intestinal oxygen consumption during arterial hypoxaemia. Am ] Physiol 1983; 244: 9278-83. 24 Karna P, Senagore A, Chou CC. Comparison of the effect of asphyxia, hypoxia and acidosis on intestinal blood flow and 0 2 uptake in newborn piglets. Pediatr Res 1986; 20: 929-32. 25 Nicolaides KH, Bilardo CM, Soothill PW, Campbell S. Absence of end-diastolic frequencies in umbilical artery: A sign of fetal hypoxia and acidosis. BMJ 1988; 297: 1026-7. 26 Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T, Pearce JMF. Doppler studies in the growth retarded foetus and prediction of neonatal necrotising enterocolitis, haemorrhage and neonatal morbidity. BM] 1987; 2 9 4 : 13--6. 27 Malcolm G, Ellwood D, Devonald R, Beilby R, Henderson-Smart D. Absent or reversed end-diastolic flow velocity in the umbilical artery and necrotising enterocolitis. Arch Dis Child 1991; 66: 805-7. 28 Eronen M, Karl A, Pesonen E, Kaaja R, Wallgren EI, Hallman M. Value of absent or retrograde end-diastolic flow in fetal aorta and umbilical artery as a prediction of perinatal outcome in pregnancy-induced hypertension. Acta Paediatr 1993; 82: 919-24. 29 McDonnell M, Serra Serra V, Gaffney G, Redman CWG, Hope PL. Neonatal outcome after pregnancy complicated

253

30

31

3Z

33

34

35 36

37

38

39

40

4I

42

43

44

45

46

by abnormal velocity wave forms in the umbilical artery. Arch Dis Child 1994; 70: F84-F89. Pattinson RC, Hope P, Imhoff R, Manning N, Marrion V, Redman CWG. Obstetric and neonatal outcome in fetuses with absent end-diastolic velocities of the umbilical artery. A case controlled study. Am ] Perinatology 1993; 10: 135-8. Pattinson RC, Odendaal HJ, Kirsten G. The relationship between absent end-diastolic velocities of the umbilical artery and perinatal mortality and morbidity. Early Human Dev 1993; 33: 61-9. Telsey AM, Merrit TA, Dixon SD. Cocaine exposure in a term neonate: necrotizing enterocolitis as a complication. Clinical Paedialrics 1988; 27: 547-50. Buyukunal C, Kilic N, Dervisoglou S, Altug T. Maternal cocaine abuse resulting in necrotising enterocolitis--an experimental study in a rat model. Acta Paediatr suppl. 1994; 396: 91-3. Nalbandian H, Sheth N, Dietrich R, Georgiou J. Intestinal ischemia caused by cocaine ingestion. Report of two cases. Surgery 1985; 97: 374-6. Porat R, Brodsky N. Cocaine: a risk factor for necrotising enterocolitis. ] Perinatology 1991; 11: 30-2. Qamar MI, Read AE, Skidmore R, Evans JM, Wells PNT. Transcutaneous Doppler ultrasound measurement of superior mesenteric artery blood flow in man. Gut 1986; 27: 100-5. Leidig E. Doppler analysis of superior mesenteric artery blood flow in preterm infants. Arch Dis Child 1989; 64: 476-80. Gladman G, Sims DG, Chiswick ML. Gastrointestinal blood flow after the first feed. Arch Dis Child 199I; 66: 17-20. Nowicki PT, Stonestreet BS, Hansen NB, Yao AC, Oh W. Gastrointestinal blood flow and oxygen consumption in awake newborn piglets: effect of feeding. Am ] Physiot 1983; 245: G697-702. Lucas A, Bloom SR, Aynsley-Green A. Development of gut hormone responses to feeding in neonates. Arch Dis Child 1980; 55: 678-82. Lucas A, Bloom SR, Aynsley-Green A. Gut hormones and "minimal enteraI feeding'. Acta Paed Scand 1986; 75: 719-23. Coombs RC, Morgan MEI, Durbin GM, Booth W, McNeish AS. Doppler assessment of human neonatal gut blood flow velocities: postnatal adaptation and response to feeds. ] Ped Gastroenterology & Nutrition 1992; 15: 6-12. Lane AJP. Characterisation of splanchnic blood flow velocity in human preterm neonates using Doppler ultrasound. PhD thesis. University of Sheffield, 1996. Beeby PJ, Jeffery H. Risk factors for necrotising enterocolitis: the influence of gestational age. Arch Dis Child 1992; 67: 432-5. Kempley ST, Gamsu HR, Vyas S, Nicolaides K. Effects of intrauterine growth restriction on postnatal visceral and cerebral blood flow velocity. Arch Dis Child 1990; 65: 115-8. Black VD, Rumack CM, Lubohen KO, Koops BL. Gastrointestinal injury in po]ycythemic term infants. Pediatrics 1985; 76: 225-31.

254

47 Kempley ST, Bennett S, Loftus BG, Cooper D, Gamsu HR. Randomised trial of umbilical arterial catheter position: clinical outcome. Acta Paed Scand 1993; 82: 173-6. 48 Han VKM, Sayed H, Chance GW, Brabyn DG, Shaheed W. An outbreak of Clostridium difficile necrotizing enterocolitis; a case for oral vancomycin therapy. Pediatrics 1983; 71: 935-41. 49 Smith MF, Borriello SP, Clayden GS, Casewell MW. Clinical and bacteriological findings in necrotising enterocolitis: a controlled study. ] hzfection 1980; 2: 23-31. 50 Rogers AF, Dunn PM. Intestinal perforation, exchange transfusion and PVC. Lancet 1969; 2: 1246. 51 Mokrohisky ST, Levine RL, Blumhagen JD, Wesenberg RL, Simmons MA. Low positioning of umbilical-artery catheters increases associated complications in newborn infants. NEJM 1978; 299: 561-4. 52 Wesstrom G, Finnstrom O, Stenport G. Umbilical artery catherisation in newborns: thrombosis in relation to catheter type and position. Acta Paed Scand 1979; 68" 575-81. 53 Kempley ST, Gamsu HR. Randomised trial of umbilical arterial catheter position: Doppler ultrasound findings. Arch Dis Child 1992; 67: 855-9. 54 Ryder RW, Shelton JD, Guinan ME. Necrotising enterocolitis: a prospective multicenter investigation. Am ] Epidemiol 1980; 112: 113-23. 55 Kanto WP, Wilson R, Breart GL, Zierler S, Purohit DM, Peckham GJ, Ellison RC. Perinatal events and necrotizing enterocolitis in premature infants. Am ] Dis Child 1987; 141: 167-9. 56 Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeish AS. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990; 65: 67-71. 57 Leung MP, Chan KT, Piu PW, Tam AUC, Chan FL, Lai C-I, Yeung C-Y. Necrotising enterocolitis in neonates with symptomatic congenital heart disease. ] Pedialr I988; 113: 1044--6.

H. R. Gamsu and S. 1". Kempley

58 Hebra A, Brown MF, Hirschl RB, McGeehin K, O'Neill JA, Norwood WI, Ross AJ. Mesenteric ischaemia in hypoplastic left heart syndrome. J Ped Surg 1993; 28: 606-11.

59 Le Blanc MH, D'Cruz C, Pate K. Necrotising enterocolitis can be caused by polycythaernic hyperviscosity in the newborn dog. ] Pediatr 1984; 105: 805-9. 60 Garstin WIH, Kenny BD, McAnaeney D, Patterson CC, Boston VE. The role of intraluminal tension and pH in the development of necrotising enterocolitis: an animal model. ] Ped Surg 1987; 22: 205-7. 61 Alexander G. Body temperature control in mammalian young. British Medical Bulletin 1975; 31: 62-8. 62 Robinson MJ, Clayden CS, Smith MF. Xanthines and necrotising enterocolitis. Arch Dis Child 1980; 55: 494-5. 63 Nowicki PT, Oh W. Methylxanthines and necrotising enterocolitis revisited. ] Ped Gastroenterol Nutr 1989; 9: 137-43. 64 Granger HJ, Norris CP. Role of adenosine in local control of intestinal circulation in the dog. Circ Res 1980; 46: 764-70. 65 Cronin CMG, Canose J, Buchanan D, Holzman IR. The effect of aminophyIline on gastrointestinal blood flow and oxygen metabolism in the conscious newborn lamb. ] Ped Gastroenterol Nutr 1959; 8: 371-5. 66 Grosfeld TL, Dalsing MC, Hull M, Weber TR. Neonatal apnoea, xanthines and necrotising enterocolitis. ] Ped Surg 1983; I8: 80-4. 67 Parodi J, Grisoni E, Ferrario C, Kramer A, Beven E. Hypertonicity of intestinal smooth muscle as a factor of intestinal ischaemia in necrotising enterocolitis. ] Ped Surg 1987; 22: 713-8. 68 Kempley ST, Gamsu HR. Superior mesenteric artery blood flow velocity in necrotising enterocolitis. Arch Dis Child 1992; 67: 793--6. 69 Bolondi L, Gaiani S, Brignola C, Campieri M, Rigamonti A, Zironi G, Gionchetti P, Belloli C, Miglioli M, Barbara L. Changes in splanchnic hemodynamics in inflammatory bowel disease. Non-invasive assessment by Doppler ultrasound flowmetry. &and ] Gastroenterol I992; 27: 501-7.