Pediatr Surg Int (1992) 7:408-414

Pediatric

Surgery International

© Springer-Verlag 1992

Main topic Intestinal microcirculation in the neonate Otto R. Velfisquezl, D. Neil Granger l, and Karen D. Crissingerl, 2 Departments of tPhysiology and 2Pediatrics, Louisiana State University Medical Center, P. O. Box 33 932, Shreveport, LA 71 130, USA

Abstract. The hypermetabolic neonatal intestine requires an appropriate supply of energy to meet its needs. Adequate regulatory mechanisms for intestinal blood flow must be present to cope with a high oxygen demand. In the developing intestine, intrinsic hemodynamic control matures as a function of postnatal age, and the newborn appears to balance this vascular immaturity by an enhanced ability to extract oxygen from the blood. When this mechanism is maximized and an additional stress is superimposed, the neonatal intestine may be at a higher risk of ischemia and injury than older intestine. Furthermore, sympathetic vasoconstrictor control predominates at birth, and the newborn is less capable of vasodilatation. This extrinsic control provides an additional ischemic risk during conditions involving sympathetic discharge. An understanding of circulatory hemodynamics in the developing intestine may allow elucidation of the role played by ischemia in mucosal injury in the newborn. Key words: Intestinal hemodynamics - Newborn - Intestinal injury - Necrotizing enterocolitis

crease the demand for energy and require an adequate supply of oxygen for optimum aerobic metabolism. The objective of this article is to provide an overview of the control mechanisms that modulate microcirculatory dynamics in the developing intestine. The first part presents the available information regarding the different parameters of intestinal perfusion in the basal state in fetal and neonatal animals, the second the role of local and remote controllers of arteriolar and precapillary sphincter tone and their influence on tissue oxygenation.

Basal hemodynamics and oxygenation During fetal development, intestinal growth occurs at an accelerated rate. In general, intestinal weight in fetal lambs increases 30-fold during the second half of gestation, and the fetal lamb intestine doubles its weight every 3 weeks in the last trimester of pregnancy [19]. The same pattern of accelerated growth is seen in the first 2 weeks after birth [20]. To cope with the increased metabolic demands, basal hemodynamic and oxygenation parameters should change throughout development. Table 1 lists baseline values for intestinal blood flow, arteriovenous oxygen difference, and oxygen uptake in several commonly used experimental

Introduction The ultimate function of the gut is to assimilate ingested nutrients and water and make them available for cells throughout the body by way of the blood and lymph circulations. The energy necessary to support the digestive, propulsive, and transport activities of the bowel is also provided by the circulation. Blood flow and oxidative demands in the developing intestine differ from those of the adult. The physiological processes of assimilation and the rapid growth of the fetal and neonatal intestines in-

Correspondence to: Karen D. Crissinger

Table 1. Resting values for intestinal blood flow, arteriovenous oxygen difference (A-VDO2), and oxygen uptake in fetal lambs, 1-day and 1-month piglets, and adult cats Parameter

Fetus

Bloodflow (ml/min. 100 g)

94-100 40-128

A-VDO2 (ml O~/100 ml)

2.1

O2uptake 2.1 (ml O2/min . 100 g)

1 day

1 month adult 27-57

Reference

20-78 11,12,14,19, 27,29,34,36, 41,47,55

3.4-3.8 4.3-4.5 4.6

12,14,19,27,47

2.9-4.3

12,14,15,19, 27,47,49

1.8L2.4 1.4

409

INTRINSIC METABOLIC FACTORS

REGULATION MYOGENIC FACTORS

NEUROHUMORAL INFLUENCES

OXYGEN PURZNE METABOLITES OSMOLALITY OTHER VASODILATOR METABOLITES

INCREASED TISSUE PRESSURE HOTZLZTY FLUID ABSORPTZON

GASTROZNTESTINAL HORMONES ACETYLCHOLINE SEROTONIN OTHERS

INTESTINAL

g

BLOOD FLOE/

) NEUP.AL INFLUENCES

HVHORAL FACTORS ¢ATECHOLAMZNES ANGEOTENSZN XI OTHERS

EXTRINSIC

SVMPATHETICS' PAI~SYMPATUETICS PURZNERGIC OTHER (E.G.HISTAHZNERGZC)

SYSTEMIC CARDIOVASCULAR FACTOnS ARTERIAL PRESSURE VENOUS PRESSURE PROPERTIES OF BLOOD

REGULATION

animal models for studying developmental changes in intestinal blood flow. Blood flow to the intestine is determined by several different mechanisms (Fig. 1). We shall discuss these major influences on blood flow and their role in the maintenance of circulatory homeostasis in the developing intestine.

Intrinsic regulation Many tissues of the body are endowed with the capacity to regulate their own blood flow after elimination of all nervous and hormonal influences [32]. These local, or intrinsic, microvascular control systems allow the microcirculation to respond to specific needs of the tissue that it subserves and result in the maintenance of the flux of oxygen and nutrients to the parenchyma. Intrinsic vascular regulation has been demonstrated in the intestine of adult animals [31]. Therefore, intestinal blood flow is normally maintained above a critical limit and changes in response to various functional stimuli [13]. Several theories have been proposed to explain the mechanistic basis for intrinsic vascular regulation. Of these, metabolic and myogenic mechanisms are considered to be of greatest physiologic significance. Other factors, such as endogenously produced vasoactive peptides and amines, may also play a role in local regulation of the intestinal circulation [ 1]. The metabolic hypothesis is based on the assumption that vascular resistance and precapillary sphincter tone are

Fig. 1. Intrinsicand extrinsicmechanisms contributingto the controlof intestinalbloodflow

linked to the metabolic status of the tissue [13, 32]. A reduction in blood flow causes a decline in tissue oxygen tension (PO2) and accumulation of metabolites, both of which dilate arterioles and relax precapillary sphincters [57]. These effects return blood flow to normal and improve the convective and diffusive flux of O2 from capillary to cell. The myogenic hypothesis is based on the inherent property of vascular smooth muscle to contract in response to a stretch stimulus [22]. According to this concept, arteriolar tension receptors modulate vascular smooth-muscle tone in response to changes in microvascular transmural pressure. Therefore, the myogenic theory predicts that resistance vessels will dilate when vascular transmural pressure is decreased, while an increase in transmural pressure causes arteriolar vasoconstriction and increased vascular resistance [38]. Local vascular reactions have been evaluated in the intestine by applying a number of stresses to the tissue. The most commonly used perturbations are alterations in arterial pressure, venous pressure (Pv), arterial oxygen concentration (CaO2), and increased metabolic demand [30].

Vascular response to arterial pressure alterations

Pressure-flow autoregulation is defined as the ability of the intestine to maintain a constant blood flow daring alterations in arterial pressure [37]. Autoregulation has been demonstrated along the gastrointestinal tract in adult ani-

410 mals [26, 33, 37], but not the intense response observed in other tissues such as kidney and brain. However, the intensity of intestinal autoregulation increases during periods of enhanced functional activity [31, 46]. The neonatal intestine, despite its high basal O2 uptake, does not show a correlation between metabolic rate and autoregulatory ability, and pressure-flow autoregulation is less intense (or absent) when compared to adult intestine [3, 49]. Autoregulation is absent in isolated intestinal segments from 3-day-old swine. In these segments, vasodilation in response to stepwise reductions in arterial pressure is not present and blood flow decreases to the same (or greater) magnitude as the imposed reduction of arterial pressure. In contrast, vasodilation occurs in intestinal segments from 35-day-old piglets in response to a reduction in perfusion pressure [49]. These observations, derived from in vitro loops from swine, confirm previous in vivo observations by Buckley et al. [3] that autoregulation of intestinal blood flow in response to perfusion pressure manipulation is absent in swine less than 2 weeks old but present in 1-month-old swine, and suggest that the efficacy of vascular control of the intestinal circulation improves with advancing postnatal age. The differences in autoregulatory capacity in the intestine of developing pigs have been attributed to maturation of vasodilator receptors with age [6]. Alternatively, it has been proposed that intestinal resistance vessels in very young animals are incapable of significant vasodilation because at rest they exist at near-maximal dilation [ 17, 20]. However, these hypotheses do not correlate with the response observed in intestine from 7- and 30-day-old swine after intra-arterial of isoproterenol. ~-adrenergic stimulation produces an equivalent degree of vasodilation in isolated jejunal segments from both groups, and indicates that swine older than 1 week maintain a substantial dilatory reserve capacity [42]. Whether the same vasodilatory response is present in piglets younger than 7 days remains to be demonstrated. Reactive hyperemia is a term used to describe a characteristic hyperemia observed after brief periods of arterial occlusion [40, 45]. Both the metabolic and myogenic hypotheses predict active dilation during arterial occlusion, the magnitude and duration of which are related to the duration of the occlusion. After a 10-s occlusion of the arterial supply to the small intestine in developing swine, mesenteric vascular resistance decreases an average of 20% in <2-day-old piglets and 50% in 2-month-old animals [3, 8]. These results indicate that the more immature intestinal circulation is less capable of vasodilation in response to arterial occlusion.

Vascular response to venous pressure elevation

The response to Pv elevation is an important criterion for determining whether metabolic or myogenic mechanisms are involved in local vasoregulation. The metabolic hypothesis predicts that elevation of Pv causes vasodilation and increased capillary density as a result of reduced blood flow and vasodilator accumulation. According to the myogenic hypothesis, vascular resistance increases and capil-

lary density decreases during Pv elevation because of a rise in intravascular (transmural) pressure [25]. Studies of the stomach, small intestine, and colon in adult animals indicate that vascular resistance rises in response to Pv elevation [38, 39, 58], findings that are consistent with a myogenic mechanism. This typical myogenic response can be abolished or reversed after increasing the O2 demands in intestine of adult animals [31], suggesting that the response to Pv elevation is also influenced by the metabolic state of the intestine. In swine 3 to 30 days of age, acute elevation of mesenteric Pv induces intestinal vasoconstriction and a reduction in intestinal O2 uptake [50]. This observation indicates an active myogenic reflex in postnatal intestine. In contrast, a unique response to Pv elevation is present in animals 1 day of age. The intestinal circulation in these very young animals dilates, rather than constricts, so that intestinal 02 uptake is not compromised by acute venous hypertension [14]. These results suggest that metabolic factors are dominant in the hypermetabolic neonatal intestine. However, since a progressive increase in the basal pre- to postcapillary resistance ratio as a function of postnatal age has been observed [14], the physiological role of the myogenic response may be underestimated in the intestine of very young swine.

Vascular response to alterations in Ca02

Because the metabolic theory predicts that any reduction in the oxygen availability-to-demand ratio should elicit vasodilation and capillary recruitment, arterial hypoxemia has been used to study the ability of the intestine to maintain tissue oxygenation. Arterial hypoxemia increases blood flow and elicits capillary recruitment in denervated intestinal preparations of adult cats [62]. The decreased vascular resistance and increased capillary density minimize the reduction in 02 uptake induced by the limited 02 availability. In the fetal lamb, the primary intestinal response to reduction in O2 supply is an increase in 02 extraction rather than a change in blood flow [18]. When CaO2 drops below a critical point, vascular resistance increases and intestinal blood flow declines. Even though O2 extraction increases further, the increase is insufficient to maintain 02 uptake at normal levels [18]. A similar response is elicited in neonatal lambs during hypoxic hypoxemia [20]. In contrast, the intestinal circulation in newborn piglets is capable of vasodilation during moderate hypoxemia (arterial PO2 3 5 55 mmHg), but vasoconstriction and intestinal ischemia supervene during severe hypoxemia (arterial PO2 _<30 mmHg) [48]. The latter vasoconstrictive response appears to be regulated by the sympathetic nervous system, since it can be abolished by intestinal denervation or c~-receptor blockade [47]. Nowicki et al. [51] demonstrated that isolated, denervated intestinal segments from 1- to 7-day-old piglets show modest vasodilation in response to perfusion with hypoxic blood (PaO2 -35 mmHg), whereas intestinal segments from older animals (14 to 30 days) exhibit a more significant fall in intestinal vascular resistance. In addition, 02

411

uptake decreased -50% in intestinal segments from 1-dayold piglets, compared to only -10% reduction in 30-dayold animals. These observations suggest that the intrinsic mechanism responsible for hypoxic vasodilation may not be fully functional at birth, and intestinal O2 uptake is more compromised during arterial hypoxia in 1- to 7-day-old piglets than in older animals. Alterations in hematocrit (Hct) also influence gastrointestinal blood flow and oxygenation. In adult dogs there is an inverse linear correlation between intestinal blood flow and Hct [59]. In the fetal lamb, intestinal blood flow increases only slightly during reductions of arterial Hct, leading to a decrease in O2 delivery [23]. In the neonatal lamb the response is similar to the anemic fetus. However, in this group the reduction in Hct elicits an increase in O2 extraction, which permits stable 02 consumption even with a Hct as low as 10% [63].

Postprandial intestinal hyperemia After ingestion of a meal, an increase in blood flow occurs within the splanchnic circulation, a phenomenon known as postprandial hyperemia [25]. The placement of nutrients into the lumen increases the metabolic demands of the intestinal parenchyma in adult animals and, as predicted by the metabolic hypothesis, leads to an increase in intestinal blood flow and 02 uptake [31, 60]. In fetal lambs, infusion of nutrients into the stomach does not affect intestinal blood flow or O2 uptake even though absorptive processes are substantially increased [9]. The physiological significance of this non-oxidative response to nutrient assimilation is unclear. In conscious neonatal lambs (7- to 10-days old), O2 consumption increases 30% to 60% over the first 3 h postprandially in association with increases in 02 extraction in the range of 30% to 40% [16]. Postprandial increases in blood flow are of short duration and are confined to the stomach, suggesting that increases in intestinal O2 demands during digestion are met entirely by increments in 02 extraction rather than by metabolic hyperemia. In contrast, intestine from conscious 2-day-old swine shows a postprandial increase in blood flow, 02 extraction, and O2 uptake in both proximal and distal small intestine [53]. The difference in response between these two species may be due to the fact that intestinal blood flow in lambs is near-maximal at rest [20]. The results of a recent study by Crissinger and Burney [ 10] in anesthetized piglets agree with the findings involving 2-day-old conscious piglets [53] and show that this response in young animals is similar to that in older swine (2 w e e k s - 2 months old). Of interest is the observation that shortly after birth newborns increase O2 uptake postprandially by a dramatic rise in O2 extraction with no change in total flow. However, this unique response rapidly changes to the adult response within 24 h [10]. These findings suggest that, since O2 extraction and mucosal blood flow appear to be near-maximal during feeding alone, newborn intestine may be at risk for tissue hypoxia and subsequent mucosal injury in the presence of superimposed cardiovascular stress.

In summary, it appears that the ability for local regulation of blood flow and oxygenation in the developing intestine improves as a function of postnatal age. The intestine of the young animal usually balances this functional immaturity with a marked increase in 02 extraction and, in this way, largely meets the metabolic demands of the tissue. However, under superimposed stress the intestine of the newborn is at increased risk of ischemia compared to the intestine of older animals.

Extrinsic regulation Neurohumoral factors are important regulators of blood flow and 02 consumption within the intestine. These factors exert their effects either directly on the intestinal microcirculation or indirectly, by affecting systemic cardiovascular function. In this context, extrinsic regulatory mechanisms serve to integrate the intestinal circulation into systemic cardiovascular reflexes, especially during periods of stress, where the major consequence of the regulatory responses in the preservation of systemic circulatory homeostasis [30].

Neural control Sympathetic noradrenergic nerves play a major role in neural control of intestinal blood flow [28, 56]. At birth, the intestinal circulation appears to be under tonic sympathetic vasoconstrictor control in swine [4]. Using norepinephrine as an c~-adrenergic receptor agonist and phentolamine as its antagonist, Buckley et al. have demonstrated that adrenergic responses of the intestinal circulation are relatively active at birth in swine and continue to mature during the 1st postnatal month [4, 5, 8]. Direct stimulation of mesenteric nerves causes vasoconstriction of intestinal resistance vessels, the magnitude of which increases with advancing postnatal age [8, 52]. This indicates that functional maturation of nerve fibers is an important factor during postnatal development of the intestinal circulation. Since isolated mesenteric arteries from swine show postnatal maturation of the response to catecholamines, especially for norepinephrine, the age-related differences noted after mesenteric nerve stimulation may be also due to changes in smooth-muscle sensitivity to neurotransmitter [24]. Autoregulatory escape is a phenomenon in which stimulation of sympathetic nerves or intra-arterial infusion of norepinephrine produces initial intense vasoconstriction and a fall in blood flow followed by a return ("escape") of blood flow toward baseline levels, despite continued nerve stimulation or norepinephrine infusion [13]. Autoregulatory escape from postganglionic mesenteric nerve stimulation is not demonstrable until swine are 2 weeks old and is well established only by the 2nd postnatal month. Similarly, vascular escape from intra-arterial norepinephrine infusion is well established by the 2nd postnatal week [8]. A postnatal delay in maturation of vasodilator capability (neural or nonneural) has been postulated to explain these observations. This suggests that sustained c~-adrenergic

412 Table 2. Vascular responses to vasoactive compounds in fetal and neonatal intestine Species

Age

Substance

Vascular response

Reference

Lamb

fetus

norepinephrine 5hydroxytriptamine angiotensin II leukotriene C4

constrictiona, b constrictionb constrictiona constrictiona

61,64 61 54 44

Rabbit

fetus

norepinephrine epinephrine

constrictiona constrictiona

21,43 21,43

Piglet

newborn norepinephrine (1-week-old) isoproterenol

constrictiona relaxationb

8

been reported. Table 2 lists the effects of different compounds on the intestinal vasculature. Whether all of these substances play a physiological role in the regulation of intestinal blood flow in the developing intestine is unknown. In summary, remote regulators of intestinal blood flow are present at birth. Neurally-induced vasoconstriction is tonic and active in newborns. This, coupled with the fact that autoregulatory escape is not significant until the 2rid postnatal week, suggests that the neonatal intestine may be at metabolic risk during stresses involving increased sympathetic discharge.

51

a In vivo observations b In vitro observations

stimulation may have an age-dependent effect on intestinal 02 transport and uptake during postnatal life. Nowicki et al. have shown that sustained stimulation of postganglionic mesenteric fibers compromises intestinal oxygenation in postnatal swine, but this effect is not age-dependent in 3-versus 35-day-old piglets [52]. However, the response of swine shortly after birth (<1 day) cannot be predicted by these observations in older animals since 1-day-old piglets have shown unique responses in other experimental settings, e.g., Pv elevation and postprandial hyperemia [10, 14].

Reflex control The developing intestinal circulation participates in systemic cardiovascular reflexes. The baroreceptor reflex has been demonstrated in fetal lambs early in gestation [2, 24]. Inflation of a balloon within the carotid sinus causes a depressor response in the intestinal circulation of postnatal swine [24]. Similarly, bilateral occlusion of the common carotid arteries results in intestinal vasoconstriction [4], although the pressor response is less intense than that observed in adult animals [7]. Therefore, it appears that the sensitivity of the baroreflex increases as a function of postnatal age. Peripheral chemoreceptor reflexes have been detected in fetal and neonatal animals. Stimulation of arterial chemoreceptors produces bradycardia and hypertension in fetal lambs [35]. After birth, the threshold for activation of chemoreceptors increases in most species, including humans [19]. The physiological importance of baroreceptors and chemoreceptors in the regulation of blood flow in developing intestine is not known.

Humoral control Information regarding the responsiveness of the intestinal vasculature to circulating vasoactive substances in the developing animal is sparse. Few studies have been done in this area, and no systematic evaluation of the role of circulating humoral agents in extrinsic regulation has as yet

Future directions

Although investigators have been interested in the regulation of the intestinal circulation in mature animals for many years, this regulation in the perinatal period has been investigated in detail only recently. Investigations to understand the physiological responses of the developing intestinal circulation to different experimental perturbations are necessary to clarify the role of these responses in the initiation of disease in the newborn. Information is lacking regarding the precise relationship between intestinal ischemia and tissue injury in the neonate. Currently, it is hypothesized that intestinal ischemia produces tissue hypoxia, which leads to mucosal injury. We do not know, however, the critical point at which tissue hypoxia compromises intestinal function and viability in the developing animal. More information is necessary to understand the processes involved in the initiation and maintenance of intestinal ischemia in the newborn. Since many vasoactive substances are found in higher concentrations in the blood of neonates than at any other time, the physiological role of intrinsic and extrinsic humoral factors in the regulation of the intestinal circulation and the initiation of ischemia also needs further investigation. Future studies of developmental circulatory physiology and pathophysiology should provide the information necessary to ascertain the role of intestinal ischemia and tissue hypoxia in the pathogenesis of intestinal disorders of the neonate, including necrotizing enterocolitis.

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