Pathophysiology of Shock in theFetus and Neonate

Lactic Acidosis in Fetal Hypoxemia

Under physiologic conditions, lactate levels are higher in the fetal than the maternal circulation. The increase in fetal lactate levels is the result of enhanced placental lactate production and decreased fetal gluconeogenic utilization of lactate. Lactic acidosis develops under pathologic conditions when compensatory increases in O ₂ extraction and cardiac output have reached the limit of their capacity to satisfy tissue O ₂ demand. Critical O ₂ delivery in fetal sheep appears to be at 12 mL/kg/min, and decrements in O ₂ delivery to less than this value are associated with impaired oxidative metabolism and accumulation of lactic acid in the fetal tissues and blood. Indeed, elevated plasma lactate has been shown to be a good indicator of fetal hypoxemia. In addition to the significant correlation between umbilical lactate levels and other measures of acidosis, a recent meta-analysis also found that plasma lactate levels predict neurologic outcome including hypoxic-ischemic encephalopathy. After 4 to 5 hours of fetal hypoxemia, blood lactate reaches a plateau despite continued anaerobic metabolism. Placental clearance of lactate is responsible for this phenomenon. Thus, despite ongoing fetal anaerobic metabolism in cases of chronic and severe fetal hypoxemia, the fetal serum lactate level does not increase beyond the point of equilibrium.

The fetus responds differently to various levels of severity of hypoxia. Maternal hypoxia-induced mild fetal hypoxia does not alter fetal acid-base balance when fetal arterial O ₂ saturations remain in the 40% range even when the hypoxemia persists for 24 hours. However, when fetal hypoxia results in fetal arterial O ₂ saturations of less than 30%, metabolic acidosis develops. Human data are consistent with the results of animal studies indicating that arterial oxygen saturation of 30% is the threshold for developing metabolic acidosis. ^, Thus the critical threshold of arterial O ₂ saturation, defined as the arterial O ₂ saturation below which metabolic acidosis develops, is approximately 30% in the maternal hypoxia-induced fetal hypoxia model in sheep. It appears that susceptibility of the fetus to hypoxia is developmentally regulated; the preterm fetus is less sensitive to the effects of maternal hypoxia than the term counterpart. ^, For instance, when maternal hypoxia results in fetal arterial O ₂ saturations of less than 30%, the preterm ovine fetus develops metabolic acidosis at a much slower pace than that described for the fetus near or at term.

The fetus also appears to respond differently to various causes of hypoxia. Due to compensatory mechanisms within the placenta, placental oxygenation is protected from maternal hypoxia to a certain degree. When fetal hypoxemia is induced by umbilical cord occlusion, the fetal response differs from that seen with maternal hypoxia. When fetal hypoxemia is caused by umbilical cord occlusion, metabolic acidosis develops more rapidly compared with maternal hypoxia-induced fetal hypoxemia. The lack of placental compensatory mechanisms in the cord occlusion model may be responsible for this difference. Finally, the fetal response to hypoxemia is also altered when hypoxia is caused by decreased uterine blood flow. In this model, the critical threshold of arterial O ₂ saturation is lower than observed in the maternal hypoxia or cord occlusion models; rapid lactate accumulation and fall in pH only occur when fetal O ₂ saturation is in the 15% to 20% range. This finding suggests that placental compensatory mechanisms remain effective when blood flow to the uterus is decreased. Because of interspecies differences, these findings obtained in the sheep should be translated to the human fetus with caution.

Endocrine Responses to Fetal Hypoxemia

In the fetus, acute hypoxemia is associated with an increase in plasma concentration of several hormones, including adrenocorticotropic hormone, β-endorphin, ^, vasopressin, glucocorticoids, norepinephrine, and epinephrine. ^{, ,} This stress hormone response facilitates fetal adaptation to hypoxemia in part by ensuring the redistribution of blood flow to vital organs.

However, the effectiveness of the fetal stress hormone response is limited by the developmentally regulated immaturity of certain endocrine organs and the cellular mechanisms of end-organ responses. For instance, although the fetal adrenal gland increases cortisol secretion in response to hypoxemic stress, the increase in the cortisol level is significantly less than occurs in mature animals, whereas the increase in the catecholamine levels is similar to that seen in the mature animal. In addition, expression of the cardiovascular adrenergic receptors and second-messenger systems is developmentally regulated, contributing to the observed differences in the stress response between the fetus and the mature animal.

The exact mechanisms of the 50- to 1000-fold increase in fetal catecholamine release to fetal stress remain to be clarified. Cohn and colleagues investigated the effect of metabolic acidosis on adrenal catecholamine secretion. In an effort to avoid the adrenal stimulatory effect of hypoxemia associated with acidosis-induced rightward shift in oxyhemoglobin dissociation curve, 100% O ₂ was administered to the pregnant ewe during the infusion of 30% lactic acid to the fetus. Under these experimental circumstances, metabolic acidosis in the absence of hypoxia did not stimulate adrenal catecholamine secretion. Conversely, studies investigating fetal catecholamine release in the presence of hypoxemia have reported increased catecholamine and vasopressin secretion in the presence or absence of associated metabolic acidosis. ^,

Cardiovascular Effects of Fetal Hypoxemia

In the fetus, the right and left ventricles work in parallel, and therefore the combined left and right cardiac output is considered the total cardiac output. In the fetal lamb, the combined cardiac output is 450 mL/kg/min, to which the right and left ventricles contribute 300 and 150 mL/kg/min, respectively. Similarly, in the human fetus, the contribution of the right ventricle to the combined cardiac output is significantly higher than that of the left ventricle. Data obtained by echocardiography show the combined cardiac output in human fetus to be similar to that of fetal sheep; however, the right ventricle contributes only approximately 60% of the combined output. ^,

In the fetal lamb, the cardiovascular response to acute hypoxemia is characterized by the rapid development of hypertension, bradycardia, increased peripheral vascular resistance, and a 15% to 20% decrease in the cardiac output. The decrease in cardiac output is primarily the result of the increased peripheral vascular resistance (afterload), bradycardia, vagal stimulation, and myocardial depression. However, significant myocardial depression occurs only if the hypoxemia is severe or prolonged or is associated with metabolic acidosis. In the fetus, adenosine may play an important modulatory role in the previously described cardiovascular “maladaptation” by influencing fetal autonomic and glycolytic responses to hypoxia. In the sheep, blockade of adenosine receptors during fetal hypoxia significantly attenuates the development of hypertension (systemic vascular resistance [SVR] increase), bradycardia, and metabolic acidosis. ^, The fetal cardiovascular response to prolonged hypoxemia is different from that seen in acute hypoxemia models. In fetal sheep with sustained hypoxemia, cardiac output drops progressively to 38%, and, not unexpectedly, right ventricular output is compromised earlier than the left ventricular output. Similarly, in a fetal lamb model using intermittent umbilical cord occlusions, metabolic acidosis is more severe with moderate variable heart rate decelerations in the chronically hypoxic fetus compared with the normoxic fetal sheep model. In addition, the recovery time from acidosis is longer in chronically hypoxic fetus.

In response to fetal hypoxemia, distribution of cardiac output and venous return is altered in an effort to maintain perfusion and O ₂ delivery to the vital organs such as the heart, brain, and adrenal glands. ^{, ,} During induced maternofetal hypoxia, the percentage of systemic venous blood recirculated to the fetal body and not sent to the placenta is decreased, whereas the proportion of umbilical venous blood contributing to fetal cardiac output is increased from 27% to 39%. As mentioned earlier, there are differences in the fetal response, including the distribution of cardiac output, venous return, and O ₂ delivery among the different models of fetal hypoxia. However, regardless of the cause of hypoxia, the blood flow and O ₂ delivery to the heart, brain, and adrenal glands are maintained, and the proportion of umbilical venous blood bypassing the liver through the ductus venosus is increased in all cases. ^{, ,}

Finally, the fetal cardiovascular and endocrine response to acute hypoxemia is altered when repeated hypoxic events occur. This is important because recurrence of hypoxic insults to the fetus may not be infrequent in human pregnancies in which blood flow to the uterus, placenta, or the fetus is repeatedly compromised. It appears that hypoxemia sensitizes the cardiac and vasoconstrictor chemoreflex responses to repeated episodes of hypoxemia. For example, enhanced femoral vasoconstriction and marked elevation in plasma norepinephrine and vasopressin have been demonstrated in response to acute hypoxemia in fetal sheep that had been previously exposed to sustained hypoxemia.

Renal Responses to Hypoxemia

Although the placental-maternal unit performs most of the effective compensatory functions, the fetal kidney has the ability to contribute to the maintenance of fetal acid-base balance. For instance, ammonium excretion and hence generation of bicarbonate, as well as sodium excretion, increase during the recovery period from hypocapnic-hypoxia in the fetal sheep. The presence of hypocapnia appears to be a key determinant in the timing of fetal renal responses. Because fetal P co ₂ is low as a result of maternal compensatory hyperventilation in response to hypoxia in this model and because CO ₂ is required for bicarbonate absorption in the proximal tubule, bicarbonate reabsorption and acid excretion in the fetus are delayed until hypoxemia subsides and maternal, and thus fetal, P co ₂ returns to normal.

In addition to the effects of hypoxemia on the renal compensatory mechanisms to maintain fetal acid-base balance, other changes in renal function are induced by hypoxemia. Fractional excretion of sodium is increased by a decrease in proximal tubule sodium reabsorption. ^, Urine osmolality also increases, and free water clearance drops secondary to increases in vasopressin release. ^, Finally, like the other organs, the immature kidney is also less susceptible to hypoxemia than the mature kidney. The renal response to lactic acidosis induced by acid infusion in the fetal sheep is confined to tubular adaptive responses with decreases in urine pH and increases in ammonium and titratable acid excretion without changes in glomerular filtration rate.