Frank van Bel

Effect of deferoxamine and allopurinol on non-protein-bound iron concentrations in plasma and cortical brain tissue of newborn lambs following hypoxia-ischemia.

Reduction of non-protein-bound iron (NPBI) using iron chelators may attenuate hypoxia-ischemia-induced reperfusion injury of the brain. This study investigated whether administration of low-dose deferoxamine and allopurinol, both having NPBI-chelating properties, reduced hypoxia-ischemia-induced NPBI formation in plasma effluent from the brain and in cerebral cortical tissue. Twenty-one newborn lambs underwent severe hypoxia-ischemia. Upon reperfusion and reoxygenation the lambs received either a placebo (n = 7), or deferoxamine 2.5 mg/kg (n = 7) or allopurinol 20 mg/kg (n = 7). The post-hypoxic-ischemic NPBI levels in plasma were significantly lower after deferoxamine but not after allopurinol as compared to placebo-treated lambs. Cortical NPBI levels in both deferoxamine and allopurinol-treated lambs were significantly lower than NPBI levels in placebo-treated lambs. We conclude that deferoxamine effectively lowers NPBI in plasma effluent from the brain, and that both, deferoxamine and allopurinol, lower NPBI in cortical brain tissue.

Interaction Between Afterload and Contractility in the Newborn Heart: Evidence of Homeometric Autoregulation in the Intact Circulation

OBJECTIVES We undertook the present study to determine whether afterload and contractility interact in the hearts of newborn lambs. We specifically investigated whether stepwise increases in afterload increase contractility. BACKGROUND Several studies in the isolated and intact adult dog heart have shown that afterload and contractility are not independent determinants of cardiac performance; rather, they interact. Afterload and contractility are unlikely to interact in the newborn heart because the factors that may mediate the interaction in the adult are missing in the newborn. METHODS We measured contractility at different steady state levels of afterload in seven newborn lambs under complete anesthesia. Contractility was measured by three different indexes: end-systolic pressure-volume relations (slope and volume position); preload-corrected first derivative of left ventricular pressure (dP/dtmax); and preload-corrected stroke work. Left ventricular pressure and volume were measured with a micromanometer and conductance catheter, respectively. Preload and afterload were manipulated by inflating or deflating a balloon catheter in the inferior vena cava and descending thoracic aorta, respectively. Data are expressed as mean value +/- 1 SD. RESULTS Stepwise increases in afterload increased contractility, independent of which of the three indexes was used. The slope of the end-systolic pressure-volume relation increased from a mean baseline value of 4.44 +/- 2.43 to 6.69 +/- 2.89 kPa/ml at the highest level of afterload. Concomitantly, volume at 14 kPa of the end-systolic pressure-volume relation decreased from 3.34 +/- 1.52 ml at baseline to 1.12 +/- 0.83 ml at the highest afterload. The other two indexes showed qualitatively similar changes. Beats selected from unloading interventions on the basis of the same end-diastolic volume for each level of afterload showed no difference in stroke volume. CONCLUSIONS This study in newborn lambs demonstrates that stepwise increases in afterload increase contractility considerably and that this enables the heart to maintain stroke volume at different levels of afterload. This forms direct evidence for the existence of homeometric autoregulation in the intact newborn heart.

Near infrared spectroscopy-measured changes in cerebral blood volume and cytochrome aa3 in newborn lambs exposed to hypoxia and hypercapnia, and ischemia: a comparison with changes in brain perfusion and O2 metabolism ☆

OBJECTIVES Validation of near infrared spectroscopy (NIRS)-measured changes in cerebral blood volume (deltaCBV) and cytochrome aa3 (deltaCytaa3) as estimators of changes in brain perfusion and oxygenation in the newborn lamb during hypoxia and hypercarbia, and additional hypotension. METHODS AND MATERIALS In 33 newborn lambs brain perfusion assessed by carotid artery blood flow (deltaQcar: ml/min)and cerebral metabolic rate of oxygen (deltaCMRO2: ml O2/min) were related to NIRS-derived deltaCBV (ml/100 g) and deltaCytaa3 (microM) during combined hypoxia and hypercarbia and additional hypotension. Combined hypoxia and hypercapnia was induced by ventilation with 6-8% of O2 and 10% of CO2 during 30 min, and additional hypotension ( < 35 mmHg for 5 min) was induced by careful withdrawal of blood. RESULTS CBV increased during hypoxia and hypercarbia, decreased during additional hypotension and was related to deltaQcar: (0.009 ml/100 g change per ml/min Qcar: P < 0.0001). Cytaa3 increased during hypoxia and hypercarbia, decreased during subsequent additional hypotension andshowed a reverse relationship with deltaCMRO2 (-1.65 microM change per ml O2/min CMRO2: P <0.0001). Cytaa3 remained above baseline during reperfusion. CONCLUSIONS deltaCBV estimates changes in brain perfusion, but overestimates brain perfusion during hypotension. The pattern of deltaCytaa3 suggests less oxygen utilisation by brain tissue during hypoxia and subsequent reperfusion.

Electrocortical brain activity during hypoxia and hypotension in anesthetized newborn lambs

Blood gas and blood pressure disturbances do influence cerebral blood flow in newborns. To what extent cerebral blood flow changes affect electrocortical brain activity remains uncertain. We studied the effect of severe hypoxia and hemorrhagic hypotension on carotid artery blood flow and electrocortical brain activity in newborn anesthetized lambs. During hypoxia carotid artery blood flow increased significantly, whereas electrocortical brain activity remained unchanged. The hemorrhagic hypotension study showed that the lower limit of the autoregulatory ability of the cerebral vascular bed was 60 mmHg. Electrocortical brain activity however remained stable until mean aortic pressure had dropped below 30 mmHg, carotid artery blood flow below 10.6 ml/kg/min, and cerebral oxygen delivery below 1.4 ml/kg/min.

Clinical Aspects and Treatment of the Hypoxic-Ischemic Syndrome

In the Western world, perinatal asphyxia is still a relatively common phenomenon in perinatal care. Since differences in causes and patterns of brain injury following perinatal asphyxia exist between full-term and preterm neonates, this chapter will focus on full-term neonates.