C.A. Dorrepaal

Social Lifestyle, Risk-taking Behavior, and Psychopathology in Young Adults Born Very Preterm or with a Very Low Birthweight

OBJECTIVE To assess social lifestyle, risk-taking behavior, and psychopathology in young adults born very preterm or with a very low birthweight. STUDY DESIGN This study was part of the 19-year follow-up in a large ongoing collaborative study in The Netherlands (the POPS study) on the long-term outcome of prematurity and dysmaturity. 656 adolescents from the POPS study without serious handicap were compared with peers in the general population in lifestyle, risk-taking behavior, psychopathology, and social participation. RESULTS Adolescents from the POPS study smoked significantly less than their peers. Compared with their peers, boys from the POPS study consumed alcohol less often, and girls from the POPS study consumed alcohol approximately as often. Lifetime drug-use was significantly lower than in the reference group. With the exception of fare-dodging, criminal behavior in POPS adolescents was significantly lower than in control subjects. Boys had more trouble in establishing a relationship. The clinical psychopathology reported by POPS subjects was not significantly higher than in control subjects. CONCLUSION Adolescents born very preterm or with a very low birthweight without serious disabilities engaged less in risk-taking behavior, did not show more psychopathology, but had more difficulties in establishing social contacts. The latter might be attributable to a more prominent internalizing behavior.

Acute Effects of Indomethacin on Cerebral Hemodynamics and Oxygenation

Although an indomethacin-induced decrease of brain perfusion in preterm infants has been well established, the acute effects of this vasoactive drug on cerebral hemodynamics and oxygenation are not well documented. Using near infrared spectroscopy we monitored in 6 very preterm infants changes in cerebral blood volume (delta CBV) and cytochrome oxidase concentration (delta Cytaa3), used as relative measures of changes in brain perfusion and as an indicator for cellular oxygenation of brain tissue, during and up to 1 h after indomethacin infusion. delta CBV showed a quick blood-pressure-related increase as compared to baseline (preindomethacin values) during indomethacin infusion (averaged maximal increase 13%), followed by a sharp decrease below baseline values (averaged maximal decrease 24%). There was a sustained recovery to baseline during the registration period. delta Cytaa3 showed a small, early increase in 4 of 6 babies, followed by a substantial decrease below baseline in 5 babies. delta Cytaa3 showed only a partial recovery in those 5 babies during the study period. We conclude that a therapeutic dose of indomethacin may cause substantial swings in brain perfusion and a marked and rather longstanding decrease in Cytaa3, suggesting a decrease in cellular oxygenation of brain tissue. Awareness of these effects may be important in sick preterm babies during periods of pulmonary and cardiac instability.

Effect of Post-Hypoxic-lschemic Inhibition of Nitric Oxide Synthesis on Cerebral Blood Flow, Metabolism and Electrocortical Brain Activity in Newborn Lambs

Since an excessive production of nitric oxide upon reperfusion/reoxygenation may play an important role in post-hypoxic-ischemic (HI) brain injury, we investigated whether immediate post-HI blockade of nitric oxide synthesis by N-omega-nitro-L-arginine (NLA) may reduce this injury. In 18 newborn lambs, subjected to severe HI, changes from pre-HI values were measured for carotid blood flow (Qcar [ml/min]) as a measure of changes in brain blood flow, (relative) cerebral metabolic rate of oxygen (CMRO2), and electrocortical brain activity (ECBA) at 15, 60, 120 and 180 min after HI. Upon completion of HI, at the onset of reperfusion and reoxygenation, 6 lambs received a placebo (control group), 6 low-dose NLA (10 mg/kg i.v., NLA-10 group), and 6 high-dose NLA (40 mg/kg i.v., NLA-40 group). Histological damage to cerebellar Purkinje cells was assessed after termination of the experiment. Only the control group showed a distinct initial post-HI cerebral hyperperfusion. From 60 min after HI onward Qcar was decreased to about 75% of pre-HI Qcar in all 3 groups, although none of these changes in Qcar reached statistical significance. Despite the decreased Qcar in all 3 groups, only the control group showed a significantly decreased CMRO2. ECBA and its bandwidth decreased in all groups, but only recovered in the NLA-10 group 180 min after HI. The brain to body mass ratio (%) and percentage necrotic Purkinje cells were, respectively: 15.3 +/- 0.8 and 56 +/- 10 (control group); 12.5 +/- 1.2 and 36 +/- 9 (NLA-10 group), and 11.3 +/- 1.0 (p < 0.05 vs. the control group) and 35 +/- 14 (NLA-40 group). Since post-HI reperfusion injury of the brain has been characterized by a decreased CMRO2 and electrical brain activity, we conclude that preservation of CMRO2 in both NLA groups, but a recovery of ECBA and its bandwidth only in the NLA-10 group, suggests that NLA, and especially low-dose NLA, may reduce post-HI brain injury.

Oxidative stress during post-hypoxic-ischemic reperfusion in the newborn lamb: the effect of nitric oxide synthesis inhibition.

Post-hypoxic-ischemic (HI) reperfusion induces endothelium and neurons to produce excessive amounts of nitric oxide and superoxide, leading to peroxynitrite formation, release of protein-bound metal ions (i.e. iron), and cytotoxic oxidants. We produced severe HI in 18 newborn lambs and serially determined plasma prooxidants (non-protein-bound iron), lipid peroxidation (malondialdehyde), and antioxidative capacity [ratio of ascorbic acid/dehydroascorbic acid (AA/DHA), α-tocopherol, sulfhydryl groups, allantoin/uric acid ratio, and vitamin A] in blood effluent from the brain before and at 15, 60, 120, and 180 min after HI. The lambs were divided in three groups: six received a placebo (CONT), six received low dose (10 mg/kg/i.v.) Nω-nitro-L-arginine (NLA-10) to block nitric oxide production, and six received high dose NLA (40 mg/kg/iv; NLA-40), immediately after completion of HI. Non-protein-bound iron increased in all groups after HI but was significantly lower in both NLA groups at 180 min post-HI (p < 0.05), the AA/DHA ratio showed a consistent decrease in CONT (at 60 min post-HI, p < 0.05), but remained stable in NLA lambs. α-Tocopherol decreased steadily in the CONT, but not in the NLA lambs [180 post-H: 1.9 ± 0.9 versus 4.2 ± 0.7 μM(NLA-40), p < 0.05). Malondialdehyde was significantly higher in CONT lambs 120 min post-H compared with NLA groups [0.61 ± 017versus 0.44 ± 0.05 μM (NLA-40), p < 0.05]. Vitamin A and sulfhydryl groups did not differ among groups. We conclude that post-H inhibition of nitric oxide synthesis diminishes non-protein-bound iron increment and preserves antioxidant capacity.

Changes in Cerebral Hemodynamics and Oxygenation during Hypothermic Cardiopulmonary Bypass in Neonates and Infants

Delay in development after open-heart surgery in infants has frequently been reported. Inadequate brain perfusion and oxygenation during deep hypothermic cardiopulmonary bypass (CPB) may play an important role. We investigated the effect of CPB on cerebral perfusion and oxygenation in 12 neonates and infants (age 0-11 months) undergoing open-heart surgery. Changes in cerebral blood volume (delta CBV; in ml/100 g brain tissue) and oxidation level of the intracerebral mitochondrial enzyme cytochrome aa3 (delta Cytaa3; in mumol/l) were measured with near infrared spectroscopy. Nasopharyngeal temperature (Tnas) for assessment of changes in brain temperature, and mean arterial blood pressure (MAP) were monitored continuously. CBV lowered during cooling and increased during rewarming. These changes were only related with changes in Tnas (p < 0.001; 0.07 ml.100 g-1/ degrees C). No relation was found with changes in MAP or pump flow rate of the heart-lung machine. During steady-state hypothermic CPB, changes in CBV were only related to changes in MAP (p < 0.001). The individual regression lines between delta CBV and MAP became steeper at lower absolute Tnas. Cytaa3 showed an increase shortly after the initiation of CPB in 9 patients, with a sustained decrease to baseline values in 8 patients towards the end of the CPB period. Two patients who had a circulatory arrest during CPB had a sharp decrease in delta cytaa3 after cessation of the heart-lung pump and showed no complete recovery of delta Cytaa3 to baseline at the end of the CPB period. We conclude that changes in CBV during CPB are related to changes in Tnas. During deep hypothermic steady-state CPB, changes in CBV and MAP were related to each other, suggesting lack of cerebral autoregulation. The large decrease in Cytaa3 in 2 patients with circulatory arrest suggests that this procedure compromises energy metabolism of the brain cell.

Cerebral Hemodynamics and Oxygenation in Preterm Infants after Low- vs. High-Dose Surfactant Replacement Therapy

In thirteen preterm infants receiving surfactant (Curosurf) replacement therapy, changes in cerebral hemodynamics and oxygenation were investigated by near infrared spectroscopy. Surfactant instillation led to an instantaneous increase in cerebral blood volume (CBV) in all infants, which was primarily due to an increase in deoxygenated hemoglobin. Five infants received a low dose (100 mg/kg = 1.25 ml/kg) of surfactant and 8 a high dose (200 mg/kg = 2.50 ml/kg). A significantly larger increase in CBV was observed in the infants receiving a high dose compared to those receiving a low dose of surfactant. We conclude that cerebral perfusion is affected more after the instillation of a high dose compared to a low dose of surfactant.

Cerebral blood volume changes during exchange transfusions in infants born at or near term

We investigated the effects on cerebral hemodynamics of blood pressure changes during exchange transfusions in infants born at or near term, using near infrared spectroscopy in eight stable infants (mean gestational age, 36.2 +/- 1.3 weeks) who underwent a total of 21 exchange transfusions for erythroblastosis fetalis (rhesus hemolytic disease). Changes in mean arterial blood pressure derived from an indwelling umbilical arterial catheter, transcutaneous arterial oxygen and carbon dioxide tension, as well as changes in cerebral oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (HbR), and total hemoglobin (Hbtot = HbO2 + HbR), were recorded continuously from 15 minutes before until the completion of the exchange transfusion. Relative change(s) in cerebral blood volume (dCBV) were calculated as follows: dCBV = change in Hbtot x 0.89/Venous hemoglobin. Changes in mean arterial blood pressure and dCBV were observed during all exchange transfusions; a decrease was found during the withdrawal period and an increase during the infusion period. The mean response of dCBV to a change in mean arterial blood pressure was 0.011 ml.100 gm-1.mm Hg. Multivariate analysis showed that dCBV were primarily associated with changes in mean arterial blood pressure, followed by changes in arterial oxygen tension and in exchange cycle duration. We conclude that in stable term and near-term infants, hemorrhagically induced blood pressure changes provoke dCBV.

Pretreatment with allopurinol in cardiac hypoxic-ischemic reperfusion injury in newborn lambs exerts its beneficial effect through afterload reduction.

Abstract The aim of this study was to determine whether allopurinol (ALLO) reduces reperfusion injury inflicted upon the heart resulting from excess production of free oxygen radicals after hypoxia and ischemia (HI) in newborn animals. We, therefore, produced severe HI in 13 newborn lambs by low O2-ventilation and blood volume reduction. One hour before HI seven lambs received ALLO (20 mg/kg i.v.), six received a placebo (CONT). Cardiac function and hemodynamic parameters were assessed by sequential measurement of left ventricular (LV) contractility through the end-systolic pressure-volume relation (ESPVR) using the conductance catheter method. Stroke volume (SV), cardiac output (CO), and aortic pressure (Pao) were measured and ejection fraction and total peripheral resistance (TPR) were calculated before HI, upon resuscitation (UR), and at 60 and 120 min post-HI. To estimate the effect of ALLO on redox status and anti-oxidative capacity, we measured concentrations of uric acid, sulfhydryl (SH), malondialdehyde (MDA), ascorbic acid (AA), and dehydroxylated ascorbic acid (DHAA) in plasma obtained from the coronary sinus and calculated the AA/DHAA ratio. Compared to CONT lambs, TPR in ALLO treated lambs decreased significantly, accompanied by a rise in CO and SV. ALLO did not affect myocardial contractility, because the ESPVR showed no significant differences between groups. AA/DHAA and SH showed a significant decrease in ALLO animals vs pre-HI, but not in CONT animals. Uric acid was significantly decreased in ALLO as compared to pre-HI and CONT animals. MDA was significantly increased in CONT animals at 15 min post-HI as compared to pre-HI, whereas in ALLO animals MDA showed a significant increase at 120 min post-HI vs CONT. We conclude that pretreatment with ALLO has a beneficial effect on the pump function by afterload reduction but not by changes in contractility. Furthermore, ALLO inhibited uric acid formation with a consequent decrease in anti-oxidative capacity.

Inhibition of nitric oxide synthesis following severe hypoxia-ischemia restores autoregulation of cerebral blood flow in newborn lambs.

Birth asphyxia impairs the autoregulatory ability of the cerebral blood flow. Inappropriate synthesis of vasodilatory nitric oxide may be important in this respect. We investigated if nitric oxide synthesis inhibition by N(omega)-nitro-L-arginine (NLA) could restore cerebral autoregulation after severe hypoxia-ischemia (HI). HI was induced in 15 newborn lambs. Cerebral blood flow (carotid artery blood flow [ml/min]: Qcar) and mean aortic blood pressure [mmHg]: MABP) were measured over a 30 min period before HI (pre-HI), 0-30 min after completion of HI (0-30 post-HI) and from 60 to 120 min post-HI (60-120 post-HI). Immediately after completion of HI, 5 lambs received a placebo (PLAC), 5 low dose NLA (10 mg/kg/iv: NLA-10) and 5 high dose NLA (40 mg/kg/iv: NLA-40). Pre-HI, all groups showed cerebral autoregulation with an upper limit of regulatory ability between 75 and 90 mm Hg. At 0-30 post-HI, all groups lacked autoregulatory ability of the cerebral vascular bed and showed an aortic blood pressure-passive Q(car). At 60-120 post-HI autoregulation was restored in NLA-10 and NLA-40-treated lambs (upper limit of autoregulation was shifted to higher MABP in NLA40-treated lambs), but not in placebo-treated lambs. At 60-120 post-HI MABP was higher in both NLA-groups than in PLAC group (83+/-15 [NLA-10] and 78+/-14 [NLA-40] vs. 65+/-9 mmHg [PLAC], P<0.05). We conclude that severe HI in newborn lambs induces impairment of the autoregulatory ability of the cerebral vascular bed. Even low-dose nitric oxide-synthesis inhibition started upon reperfusion restored autoregulation, suggesting a role for nitric oxide-induced vasodilation in the impairment of autoregulation of the cerebral blood flow after birth asphyxia.

Effect of Deferoxamine on Post-Hypoxic-Ischemic Reperfusion Injury of the Newborn Lamb Heart

Post-hypoxic-ischemic (HI) reperfusion induces excess production of non-protein-bound iron (NPBI), leading to formation of the highly reactive hydroxyl radical. We investigated whether the iron-chelator deferoxamine (DFO) could reduce reperfusion injury and improve left ventricular (LV) function. We produced severe HI in 14 newborn lambs and measured pre-HI, upon reperfusion, 60 and 120 min after HI the following parameters: mean aortic blood pressure, total peripheral resistance, stroke volume (SV), ejection fraction (EF) and LV contractility (pre-HI, 60 and 120 min post-HI). These parameters were assessed by measuring LV pressure (tip manometer) and volume (conductance catheter), using inflow occlusion to obtain slope (Ees) and volume intercept of the end-systolic P-V relationship (V10). We determined the antioxidative capacity, i.e. the ratio of ascorbic acid and dehydroascorbic acid (AA/DHAA) and malondialdehyde from coronary sinus blood at pre-HI and at 15, 60 and 120 min post-HI. Seven lambs received DFO (10 mg/kg i.v.) immediately after HI, 6 control lambs received a placebo. While neither Ees nor EF changed significantly in either group, the volume intercept V10 in the DFO-treated group was significantly smaller (0.25 ± 0.03 vs. 0.70 ± 0.09, p < 0.05), whereas SV was larger (3.6 ± 0.6 vs. 2.2 ± 0.2 ml, p < 0.05) and the AA/DHAA ratio was significantly lower at 15 min post-HI (p < 0.05) providing evidence for HI damage and for the protective effect of DFO. In conclusion: post-HI treatment of the newborn lamb with DFO has a modifying effect on free radical-induced damage to the myocardium and protects myocardial performance.