M. van de Bor

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.

Cerebral blood flow velocity pattern in healthy and asphyxiated newborns: a controlled study.

In a controlled study serial determinations of cerebral blood flow velocity using Doppler ultrasound and repeated real-time ultrasonographic- or computerized axial tomographic studies of the brain were performed in 17 (nearly) full-term newborns who experienced perinatal asphyxia and in 17 healthy matched controls during the first week of life. A higher cerebral blood flow velocity was found during the first 4 days of life, indicating a lower cerebrovascular resistance in the asphyxiated infants compared to the control infants. These haemodynamic changes coincided with cerebral oedema and neurological abnormalities. It is speculated that the changes in the cerebral circulation in asphyxiated infants are at least partly caused by cerebral oedema-induced increase of intracranial pressure due to severe perinatal asphyxia. Serial Doppler ultrasound investigations of the brain may be a useful non-invasive method for early detection and follow-up of the consequences of severe perinatal asphyxia.

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.

Haemodynamic consequences of phototherapy in term infants

Abstract The effect of blue-light phototherapy on cardiac output and brain and kidney perfusion was studied in 12 term infants with pulsed Doppler ultrasound. Mean (±SD) gestational age and birth weight were 39.0 (±1.6) weeks and 3438 (±533) g respectively. Mean (±SD) age of the infants at which phototherapy was initiated was 3.5 (±0.8) days. Left ventricular output (LVO), mean left pulmonary artery blood flow (LPA), mean blood flow velocities of the internal carotid (CBFV) and renal (RBFV) arteries were studied in all infants prior to the onset of phototherapy, 30 min, 2 h, and 12 h after initiation of phototherapy, and before and 12–24 h after discontinuation of phototherapy. LVO decreased immediately after the onset of phototherapy. However, after 12 h, LVO returned to pre-phototherapy values. LPA increased significantly after 12 h of exposure. LPA returned to pre-phototherapy values after discontinuation of phototherapy. CBFV increased, whereas RBFV decreased significantly after 2 h of exposure. After discontinuation of phototherapy CBFV as well as RBFV values returned to pre-phototherapy values. Conclusion Phototherapy does affect cardiac output and organ blood flow velocity in term infants. After termination of phototherapy the effect of phototherapy disappears.

Blood flow velocity pattern of the anterior cerebral arteries. Before and after drainage of posthemorrhagic hydrocephalus in the newborn.

The blood flow velocity pattern of the anterior cerebral artery (ACA) was investigated using transcutaneous Doppler technique in ten preterm infants with posthemorrhagic hydrocephalus (PHH), before and after drainage of cerebrospinal fluid. The pulsatility index of the ACA was elevated during PHH, mainly due to an increase of peak systolic flow velocity, explained by an increased compliance of the vascular wall. The end diastolic flow velocity and the area under the velocity curve were not different before and after drainage, indicating that cerebrovascular resistance was not changed and blood flow through the ACA was not affected in the studied infants during PHH.

Inhalation of nitric oxide : effect on cerebral hemodynamics and activity, and antioxidant status in the newborn lamb

Ventilation with nitric oxide (NO) is increasingly being used to treat pulmonary hypertension in the newborn. In the brain, NO has vasoactive properties and is involved in neurotransmission. However, the effect of inhaled NO on the cerebral blood flow (CBF) and on the cerebral activity is not known. Furthermore, there is little information on the influence of this free radical gas on the redox status in pulmonary vessels. We therefore investigated the effect of inhaled NO (2-60 ppm) on CBF, cerebral activity and redox status in blood effluent from the pulmonary circulation in 6 ventilated newborn lambs before and during group B streptococci (GBS)-induced pulmonary hypertension. Blood pressure in the pulmonary artery (P(ap)) and aorta (Pao), carotid artery blood flow (Qcar) to assess changes in CBF, and electrocortical activity were measured. Blood gases, indices of free radical status and methemoglobin were determined in blood samples obtained from the left ventricle. Inhalation of NO, before and during GBS-induced pulmonary hypertension, decreased P(ap) and PCO2 and increased PO2. Multiple linear regression revealed that Qcar was positively related to PCO2, but not to inhaled NO or PO2 before or during GBS conditions. Electrocortical activity and indices of antioxidative capacity and lipid peroxidation did not change significantly. Methemoglobin was not detected. In conclusion, inhalation of NO (up to 60 ppm) lowered P(ap) without directly affecting CBF, electrocortical activity, and redox status in the pulmonary vessels. CBF, however, can indirectly be influenced by NO-mediated changes in PCO2.

The Effect of Phototherapy on Renal Blood Flow Velocity in Preterm Infants

Mean renal blood flow velocity (RBFV) was studied with two-dimensional/pulsed Doppler ultrasound and relative renal vascular resistance (RVR) was calculated before, during, and after phototherapy treatment in 30 preterm infants (gestational age ≤32 weeks) who were treated for a minimum of 12 h with phototherapy for nonhemolytic hyperbilirubinemia. RBFV decreased, whereas RVR increased significantly after the initiation of phototherapy. In ‘healthy’ (nonventilated) infants RBFV and RVR returned to baseline values after discontinuation of phototherapy. Whereas in ‘unhealthy’ (ventilated) infants, RBFV and RVR did not return to baseline values after discontinuation of phototherapy. In 16 infants (>50% of the cases) the ductus arteriosus reopened during phototherapy.

Renal Blood Flow Velocity in Non-Distressed Preterm Infants during the First 72 Hours of Life

Renal blood flow velocity (RBFV) was studied with two-dimensional/pulsed Doppler ultrasound in 28 non-distressed very preterm infants (mean +/- SD gestational age was 27.3 +/- 2.1 weeks and birth weight 907 +/- 214 g) at 6, 12, 24, 36, 48, and 72 h of age. Mean arterial blood pressure (MABP), PaCO2, PaO2, and Hct were determined simultaneously. Mean RBFV increased significantly from 14.5 +/- 1.9 cm/s at 6 h to 20.2 +/- 2.5 cm/s at 72 h (p < 0.005). MABP decreased slightly though significantly between 6 h (36.5 +/- 1.8 mm Hg) and 12 h (34.3 +/- 1.5 mm Hg), but rose thereafter to significantly higher values at 72 h (41.4 +/- 1.3 mm Hg). Renal vascular resistance (RVR = MABP/RBFV) decreased rapidly during the first day of life (2.6 +/- 0.1 mm Hg/cm.s-1 at 6 h vs. 2.0 +/- 0.05 mm Hg/cm.s-1 at 24 h). In conclusion, RBFV increases whereas RVR decreases during the first days of life.Renal blood flow velocity (RBFV) was studied with two-dimensional/pulsed Doppler ultrasound in 28 non-distressed very preterm infants (mean ± SD gestational age was 27.3 ± 2.1 weeks and birth weight 9

Changes in electrocortical brain activity during exchange transfusions in newborn infants

Electrocortical brain activity (ECBA) was recorded continuously with a cerebral function monitor during 17 exchange transfusions in 13 infants (mean gestational age 36.3 ± 1.9 weeks, birth weight 2,800 ± 635 g). The minimum and maximum amplitudes, and bandwidth of the ECBA signal were determined at the end of each withdrawal and infusion period. Mean arterial blood pressure (MABP), and the minimum and maximum amplitudes decreased during the withdrawal period and increased during the infusion period. The minimum and maximum amplitude changes were very small (< 6% of baseline) and appeared to be primarily associated with MABP changes. We conclude that exchange transfusions do cause minor changes in ECBA, which are probably not clinically relevant.

Cerebral cortical tissue damage after hemorrhagic hypotension in near-term born lambs.

Hypotension reduces cerebral O2 supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the cerebral cortex, as measured with electrocortical brain activity (ECBA), is related to cerebral cortical tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of cerebral cortical tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O2 supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO2 and NO3 (NOx) in plasma, and cGMP in cortical brain tissue were determined in both conditions. CSF and brain tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of cerebral cortical damage.