Principles of Clinical Management of Patent Ductus Arteriosus in Extremely Preterm Neonates.

The clinical management of a patent ductus arteriosus (PDA) in preterm newborns is a controversial topic, and despite nearly three decades of research, varying opinions remain. This dilemma stems from uncertain causal linkage between PDA and neonatal comorbidities, as well as the lack of clear evidence showing that benefits of treatment outweigh risks. There has been a general shift in the management of PDA in preterm newborns from early and aggressive closure to a more conservative approach of watchful waiting and spontaneous closure. However, a firm recommendation cannot be made due to a lack of randomized controlled trials validating either treatment strategies. Although cyclooxygenase inhibitors, namely indomethacin and ibuprofen, are approved pharmacological treatments for PDA, there is a need to explore alternative medical therapies in view of lack of clinical response in many newborns and concerns over adverse effects. One such recent interest is the use of acetaminophen as a pharmacological agent. This present review tries to address the questions at hand, integrate the current evidence, highlight the principles of PDA management in preterm newborns, and suggest areas for possible future research.

Intravenous thrombolysis in thromboembolic occlusion of the A1 segment of the left anterior cerebral artery only.

This case describes the treatment of an 84-year-old male patient with acute bi-frontal ischemic stroke, due to thromboembolic occlusion of the A1 segment of the left anterior cerebral artery (ACA) only. The National Institutes of Health Stroke Scale (NIHSS) was 11. Intravenous fibrinolysis was performed with a good outcome. Repermeabilization of both ACA was demonstrated by imaging and, 24 h after treatment, NIHSS was 0. Although intravenous thrombolysis is mostly used for middle cerebral artery occlusion, this case emphasizes the benefit of this treatment for an ischemic stroke due to embolization of the A1 segment of the left ACA only. It is all the more original in that it describes an unusual treatment for this arterial territory, and with this anatomic particularity.

Differences between cerebrovascular reactivity to L-arginine in the anterior and posterior cerebral circulation.

BACKGROUND: Cerebral endothelial function might be different in distinct cerebrovascular territory, thereby making these areas more susceptible to ischemia and stroke. Higher incidence and prevalence of stroke in males suggest that gender could have a strong influence on this difference. In order to evaluate cerebral endothelial function, we compared cerebrovascular reactivity (CVR) to L-arginine in the anterior and posterior cerebral circulation in healthy young males and females. METHODS: Thirty healthy subjects, 15 females (32.1 ± 7.1 years) and 15 males (32.2 ± 6.3 years), were included. The mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by transcranial Doppler sonography before and after intravenous infusion of L-arginine, and CVR to L-arginine was then calculated. RESULTS: CVR to L-arginine was significantly higher in PCA than in MCA in all subjects (19.2 ± 8.2 vs. 13.6 ± 7.1%, p ≤ 0.01). In addition, CVR to L-arginine was significantly more pronounced in females compared to males in PCA (22.7 ± 8.3 vs. 15.8 ± 6.7%, p ≤ 0.01) and MCA (16.8 ± 6.4 vs. 10.4 ± 6.4%, p < 0.05). CONCLUSIONS: Lower CVR to L-arginine and therefore lower cerebral endothelial function in the anterior cerebral circulation and in males might be related to the higher incidence of ischemia and stroke in the anterior cerebral circulation, particularly in males.

Cerebrovascular reactivity to l-arginine in the anterior and posterior cerebral circulation in migraine patients.

OBJECTIVE - Cerebral infarction preferentially affects the posterior cerebral artery distribution in migraine patients. The results obtained from the few known studies that have compared the anterior and posterior cerebral endothelial function are contradictory. To the best of our knowledge, cerebrovascular reactivity to L-arginine (CVR), measured by transcranial Doppler sonography (TCD), has not been previously used to determine the posterior cerebral endothelial function in migraine patients with (MwA) and without aura (MwoA). MATERIALS AND METHODS - Forty migraine patients without comorbidities (20 MwA, 20 MwoA) and 20 healthy subjects were included. By employing strict inclusion criteria, we avoided the possible vascular risk factors. Mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by TCD before and after infusion of L-arginine, and CVR to L-arginine was then calculated. RESULTS - All migraine patients had lower CVR to L-arginine in PCA (P = 0.002) and similar in MCA (P = 0.29) compared to healthy subjects. This difference was also present in MwA and MwoA compared to healthy subjects (P = 0.003). CONCLUSIONS - Lower CVR to L-arginine in PCA in migraine patients could associate migraine and cerebral infarcts that are more common in the posterior cerebral artery distribution.

EEG and cerebral blood flow velocity abnormalities in chronic cocaine users.

EEG and cerebral blood flow abnormalities have been documented in chronic cocaine abusers. To identify possible relationships between EEG and blood flow changes and their relationship to the intensity of cocaine use, we recorded the resting eyes-closed EEG and anterior (ACA) and middle (MCA) cerebral artery blood flow velocity during systole (V(S)) and diastole (V(D)) by transcranial Doppler (TCD) sonography of 99 (76 male, 23 female; mean [SD] age 34.3 [5.2] years, 8.6 [5.5] years of cocaine use, 17.8 [7.7] days of cocaine use in month prior to screening) cocaine users within 5 days of admission to a closed research unit. Forty-two non-drug-using, age-matched control subjects (22 male, 20 female) were tested as outpatients. A 3-minute period of resting EEG was recorded from 16 standard scalp electrodes. Artifact-free EEG was converted to six frequency bands (delta, theta, alpha1, alpha2, beta1 and beta2) using a Fast Fourier Transform. Pulsatility index (PI) was calculated as a measure of small vessel resistance. Cocaine users had decreased VD and increased PI in the MCA, with no difference in V(S), and reduced EEG theta, beta1 and beta2 absolute power in posterior brain regions. Recent cocaine use was positively associated with MCA PI (r = 0.27, p < 0.001) and negatively associated with low frequency EEG power (delta power: r = -0.25, p < 0.002; theta power: r = -0.29, p < 0.001). EEG beta1 (r = -0.211, p < 0.05) and beta2 (r = -0.176, p < 0.05) power measures were correlated with PI. These observations suggest that EEG and TCD changes reflect related physiological processes during early cocaine abstinence.

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects.

RATIONALE: Although the subjective effects of caffeine abstinence, acute and chronic administration, and tolerance are well described, the corresponding neurophysiological effects are not. OBJECTIVES: Caffeine withdrawal, acute caffeine effects, caffeine tolerance, and net beneficial effects of chronic caffeine administration were investigated using cerebral blood flow velocity, quantitative electroencephalography (EEG), and subjective effects. MATERIALS AND METHODS: Sixteen regular caffeine users participated in this double-blind, within-subject study during which they received acute caffeine and placebo challenges (1) while maintained on 400 mg caffeine daily for > or =14 days and (2) while maintained on placebo for > or =14 days. Blood flow velocity was determined for the middle (MCA) and anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded from 16 scalp sites. Subjective effects were assessed with questionnaires. RESULTS: Acute caffeine abstinence (evaluated 24 h after placebo substitution) increased mean, systolic, and diastolic velocity in the MCA and ACA and decreased pulsatility index in the MCA. Acute caffeine abstinence increased EEG theta and decreased beta 2 power. Acute caffeine abstinence also increased measures of Tired, Fatigue, Sluggish, and Weary and decreased ratings of Energetic, Friendly, Lively, and Vigor. Acute caffeine effects were demonstrated across a wide range of measures, including cerebral blood flow, EEG, and subjective effects. Tolerance and "complete" tolerance were observed on subjective but not physiological measures. Chronic caffeine effects were demonstrated only on the measure of EEG beta 2 power. CONCLUSION: Acute caffeine abstinence and administration produced changes in cerebral blood flow velocity, EEG, and subjective effects. Tolerance to subjective but not physiological measures was demonstrated. There was almost no evidence for net effects of chronic caffeine administration on these measures. Overall, these findings provide the most rigorous demonstration to date of physiological effects of caffeine withdrawal.

Intracerebral regional distribution of blood flow in response to uterine contractions in growth-restricted human fetuses.

OBJECTIVE: To explore middle cerebral artery (MCA) and anterior cerebral artery (ACA) blood flow responses to superimposed acute hypoxemia in growth-restricted fetuses with and without established brain-sparing flow during basal conditions. MATERIAL AND METHODS: 47 term fetuses suspected of growth restriction were exposed to an oxytocin challenge test with simultaneous cardiotocography and Doppler velocimetry in the umbilical artery, MCA and ACA. The MCA-to-ACA pulsatility index (PI) ratio was calculated during basal conditions, contractions and relaxations. Basal brain-sparing flow was defined as an MCA-to-umbilical artery PI ratio of<1.08, de novo brain-sparing flow in the MCA as an MCA PI decrease with> or =1 standard deviation during uterine contractions or relaxations compared with basal measurements, and de novo brain-sparing flow in the ACA as an ACA PI decrease with > or =1 standard deviation. Non-parametric statistical tests were used with P<0.05 considered significant. RESULTS: MCA and ACA PI were both significantly lower in the brain-sparing flow group (N=8) during basal conditions (P< or =0.01). During the oxytocin challenge test, MCA and ACA PI both decreased in the non-brain-sparing flow group (N=39) (P< or =0.02) but not in the brain-sparing flow group (P> or =0.4). The MCA-to-ACA PI ratio remained unchanged in both groups. de novo brain-sparing flow calculations revealed no preferential flow to any cerebral artery. CONCLUSION: Cerebral circulatory responses to acute hypoxemia are synchronized in the middle and anterior cerebral arteries without any preferential regional flow distribution.

Effects of a divided high loading dose of caffeine on circulatory variables in preterm infants.

BACKGROUND: A single high loading dose of 25 mg/kg caffeine has been shown to be effective for the prevention of apnoea, but may result in considerable reductions in blood flow velocity (BFV) in cerebral and intestinal arteries. OBJECTIVE: To assess the effects of two loading doses of 12.5 mg/kg caffeine given four hours apart on BFV in cerebral and intestinal arteries, left ventricular output (LVO), and plasma caffeine concentrations in preterm infants. DESIGN: Sixteen preterm neonates of <34 weeks gestation were investigated one hour after the first oral dose and one, two, and 20 hours after the second dose by Doppler sonography. RESULTS: The mean (SD) plasma caffeine concentrations were 31 (7) and 29 (7) mg/l at two and 20 hours respectively after the second dose. One hour after the first dose, none of the circulatory variables had changed significantly. One hour after the second caffeine dose, mean BFV in the internal carotid artery and anterior cerebral artery showed significant reductions of 17% and 19% (p = 0.01 and p = 0.003 respectively). BFV in the coeliac artery and superior mesenteric artery, LVO, PCO2, and respiratory rate had not changed significantly. Total vascular resistance, calculated as the ratio of mean blood pressure to LVO, had increased significantly one and two hours after the second dose (p = 0.049 and p = 0.023 respectively). CONCLUSION: A divided high loading dose of 25 mg/kg caffeine given four hours apart had decreased BFV in cerebral arteries after the second dose, whereas BFV in intestinal arteries and LVO were not affected.

U-46619 but not serotonin increases endocannabinoid content in middle cerebral artery: evidence for functional relevance.

Cerebral vascular smooth muscle cells express the CB(1) cannabinoid receptor, and CB(1) receptor agonists produce vasodilation of cerebral arteries. The purpose of this study was to determine whether vasoconstriction of rat middle cerebral artery (MCA) results in the local formation of endocannabinoids (eCBs), which, via activation of CB(1) receptors, oppose the vasoconstriction in a feedback manner. The thromboxane A(2) (TXA(2)) mimetic U-46619 significantly increased N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) content of isolated MCA, whereas 5-hydroxytrypamine (5-HT) decreased AEA and 2-AG content. If eCBs play a feedback role in the regulation of MCA tone, then CB(1) receptor antagonists should enhance the constriction of MCA produced by U-46619 but not 5-HT. U-46619 caused concentration-dependent constrictions of endothelium-denuded MCA. Two CB(1) receptor antagonists SR-141716 and AM-251 decreased the EC(50) value for U-46619 to constrict endothelium-denuded MCA without affecting the maximal effect. A low concentration of CB(1) receptor agonist Win-55212-2 (30 nM) produced vasodilation of MCAs constricted with low but not saturating concentrations of U-46619. SR-141716 had no effect on the 5-HT concentration-contraction relationship. These data suggest that TXA(2) receptor activation increases MCA eCB content, which, via activation of CB(1) receptors, reduces the constriction produced by moderate concentrations of the TXA(2) agonist. Although 5-HT-induced vasoconstriction is reduced by exogenous CB(1) receptor agonist, activation of 5-HT receptors does not increase eCB content. These results suggest that MCA production of eCBs is not regulated by constriction per se but likely via a signaling pathway that is specific for TXA(2) receptors and not 5-HT receptors.

Local intra-arterial fibrinolysis in acute hemispheric stroke: effect of occlusion type and fibrinolytic agent on recanalization success and neurological outcome.

BACKGROUND: To evaluate the effect of occlusion type and fibrinolytic agent on recanalization success and clinical outcome in patients undergoing local intra-arterial fibrinolysis (LIF) in acute hemispheric stroke. METHODS: LIF was performed in 137 patients with angiographically established occlusion in the carotid circulation within 6 h of stroke onset. Retrospective analysis included recanalization success, recanalization time, type of occlusion and fibrinolytic treatment mode. Five types of occlusion were categorized: intracranial bifurcation (carotid 'T') of the internal carotid artery (ICA; n = 35); proximal segment of the middle cerebral artery (MCA; n = 66); distal segment of the MCA (n = 20); extracranial ICA with MCA embolism (n = 8); multiple peripheral branches of the anterior cerebral artery and the MCA (n = 8). Neurologic outcome was evaluated after 3 months by Barthel Index (BI) as good (BI >90), moderate (BI 50-90), poor (BI <50) or death. RESULTS: Recanalization was achieved in 74 patients (54%). Mean recanalization time in recanalized patients was 91 min. Neurologic outcome was good in 48 patients (35%), moderate in 34 (25%), poor in 30 (22%) and 25 died (18%). Outcome was significantly better in recanalized than in nonrecanalized patients (p < 0.001). Treatment results were significantly better in proximal and distal MCA occlusion than in carotid 'T' occlusions (p < 0.001). Recanalization success hardly differed between urokinase and rt-PA. Combined treatment with rt-PA and lys-plasminogen tended toward a faster recanalization. Parenchymal hemorrhage occurred in 13 patients (9%). CONCLUSION: The type of occlusion is of high prognostic value for successful fibrinolysis in the anterior circulation. However, recanalization is a time-consuming process even with an intra-arterial approach. Recanalization did not differ between type or dosage of plasminogen activators. Further innovative attempts are warranted towards hastening recanalization time in endovascular acute stroke treatment.

Methadone treatment induces attenuation of cerebrovascular deficits associated with the prolonged abuse of cocaine and heroin.

Opiate replacement therapy has been useful in reducing heroin use and in keeping patients in treatment programs. However, neuropsychological and neurophysiological effects of this treatment regimen have not been evaluated systematically. To determine whether methadone treatment reduces the magnitude of cerebral blood flow alternations in polysubstance (heroin and cocaine) abusers, we compared blood flow parameters in control subjects (n=26), polysubstance abusers (n=28) maintained on methadone for 24 weeks, and polysubstance abusers (n=22) who were not seeking treatment. Blood flow velocity was recorded from the anterior and middle cerebral arteries using transcranial Doppler sonography on an outpatient visit. The pulsatility index, a measure of cerebrovascular resistance, was significantly (p&<0.05) increased in both groups of polysubstance abusers compared to control subjects. Increased pulsatility in the two groups of substance abusers suggests constriction of the small cortical arteries. Nevertheless, the methadone-maintained polysubstance abusers had significantly lower pulsatility values than the nontreatment substance-abusing group. These findings suggest that maintenance on methadone might have significant beneficial neurovascular effects on this population of patients.

Efficacy and safety of nicardipine prolonged-release implants for preventing vasospasm in humans.

BACKGROUND AND PURPOSE: Despite extensive investigative efforts, there are few treatments that can prevent vasospasm after subarachnoid hemorrhage. This study was conducted to examine the efficacy and safety of nicardipine prolonged-release implants (NPRI) for humans, which have already been proven in dogs. METHODS: Twenty consecutive subarachnoid hemorrhage patients with thick subarachnoid clot were treated with NPRI (a pellet of diameter 2 mm, length 10 mm, containing 4 mg of nicardipine) during surgery after clipping of their aneurysm. The number and location of pellets depended on the amount and site of subarachnoid clot on preoperative CT and on craniotomy. RESULTS: Two to 10 pellets were implanted in the cistern of the internal carotid, middle cerebral, and/or anterior cerebral artery, where thick clots existed and therefore vasospasm related to delayed ischemic neurological deficits was highly likely. Delayed ischemic neurological deficits and cerebral infarctions were seen in 1 patient. Angiography performed on days 7 to 12 revealed no vasospasm in any arteries near which NPRI were placed. No complications were experienced. CONCLUSIONS: Vasospasm was completely prevented for the arteries in thick clot cisterns, when NPRI were placed adjacent to the arteries during surgery. This drug-delivery system offers a promising approach for preventing vasospasm.

Antiviral medications improve cerebrovascular perfusion in HIV+ non-drug users and HIV+ cocaine abusers.

Antiviral medications have been useful in delaying the time course of HIV infection. Antiviral medications have also been reported to delay or reduce symptoms associated with AIDS related dementia and to improve cortical perfusion. The mechanism for this improvement is unclear. Thus, this report studies the effects of antiviral medications on cerebral blood flow velocity in HIV+ cocaine abusers, HIV+ control individuals and appropriate control individuals. Thirty-two unmedicated HIV+ individuals (28 cocaine abusers and 4 control individuals), 22 HIV+ individuals using antiviral medications (16 cocaine abusers and 6 HIV+ control individuals), 47 HIV- cocaine abusers, and 27 control HIV- subjects were studied. Blood flow velocities were determined for the anterior and middle cerebral arteries using transcranial Doppler sonography. HIV+ individuals on antiviral medications had lower pulsatility values, suggesting decreased resistance in the cerebral blood vessels, in comparison to HIV+ individuals not taking antiviral medications. HIV+ cocaine abusers and HIV+ control individuals using antiviral medications had pulsatility values similar to HIV- control subjects. Antiviral medications appear to reduce these cerebrovascular perfusion deficits in HIV+ individuals. The antiviral medications appear to have a direct neuroprotective effect in addition to their antiviral effects. The neuroprotective role of antiviral medications requires further investigation.

Zinc sulphate-induced anosmia decreases the nerve fibre density in the anterior cerebral artery of the rat.

Detailed quantitative studies have demonstrated a topographical heterogeneity of nerve fibre densities in the cerebral arteries at the base of the brain as well as local changes in ageing and Alzheimer's patients. In this study, we test the hypothesis that local patterns of innervation are influenced by changes in flow fluctuations. This was investigated by inducing chronic anosmia and monitoring the nerve fibre density in the basal cerebral arteries in the adult rat. The olfactory epithelium was examined after staining with hematoxylin and eosin and showed a marked reduction of thickness in the anosmic group compared to the control group. The olfactory bulb was histochemically stained for succinate dehydrogenase (SDH) activity and showed a reduced staining in the anosmic group compared to the controls. Whole mount preparations of the basal cerebral arteries were immunostained for the general neural marker protein gene product (PGP) 9.5. The nerve fibre densities of the vessel walls were quantified by image analysis and expressed as area percentage and intercept density. This analysis showed a significant reduction in area percentage for the first part of the anterior cerebral artery, as well as for the second part of the anterior cerebral artery, and a significant reduction in intercept density for the second part of the anterior cerebral artery in the anosmic group. We conclude that peripherally induced anosmia decreases nerve fibre density in the anterior cerebral artery that may be due to a decreased metabolic activity in the rhinencephalon and, as a consequence, a reduction of flow fluctuations in the blood vessels supplying this area occurs.