Neurogenic hypertension and elevated vertebrobasilar arterial resistance: is there a causative link?

There is evidence of sympathetic overdrive in a significant proportion of patients with essential hypertension and an animal model of the condition, the spontaneously hypertensive rat (SHR). The reasons for this remain elusive. However, there is also evidence of narrowing of the arteries supplying the brainstem in the SHR and hypertensive humans. In this review, we discuss the possible role of brainstem hypoperfusion in driving increased sympathetic activity and hypertension.

Regular treatment with formoterol for chronic asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between beta(2)-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe. OBJECTIVES: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists. SEARCH METHODS: We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol. The date of the most recent search was January 2012. SELECTION CRITERIA: We included controlled, parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular formoterol and were of at least 12 weeks' duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second author checked them. We sought unpublished data on mortality and serious adverse events. MAIN RESULTS: The review includes 22 studies (8032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease-specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Peto odds ratio (OR) 1.57; 95% CI 1.06 to 2.31). One extra serious adverse event occurred over 16 weeks for every 149 people treated with regular formoterol (95% CI 66 to 1407 people). The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicate that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline. AUTHORS' CONCLUSIONS: In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all severities of adverse events or limited to those events that are thought by the investigator to be drug-related.

Hypertension before and after posterior circulation infarction: analysis of data from the South London Stroke Register.

BACKGROUND: Postmortem data have shown that blood pressure before death correlates more closely with a narrowing of the vertebral arteries than any other vessel studied. This study explores a possible association between hypertension, both before and after posterior circulation infarction (POCI) compared to anterior circulation infarction (ACI). METHODS: Patients with a first-ever stroke enrolled in the South London Stroke Register between 2000 and 2006 were included. Chi-square tests and multivariable logistic regression were used to compare risk factors including hypertension, sex, smoking history, diabetes, and hypercholesterolemia in patients with POCI compared to ACI. Chi-square testing was used to compare the incidence of newly diagnosed hypertension after POCI and ACI. Absolute blood pressure readings recorded before stroke and 7 days after stroke were also compared between groups. RESULTS: On multivariable analysis, POCI was significantly associated with male sex (odds ratio [OR] 2.24; 95% confidence interval [CI] 1.55-3.22; P < .001) and hypertension (OR 1.69; 95% CI 1.15-2.50; P = .008). After stroke, patients with POCI were more likely to be newly diagnosed with hypertension during a 1-year follow-up period (OR 2.15; 95% CI 1.20-3.86; P = .009) and as an inpatient (OR 3.27; 95% CI 1.49-7.13; P = .002). Systolic blood pressure was significantly higher in the POCI group before stroke (152 v 146 mm Hg; P = .027). Diastolic blood pressure was significantly higher 7 days poststroke (81 v 74 mm Hg; P = .01) in patients not previously diagnosed with hypertension. CONCLUSIONS: This study has shown a significant association between hypertension before and after POCI compared to ACI. We believe further investigation with brainstem imaging and recordings of sympathetic nervous system activity after stroke is warranted.

Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats.

There is a strong correlation between increased vertebral artery resistance and arterial blood pressure in humans. The reasons for this increased resistance at high systemic pressure remain unknown, but may include raised sympathetic activity. With the recent finding that prehypertensive spontaneously hypertensive (PHSH) rats, which have raised sympathetic nerve activity, but a blood pressure comparable to normotensive rat strains, we hypothesized that its vertebrobasilar vascular resistance would already be raised and, as a consequence, would exhibit a more responsive Cushing response (e.g., brain ischemia evoked sympathoexcitation and a pressor response). We report that PHSH rats exhibited a remodeling of the basilar artery (i.e., increased wall thickness and lower lumen-to-wall thickness ratio) that occurred before the onset of hypertension. In a novel in vitro vascularly isolated, arterially perfused brain stem preparation of PHSH rats of 4-5 wk of age, brain stem vascular resistance was raised by ∼35% relative to age- and sex-matched normotensive rats (P < 0.05). In the in situ arterial perfused working heart-brain stem preparation, occlusion of both vertebral arteries in the PHSH rat resulted in a significantly greater increase in sympathetic activity (57 vs. 20%, PHSH vs. control; P < 0.01) that triggered a greater increase in arterial perfusion pressure (8 vs. 3 mmHg, PHSH vs. control; P < 0.01) compared with normotensive rats. These data indicate raised vertebrobasilar artery resistance before the onset of hypertension in the PHSH rat. With the raised responsiveness of the Cushing response in the PHSH rat, we discuss the possibility of brain stem perfusion as a central nervous system determinant of the set point of vasomotor sympathetic tone in the hypertensive condition.

Regular treatment with formoterol for chronic asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between beta-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe. OBJECTIVES: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists. SEARCH STRATEGY: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was July 2008. SELECTION CRITERIA: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol and were of at least 12 weeks duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review. Outcome data were extracted by one author and checked by the second author. Unpublished data on mortality and serious adverse events were sought. MAIN RESULTS: The review includes 22 studies (8,032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Odds Ratio 1.57 [95% CI: 1.05 to 2.37]). One extra serious adverse event occurred over 16 weeks for every 179 people treated with regular formoterol [95% CI: 75 to 2022]. The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicates that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline. AUTHORS' CONCLUSIONS: In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age-groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all adverse events or limited to those events that are thought by the investigator to be drug-related.

Regular treatment with salmeterol for chronic asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between beta-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe. OBJECTIVES: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular salmeterol versus placebo or regular short-acting beta(2)-agonists. SEARCH STRATEGY: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and FDA submissions in relation to salmeterol were also checked. The date of the most recent search was October 2007. SELECTION CRITERIA: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular salmeterol and were of at least 12 weeks duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review. Outcome data was extracted by one author and checked by the second author. Unpublished data on mortality and serious adverse events was sought. MAIN RESULTS: The review includes 26 trials comparing salmeterol to placebo and 8 trials comparing with salbutamol. These included 62,630 participants with asthma (including 2,380 children). In 6 trials (2,766 patients), no serious adverse event data could be obtained. All cause mortality was higher with regular salmeterol than placebo but the increase was not significant, Odds Ratio 1.33 [95% CI: 0.85, 2.10]. Non-fatal serious adverse events were significantly increased when regular salmeterol was compared with placebo, Odds Ratio 1.14 [95% CI: 1.01, 1.28]. One extra serious adverse event occurred over 28 weeks for every 188 people treated with regular salmeterol [95% CI: 95 to 2606]. There is insufficient evidence to assess whether the risk in children is higher or lower than in adults. No significant increase in fatal or non-fatal serious adverse events was found when regular salmeterol was compared with regular salbutamol. Individual patient data from the SNS study have been combined with the results of the SMART study; in patients who were not taking inhaled corticosteroids, compared to regular salbutamol or placebo, there was a significant increase in risk of asthma-related death with regular salmeterol, Odds Ratio 9.52 [95% CI: 1.24, 73.09]. The confidence interval for patients taking inhaled corticosteroids is too wide to rule out an increase in asthma mortality in this group. AUTHORS' CONCLUSIONS: In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol. There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies. Although the increase in asthma-related mortality was smaller in patients taking inhaled corticosteroids at baseline, the confidence interval is wide, so it cannot be concluded that the inhaled corticosteroids abolish the risks of regular salmeterol. The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied.