Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms. Beta-adrenoceptor blockade in the treatment of postoperative adynamic ileus. Low dose beta blockade in acute stroke ("BEST" trial): an evaluation. Effect of combined blockade of beta-adrenoceptors and acetylcholinesterase in the treatment of postoperative ileus after cholecystectomy. Randomized double-blind controlled trial of roxithromycin for prevention of abdominal aortic aneurysm expansion.
To study the propranolol treatment of small abdominal aortic aneurysms (AAA) concerning intention to treat, side effects, and inhibition of expansion.
                
                Two-year lasting prospective randomised double-blinded intervention trial.
                Hospital-based mass screening for AAA with annual ambulatory control of small AAA.
                Of 122 screening-diagnosed small AAA, 51 (42%) were excluded because of contraindications or present beta-blockage, and 17 refused participation. Thus, 54 (44.3%) were included.
                Participants were randomised to 40 mg propranolol twice a day or placebo.
                The same observed was used to follow-up AAA-expansion, side effects, quality of life (QL), branchial and ankle blood pressure (ABI), and pulmonary function (FEV1 and FVC).
                Sixty percent in the propranolol group, and 25% in the placebo group dropped out, mainly caused by dyspnoea in the propranolol group (RR=1.74, 95% C.I.: 1.06-2.86). Five (16.7%) died in the propranolol group, while 1 (4.2%) died in the placebo group (RR=1.6 (1.02-2.51)). Furthermore, decreased pulmonary function, ABI, and QL was noticed in the propranolol group. Consequently, the trial was stopped after two years. Ninety-five percent of the measurements of the AAA were measured within 2 mm variation. If expansion was defined as above 2 mm annually, the relative risk of expansion in the placebo group was 1.17 (0.74-1.85), and 2.44 (0.88-6.77) among the non-drop-outs.
                Only 22% of small screenings-diagnosed AAA were treatable with propranolol for two years. Consequently, only large scale studies are capable of showing potential minor inhibition of expansion by propranolol. However, whether such treatment ever becomes ethically acceptable is debatable. Abdominal trauma, such as surgery and peritonitis, leads to inhibition of intestinal motility, partly mediated by alpha- and beta-adrenoceptors. To investigate the effect of nonselective beta-blockade on adynamic ileus, propranolol was compared with placebo in the postoperative course after elective colonic surgery in a double-blind randomized study. Ten patients received 4 mg propranolol intravenously twice daily, and ten received 10 mg intravenously twice daily. Nineteen patients received placebo. The time to first passage of stool was 110 +/- 9 h in the placebo group and 82 +/- 11 h in the 4-mg propranolol group. In the 10-mg propranolol group, the time was 79 +/- 8 h. The difference between the placebo-treated group and the propranolol-treated groups was significant (p less than 0.01). The effect of propranolol was most marked in older patients and after surgery on the distal colon. In patients older than 60 years the time to first stool in the placebo group was 127 +/- 13 h (n = 8), compared with 73 +/- 8 h (n = 11) in the propranolol group (p less than 0.01). In patients who had undergone surgery on the distal colon the time to first stool was 125 +/- 13 h (n = 8) in the placebo group and 76 +/- 8 h (n = 11) for propranolol (p less than 0.01). Adverse effects on the respiratory or cardiovascular system were not seen during medication. It is concluded that propranolol shortens the period of adynamic ileus after colonic surgery. The beta blocker stroke ("BEST") trial was designed to see if the apparent protective effect of propranolol on cerebral function in patients with subarachnoid haemorrhage applied also to patients suffering from acute stroke. Three hundred and two conscious patients with clinically diagnosed hemispheric strokes sustained within the past 48 hours were randomly assigned to receive atenolol, propranolol, or matching placebo capsules for three weeks. More early deaths occurred among the patients allocated to receive beta blockers, but this was largely explained by differences in the initial characteristics of the patients among the different treatment groups. By contrast, the outcome in a further 60 patients, who had been taking beta blockers at the time of their stroke but were otherwise similar to the patients in the trial, was considerably better, suggesting that prior treatment with beta blockers might be protective. The search for an effective medical treatment for acute stroke must continue. The approach used here, in which neurological outcome was assessed in a modest number of patients with a view to proceeding subsequently to a full scale trial of functional outcome, allows practical benefits of a treatment to be evaluated under realistic conditions and an ineffective treatment to be eliminated without undue cost. The effect of treatment with a non-selective beta-adrenoceptor blocker (propranolol) and an acetylcholinesterase blocker (neostigmine) on the duration of postoperative ileus after cholecystectomy was investigated in a double-blind, randomized study comprising 51 patients. Propranolol (P), 10 mg intravenously twice daily was, together with neostigmine (N), 0.5 mg subcutaneously twice daily, administered to 16 patients. Eighteen patients were treated with neostigmine, 0.5 mg subcutaneously twice daily only, and 17 patients were placebo-treated controls (C). The medical treatment started in the evening of the day of operation. The time to first passage of stool after operation was determined and used as a measure of duration of the postoperative ileus. The mean time was 68 +/- 6 h in the P + N-treated group, 82 +/- 6 h in the N group, and 90 +/- 7 h in the C group. The difference between the P + N group and controls was significant (p less than 0.01). P + N was effective in patients older than 60 years (p less than 0.01), whereas no effect was seen in patients younger than 60 years. In conclusion, treatment with a combination of propranolol and neostigmine shortened the duration of postoperative paralytic ileus after cholecystectomy. This effect was not seen after treatment with neostigmine only. The effect of P + N was most marked in patients older than 60 years. Macrolide treatment has been reported to lower the risk of recurrent ischaemic heart disease. The influence of macrolides on the expansion rate of abdominal aortic aneurysms (AAAs) remains unknown. The aim was to investigate the effect of roxithromycin on the expansion rate of small AAAs.
                A total of 92 subjects with a small AAA were recruited from two populations. One population consisted of 6339 men aged 65-73 years who were offered a hospital-based mass screening programme for AAA. From this population 66 subjects were recruited. The remaining 26 men were recruited from among 49 subjects diagnosed at interval screening for an initial aortic diameter between 25 and 29 mm. Subjects were randomized to receive either oral roxithromycin 300 mg once daily for 28 days or matching placebo, and followed for a mean of 1.5 years.
                During the first year the mean annual expansion rate of AAAs was reduced by 44 [corrected] per cent in the intervention group (1.56 mm per year), compared with 2.80 mm per year following placebo (P = 0.02). During the second year the difference was only 5 per cent [corrected]. Multiple linear regression analysis showed that roxithromycin treatment and initial AAA size were significantly related to AAA expansion when adjusted for smoking, diastolic blood pressure and immunoglobulin A level of 20 or more [corrected]. Logistic regression analysis confirmed a significant difference in expansion rates above 2 mm annually between the intervention and placebo groups: odds ratio = 0.09 (95 per cent confidence interval 0.01-0.83) [corrected].
                In comparison to placebo, roxithromycin 300 mg daily for 4 weeks reduced the expansion rate of AAAs.
There is some limited evidence that antibiotic medication may have a slight protective effect in retarding the expansion rates of small AAAs. The quality of the evidence makes it unclear whether this translates into fewer referrals to AAA surgery, owing mainly to the small sample sizes of the studies.
Antibiotics were generally well tolerated with minimal adverse effects. Propranolol was poorly tolerated by patients in all of the beta-blocker trials and demonstrated only minimal and non-significant protective effects. Further research on beta-blockers for AAA needs to consider the use of drugs other than propranolol.
In general, there is surprisingly little high quality evidence on medical treatment for small AAAs, especially in relation to the use of newer beta-blockers, ACE inhibitors and statins.