How the risk:benefit of bisoprolol became a medic:psychiatry trade off

A patient has anoxic brain injury followed an MI a few months ago. He was fit and well both mentally and physically before this, with only well controlled asthma blotting his otherwise pristine medical record. The brain injury has left him with mostly frontal signs. He has been disinhibited and had been becoming increasingly aggressive. Several members of the nursing staff had been at risk from physical aggression.

Post MI, he was started on the usual medications:

  • Simvastatin 40mg NOCTE
  • Bisoprolol 1.25mg OD (down from 1.25mg BD a few weeks before)
  • Ramipril 2.5mg BD
  • Clopidogrel 75mg OD
  • Aspirin 75mg OD

For the psychiatric symptoms, he was been on various atypical antipsychotics. The concern with most of them is the QT prolongation, especially post MI. Aripiprazole seems to have the least effect on the QT interval and was initially used. However, this failed to adequately control his symptoms. Quetiapine seemed to be more effective, but came with a risk of QTc prolongation.

He was also on diazepam 5mg TDS, with an aim to titrate down if his behaviour allowed. He also had PRN diazepam and quetiapine.

Every morning, his observations were relatively consistent. His pulse was between 50 and 60 and his blood pressure about 95-105/60. His saturations would vary considerably, dropping as low a 84%. They would pick up with a salbutamol nebuliser. He would have about 2-3 episodes of sats in the low 90s a week. Since his anoxic brain injury, he has not been compliant with inhaled medication, even with a spacer.

I was called to authorise PRN diazepam when he was being particularly aggressive with staff whilst having saturations of 92%, BP 94/47 and pulse 48. This was a difficult call. I could hear a wheeze in between his verbal threats, so I decided to give a salbutamol nebuliser first, which I hoped would perhaps pick up his pulse as well as improve his saturations. He tolerated it remarkably well, although his saturations stayed the same afterwards, with a pulse of 51 and BP 104/67. I decided to give 2mg of diazepam and observe closely.

Diazepam given orally has a rapid onset of action, and takes 1 hour to reach its peak effect. It then has a half life in the region of 20-50 hours.  Once he has got through the first hour, it is less likely he will then go into respiratory depression/cardiovascular collapse, which is why particularly close attention to his obs is paid in that crucial first hour.

This case illustrated the difficulty of managing antipsychotics and benzodiazepines in a patient demonstrating aggression with a previous MI and low pulse, BP and saturations. The aggression has been getting quite serious; staff have been injured. How could we tweak the medications to get the most benefit medically and also boost his BP, pulse and asthma control to make PRN doses of diazepam safer?

Plan A: Stop bisoprolol

In favour: This would increase his pulse and blood pressure, and we could always titrate ramipril for any worsening blood pressure control. It may also help his asthma.With improved observations, we could give diazepam more safely as needed.

Against: How much benefit from post MI beta blockade would we be sacrificing? And is it even likely that such a small dose of a cardioselective beta blocker was really worsening his asthma?

I discussed this with a medical consultant. He said that it was unlikely that bisoprolol would be to blame for the asthma worsening, and it was far more likely that lack of compliance with his medications was the problem. He said that if the flares continued, it would be worth stopping bisoprolol and titrating ramipril.

I still wanted to know how much benefit it would cost to drop the beta blocker. There was a summary published in Circulation in 2002. It was first shown in 1965 that giving propanolol indefinitely post MI improved mortality. A RCT in 1982 was PICO’d as follows:

P: 3,837 post MI patients aged 30-69
I: Daily propanolol (180/240mg OD, depending on serum levels) started 5-21 days post MI, continued over the follow up period (average 24 months)
C: Placebo
O: Total mortality during the average 24-month follow-up period was 7.2% in the propranolol group and 9.8% in the placebo group

With the addition of ACE-inhibitors, PCI, antiplatelets and all other exciting treatments since this trial, some then questioned whether beta blockers really have that much benefit compared to the new treatments, and whether the absolute benefit from the beta blockers was reduced now that there were so many other interventions to reduce mortality. The SAVE trial looked at whether beta blockers made a difference post MI over and above ACE inhibitors. They did.

The next question was whether cardioselective beta blockers are safe in people with asthma. The only meta-analysis I found looking at this question directly found that in patients with mild to moderate airway reactivity, the first dose of a cardioselective beta blocker does reduce FEV1, but over continous dosing this effect diminishes. This meta-analysis had asthma patients with a mean age of 40 however, which is much younger than the age of most patients on beta blockers. It also did not look at patients with severe asthma.

Comparing the risk of asthma against the risk of MI alone, bisoprolol should probably continue.

The complicating factor was the observations during the day at times when the patient was aggressive and needed PRN diazepam. The patient was clearly agitated at times and improved considerably on diazepam. Would it not be better for his mental health and safer for the staff to be able to safely use diazepam when all else fails? You could argue we should treat the patient not the obs, and a patient who is up and about and swinging violently clearly has a more than decent A, B and C. My concern is that whilst at the time of considering diazepam he seemed well, if he were to have a bad reaction then with a PMHx of unmedicated asthma and previous catastrophic MI, the risks of respiratory depression and cardiovascular collapse are probably heightened. It is in his medical interest to ensure his observations were optimised to give him more slack to comfortably tolerate diazepam doses.

Plan B: Nebulised steroid daily as preventative

The patient was able to tolerate nebulised salbutamol, even though he would not use a spacer. Perhaps it would be worth using step 2 of the BTS ladder, giving the same dose of steroid (200 micrograms BD) via a nebuliser to help his long term control.

It would be great to hear what, if any, changes to his medications you would make. What do you think should be done?


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