Richard Lehman’s journal blog, 14 April 2009

Richard Lehman

Human brown fat deposits and the effectiveness of nicotine replacement therapy are just two of the subjects touched on this week by Richard Lehman in his journal review, which also includes a parody of a T S  Eliot poem read by Dylan Thomas.

JAMA  8 Apr 2009  Vol 301

Whenever you look at a trial with heart failure in the title, bear in mind that the average age of patients with breathlessness attributable to impaired circulation in the UK is 76, most of them have co-morbidity, and about half of them have a systolic ejection fraction over 45%. I have read most of the HF trials carried out up to 2006, and many beyond, and I can’t think of a single one which has recruited a population like this. However, if you have some younger male patients with an ejection fraction under 35, then you might like to look at this randomised control of exercise, because 72% of the recruited patients were male and their mean age was 59. Thirty-six sessions of exercise failed to make any significant difference to survival or hospitalisation. The crumbs of comfort which the investigators gather are (a) you can do some retrospective subgroup tweaking and create a 13% benefit to fitter patients (but this is what is known as cheating), (b) patients with this type of HF did not die during exercise, and (c) using the Kansas City Cardiomyopathy Questionnaire you can extract a small but statistically significant improvement in score, for all this effort. See p.1451 if you want to decide if this is clinically relevant.

“As we get older we do not get any younger” begins a wonderful parody which sums up the message of TS Eliot’s Four Quartets. Like everyone between the ages of fifty and sixty, Eliot was struck by the feeling that increasing age does not bring any increase in wisdom or tranquillity. This is the message of the brown-baked compound familiar ghost in section II of Little Gidding, ending
From wrong to wrong the exasperated spirit
Proceeds, unless restored by that refining fire
Where you must move in measure, like a dancer.
I suppose ghosts are allowed to jumble their metaphors a bit. It is true that old age brings no relief from exasperation, or generalised anxiety: but cognitive behavioural therapy can be used with good effect, as this randomised trial in 67-year olds shows. But in this instance the comparator was usual care, rather than dancing in that refining fire.

NEJM  9 Apr 2009  Vol 360

There is a two-way relationship between asthma and acid reflux: if acid trickles up your oesophagus at night, you are more likely to cough and wheeze, and if you cough and wheeze you push your gastro-oesophageal sphincter up through your diaphragm and get more reflux. So how about trying a proton pump inhibitor for your poorly controlled asthmatics? Don’t bother, is the message of this double-blind randomised trial which used an expensive new PPI, esomeprazole, even though it wasn’t sponsored by the drug’s manufacturers. Not only does this study bin the idea of treating asthma with PPIs, but it also goes a long way to disproving the notion that asymptomatic reflux has an important role in refractory asthma.

Large sections of this week’s New England Journal are covered in brown fat, as if it had been left near the oven and someone had rested the Easter roast on it. The fat in question, however, has not bubbled from some delicious piece of meat but from the hidden recesses of healthy adults. You probably have some yourself, although in your pre-clinical course you were taught that it only occurs in newborn babies and small rodents. But if you look hard enough, especially in the supraclavicular area, you will probably find some scattered deposits of cold-activated brown adipose tissue, just as if you were an infant or a vole. And their function is probably the same – to convert energy into heat and so preserve core temperature through thermogenesis. The thinner you are, the more likely you are to have brown fat, and the colder you are, the more likely it is to show metabolic activity. This is illustrated in three papers which display some stunning feats of scientific technique, based on PET-CT scanning after the injection of 18F-flourodeoxyglucose. In this first study, we are shown the distribution of brown fat in 24 healthy young men of varying adiposity.

The next study looks at the presence of brown fat in nearly two thousand patients who had had PET-CT isotope scans performed for diagnostic purposes in a single US centre. It seems that three times as many women as men have substantial reserves of brown fat, but that the amount falls with age in both sexes. Oddly enough, if you take a beta-blocker you are ten times less likely to show brown fat activity.

The third study goes studies the metabolic function of human brown fat in greater detail thanks to the altruism of five healthy volunteers from Finland and Sweden. They submitted themselves to the afore-mentioned PET-CT scans and radioactive isotopes, exposed one foot to immersion in icy water, and also allowed a plastic surgeon to delve into their supraclavicular regions in search of the elusive brown adipocytes. As a result we know a lot more about the cellular function of human brown fat cells and the fact that their metabolism increases fifteen-fold during exposure to cold. But now that we have found this “hidden organ” which turns fat into heat, can we switch it on to treat obesity by a process of autocombustion? Alas, the prospects seem poor, for reasons discussed in the useful editorial on p.1553.

Myocarditis may perhaps be commoner than we think, since much of it occurs following viral illnesses and remits spontaneously after an initial phase of dilated cardiomyopathy. Without doing echocardiograms on everyone who feels tired and easily exhausted after flu, we’ll never know and it probably doesn’t matter. But in other circumstances, inflammation of the cells we depend on to keep us alive can be a very serious business indeed, and this review is an excellent single-author guide to the clinical scenarios by which it presents and their consequences – table 1 is required reading for anyone mugging up for medical membership.

Lancet  11 Apr 2009  Vol 338

Taking an oral bisphosphonate is a ritual lasting at least half an hour, during which you must drink lots of water and stay upright. Intravenous zoledronic acid on the other hand can achieve the same effect in 15 minutes once a year. This multicentre trial (HORIZON) in patients taking long-term oral glucocorticoids doesn’t really tell us much that we didn’t already know: it shows that in these patients IV zoledronic acid is superior to daily risedronate on all counts except immediate side-effects, both for treatment and prevention of osteoporosis. The end-points were bone density by dual energy X-ray absorptiometry at 6 and 12 months, and four measurements of two biomarkers for bone turnover: β-C-terminal telopeptides of type 1collagen (βCTx) and procollagen type1aminoterminal propeptide (P1NP). It’s time we gave up oral bisphosphonates and got our practice nurses trained up to give IV zoledronic acid to all our patients needing osteoporosis prevention and treatment.

The noble tradition of the healthy volunteer is alive and well in medicine, and we should salute such individuals whenever we hear of them. In my overlong piece on bed bugs last week, I failed to mention RL Usinger who fed himself to a colony of them every week for seven years to study his reactions to their bites. I make amends here. I also hail the heroes of this study on the effect of avotermin on the healing of scars. These volunteers were literally scarred for life by this experiment, but those who had avotermin injected before full-thickness skin wounds were inflicted on them showed better healing, as judged blindly by a panel of doctors and lay people. It seems that we need more trials of this transforming growth factor in real surgical situations such as cosmetically prominent procedures, or in individuals with a tendency to form keloid.

The avotermin study was a nice simple proof-of-concept job, but this next proof-of-concept study is anything but straightforward. It seems to prove the concept that catheter ablation of the renal sympathetic nerves can cure resistant hypertension. The results are certainly impressive: reductions of a mean 27/17 mm Hg at one year of follow-up in patients who had previously stayed above 177/101 despite treatment with three or more drugs. But there are some very pertinent questions raised about the entry criteria in the accompanying editorial (p.1228), and it is likely to be some time before we send off our uncontrolled hypertensives to the renal catheter lab.

Everybody should take regular salicylates: that’s not as controversial a statement as it sounds, because salicylates are abundant in most fresh vegetables and fruits. The real question addressed by this systematic review is whether everybody should take artificial salicylate (aspirin) to prevent cancer. Pretty well all the evidence – observational and interventional – suggests that aspirin confers some protection against colonic cancer, but probably only after ten years of continuous dosing. Similar regular intake may also protect against cancers of the oesophagus, stomach and breast: an effect shared by other NSAIDs and rapidly lost on discontinuation.

BMJ  11 Apr 2009  Vol 338

Those of you who follow guidelines probably prescribe nicotine replacement therapy as first line treatment when people ask for help to stop smoking. Very well: you will double cessation rates compared with nothing, but for long term abstinence the number-needed-to-treat is 29. This systematic review does not discuss other treatments or whether patients benefit from long-term maintenance therapy, since these questions are not addressed by the trials they examine. But the fact is that there are more effective alternatives, especially combined treatment, and since nicotine addiction is harder to break and much more harmful than opioid addiction, long-term substitution therapy is quite logical. For more useful studies, see Ann Intern Med.

I spent my student elective in 1974 staying with a family in Iran, which ever since then I have regarded as the most hospitable and civilised country in the world. I refer to individuals rather than governments, of course; and I write, admittedly, as a male who has visited only a few countries in the world. If you go anywhere near a native person in Iran, you will be approached courteously and offered a glass of scalding hot tea, with a lump of sugar to hold between your teeth as you drink it. The harmful effect on the incisor teeth of some Iranians is easy to observe, but the effect on the Iranian oesophagus has only just come to be realised. This case-control study examines tea-drinking habits in relation to the extraordinary incidence of oesophageal cancer in northern Iran. The hotter the tea and the faster you gulp it, the more likely you are to get cancer of the oesophagus.

cover image7699Here is a good practical account of the cauda equina syndrome, beautifully illustrated with a horse’s tail of nerves on the front cover of this week’s BMJ. Fortunately, it is rare, and any given GP may never see a case in her/his life; by the same token, it is unfortunately easy to miss. The moral here is that anyone with increasing urinary difficulty or retention should be tested for loss of perianal sensation, whether or not there are any back or leg symptoms. This article is unusual (and commendable) for its inclusion of medicolegal data, which show that although orthopaedic surgeons may be more likely to get sued, GPs also need to watch out.

Investigating hypertension in a young person is certainly a challenge to Rational Testing, but I continue to find this series disappointing. Hypertension presents to GPs, and we have to do the testing: we are accustomed to being told how to be rational by clinical biochemists and academics, but also accustomed to ignoring them. The fact is that primary aldosteronism is a difficult diagnosis to establish, which is why we miss most of it, and this piece skates over the difficulties in order to reach the unusually neat outcome in their chosen patient, who became normotensive following removal of a solitary right adrenal tumour. In real life, this is a minefield of inadequate sampling conditions, incidentalomas, and variable responses to targeted treatment. To pretend it is simple is a bit of a Conn.

Ann Intern Med  7 Apr 2009  Vol 150

One of the questions raised in this week’s BMJ systematic review of nicotine replacement is whether psychological support really does have an effect beyond the effect of the nicotine. This Kansas study attempted to address a slightly wider question, using a range of options, including nicotine replacement or bupropion, with or without psychological support, or the latter alone, at one of two levels of intensity. All smokers were targeted, whether or not they were “ready to quit”, and the study ran for two years, so that people could have more than one go at quitting. The outcome was self-reported cessation, which was about the same in all groups, and pretty impressive at 23-27%. Nonetheless the investigators conclude that more psychological support can produce better results.

For the great majority of smokers, the greatest health benefit we can offer them is help to give up smoking. This is especially true of medically ill smokers, and this trial randomised 127 of them to receive either a nicotine patch alone for 10 weeks or as many patches, inhalators or prescriptions for bupropion as they liked for as long as they liked. This was a small, rather crude unblinded trial with 25% of participants lost to follow-up, but the combination group did almost twice as well.

Confused about the association of low-density lipoprotein subfractions with cardiovascular outcomes? Don’t worry: this systematic review shows that everybody is. And will probably stay that way, harmlessly.

Parody of the Week: Chard Whitlow by Henry Reed (1941)

If you know the Four Quartets by TS Eliot, you will never be able to read them in quite the same way again once you’ve heard or read this parody, written at the time of the London Blitz when Eliot was a fire warden – hence the references to hiding under the stairs or in the Tube, and to stirrup-pumps.

As we get older we do not get any younger.
Seasons return, and today I am fifty-five,
And this time last year I was fifty-four,
And this time next year I shall be sixty-two.
And I cannot say I should like (to speak for myself)
To see my time over again— if you can call it time:
Fidgeting uneasily under a draughty stair,
Or counting sleepless nights in the crowded Tube.

There are certain precautions— though none of them very reliable—
Against the blast from bombs and the flying splinter,
But not against the blast from heaven, vento dei venti,
The wind within a wind unable to speak for wind;
And the frigid burnings of purgatory will not be touched
By any emollient.
I think you will find this put,
Better than I could ever hope to express it,
In the words of Kharma: “It is, we believe,
Idle to hope that the simple stirrup-pump
Will extinguish hell.”
Oh, listeners,
And you especially who have turned off the wireless,
And sit in Stoke or Basingstoke listening appreciatively to the silence,
(Which is also the silence of hell) pray not for your selves but your souls.
And pray for me also under the draughty stair.
As we get older we do not get any younger.

And pray for Kharma under the holy mountain.
You can hear Dylan Thomas reading it here