Richard Lehman’s journal review – 4 July 2011

Richard LehmanNEJM  30 June 2011  Vol 364
The world of African emergency medicine is one which many noble British GPs have visited, but I alas am not of their number. I have merely braved the acute takes of celebrated New England hospital, where I learned yesterday that emergency departments throughout the world exhibit a hypotension-fluid bolus reflex. It is a sort of iatrogenic renin-angiotensin system: if blood pressure drops, the doctor immediately inserts fluid and sodium. Never mind if the patient is in renal or cardiac failure, in it goes. A similar procedure is routine in many hospitals looking after children with severe infection throughout the world. In the old days the doctor would bleed them: now we give them false blood in the form of regular bolus saline with or without albumin. Like bleeding for two thousand years, everyone knew this must be right, until somebody did this trial in several African hospitals and found that saline boluses increase mortality. See the editorial, “Fluid Resuscitation in Acute Illness — Time to Reappraise the Basics.”

2496   In real life, oncology is a gruelling specialty, where you discharge your successes early, and stay with your other patients until they are too desperately ill for you to do anything more. By contrast, the armchair oncologist lives in a world of optimism and success, as three papers in this week’s NEJM illustrate perfectly. I don’t suggest you actually read them: after all, genomics is best left to gene gnomes and chemo is definitely best left to people in protective clothing and facemasks. But it is great to see some old bastions of disease begin to crumble, even if we can’t understand all that is involved. For example, do you understand myelodysplasia? Of course not: nobody does. But it’s in a diffuse disease spectrum like this that genomics can really prove a help, allowing the characterization of different subtypes with different patterns of progression and prognosis. Don’t even try to remember them – just know that they’re known.

2507   The next stage is to use these genomic tumour characteristics to develop targeted therapy, and here some of the most exciting work seems to be going on in disseminated malignant melanoma, previous the inexorable killer of many young patients. Here the most common mutation is BRAF (BRAF V600E), found in 30 to 60% of melanomas. Venurafenib is a potent, orally available inhibitor of this BRAF variant and proved much better at preventing death and disease progression than dacarbazine in this trial. Whether it can achieve long-term remission, we don’t yet know: but we do know from a very recent trial of a similar agent that this is occasionally possible.

2517   Ipilimumab works on a different pathway altogether and is, as you can tell from its name, a monoclonal antibody. It blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negative regulator of T cells, in case you want to know. The fact is that it is inevitably less specific than venurafenib but nonetheless this trial (combined with dacarbazine v dacarbazine alone) shows once again that small increments of progress in cancer can build up to considerable therapeutic advances. If you really want to know the current state of play in this fast-moving game, see the editorial, “Been There, Not Done That — Melanoma in the Age of Molecular Therapy.”

Lancet  2 July 2011  Vol 378
   The Lancet does this so well – inspires dozens of researchers to spend months in close confinement collating global data from hundreds of observational studies so that you can have a few interesting charts to look at between sets at Wimbledon. The subject here is trends in fasting blood glucose and diabetes since 1980, and for once Richard Horton does not accompany the paper with waffle about what governments around the world must do, etc, because he is too busy attacking Great Ormond Street Hospital in his printed blog  instead. At least that means we get a sensible editorial from Martin Tobias instead, warning of “paralysis by analysis”, because we all know pretty well what these charts are likely to show, and also that they are going to be exactly the same for blood sugar as for diabetes, by definition. The upward trend is lowest for highly developed countries, Japan and central Europe, and highest for populations highly evolved for periods of starvation – so supporting the “thrifty genotype” hypothesis. We know that some boatloads of Polynesians got lost in the Pacific a thousand years ago and only 13 made it to the Island of the Long White Cloud. Small wonder that many modern Maori are obese and diabetic, and that “Oceania” shows the fastest rise in the modern epidemic of type 2 diabetes.

41   When I first started writing these reviews 13 years ago, it didn’t take any special prescience to foretell the outpatient management of deep venous thrombosis based on D-dimer, rapid access ultrasound and long-acting heparin, though in fact it was quite a long time coming. So why not move on to the OP management of pulmonary embolism? The simple answer is because some people will die, and even though this may not be statistically significant, it ain’t half psychologically significant. A previous trial was stopped prematurely because this happened in the OP group and not in the inpatient group, and the same happened in this French-Swiss trial. The trial is declared a success for non-inferiority in low-risk patients, but I think it will take more than this to bring about a change of practice.

57   A really first-rate readable review of tuberculosis claims that its incidence world-wide is now the highest in history. I wonder if that can really be substantiated? Anyway, you’re not likely to find a more comprehensive or better illustrated an account of what we know about this slouchy old killer, the factors which make people susceptible to it, how to use modern diagnostic testing, or how we might address the still growing problem of multiple drug resistant TB and its even deadlier successor, XDR-TB. The authors rightly call TB (rather than pneumonia) “Captain of the men of Death” as per John Bunyan, who also knew a thing or two about the role of comorbidity:

“ATTEN. Pray of what disease did Mr. Badman die, for now I perceive we are come up to his death?
WISE. I cannot so properly say that he died of one disease, for there were many that had consented, and laid their heads together to bring him to his end. He was dropsical, he was consumptive, he was surfeited, was gouty, and, as some say, he had a tang of the pox in his bowels. Yet the captain of all these men of death that came against him to take him away, was the consumption, for it was that that brought him down to the grave.”

— John Bunyan The Life and Death of Mr Badman (1680).

86   Post-splenectomy and hyposplenic states may seem a somewhat unlikely topic to carry one’s attention through ten pages, but a skim-read of this review reveals a lot of interesting and practical information. Although I am somewhat widely read in the topic of coeliac disease, I was surprised to learn that it can cause hyposplenism in a considerable proportion of undiagnosed patients: so much so that I wonder if it wouldn’t be worth doing a postmortem study measuring endomysial antibody in all non-splenectomised patients dying of overwhelming sepsis due to encapsulated bacteria.

BMJ  2 July 2011 Vol 343 (although all refs are 342)

Podiatry has long been the butt of medical jokes, and even a distinguished past president of the RCGP in his earlier, funnier days described the main entry requirements to the profession as “anosmia and a sharp pair of scissors.” Admittedly that was before chiropody had morphed into the higher discipline of podiatry, now blessed with its own professors and doctorates and research papers in the BMJ. Enough of this badinage: anyone who can stop old people with foot pain having falls is worth his or her salt. These academic podiatrists from Australia have done just that, and validated a clutch of simple interventions that can easily be acted on.

Another kind of study it is easy to sniff at is the qualitative investigation of patients’ priorities for management. In fact this kind of study is going to be critical to drive the necessary transformation from health professional driven care to patient driven care. Women with lymphoedema due to breast cancer treatment are here followed up and tell us what they really experience and what they really want. More of this, please. 

Arch Intern Med  27 June 2011  Vol 171

1061    “The main function of insoluble fiber is to increase fecal bulk.” Normally that is about all I am prepared to concede on the subject of dietary fibre before proceeding to coarse jests about its similar effect on the medical literature. But every sceptic should conscientiously read anything which might change his views, and so I have spent just a few more minutes than usual reading this paper, Dietary Fiber Intake and Mortality in the NIH-AARP Diet and Health Study. In line with some other population studies using food diaries, it seems to show that men increase their life expectancy by eating dietary fibre (soluble as well as insoluble), and even claims to have adjusted for the obvious confounder of fruit and vegetable intake. I suppose that this will be used by the “healthy food” industry to add even more indigestible rubbish to their artificial products. Writing from the benighted USA, I renew my plea for everyone to eat only real food and eat only what they enjoy. That way you will enjoy living; and if you live a bit longer, regard it as a bonus. As for the bulk of your stools, pay no attention to it but read a good book instead. This is the sum of what I have to say about dietary fibre.

1082   What should we call heart failure which is not due to systolic dyfunction? The two candidate terms are diastolic heart failure and heart failure with preserved ejection fraction (HF-PEF) and of the two I prefer the latter, though I don’t think it captures the full nature of the syndrome. I gave up reading the specialist literature about ten years ago, at which time it was still considered a grave crime to mention anything of this kind in British cardiological circles: at that point I had persuaded myself that the syndrome is not merely due to impaired ventricular filling but also due to reflected pressure waves from stiffened capacitance arteries and impaired myocardial perfusion during diastole (which is when the coronary arteries actually fill). I may well be wrong, since I have never carried out a single echocardiogram, and people now seem agreed on how to measure diastolic filling and to grade dysfunction as mild, moderate or severe. This single center study shows that the prognosis of HF patients in the latter two categories is fully as bad as with the higher degrees of left systolic dysfunction.

1100   “Although seeding trials are not illegal, they are unethical.” This nice clear statement comes at the beginning of a detailed narrative study of such a trial, the Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS). The trial dates back 15 years to the time when gabapentin was a new drug and Parke-Davis (now part of Pfizer) created the trial so that doctors would titrate up doses as much as possible. I can say that freely because company documents showing this are in the public domain, thanks to subsequent litigation. The authors of this paper go through the seedy process step by step. Lots of seeding studies are still carried out by drug manufacturers, increasingly outside the USA and Western Europe: hundreds of individual doctors are paid to carry out unblinded “investigation” of newly licensed products on their patients. These “trials” are usually scientifically valueless and designed to promote the use of unnecessary expensive medication by health systems and individuals who cannot afford it. They are indeed unethical.

Plant of the Week: Prunus “Apriplum”

It’s strange how even the plants and fungi of a country take on national characteristics. The toadstools on the lawns of America are big and bright and stocky and abundant. American fruit and vegetables tend to be the same, and often taste superior to their watery, half-ripe English counterparts. But the fruit flown here from California tends to be excessively firm in texture and indifferent in taste. We haven’t yet found our way to local New England producers, of whom much might be expected.

I wouldn’t buy a California plum (though they are already on sale), but I did buy a few Apriplums the other day. It seems that this is one of many recent hybrids between the ancient apricot from the Near East (Prunus armenaica) and one of the infinite modern varieties of  Prunus domestica, the plum tree. Here is a perfect balance between the pulpiness of the apricot and the firmness of the modern American plum, with the sweetness of both, and a stone (or pit) that comes away of its own. An excellent fruit, which might very well be growable in southern England, or failing that, in France or Spain.