Richard Lehman reviews the latest research in the top medical journals

NEJM  19 Jul 2018

Glutamine reduces sickle crises

I am a fool to the last. When I read the headline message of this study, I thought “Great! Glutamine helps kids with sickle-cell anaemia have fewer pain crises. It is a cheap, non-toxic amino acid that you can buy anywhere, so that’s terrific news.” The effect is not massive—three crises rather than four on average per year—but coming at negligible cost, it’s certainly worth going for. But then I saw that the trial was run by Emmaus Medical, a new company specialising in drugs for rare diseases. Emmaus, you may remember, is the name of the place where Jesus was given a free meal to build him up a bit after spending some time dead. L-glutamine costs about £2 per 100g if you buy it online. Emmaus Medical’s prescription-only Endari sells at about $1000 – $3000 per month. No free meals here, Caravaggio.    

Adrenaline, CPR & a fate worse than death

The PARAMEDIC2 blinded randomised trial shows that the 30-day survival rate for out-of-hospital cardiac arrest in the UK is at best around 3.2%. This is the figure for 4017 patients who were given parenteral adrenaline (called epinephrine in the US) by ambulance crew at the scene of arrest. For the 3999 people given saline as a placebo it was 2.4%. But a higher proportion of the adrenaline/epinephrine group showed severe brain damage at 30 days, so that “in adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.”

Procalcitonin promise unfulfilled

Antibiotics in a Spin is the title of one of the many books I will never write. The true problem of emergent antimicrobial resistance in a small subset of specialised pathogens has become conflated with a general we’re-all-doomed narrative in which the culprits are doctors who show inadequate “antibiotic stewardship.” There’s more about this in JAMA Intern Med below. As a GP who fell under this cosh I used to long for the emergence of a reliable method for distinguishing between bacterial and viral infection. And then came procalcitonin. It’s a blood marker that goes up if you are fighting bacterial infection, and down when you are winning. It doesn’t respond to viruses. Several European trials have seemed to show that when used within their strict protocols, calcitonin-guided treatment can reduce antibiotic prescribing for lower respiratory infection without apparent risk. And this is taken to be a good thing. In this trial, the idea is tested in 14 high-performing American hospitals, which already have high adherence to national quality measures for the treatment of pneumonia.

There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively) or the proportion of patients with adverse outcomes (11.7% and 13.1%) within 30 days.

JAMA 17 Jul 2018

“ADHD” & “digital media use”

Attention-deficit hyperactive disorder is what I’ve experienced over the last thousand weekends of my life. Each Saturday I’ve sat down to look over the best papers in the main medical journals, which involves skimming through quite a few terrible ones too. My eyes glaze over, I spit coffee, I stomp about, I shout at the bookshelves, I write a few immoderate sentences, and then delete them. Believe me, dear reader, you have only seen my milder side over the last 20 years. It might be fun to let rip over this article which reveals that “In this longitudinal cohort survey study of adolescents aged 15 and 16 years at baseline and without symptoms of ADHD, there was a significant association between higher frequency of modern digital media use and subsequent symptoms of ADHD over a 24-month follow-up (odds ratio, 1.11 per additional digital media activity).” It’s a wonderful teaching example of association-mongering in its full glory. Loose definitions at both ends, reverse causality, wrong timescale, all the confounders of rampant adolescence: you name it, it’s here. I will content myself with quoting Wolfgang Pauli one last time, “This paper is not good. It is not even bad!”

JAMA Intern Med July 2018

The unsleeping ward

I would love to see a straight performance of Macbeth replete with kilted warriors and mobile forests, with smelly cauldrons, and lots of gore. But since modern directors lack the skill, a few of them have tried setting the play in a hospital. This is obviously appropriate for the themes of potion-mixing and blood-letting, but it is just as much so for another major theme of Macbeth: sleeplessness. Sleep—”balm of hurt minds, great Nature’s second course”—is in short supply to the sick within our palaces of healing. In a study conducted in a large Dutch hospital, all aspects of sleep quality measured using PROMIS questions were rated worse during hospitalization than at home. The most reported sleep-disturbing factors were noise of other patients, medical devices, pain, and toilet visits.The sleeve of care remains unravelled. Healthcare hath murdered sleep.

US first-contact antibiotic prescribing

Now that private primary care tele-systems have become popular in metropolitan England, they are competing on how quickly they can get amoxicillin delivered to your door. There is already a mixed economy in the USA, such that only 60% of antibiotic prescriptions originate from doctors’ offices or emergency departments. The remaining 40% come from retail clinics and urgent care centers. Using a huge prescribing database, this study found that antibiotic prescriptions were linked to 39.0% of 2.7 million urgent care center visits, 36.4% of 58 206 retail clinic visits, 13.8% of 4.8 million ED visits, and 7.1% of 148.5 million medical office visits. Visits for antibiotic-inappropriate respiratory diagnoses accounted for 17% of retail clinic visits, 16% of urgent care center visits, 6% of medical office visits, and 5% of ED visits. I find those figures quite reassuring, but as you will gather, I am not quite politically correct on this subject. 

Ann Intern Med 17 Jul 2018

The dreaded bed

When Harlan Krumholz first published his celebrated article defining post-hospital syndrome in 2013, I was quick to send him the classic Richard Asher paper from 1947,”The Dangers of Going to Bed.” I imagined that this showed British priority over the US in recognising the dangers of bed rest, but actually the opposite is true. In 1944, an American physician, Dr D.Dock, published an article “The evil sequelae of complete bedrest” in JAMA, in which he stated that “The physician must always consider complete bed rest as a highly un-physiologic and definitely hazardous form of therapy, to be ordered only for specific indications and discontinued as early as possible”. At exactly that time, Albert Speer in Germany was being put on total bedrest by an SS physician, and even then he suspected that this was because his rival Himmler wanted him to die from a deep vein thrombosis. So despite the just fame of Asher’s sprightly essay, the dangers of going to bed were well known by the time he wrote it. What more is there to say? Ah yes, the fact that in 2018, it is still a dangerous part of hospital practice worth explaining to hospitalists in the Annals of Internal Medicine   

As Asher concluded,

“Teach us to live that we may dread

Unnecessary time in bed.

Get people up and we may save

Our patients from an early grave.”

The Lancet 21 Jul 2018

Time to burst the biomedical bubble?

All the time I’ve been writing these reviews, there has been a disconnect between the rhetoric and practice of The Lancet. It used to be a source of wonder and amusement to me, but since then we’ve all had to learn to survive by forgetting the meaning of irony. This week, The Lancet, in its loftiest, anonymous mode, suggests that “A radical shift of life sciences funding priorities, away from the biomedical bubble and towards the social, behavioural, and environmental determinants of health, is now needed.” The writer makes an appeal to the integrity of Theresa May, no less. She should override the interests of industry and the Oxford-London-Cambridge triangle universities who have shown the dangers of concentrating power and money on a profit-driven biomedical research agenda, but show too little integrity of their own. Well, The Lancet is certainly well-placed to provide examples of that. And Mrs May is certainly in an excellent position to improve the social, behavioural, and environmental determinants of health in the UK. All she needs to say is “I was right about Brexit before the referendum, and I shall do my utmost to stop it happening.”   

The BMJ 21 Jul 2018

Scoping the shoulder

My attitude to overdiagnosis is that of a disappointed lover. I loved the positive flow of diagnostic technology in my working life: dubious guesswork informed by physical signs and plain X-rays in 1976 gave way to ultrasound, CT scanning, MRI and endoscopy over little more than a decade. Lesions! Lesions! Legions of new lesions. For orthopaedic surgeons those were the halcyon days of arthroscopic trimming for everything. But a few noble souls among them then began to do randomised controlled trials: even sham-controlled randomised trials. Knee arthroscopic procedures were the first to fail the criteria of evidence based medicine. Now it’s the turn of the shoulder. I say “now” although this Finnish study debunking subacromial decompression is only the latest of a succession. Deadoption is a slow process. To paraphrase Upton Sinclair, it is difficult to get a man to understand something when his new Porsche depends on his not understanding it.

Sulfonylureas: dangerous drugs for diabetes

“Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.” This conclusion is based on data from UK primary care (the Clinical Practice Research Database) analysed in Canada. It’s an association, derived from a rather fallible source: but it “triangulates” strongly with data from other sources. The time has long gone for a randomised controlled trial of sufficient power to determine the cardiovascular risk of sulfonylureas in type 2 diabetes. But I think the time may have come to retire sulfonylureas as a therapeutic class altogether.

Liver cirrhosis and liver cancer in the USA

If you want to read about the epidemiology of liver cirrhosis and cancer in the USA, The BMJ is your place to look. If you want to learn about living and dying of cirrhosis and liver cancer in the UK (or anywhere else), The BMJ is not your place to look. That’s qualitative research and BMJ readers simply don’t want that kind of thing.

Plant of the Week: Gladiolus “Peach Blossom”

Graham Stuart Thomas wrote definitive volumes on most garden plants, which I consult frequently with reverence. Until today, however, I had avoided the section on Gladiolus in his Perennial Garden Plants or the Modern Florilegium (3rd ed, 1990). A couple of years ago we bought a gladdie, knowing Mr Thomas was safe in the ground, and hoping its corms would be safe in ours. Here he is on the subject, turning in his grave: “The size and vulgarity of the large-flowered hybrids, evolved from tender South African species, are only surpassed by the very large dahlias and chrysanthemums.”

Gladiolus “Peach Blossom” does not resemble peach blossom, or indeed peaches at all. Rather, its blossoms are the colour of apricot. How vulgar. But actually how joyfully attractive when appearing freshly after seven weeks of drought, amongst the trails of a blue clematis.

To be fair, I don’t think this can be the progeny of tender vulgarians from South Africa. It and its flowers are of moderate size only. Dame Edna Everidge would disdain to accept them. It lives in clayish soil which is baked in summer and sodden in winter, which is exactly the opposite of what South African plants like. The ground must have gone below minus 8 degrees Celsius this year, but “Peach Blossom” is actively happy and spreading. If you see it for sale, cast all doubt aside, and buy it.