Richard Lehman’s journal review—5 March 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM 1 Mar 2018
Corticosteroids for septic shock
The first of two trials of steroids in septic shock is an exemplary Australia based study of 3800 patients in ICUs across five countries. For once, the abstract of the paper underplays the results by declaring that the administration of hydrocortisone did not result in lower 90 day mortality than placebo among patients with septic shock. But in the main text they go on to say: “This effect did not differ in any of the six prespecified subgroups. We observed a more rapid resolution of shock and a lower incidence of blood transfusion among patients who received hydrocortisone than among those who received placebo. Patients who had been assigned to receive hydrocortisone had a shorter time to ICU discharge and earlier cessation of the initial episode of mechanical ventilation than did those who had been assigned to receive placebo.” So, there is still a case for giving continuous intravenous hydrocortisone.

Now add a pinch of mineralocorticoid. When this French trial of steroids in septic shock was designed, there was a drug called drotrecogin alfa (activated) on the market, which was to be given in one of three arms of the study, but it was subsequently withdrawn, leaving just two arms: placebo or hydrocortisone plus fludrocortisone. Mortality in the HC-FC group was lower than in the placebo group: 43% versus 49%. But it’s impossible to compare this directly with the Australian study, because the patient characteristics were markedly different and the French mortality rate was very much higher: in fact, it’s the same as in the original trials of steroids in sepsis done in the early 1960s. So, the message seems to be that hydrocortisone is of marginal benefit to a few patients with septic shock and that we don’t really know whether added fludrocortisone makes a lot of difference.

Balancing the crystalloids
It’s a bit odd that 200 million litres of intravenous normal saline are given in the US alone each year, yet this “normal” fluid is actually hyperchloric compared with human plasma, and so liable to induce hyperchloraemic acidosis. So should we move wholesale towards more balanced crystalloid solutions for fluid replacement, such as lactated Ringer’s solution or Plasma-Lyte A? The first of two trials sought the answer in hospital patients who did not need admission to intensive care—13 347 in a single US centre. There was no difference between saline replacement and balanced crystalloid replacement groups in hospital admission time, and only a marginal difference in renal outcomes.

Next: a study of 15 802 really sick patients who needed admission to ICU in the same institution. Here it seems to be a different story. “Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.” But look at the confidence intervals: for major kidney events the odds ratio was 0.91, 95% CI 0.84-0.99; for 30 day mortality, the OR is not given but benefit is asserted on the basis of percentages—10.3% in the balanced crystalloids group and 11.1% in the saline group (P=0.06). So the first barely slips in to the 1 in 20 level of significance, and the other just slips out. As for clinical significance, I’d say there’s a weak but reasonable case for preferring the balanced crystalloids.

JAMA 27 Feb 2018
Varicose veins and DVT
Do giraffes get varicose veins? Basic mammalian haemodynamics apply to everything from dwarf rodents to blue whales, but what amazing adaptations abound! We’re bipedal outliers with thick muscular legs and thin skin. If we can’t pump blood continuously from our deep leg veins, it can clot and fly into our lungs. That’s not supposed to happen with superficial varicose veins. They can certainly clot up, but the clot isn’t supposed to go anywhere. And yet here’s a study of 213 000 people in Taiwan with varicose veins, which shows they get five times as many deep vein thromboses and pulmonary emboli as a propensity matched control group. Next question: do blue whales get pulmonary emboli? If so, where do they come from and what is their average weight (in kilograms)?

The guises of gabapentin
Let me start by putting in a good word for gabapentin. It is a reasonably useful second line drug for partial epilepsy. And an evidence synopsis by Andrew Moore and colleagues suggests that it is worth trying—as we all do—for neuropathic pain. “In people with moderate or severe neuropathic pain, oral gabapentin (1200-3600 mg/d) was associated with greater achievement of substantial or moderate benefit than placebo. In patients with post-herpetic neuralgia, gabapentin was associated with higher rates of substantial benefit (32%for gabapentin vs 17%for placebo)and moderate benefit (46% for gabapentin vs 25%for placebo).”

So far so good. But gabapentin has been the poster child for mission creep ever since 2004, when the manufacturer settled litigation for $430 million and admitted guilt in connection to charges that the company illegally promoted gabapentin for uses not approved by the FDA. By that stage it is estimated that 90% of gabapentin prescribing was for “off-label” indications such as migraine, cancer pain, and psychiatric disorders. Did the 2004 settlement put a stop to this? Hardly. Two of my Yale friends write succinctly about this: “Twenty-five years after the initial FDA approval of gabapentin, there is still limited evidence to support its widespread use for the majority of indications for which it is prescribed, many of which are off-label.”

JAMA Intern Med Mar 2018
Collaborative care for heart failure
When Goethe published The Sorrows of Young Werther in 1774, it was a literary sensation and led to a new vogue in men’s clothing and a spate of young suicides. When I get round to writing The Sorrows of Old Lehman I doubt that it will have quite the same effect on male fashion or the suicide rate. It will mostly be about how medicine goes around in the same circles and old lessons have to be learnt time and again. Take “heart failure.” Properly speaking, this is a mode of death, not a diagnosis. If somebody is dying from a failing heart around the age of 80, then your expectations of any intervention need to be modest. If you can relieve symptoms of depression and fatigue, as they did in this US trial, that will be a very worthwhile success in its own right. The trajectory for general wellbeing is bound to be downwards whatever you do. The comparator here was usual care: let’s try to improve this too. When I helped put together the first book on Heart Failure and Palliative Care in 2006, our subheading was “a team approach.” Wherever you are in the system, do all you can to encourage humane care that supports the patient and carers through what is bound to be a sad and difficult journey. Count your success by what you can achieve, and don’t be put off by what can’t be achieved.

LVADs and shared decision making
It’s unusual for the same authors to get published twice in the same issue of a journal, but it’s happened twice this week (see the NEJM balanced crystalloid trials). Larry Allen, co-author of the previous paper, certainly deserves this honour for his patient centred work on heart failure. This study looks at the effect of a shared decision making intervention on patients facing the choice of having a left ventricular assist device (LVAD) as “destination therapy”, i.e. not as a bridge to transplantation or recovery, but for as long as the LVAD can maintain a circulation. The results were somewhat paradoxical: “A shared decision making intervention for DT LVAD modestly improved patient decision quality as measured by patient knowledge and concordance between stated values and patient reported treatment choice, but did not improve concordance between stated values and actual treatment received. The rate of implantation of LVADs was substantially lower in the intervention compared with the control group.” “Did not improve concordance between stated values and treatment received.” So what kind of “shared decision making” was really going on?

The Lancet 3 Mar 2018
Mesh best for small umbilical hernias
Last week you might have wondered if you should have simple suturing or mesh for the repair of your small umbilical hernia. This week you don’t need to wonder, because a Dutch led trial gives the answer. It provides “high level evidence for mesh repair in patients with small hernias of diameter 1–4 cm. Hence we suggest mesh repair should be used for operations on all patients with an umbilical hernia of this size.” Sometimes evidence actually settles a question.

Home lowering of BP
At a population level, blood pressure is one factor that contributes to cardiovascular risk. That’s about all that I would be willing to concede in the current state of knowledge. This trial shows that people with blood pressure above 140/90 (labelled “hypertensive patients” in this paper: isn’t it time we dropped these terms?) can monitor their blood pressure at home and bring it down more effectively by self-titration than through the usual tedious process of repeated visits to a GP surgery. Adding telemedicine contributes nothing extra. This is useful knowledge, but now we must start to get to grips with shared decision making and the individuation of treatment for total cardiovascular risk.

CIN2—the “precancer” that often disappears
This systematic review combines data from seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts to come up with just 3160 women whose cervical CIN2 was watched for three months or more. The overall spontaneous regression rate was 50% at two years; in those under 30 it was 60%. “Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.”

Plant of the Week: Lonicera x purpusii

If you are not too concerned about scent, it is possible to have honeysuckle blossom in every month of the year. But of course you are concerned about scent, so you may have to forgo a couple of months. What indeed is the point of honeysuckle without fragrance?

The honeysuckle called fragrantissima is winter flowering, and very good it is too. Nurserymen in the 1920s created a number of hybrids with L standishii, of which the most popular is “Winter Beauty.” It sometimes begins to flower before Christmas and can go on well into March.

The winter flowering honeysuckles all carry a scent of amazing sweetness and penetration, but for the rest of the year they are tousled, untidy shrubs, which can seem a waste of garden space. The exception is L strophiophora, a species with purplish leaves and good habit, which seems to have gone out of circulation. The great virtue of all of them is that their flowers pay no attention to frost, snow, and high winds—as last week demonstrated. No garden can afford to be without them.