Category Archives: Director’s Choice – From the Journals

Raising Blood Pressure in Sepsis Patients

I never cease to be amazed at the number of treatments that were received wisdom, but which have been shown to be harmful – sometimes thoroughly harmful.

I well remember my professor of surgery extolling the virtues of completely restoring blood pressure in patients who were bleeding heavily. It turns out that this sensible sounding treatment is plain wrong. One should raise the blood pressure sufficiently to keep the patient awake and the kidneys perfused, but no more. Likewise, I was always taught that in cases of septic shock, fluid replacement should be sufficient to restore blood volume. The latter idea was critically questioned after a randomised trial of a bolus of fluid for critically ill children [1] (which we featured in the quiz in our last News Blog). Here, the fluid bolus was associated with a striking increase in the risk of death.

Now a somewhat similar trial has been carried out among critically-ill adults.[2] The study was carried out in Zambia among patients with septicaemia. Over 200 patients were randomised to receive fluids (and sometimes drugs) to restore blood volume and raise the blood pressure versus less intensive therapy. The results of this trial among adults with sepsis are striking; there was a considerable increase in death rates among those in the intervention group. The difference was considerable at 15 percentage points. Patients in the intervention group received a mean of 3.5 litres of intravenous fluid compared with only 2 litres among controls. Further, 14% received a medicine to support blood pressure in the intervention group compared to only 2% in the control group.

Not surprisingly most of the patients in the study were HIV positive, but there is little reason to think that these results cannot be generalised more widely. A picture is starting to emerge in the literature in favour of not trying to completely restore blood volume in critically-ill patients, at least in African settings. There is a single RCT in North America that produced contradictory findings.[3] It is hard to explain why treatment should produce such different findings across African and North American settings.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Maitlan K, Kiguli S, Opoka RO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011; 364: 2483-95.
  2. Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension. A Randomized Clinical Trial. JAMA. 2017; 318(13):1233-40.
  3. Rivers E, Nguyen  B, Havstad  S,  et al.  Early goal-directed therapy in the treatment of severe sepsis and septic shockN Engl J Med. 2001; 345(19): 1368-77.
Advertisements

Autism and Allergies

The prevalence of autism spectrum disorder (ASD) is increasing, with the US Centers for Disease Control and Prevention estimating that 1 in 68 people have the disorder. While there is no single known cause of ASD, research has suggested that the immune system may have a role, and that activation of the maternal immune response during pregnancy may increase the risk of ASD developing in the unborn child. A recent paper in Nature investigated associations between the maternal immune activation (MIA) and the severity of ASD symptoms in their child.[1]

The authors analysed an existing cohort of 220 children diagnosed with autism spectrum disorder (ASD) and found that the children whose mothers had a history of allergies and/or asthma had significantly higher scores on the social responsiveness scale (SRS) (p=0.016), compared to those whose mothers did not. The SRS measures social interaction, language, and repetitive/restricted behaviours and interests in the child; a higher score is suggestive of a greater degree of social impairment symptoms. The association was not seen when looking at autoimmune conditions, but many of the mothers were diagnosed with autoimmune problems post-pregnancy, which may have affected the findings.

Although no causal relationship was shown, the study does suggest that the immune system may have a role in ASD.

— Peter Chilton, Research Fellow

Reference:

  1. Patel S, Masi A, Dale RC, Whitehouse AJO, Pokorski I, Alvares GA, Hickie IB, Breen E, Guastella AJ. Social impairments in autism spectrum disorder are related to maternal immune history profile. Mol Psychiatry. 2017.

Oxygen Supplementation After Stroke

A drop in blood oxygen levels is common in the first few days after an acute stroke. One imagines that this oxygen deficit would be harmful in someone whose brain cells were already under attack. It is known that the area where cells have died in a stroke is surrounded by an area (penumbra) where cells are damaged, but may recover.

But plausible hypotheses are often not confirmed when put to a scientific test. So a randomised trial was conducted in over 8000 stroke patients to get better information on this point.[1] The resulting paper, published in JAMA, showed almost identical results when patients were treated with or without prophylactic oxygen supplementation. The primary outcome was a score of disability assessed at 90 days after the original insult.

Outcomes were measured within narrow confidence limits and the therapy was unhelpful across various subgroups and irrespective of baseline oxygen levels.  So here is another example of a superficially appealing treatment, which confers no benefit when put to the test. Administering supplemental oxygen is intrusive and I do not recommend this therapy.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Roffe C, Nevatte T, Sim J, et al. Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke The Stroke Oxygen Study Randomized Clinical Trial. JAMA. 2017; 318(12):1125-35.

Sniffing Out Trouble

The scent of freshly baked bread; the smell of a recently-mown lawn on a summer’s breeze; the aroma of an open bottle of wine – people often take particular delight in smell. But as we get older our olfactory function starts to decline. Interestingly, previous research has shown that adults with dementia have more difficulty distinguishing smells, compared to adults without dementia. However, we do not know whether this olfactory dysfunction is predictive of subsequent dementia.

A longitudinal study of 2,906 US adults aged 57-85 measured their ability to identify five odours (rose, leather, orange, fish and peppermint) using a validated test, then looked at the incidence of dementia five years later.[1] They found that adults who had difficulty identifying the smells at baseline were more than twice as likely to have developed dementia by the five year follow up (odds ratio = 2.13, 95% CI 1.32-3.43). This was after controlling for age, sex, race and ethnicity, education, comorbidities, and cognition at baseline. Further, more errors in identification was associated with greater probability of dementia diagnosis (p=0.04). Unfortunately, as the authors admit, they did not control for confounders already associated with olfactory function, such as smoking or depression.

It is hoped that using such an odour identification test will be an efficient and cost-effective addition to current examinations that assess an individual’s risk of dementia, thereby allowing early interventions and give individuals more time to plan for their future. It may also be a useful tool for early diagnosis of Parkinson’s disease, which is also associated with olfactory dysfunction.

— Peter Chilton, Research Fellow

Reference:

  1. Adams DR, Kern DW, Wroblewski KE, McClintock MK, Dale W, Pinto JM. Olfactory Dysfunction Predicts Subsequent Dementia in Older U.S. Adults. J Am Geriatr Soc. 2017.

So What About Oxygen for Heart Attacks Then?

A heart attack is caused by blockage of one of the arteries that supplies oxygen to the heart muscle. When this happens some of the heart muscle dies quickly and, as with stroke, this area of necrosis is surrounded by a penumbra where the heart muscle cells are damaged but not dead. Oxygen administered through a face-mask results in an increase in the amount of oxygen dissolved in the blood. Surely then, oxygen makes sense in people who are having a heart attack? Such therapy has been standard since my days as a medical student.

Well, it turns out that while oxygen therapy does no harm in heart attack victims, it also does no good whatsoever. This is the result of a randomised trial of over 6600 patients.[1] Death rates, a test for heart cell damage, and re-hospitalisation rates were almost identical across the two groups. The null result was consistent across all pre-specified subgroups of patients.

A picture is starting to emerge: oxygen therapy does not limit tissue loss in patients with acute ischemic injury.

It is quite difficult to improve on the bodies evolutionary adaptations to injury as the following report will further reinforce.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Hoffman R, James SK, Jernberg T, et al. Oxygen Therapy in Suspected Acute Myocardial Infarction. New Engl J Med. 2017; 337: 1240-9.

Another Study on the Hazards of American Football

Head impacts seem to be a common occurrence in American Football, with studies of youth players suggesting they experience around 240-252 impacts per season.[1] [2] In the previous News Blog we looked at research on brain injury in ex-American Football players, which found widespread chronic traumatic encephalopathy.[3] Now a cross-sectional study by Alosco, et al. has looked at the impact playing from an early age has on behaviour, mood and cognition.[4] The authors assessed 214 former amateur and professional football players (who hadn’t played any other contact sport) on a number of psychiatric tests. Multivariate regression analysis showed that those who had begun playing before the age of 12 had at least twice the risk of significant impairments in behavioural regulation, apathy and executive function, and three times the risk for clinically elevated depression, compared with those who were began playing when they were 12 or older. These effects were not linked to age, education or even how long the individual played football for. There were also no differences in the level of play, i.e. those who played professional fared similar to those who only played at high school-level. The authors hypothesise that 12 years old is a critical time for key neurodevelopmental milestones that occur within the hippocampus and amygdala (where clinical functions such as emotion regulation and behaviour are modulated).

— Peter Chilton, Research Fellow

References:

  1. Munce TA, Dorman JC, Thompson PA, Valentine VD, Bergeron MF. Head impact exposure and neurologic function of youth football players. Med Sci Sports Exerc. 2015; 47: 1567–76.
  2. Cobb BR, Urban JE, Davenport EM, Rowson S, Duma SM, Maldjian JA et al. Head impact exposure in youth football: elementary school ages 9-12 years and the effect of practice structure. Ann Biomed Eng. 2013; 41: 246373.
  3. Lilford RJ. Two Hundred and Two Ex-(American) Footballers’ Brains Analysed After Death – This You Must Read. NIHR CLAHRC West Midlands News Blog. 15 September 2017.
  4. Alosco ML, Kasimis AB, Stamm JM, et al. Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes. Transl Psychiatry. 2017; 7: e1236.

Alternative Therapies for Cancer

We often read of cancer patients who forgo or delay traditional conventional options, such as chemotherapy, and instead opt for alternative therapies, such as spiritual healing or herbal remedies given by non-medical personnel. Unfortunately this can have serious survival implications for the patient – in many cases the treatment fails to stop the cancer. However, there is a paucity of actual clinical evidence on the use and effectiveness of alternative therapies. Step in Johnson and colleagues who examined the United States Cancer Database to compare the survival outcomes of patients who underwent alternative therapies with those who received conventional therapies for four cancer types (breast, prostate, lung and colorectal).[1] Although rare, they found 281 patients who had chosen alternative therapies exclusive of any other treatment – these patients were more likely to be younger, female, have a lower comorbidity score, higher income, higher education, and a more advanced cancer stage. When matched with patients who received conventional treatments (on cancer type, age, clinical stage, etc.), they found that alternative therapies were associated with significantly lower five-year survival overall – 78.3% of patients who underwent conventional therapies survived, compared to 54.7% of those who had alternative therapies only (hazard ratio 2.21, 95% CI 1.72-2.83). When looked at by cancer type increased hazard ratios were found for breast (HR 5.68, 95% CI 3.22-10.04), lung (HR 2.17, 95% CI 1.42-3.32) and colorectal cancer (HR 4.57, 1.66-12.61), but there was no significant difference for prostate cancer (HR1.68, 95% CI 0.68-4.17) – the authors suggest this may be because of the long natural history of prostate cancer and the short follow-up of the study.

By itself, undergoing alternative therapies isn’t likely to be harmful, but it should be taken in combination with conventional therapy, and health practitioners need to ensure that patients are fully aware of the impact of their decisions regarding cancer treatment.

— Peter Chilton, Research Fellow
Reference:

  1. Johnson SB, Park HS, Gross CP, Yu JB. Use of Alternative Medicine for Cancer and Its Impact on Survival. J Natl Cancer Inst. 2017.

Improving Access to Fresh Food in Low-Income Areas

In a previous News Blog we looked at a paper that found an association between adherence to the Mediterranean diet (i.e. high consumption of fruit, vegetables, and legumes) and reduction in cardiovascular disease risk.[1] So, it can be argued, that for those in low-income areas there is a need to improve their access to fresh fruit and vegetables. But how best to achieve this? Breck and colleagues, on behalf of the CDC, looked at one possibility in a cross-sectional survey analysis.[2]

Previously, the city of New York had attempted to address the issue by granting new licenses for mobile fruit and vegetable carts in those neighbourhoods with poor availability of fresh food. However, only some of the carts (27%) had the capacity to accept the Supplemental Nutrition Assistance Program (SNAP) benefits (a federal aid program to provide food-purchasing assistance) through use of Electronic Benefit Transfer (EBT) machines.

The authors conducted a survey analysis of 779 adults shopping at four carts in the Bronx neighbourhood of New York over several time periods. After controlling for cofounders, they found that those shoppers who were able to pay using their SNAP benefits purchased significantly (p<0.001) more fruit and vegetables (an average of 5.4 more cup equivalents), than those who were only able to pay with cash. While there are promising results from providing consumers with more ways to pay, there are challenges that could prevent widespread roll out of EBT, chiefly the high initial, monthly, and transaction fees that the cart vendors need to pay. Even when provided with financial support, less than one-third of carts were equipped with EBT machines at the time of this study. Although the study has a number of limitations that means causal inferences cannot be drawn, it can be seen as a possible avenue for future research.

— Peter Chilton, Research Fellow

Reference:

  1. Chilton P. Diet and Socioeconomic Status. 18 August 2017.
  2. Breck A, Kiszko K, Martinez O, Abrams C, Elbel B. Could EBT Machines Increase Fruit and Vegetable Purchases at New York City Green Carts? Prev Chronic Dis. 2017; 170104.

Not Taking a Full Course of Antibiotics

The Academic edition of the BMJ comes out once a month; readers may have noticed that one or more BMJ articles feature in alternate News Blogs. The most recent issue of the BMJ had less papers that caught my eye than most. There was lots of worthy stuff. For example, age-specific dementia incidence is declining slightly,[1] antidepressants may very slightly increase the risk of autism if taken during pregnancy,[2] specialist palliative care has rather small effects on quality of life,[3] exercise and diet reduce the risk of high blood pressure in women who had high blood pressure in pregnancy.[4] There was also an excellent article on the precision of cluster randomised trials by CLAHRC WM collaborator Karla Hemming.[5] But the article that really caught my eye was a commentary on the importance of completing a full course of antibiotics as prescribed.[6]

Of course, we always love articles that confirm our prior beliefs. I have always thought that insisting that people take a ‘full course’ of antibiotics to reduce resistance is illogical. Prolonging exposure of the bacterial population to the antibiotic is likely to increase the chance for selection to take place. And that is exactly what this study confirms. Apparently the idea that it was important to take the full course of treatment was based on Albert Alexander’s Staphylococcal sepsis, which re-established itself when Howard Florey’s penicillin ran out.[7] However, the wisdom of continuing antibiotics until the infection is quelled somehow became translated into instructions to finish the course even if infection is no longer a threat. Remember, genetic mutations arise spontaneously and are only selected for when the antibiotic is present in the environment. It follows that the shortest course of antibiotics compatible with effective treatment should be used. And, of course, resistance does not just appear among the organisms causing the infection, but among all the organisms carried in the patient’s body, some of which may go on to infect another person. The argument against continuing to take antibiotics once the threat has passed is therefore unequivocal. It may be necessary to continue antibiotic treatment to prevent a relapse, as was the case for the hapless Alexander, and middle ear infections have a tendency to relapse, but we should not insist on taking a full course simply to prevent antibiotic resistance; the opposite is the case.

— Richard Lilford, CLAHRC WM Director

References:

  1. Ahmadi-Abhari S, Guzman-Castillo M, Bandosz P, et al. Temporal trend in dementia incidence since 2002 and projections for prevalence in England and Wales to 2040: modelling study. BMJ. 2017; 358: j2856.
  2. Rai D, Lee BK, Dalman C, et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.
  3. Gaerner J, Siemens W, Meerpohl JJ, et al. Effect of specialist palliative care services on quality of life in adults with advanced incurable illness in hospital, hospice, or community settings: systematic review and meta-analysis. BMJ. 2017; 357: j2925.
  4. The International Weight Management in Pregnancy Collaborative Group. Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials. BMJ. 2017; 358: j3119.
  5. Hemming K, Eldridge S, Forbes G, Weijer C, Taljaard M. How to design efficient cluster randomised trials. BMJ. 2017; 358: j3064.
  6. Llewelyn M, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ. 2017; 358: j3418.
  7. Abraham EP, Chain E, Fletcher CM, et al. Further observations on penicillin. Lancet. 1941; 358: 177-89.

Association Between Cigarette Price and Infant Mortality

In an effort to reduce smoking rates governments often increase the taxation levied on cigarettes. Previous research has shown that this is an effective strategy, including improvements in child health outcomes. However, tobacco companies often use differential pricing strategies to move the increased taxation on to their premium cigarettes. This lessens the effectiveness of increased taxes as it allows people to switch to the cheaper cigarettes instead. Researchers from Imperial College London set out to assess any associations between price rises, differential pricing (using data on the minimum and median cigarette prices) and infant mortality across 23 European countries.[1] This longitudinal study looked at more than 53.7m live births over a period of ten years. During this time the authors found that a median increase of €1 per pack of cigarettes was associated with 0.23 fewer deaths per 1000 live births in the year of the price hike (95% CI, -0.37 to -0.09), and a decline of 0.16 deaths per 1000 live births in the subsequent year (95% CI, -0.30 to -0.03). Using a counterfactual scenario, the authors estimated that, overall, cigarette price increases were associated with 9,208 fewer infant deaths (i.e. if cigarette prices had remained unchanged then there would have been 9,208 more deaths). Analysis of the price differentials showed that a 10% increase in the differential between the minimum and median priced cigarettes was associated with 0.07 more deaths per 1,000 live births the following year. Further, had there been no cost differential, they estimated that 3,195 infant deaths could have been avoided.

So, while increasing cigarette taxation can have a positive effect, there needs to be more of an effort to try to eliminate budget cigarettes. This is especially true in low-income countries where price differentials tend to be significantly higher than in high-income countries.

— Peter Chilton, Research Fellow

Reference:

  1. Filippidis FT, Laverty AA, Hone T, Been JV, Millett C. Association of Cigarette Price Differentials With Infant Mortality in 23 European Union Countries. JAMA Pediatr. 2017.