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.
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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.

Towards a Unifying Theory for the Development of Health and Social Services as the Economy Develops in Countries

In a previous news blog I proposed grassroots solutions to the transportation of critically ill patients to hospital.[1] Other work has demonstrated the effectiveness of community action groups in many contexts, such as maternity care.[2] More recently I have read that the Kenyan government is proposing a combination of local authority and community action (Water Sector Trust Fund) to improve water and sewage in urban settlements.[3] The idea is for the local authority to provide the basic pipe infrastructure and then for local communities to establish linkages to bring water and sewage into homes. The government does not merely lay pipes, but also stimulates local involvement, including local subsidies and micro-enterprises. This epitomises collaboration between authorities and community groups.

In an extremely poor, post-conflict country, such as South Sudan, it is hard to find activities where the authorities and local people work together to improve health and wellbeing. On the other hand, in extremely rich countries like Norway and Switzerland, the government provides almost all that is required; all the citizen has to do is walk into the bathroom and turn on the tap.

The idea that is provoked by these many observations is that different solutions suit different countries at different points in their development. So much so obvious. Elaboration of the idea would go something like this. When a country is at the bottom end of the distribution for wealth, there is very little to be done other than put the basics of governance and law and order into place and try to reduce corruption. Once the country becomes more organised and slightly better off, a mixture of bottom-up and top-down solutions should be implemented. At this point, the tax base is simply too small for totally top-down, Norwegian style, solutions. In effect the bottom-up contribution makes good the tax deficit – it is a type of local and voluntary taxation. As the economy grows and as the middle class expands, the tax base increases and the government can take a larger role in funding and procuring (or providing) comprehensive services for its citizens.

This might seem anodyne written down as above. However, it is important to bear in mind that harm can be done by making the excellent the enemy of the good. Even before a substantial middle-class evolves in society, wealth is being generated. I recently visited a number of urban settlements (slums) in Nigeria, Pakistan and Kenya. All of these places were a hive of economic activity. This activity was mostly in the informal sector, generating small surpluses. Such wealth is invisible to the tax person, but it is there, and can be used. Using it requires organisation: “grit in the oyster”. The science base on how best to provide this ‘grit’ is gradually maturing. In order for it to do so, studies must be carried out across various types of community engagement and support. I expect this to be a maturing field of inquiry to which the global expansion of the CLAHRC message can contribute. Members of our CLAHRC WM team are engaging in such work through NIHR-funded programmes on health services and global surgery, and we hope to do so with regard to water and sanitation in the future.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Transport to Place of Care. NIHR CLAHRC West Midlands News Blog. 29 September 2017.
  2. Lilford RJ. Lay Community Health Workers. NIHR CLAHRC West Midlands News Blog. 10 April 2015.
  3. Water Sector Trust Fund, GIZ. Up-scaling Basic Sanitation for the Urban Poor (UBSUP) in Kenya. 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.

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.

Transport to Place of Care

Availability of emergency transport is taken for granted in high-income countries. The debate in such countries relates to such matters as the marginal advantages of helicopters over vehicle ambulances, and what to do when the emergency team arrives at the scene of an accident. But in low- or low-middle-income countries, the situation is very different – in Malawi, for example, there is no pretence that a comprehensive ambulance system exists. The subject of transport does not seem to get attention commensurate with its importance. Researchers love to study the easy stuff – role of particulates in lung disease; prevalence of diabetes in urban vs. rural areas; effectiveness of vaccines. But study selection should not depend solely on tractability – the scientific spotlight should also encompass topics that are more difficult to pin down, but which are critically important. Transport of critically ill patients falls into this category.[1]

Time is of the essence for many conditions. Maternity care is an archetypal example,[2] where delayed treatment in conditions such as placental abruption, eclampsia, ruptured uterus, and obstructed labour can be fatal for mother and child. The same applies to acute infections (most notably meningococcal meningitis) and trauma where time is critical (even if there is no abrupt cut-off following the so called ‘golden hour’).[3] The outcome for many surgical conditions is affected by delay during which, by way of example, an infected viscus may rupture, an incarcerated hernia may become gangrenous, or a patient with a ruptured tubal pregnancy might exsanguinate. However, in many low-income countries less than one patient in fifty has access to an ambulance service.[4] What is to be done?

The subject has been reviewed by Wilson and colleagues in a maternity care context.[5] Their review revealed a number of papers based on qualitative research. They find the theory that one might have anticipated – long delays, lack of infrastructure, and so on. They also make some less intuitive findings. People think that having an emergency vehicle at the ready could bring bad luck, and that it is shameful to expose oneself when experiencing vaginal bleeding.

Quite a lot of work has been done on the use of satellites to develop isochrones based on distances,[6] gradients, and road provision. But working out how long it should take to reach a hospital does not say much about how long it takes in the absence of a service for the transport of acutely sick patients.

We start from the premise that, for the time being at least, a fully-fledged ambulance service is beyond the affordability threshold for many low-income countries. However, we note that many people make it to hospital in an emergency even when no ambulance is available. This finding makes one think of ‘grass-roots’ solutions; finding ways to release the capacity inherent in communities in order to provide more rapid transfers. An interesting finding in Wilson’s paper is that few people, even very poor people, could not find the money for transfer to a place of care in a dire emergency. However, this does not square with work on acutely ill children in Malawi (Nicola Desmond, personal communication), nor work done by CLAHRC WM researchers showing the large effects that user fees have in supressing demand, especially for children, in the Neno province of Malawi.[7] In any event, a grass roots solution should be sought, pending the day when all injured or acutely ill people have access to an ambulance. Possible solutions include community risk-sharing schemes, incentives to promote local enterprises to transport sick people, and automatic credit transfer arrangements to reimburse those who provide emergency transport.

I am leading a work package for the NIHR Global Surgery Unit, based at the University of Birmingham, concerned with access to care. We will describe current practice across purposively sampled countries, work with local people to design a ‘solution’, conduct geographical and cost-benefit analyses, and then work with decision-makers to implement affordable and acceptable improvement programmes. These are likely to involve a system of local risk-sharing (community insurance), IT facilitated transfer of funds, promotion of local transport enterprises, community engagement, and awareness raising. We are very keen to collaborate with others who may be planning work on this important topic.

— Richard Lilford, CLAHRC WM Director

References:

  1. United Nations. The Millennium Development Goals Report 2007. New York: United Nations; 2007.
  2. Forster G, Simfukew V, Barber C. Use of intermediate mode of transport for patient transport: a literature review contrasted with the findings of Transaid Bicycle Ambulance project in Eastern Zambia. London: Transaid; 2009.
  3. Lord JM, Midwinter MJ, Chen Y-F, Belli A, Brohi K, Kovacs EJ, Koenderman L, Kubes P, Lilford RJ. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014; 384(9952): 1455-65.
  4. Nyamandi V, Zibengwa E. Mobility and Health. 2007. In: Wilson A, Hillman S, Rosato M, Costello A, Hussein J, MacArthur C, Coomarasamy A. A systematic review and thematic synthesis of qualitative studies on maternal emergency transport in low- and middle-income countries. Int J Gynaecol Obstet. 2013; 122(3): 192-201.
  5. Wilson A, Hillman S, Rosato M, Skelton J, Costello A, Hussein J, MacArthur C, Coomarasamy A. A systematic review and thematic synthesis of qualitative studies on maternal emergency transport in low- and middle-income countries. Int J Gynaecol Obstet. 2013; 122(3): 192-201.
  6. Frew R, Higgs G, Harding J, Langford M. Investigating geospatial data usability from a health geography perspective using sensitivity analysis: The example of potential accessibility to primary healthcare. J Transp Health 2017 (In Press).
  7. Watson SI, Wroe EB, Dunbar EL, Mukherjee J, Squire SB, Nazimera L, Dullie L, Lilford RJ. The impact of user fees on health services utilization and infectious disease diagnoses in Neno District, Malawi: a longitudinal, quasi-experimental study. BMC Health Serv Res. 2016; 16(1): 595.

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.