Tag Archives: Richard Lilford

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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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.

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.

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.

The Most Dangerous Animal

It is very difficult to know which animal is the most dangerous (human beings aside). The mosquito would be a good answer, while game rangers are fond of surprising tourists by saying that it is the hippopotamus. The latter is almost certainly wrong and you can surprise the game ranger by asking him or her for evidence. There is none. But the snake is undoubtedly a very dangerous creature. Cobras and mambas are lethal, but apparently the greatest number of animal deaths worldwide is from a small, but agile viper, called the saw-scaled viper. This is a viper that likes to bite and it is ubiquitous in areas lacking modern medical facilities.

The problem, recently discovered, is that the anti-venom for this snake tends to be specific to the area in which the viper is found.[1] Small geographical differences in the structure of the protein toxin that causes blood to clot in the vessels accounts for this spatial specificity. This means that anti-venoms must be made locally.

The real problem with snake bite treatment is that anti-venoms are not available when needed or they become damaged during transit and storage. Snakes are very important for local ecologies. A campaign of extermination would probably do humans more harm than good. So the battle between person and snake, which started all those years ago in the Garden of Eden, is set to continue.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Rogalski A, SOerensen C, op den Brouw B, Lister C, Dashevsky D, Arbuckle K, Gloria A, Zdenek CN, Casewell NR, Gutiérrez JM, Wüster W, Ali SA, Masci P, Rowley P, Frank N, Fry BG. Differential procoagulant effects of saw-scaled viper (Serpentes: Viperidae: Echis) snake venoms on human plasma and the narrow taxonomic ranges of antivenom efficacies. Toxicol Lett. 2017; 280: 159-70.

Two Hundred and Two Ex-(American) Footballers’ Brains Analysed After Death – This You Must Read

Who would have thought that American football could be so damaging to the brain? Boxing yes. Here force is targeted at the container for the brain. However, it turns out that other contact sports may also damage the brain according to a recent study of 202 ex-footballers who donated their brains before death.[1] The clinical condition of the patients was recorded and correlated with histopathological finding. The mean age at death is rather young at 66. Hold on to your seat and read on to learn that fully 87% of football players’ brains fulfilled the histopathological criteria for chronic traumatic encephalopathy (a progressive neurodegenerative disorder associated with repetitive head trauma). In fact it was present in 110 of the subsample of 111 footballers who were lucky (unlucky) enough to make the National Football League (NFL). Further, 86% of these NFL players had severe pathology. Yes, brains may be more willingly donated when cognitive deterioration is present than when it is not, leading to inclusion bias. A prospective study is needed. But should we wait the 20-40 years needed for the results? Even if this study has overestimated the effect, the bias could not create so large an association if there were none. Would you encourage your grandchildren to play? If your heart packs up, your lungs fail or your pancreas turns cancerous, you die as yourself. But if your cerebral cortex is damaged you live as someone else.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Mez J, Daneshvar DH, Kiernan PT, et al. Clinopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017; 318(4): 360-70.

Class Lectures in Medical School – Nearly Obsolete?

The University of Vermont’s College of Medicine advertises “no lectures required.” And empirical enquires show that content heavy, PowerPoint loaded, lectures are ineffective. But a thoughtful article in the New England Journal of Medicine [1] suggests that the class lecture should change rather than go. In fact, the classroom is well suited to active learning, with students who have already assimilated the core material at their own pace through private study. The lecturer interacts with the students who sit around tables and are provided with opportunities to discuss issues in small groups as the need arises. I learned that this is called the ‘flipped-classroom’ approach. Such an approach resulted in better outcomes when compared to traditional problem-based learning approaches in a randomised trial.[2] So a little bit of this and a little bit of that. And there is still a place for a little theatre. As to problem-based learning as a method to propel a new topic – forget it. It is sub-optimal, as discussed in a previous News Blog.[3]

— Richard Lilford, CLAHRC WM Director

References:

  1. Schwartztein RM & Roberts DH. Saying Goodbye to Lectures in Medical School – Paradigm Shift or Passing Fad? N Engl J Med. 2017; 377(7): 605-7.
  2. Krupat E, Richards JB, Sullivan AM, Fleenor TJ Jr, Schwartzstein RM. Assessing the effectiveness of case-based collaborative learning via randomized controlled trial. Acad Med. 2016; 91: 723-9.
  3. Lilford RJ. Bring Back the University Lecture: More on Evidence-Based Teaching. NIHR CLAHRC West Midlands News Blog. 26 September 2016.

Stop Being Beastly to Malthus!

I never understand why people think that Malthus got it so badly wrong. His argument (the Malthusian trap) was that resources are finite and that, therefore, there must be some limit to the number of people that the world can feed.[1] While it certainly turned out that the world can feed many more people than he thought, this does not disprove the underlying theorem. At some point there must come a threshold, where food supply really fails to meet the demand. If we generalise from food to include water, then that point might not be as far away as complacent people think. Of course, we also have to take into account the environmental damage associated with feeding, transporting, and keeping a large number of people warm.

Malthus has become almost a figure of derision. While he may have been wrong about when, the jury is still out about whether. He was right about the generic point, that there is a limit to the carrying capacity of our planet. Food is central to this, because even if we do not run out of food, much environmental damage is caused in its production.

The world’s population will stabilise in about 50 years, although African populations will continue to expand for a while longer.[2] So we should mitigate the environmental effects of food production. I like to eat beef from time to time. However the production of beef is very energy intensive and the methane released by cattle contributes about 20% of the total global warming.[3] So I favour a tax on all beef, similar to that on fuel. Such a tax is more justifiable even, then a tax on sugar and tobacco. This is because consumption of sugar and tobacco does not have the strong externalities associated with fossil fuels and production of beef. There is no proper libertarian argument against taxation in circumstances where strong externalities apply.[4] Pigovian taxes are taxes designed to compensate for externalities and to reduce behaviour that harms others; they would seem entirely justified in this case. I am less of a fan of Pigovian taxes to deal with internalities – that is to stop people from harming themselves. But as it turns out, red meat is bad for our health, as discussed in a recent news blog.[5]

So let us give Malthus his due. He might have got the detail wrong, but his principle still stands. I vote for the rehabilitation of Malthus.

— Richard Lilford, CLAHRC WM Director

References:

  1. Malthus TR. An Essay on the Principle of Population. London, UK: J. Johnson, 1798.
  2. Lilford RJ. The Population of the World – Will Depend on What Happens in Africa. NIHR CLAHRC West Midlands News Blog. 9 January 2015.
  3. Steinfeld H, Gerber P, Wassenaar T, Castel V, Rosales M, de Hann C. Livestock’s Long Shadow: Environmental Issues and Options. Rome, Italy: Food and Agriculture Organization, 2006.
  4. Lilford RJ. An Issue of BMJ with Multiple Studies on Diet. NIHR CLAHRC West Midlands News Blog. 4 August 2017.
  5. Capewell S, Lilford R. Are nanny states healthier states? BMJ. 2016; 355: i6341.