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1. Was the inclusion group in this trial too wide, especially in regards to ages (from a 60 day old baby to a 12 year old child)?

 2. An editorial in the Archives of Disease of Childhood criticised the study and highlighted what they felt was the most harmful limitation, the reliance on one non-specific clinical feature for the diagnosis of hypovolaemic shock (see this BMJ rapid response for further details). Does this make the study invalid for evaluating fluid boluses in children with hypovolaemic shock?

3. How applicable are these results to the use of fluid boluses in febrile children in the developed world?

 4. Does there need to be a similar study in developed countries? If so, would such a study ever get ethical approval?

Thank you to @welsh_gas_doctor, @trufflethebendy and @Bokarelli for proof-reading the discussion points for me

A huge number of studies are published in journals everyday. Most are read with interest by people involved in the area in which they are published but few every reach the attention of the world’s media. The FEAST study is an exception to this; it attracted a huge amount of attention, the headline from the BBC news story – “Africa trial questions shock treatment for children” was typical of coverage of this trial.

 The use of fluid boluses for shock is an international standard, the American College of Critical Care Medicine recommend the use of 60mls per kg of fluid for a child with a fever who has shock. However, in resource-poor countries these boluses are simply not available.

FEAST – Fluid Expansion as Supportive Therapy – was published in June 2011 in the New England Journal of Medicine with the aim of evaluating the effect of fluid boluses and early fluid resuscitation for shock in febrile children in Sub-Saharan Africa. This was a randomised controlled trial carried out in 6 hospitals inKenya,Tanzania and Uganda. The trial assessed the effects of giving a fluid bolus to children with a febrile illness and impaired perfusion (i.e. children with hypovolaemic shock). Children were randomised into two groups:

  • Stratum A – children without severe hypotension – randomised to receive either a saline bolus (20mls per kg), an albumin bolus (20mls per kg) or no bolus (control group)
  • Stratum B – children with severe hypotension – randomised to receive saline bolus (40mls per kg) or albumin bolus (40mls per kg)

 The protocol was changed in June 2010 and initial boluses were increased to 40ml per kg in stratum A and 60mls per kg in stratum B. Children from the age of 60 days to 12 years were included and the exclusion criteria were children with severe malnutrition, diarrhoea, burns, surgery and trauma. All children received appropriate treatment for their condition as well as being involved in the trial.

 The primary endpoint was mortality at 48 hours after randomisation.

 The study was stopped in January 2011 after the independent data and safety monitoring committee reviewed the 5th interim analysis from the study and recommended stopping owing to safety concerns in both fluid bolus groups.

 The headline finding – 48 hour mortality:

  • 10.6% in the albumin bolus group
  • 10.5% in the saline bolus group
  • 7.3% in the control group

 The relative risk for any bolus vs control was remarkable – 1.44 (P=0.003). The results were found to be consistent across the trial sites and across the subgroups even in respect to the underlying conditions (malaria, coma, sepsis, acidosis and severe anaemia).

The authors of the paper concluded:

The results of this study challenge the importance of fluid resuscitation as a lifesaving intervention in resource limited setting for children with shock who do not have hypotension and raise questions regarding fluid-resuscitation guidelines in other settings as well

 This week I emailed Professor Kathryn Maitland for her thoughts ahead of our discussion and I thank her for taking the time to email me back. Her response:

The major take home message is that we were all surprised by the result. There was no ‘signal’ from the SAE’s and the clinicians involved in the trial — said they all saw children ‘improve’ on boluses and believed that boluses were good. This is why trials are important. 

 Overall, mortality was lower than they had previously experienced– which was probably due to training of all staff involved in paediatric care.

 Professor Maitland also highlights the FEAST study trial video which in her words “takes you to the bedside and puts the trial into context”.

                                                                                                          * * *

Tomorrow I will be posting the discussion points for Sunday evening’s journal club meeting and I look forward to critiquing this fascinating paper.

Thank you to @welsh_gas_doctor for his help with this summary.

Please see the introduction for a summary of the paper itself.

Beta blockers are widely prescribed for a range of conditions and are now widely used in the management of cardiovascular disease. There has been concerns regarding the prescription  β-blockers in patients with COPD due to worries about the effect it may have on their respiratory function, particularly  inhibition of the bronchodilator response to beta agonists.

This BMJ paper examined the use of  β-blockers in patients with COPD to assess the effect on mortality, hospital admissions and exacerbations when used in combination with established therapy for COPD.

This was a retrospective cohort study: it identified cases from a disease-specific database in Tayside which is used by GPs and secondary care respiratory physicians. During the discussion, some concerns were raised over the observational nature of the study, and it was felt that while observational studies can be very useful, we need to be aware of their limitations.

@alasdairforrest also commented on the practicality of such a study versus a prospective study:

The Regional Ethics Committee may have preferred a retrospective study to a therapeutic trial. Or 1/5 paperwork?

The key issue was the balance between simplicity, reduced costs and increased patient numbers usually associated with an observational study, and the difficult with being as “controlled” as a prospective study. @silv24 also added that observational studies take less time to carry out.

The consensus reached was that while observational studies have their limitations, such as the need to consider randomisation problems and confounding factors, they “can also lead to more definitive questions and enable better RCTs in the future” (@mgtmccartney).

As for whether observational studies can be used to change clinical practice, again the responses were mixed. Some agreed that they could be used, but that it was dependent on the strength of the evidence. Alternatively, observational studies could act as a good starting point for other research. Others felt that observational studies alone were inadequate, but that they can add the evidence in favour of a particular practice. As @drgandalf52 pointed out, “to convince the bulk of GPs [we] need to convince NICE”.

An important issue raised with the paper was the lack of information on the patient:

  • “we don’t actually know why any of these patients were on beta blockers for one thing!” (@silv24)
  • “Although database sounds comprehensive, past history of patients is unknown and no record of indication for starting BBs” (@northern_doctor)
  • “the biggest bias might have been that beta blockers were only prescribed to less seriously ill [patients] in [the] first place” (@amcunningham)
The discussion then moved onto whether the end-points used in the study were robust enough to show that beta blockers are safe in COPD in this patient population. @alasdairforrest felt that “hazard ratio for emergency steroids is a good endpoint”, and @northern_doctor pointed out that this shows there was no adverse effect of beta-blockers on airway. Furthermore, @silv24 “found the data on reductions in hospital admissions and emergency oral corticosteroid use very interesting”.
I think @northern_doctor neatly summed the issue up:
I think authors were very thorough with statistical and subgroup analysis to anticipate possible limitations – Couldn’t have done more with data that was available
The paper only considers one geographical area, so did this affect the application of the results to other populations? There was a bit of debate over whether the population studied was representative of the wider population in the UK, but @citylivindundee, first author of the paper, clarified that:
database covers tayside, population >200,000. we believe it to be typical of general population
We discussed the possibility of a nationwide database for patient details, either specific for a study, or as a general NHS database. @northern_doctor pointed out the pre-existing SITS-MOST data for stroke thrombolysis, which perhaps shows the idea would be feasible for a study such as this, although there would need to be a reason for collating this data (for example a study) due to costs.

Some felt that the paper, on its own, did not provide adequate evidence for using beta blockers in COPD patients, and that further studies, such as RCTs, would be necessary to confirm the findings. However others felt that since this paper contributed to a pre-existing body of research into the safety of beta-blockers in COPD (such as this Cochrane Review via @mgtmccartney), it may not be ethical to conduct an RCT.

Overall, it was felt that while this paper has its flaws and needs to be considered in context, it provides further evidence towards the idea that all patients with cardiovascular disease can be prescribed beta-blockers, regardless of co-existing COPD.
We would like to thank Phil Short (@citylivindundee), first author of the paper, for contributing to the discussion.

Anyone who enjoyed the discussion on Rose’s Prevention Paradox back in June may find Barton et al’s paper in the BMJ this week interesting. The study aimed to model the cost-effectiveness of population-wide risk-reduction strategies in preventing cardiovascular disease (CVD). Currently, CVD costs the NHS around £30bn each year and this study has been devised to inform the Department of Health via NICE.

While previous studies have already shown that anti-smoking and anti-salt campaigns are cost effective in reducing CVD incidence, this new studies also looked at the effect of other dietary approaches such as trans-fats and saturated fats. Outcomes were measured using mortality figures, life years and QALYs, though the emphasis was on cost savings to the NHS from cases prevented or postponed. A key limitation was the assumption that interventions would result in equal benefit across age groups and socioeconomic groups, and while consideration was made for changes in risk of CVD following the patient’s first event, none was made for subsequent events. The model also did not consider individuals over the age of eighty.

As we would expect from Rose’s theory, a small change in individuals was found to result in a large financial saving to the NHS as well as improved health in the population. This model found that a 1% reduction in the risk of cardiovascular events would save the NHS £30m each year and prevent 25,000 cases of CVD. Furthermore, a reduction in cholesterol concentrations or blood pressure levels of 5% was modelled as saving the NHS between £80m and £100m a year, while lowering mean salt intake from 8.5g to 5.5g would result in around 30,000 fewer cardiovascular events, with savings worth at least £40m a year. The authors also argue that the nature of their model means the calculations are conservative, and the true savings may be worth even more.

The points for this evening are as follows:

  1. Does the single-centre design mean that there are too few physicians being surveyed? Does it limit the range of viewpoints and practices that are examined?
  2. If most patients spoke to their doctor for at least five minutes about PCI, why did 88% still believe it would reduce their risk of MI?
  3. Why would 43% of cardiologists who identified no benefit in PCI in a hypothetical scenario proceed with it anyway?
  4. What can doctors do differently to communicate the benefits of treatment with their patients?
  5. With regards to the consent form, does this paper raise questions about the nature of informed consent?

Please note you can find the consent form and patient questionnaire online. (Thanks to @dean_jenkins for finding these).

Percutaneous Coronary Intervention (PCI) is a surgery in which obstruction in a stenotic coronary artery is cleared either by balloon angioplasty or stenting. It is a very common procedure, with a 2006 American Heart Association report estimating 1.2 million procedures in 2003 in the US.

PCI is not generally effective in reducing numbers of myocardial infarctions (MI) or mortality in patients with chronic stable angina, but rather only improves quality of life. (This is according to a number of randomised trials and meta-analyses, most notably the highly-publicised COURAGE trial.) Conversely, PCI can be effective in reducing morbidity and mortality in unstable angina.

This study looked at 153 patients who were undergoing diagnostic cardiac catheterisation, but who had also signed consent form for PCI to be performed if it was deemed to be necessary by the interventional cardiologist. They were asked about demographic characteristics, history of angina, whether they felt they were adequately informed about the procedure, and what their expectations of its benefits were.

The study also looked at physicians’ responses to a similar survey. Ten interventional cardiologists and 17 referring cardiologists were asked about their beliefs on the benefits of PCI, and expected outcomes for various hypothetical patients. With interventional cardiologists, the authors also asked about beliefs for study patients undergoing surgery. From my perspective, the numbers here are strikingly small, though since this is a single-centre survey, this probably placed limits on the number of cardiologists who could be asked. It does, however, mean that some of the n numbers in the results section are very small.

The key finding of the paper is that, among patients, 88% believed PCI would reduce their risk of MI, and 82% believed it would reduce their risk of fatal MI; however, among physicians, only 17% believed PCI would reduce the risk of MI and 15% believed it would reduce fatal MI. Furthermore, there was little agreement between individual patients’ and their cardiologists’ responses.

Despite this disparity, most patients reported their doctor spending at least 5 minutes explaining the procedure to them, and over half received some written information on the matter. Furthermore, 96% believed they knew why they might undergo PCI, and more than half felt they had been actively involved in decision making. With patients on whom PCI was carried out, physicians were more likely than patients to believe that the patient had been involved in decision making (78% v 94%). Also of note: patients felt they were at greater risk of MI than their cardiologists did (according to a 5 point Likert scale). Perhaps bizarrely, patients who thought they knew why there were getting PCI were more likely to hold the inaccurate belief that PCI prevented MI though this did not reach significance (Odds ratio = 5.3, CI 0.82-34.53).

The physician responses to hypothetical scenarios also generated some interesting results, perhaps most significantly:

In the first 2 scenarios, 70% of cardiologists did not identify any bnefit associated with PCI, yet 43% of these indicated that they would proceed to PCI anyway

I can’t help but question why a doctor would go ahead with a procedure from which they could foresee no benefit. In addition, this recent study also showed that for non-acute indications, 12% of PCIs were classified as inappropriate. The majority of these procedures performed in patients with little to no angina or with low-risk ischemia on stress testing.

Patients overestimating the benefits of drugs is not limited to PCI and cardiology, but why is it that patients perceive benefit when there is none? Given that most patients in this study had a discussion with their cardiologist, why were they not better informed about the potential outcomes of PCI? Is it a failure to adequately distinguish between unstable and stable angina? It does follow logically that alleviating the symptoms of cardiovascular disease would alter some underlying mechanisms to reduce the risk of MI, but shouldn’t cardiologists be making it clear to patients that this is not the case? What can doctors do differently to communicate effectively with their patients?


If you have any other comments on the paper, please do raise them this evening. As usual, a bit before 8 o’clock this evening (UK time, so 7pm GMT) I’ll post the key points for discussion.

The discussion points for this week are as follows:

1. This paper is a retrospective cohort study – what is the place of observational studies in influencing or changing clinical practice?

2. Endpoints measured – where they robust enough to show that beta blockers are safe in COPD in this patient population?

3. The paper used a database of patients in one geographical area. Should we be trying to build up the links needed to produce this kind of data across the UK more generally?

4. Is there a need for prospective research into whether beta blockers are safe in patients with COPD?

Beta blockers are widely prescribed for a range of conditions and are now widely used in the management of cardiovascular disease. Patients with chronic obstructive pulmonary disease (COPD) often have concurrent co-morbidities including cardiovascular disease. However there has been concerns regarding the prescription  β-blockers in these patients due to worries about the effect it may have on their respiratory function:

  • evidence that the use of  β-blockers in patients with COPD may lead to a reduction in their lung function (by reducing their FEV1 – Forced expiratory volume in one second)
  • β-blockers may increase airway hyperresponsiveness

One of the mainstays of treatment of COPD is the use of beta-agonists and there have been concerns that  β-blockers may lead to inhibition of the bronchodilator response to these drugs.

As such there has been some reluctance to prescribe  β-blockers in these patients. This paper published in the BMJ looked at the use of  β-blockers in patients with COPD to assess the effect on mortality, hospital admissions and exacerbations when used in combination with established therapy for COPD.

This was a retrospective cohort study which identified cases from a disease-specific database in Tayside which is used by GPs and secondary care respiratory physicians. All patients fulfil the GOLD guidelines for diagnosis of COPD and data on these patients was collected by respiratory nurses at yearly visits. The authors then identified patients who had an admission to hospital due to COPD and also gathered data on the prescription of respiratory and cardiovascular drugs and on deaths from the general register.

The main outcome measures were hazard ratios from all cause mortality, emergency oral corticosteriod use (use to treat exacerbations of COPD) and respiratory related hospital admissions. In these patients 88% of the β-blockers used were cardioselective.

The results – this paper showed a 22% reduction in all cause mortality in patients prescribed  β-blockers. There was a reduction in the adjusted hazard ratio for patients prescribed β-blockers with standard treatment for COPD compared to those who weren’t (0.28 vs 0.43). The paper also showed a reduction in oral corticosteriod use and hospital admission. There was no adverse effect on lung function detected at all stages of the stepwise treatment approach to COPD.

The authors of this paper concluded that:

 β blockers may reduce mortality and COPD exacerbations when added to established inhaled stepwise therapy for COPD, independently of overt cardiovascular disease and cardiac drugs, and without adverse effects on pulmonary function

A list of discussion points will be posted shortly. Thank you to @amcunningham for suggesting this paper.

Apologies for the delay in posting the summary of last Sunday’s discussion. A week of nights on call in A&E didn’t leave much time for anything but sleeping.  The summary will be posted as soon as possible and I will tweet a link as soon as I do this. Thank you all for continuing to join in the journal club discussions and I am looking forward to tomorrow night’s discussion already.

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