In March we gathered at the London Chest Hospital for a day of allergy, ventilation and surgery. Many thanks to Marilu (Dr Marilu Nuila) for co-ordinating the day.
Interesting facts about the London Chest Hospital:
- The London Chest Hospital was founded in 1848 at a meeting held at the London Tavern in the City of London by a group of 19 philanthropic bankers, and City merchants, 13 of whom were Quakers.
- Lord Lister, famous for his pioneering work in the development of antiseptics, was on the staff of the hospital when it opened in 1855.
- Fabrice Muamba, the Zaire native who played for England’s Bolton Wanderers, was taken here after suffering a cardiac arrest on the pitch on 17 March 2012. He made a good recovery but retired from football.
The day began with a GIM session on drug allergy, delivered by Dr Joanna Lukawska. We began with a helpful reminder of some basic definitions and a reminder of some immunological principles. An illustrated case which ended in tragedy ensured that Dr Lukawska had our full attention.
- Type A drug reactions: predictable, related to dose/pharmacokinetics
- Type B drug reactions: unpredictable –> hypersensitivity reactions
- Immediate IgE: ‘silent’ sensitization which is well tolerated, then rapid development of symptoms on re-exposure eg urticaria, anaphylaxis
- Delayed type T cell: sensitization and symptoms often at 8-10th day of therapy (exanthem)
We were reminded that although history and examination are important, they only yield a diagnosis 50% of the time. Tests are helpful in this area but must be selected appropriately.
- Diagnosing allergic diseases in children. Practical recommendations for consulting pathologists. Arch Pathol Lab Med. 2004 Sep;128(9):1028-31.
IgE mediated reactions are likely when: there has been exposure on >1 occasion; there is a clear temporal association; the patients exhibits classical symptoms of urticaria, angioedema, sinus symptoms, dyspnoea or collapse. It is unlikely when: symptoms occur hours after ingestion; there is isolated diarrhoea and vomiting; or there is isolated fever. Penicillin allergy has a reported incidence of 10%, or 20% in inpatients. The true incidence of anaphylaxis is thought to be 0.004-0.0015%. A childhood history is not always helpful as there is some loss of sensitivity. Worryingly, 50% of people with the label of penicillin allergy will be represcribed penicillin. In the case of anaphylaxis this could be life threatening. The challenge is knowing who to test for drug allergy. The World Allergy Organisation provides some guidance and suggests that anyone with a suggestive history who is likely to need antibiotics in the future should be tested. This would include anyone with a chronic condition, and anyone over 65years old. The risk of pencillin-cephalosporin cross-reactivity is unknown. It is estimated to be 4-10% so caution should be exercised. Investigations used in drug allergy include:
- skin prick testing
- RAST IgE
- Intradermal testing
- Challenge testing
If all these are negative the patient can confidently be told they do not have an allergy and can be given the medication in the future. Patch testing is used for testing for delayed type/T cell mediated reactions. Such reactions can lead to maculopapular rashes, pustulae, and bullae, If the drug is continued this can progress to erythroderma, Steven Johnson syndrome, and TEN. Dr Lukawska provided some illustrative horror stories of the clinical and financial consequences of adverse drug reactions. It is estimated that adverse events occur in 10% of NHS admissions and that 3500 people a year die as a result (compared to 2946 deaths due to RTAs). Medication errors account for 25% of all adverse events in hospitals. The NHS spent £15.7 billion in 2009-10 in negligence settlements. For those with severe allergy, desensitization protocols can be effective in creating temporary tolerance. The most famous example of this is King Mithradates of Pontus who induced tolerance to poison so successfully that he was unable to kill himself when defeated by Pompey, and had to ask a friend to run him through with a sword.
Ventilatory strategies for the management of OHS
We moved on to hear from Paddy (Dr Patrick Murphy) on what we can offer the growing number of patients with OHS. OHS is a syndrome rather than a distinct pathological entity, defined by the American Academy of Sleep Medicine as:
- obesity (BMI >30kg/m2)
- awake arterial hypercapnia (PaCO2 >45mmHg)
- the absence of other causes of hypoventilation
Patients with OHS may have obstructive sleep apnea/hypopnea syndrome with hypercapnia, sleep hypoventilation syndrome or a combination of sleep-related breathing disorders. 25% patients have a BMI >40 kg/m2. OHS affects 10% patients attending sleep clinic. 10% patients with OHS have no co-existent OSA. A study by Nowbar and colleagues found that when unselected medical admissions who were obese (BMI >35kg/m2) were screened and followed up, 31% had OHS and this was associated with excess morbidity and mortality. In this US cohort <10% had longterm NPPV. This is despite Budweiser demonstrating that therapy offered a significant survival advantage.
- Nowbar, Sogol, et al. “Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome.” The American journal of medicine116.1 (2004): 1-7
- Pépin, Jean-Louis, Jean-Christian Borel, and Jean-Paul Janssens. “Obesity hypoventilation syndrome: an underdiagnosed and undertreated condition.”American journal of respiratory and critical care medicine 186.12 (2012): 1205-1207
- Cuvelier, Antoine, and Jean-François Muir. “Acute and Chronic Respiratory Failure in Patients With Obesity-Hypoventilation Syndrome A New Challenge for Noninvasive Ventilation.” CHEST Journal 128.2 (2005): 483-485
- Budweiser, S., et al. “Mortality and prognostic factors in patients with obesity‐hypoventilation syndrome undergoing noninvasive ventilation.” Journal of internal medicine 261.4 (2007): 375-383
The cost implications of NPPV for an increasing population of patients with OHS is important. NPPV has therefore been compared to CPAP (cheaper, easier to setup and supply).
- Piper, Amanda J., et al. “Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation.” Thorax 63.5 (2008): 395-401.
This paper found that both CPAP and bilevel support were equally effective in improving daytime hypercapnia in patients with OHS without severe nocturnal hypoxaemia. However, the trial excluded 20% of patients due to CPAP failure, excluded patients with nocturnal hypoventilation, was a small trial, and used low settings on NPPV. The settings for bilevel support were IPAP 16+/- 2 EPAP 10+/-2 spontaneous mode with no back up rate. This does not reflect our practice of NPPV use in this group of patients so results should be interpreted with caution. A major concern with this trial is that the NPPV was not optimised, which may explain the lack of difference between CPAP and NPPV. CPAP is certainly more effective for patients with OSA alone, than those with OHS and OSA.
- Salord, Neus, et al. “Continuous positive airway pressure in clinically stable patients with mild‐to‐moderate obesity hypoventilation syndrome and obstructive sleep apnoea.” Respirology 18.7 (2013): 1135-1142.
CPAP treatment improved night-time oxygenation and daytime hypoventilation in selected clinically stable OHS patients who also had OSA. Patients with worse night-time saturation while on CPAP and higher daytime PaCO2 at 1 month were more likely to fail CPAP treatment. This editorial neatly summaries ongoing questions and need for further well designed trials in this area:
- Mokhlesi, Babak. “Positive Airway Pressure Titration in Obesity Hypoventilation SyndromeContinuous Positive Airway Pressure or Bilevel Positive Airway Pressure.” CHEST Journal 131.6 (2007): 1624-1626.
In an RCT comparison of nocturnal NPPV vs lifestyle advice, NPPV improved sleep architecture, decreased pCO2, increased SpO2 and decreased arousals. There was however, no improvement in ESS (a patient reported measure and therefore arguably more relevant). This trial was for 1 month only, and the participants were a ‘mild’ phenotype, again limiting generalisability of results.
- Borel, Jean-Christian, et al. “Noninvasive Ventilation in Mild Obesity Hypoventilation SyndromeNoninvasive Ventilation in Obesity HypoventilationA Randomized Controlled Trial.” CHEST Journal 141.3 (2012): 692-702.
There has been some interest in different modes of ventilation for OHS, particularly AVAPS.
- Storre, Jan Hendrik, et al. “Average Volume-Assured Pressure Support in Obesity HypoventilationA Randomized Crossover Trial.” CHEST Journal 130.3 (2006): 815-821.
- Murphy, P., et al. “S65 Interim data from a randomised controlled trial of average volume-assured pressure support (AVAPS) versus spontaneous-timed (ST) pressure support in Obesity Hypoventilation Syndrome (OHS).” Thorax65.Suppl 4 (2010): A31-A31.
- Janssens, Jean-Paul, Marie Metzger, and Emilia Sforza. “Impact of volume targeting on efficacy of bi-level non-invasive ventilation and sleep in obesity-hypoventilation.” Respiratory medicine 103.2 (2009): 165-172.
The LCH experience is that there is no difference between AVAPS and PS if they are titrated to control sleep disordered breathing. An inpatient protocol is required. A backup rate is essential and therefore spontaneous mode is not recommended. Overall, the question of whether bilevel support is significantly better than CPAP, and in which patient subgroups, remains unclear. Most evidence is extrapolations from small uncontrolled studies. As ever, more research is needed…..
Debate: home mechanical ventilation for COPD
Following this Marilu and Paddy debated the proposition “Home mechanical ventilation is beneficial in the management of chronic respiratory failure in COPD.” The arguments for the proposition consisted mainly of pointing out the flaws in the studies used against it:
- Casanova, Ciro, et al. “Long-term controlled trial of nocturnal nasal positive pressure ventilation in patients with severe COPD.” CHEST Journal 118.6 (2000): 1582-1590.
This study showed over 1 year, NPPV did not affect the natural course of the disease and was of marginal benefit in outpatients with severe COPD in stable condition. There was no difference in survival, number of exacerbations or lung function between the usual care group (LTOT) and NPPV+usual care group. Unfortunately pCO2 was not measured as an outcome, and QoL was not assessed. Perhaps the wrong outcomes were chosen as endpoints?
- Clini, E., et al. “The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients.” European Respiratory Journal20.3 (2002): 529-538
The authors of this study concluded that compared with long-term oxygen therapy alone, the addition of NPPV in stable COPD patients with chronic ventilatory failure: 1) slightly decreased the trend to carbon dioxide retention in patients receiving oxygen at home and 2) improved dyspnoea and health-related quality of life. However, they did not demonstrate any difference in hospital admissions or mortality.
- Diaz, O., et al. “Physiological and clinical effects of diurnal noninvasive ventilation in hypercapnic COPD.” European Respiratory Journal 26.6 (2005): 1016-1023
There are a lack of RCTs in this area, so it was good to see an attempt at robust evidence from this Chilean group. However they may have over stated their findings. Despite this study only lasting 5 weeks in total (3 weeks study, 2 weeks follow-up) the authors claim that NPPV has “significant and sustained” clinical impact in stable hypercapnic COPD. The NPPV settings used in the studies up to now were strongly highlighted as being relevant to this debate:
- Windisch, Wolfram, et al. “High-intensity non-invasive positive pressure ventilation for stable hypercapnic COPD.” International journal of medical sciences 6.2 (2009): 72
In this study high-intensity NPPV improved blood gases, lung function and hematocrit, and was also associated with low exacerbation rates and a favourable long-term outcome (5 year survival rates cited). The primary conclusion of this study was that there is a need for RCTs evaluating the role of high-intensity NPPV in stable hypercapnic COPD patients. The ‘for’ team felt that the statement from Rossi et al (ATS/ERS task force statement) summed up the current status of the evidence in this area “NIV has not been shown to be ineffective in COPD.” The arguments against the proposition consisted mainly of listing the number of negative studies, trials, systematic reviews and meta-analyses:
- Chu, C. M., et al. “Readmission rates and life threatening events in COPD survivors treated with non-invasive ventilation for acute hypercapnic respiratory failure.” Thorax 59.12 (2004): 1020-1025
This study showed poor outcomes following acute hypercapnic exacerbation of COPD in the UK. patients had high readmission rates. It concluded that further studies were urgently needed to devise strategies to reduce readmission and life threatening events in this group of patients (perhaps longterm home NPPV…?)
- Lloyd-Owen, S. J., et al. “Patterns of home mechanical ventilation use in Europe: results from the Eurovent survey.” European Respiratory Journal 25.6 (2005): 1025-1031
A questionnaire based study led by researchers from our own deanery showed a wide variation in practice across Europe. The estimated prevalence of home mechanical ventilation in Europe was 6.6 per 100,000 people (all causes, including neuromuscular disease in addition to COPD). Interestingly home NPPV for COPD is not funded in the USA.
- Wijkstra, Peter J., et al. “A meta-analysis of nocturnal noninvasive positive pressure ventilation in patients with stable COPD.” CHEST Journal 124.1 (2003): 337-343
The introduction to this study highlighted the fact that many trials were uncontrolled and contained small numbers of patients. This meta-analysis therefore analysed individual data from RCTs that compared NPPV with conventional management of patients with COPD and stable respiratory failure. Although the number of trials was small, this meta-analysis provided an up-to-date summary of the results of this management approach. It showed that ventilatory support did not improve lung function, gas exchange, or sleep efficiency. The high upper limit of the confidence interval for the 6MWD suggested that some people do improve their walking distance. The discussion suggested many reasons for the negative result and is worth reading.
- McEvoy, R. Douglas, et al. “Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial.” Thorax 64.7 (2009): 561-566
This RCT from Australia showed an early improvement in adjusted mortality rates in the NPPV group (vs LTOT alone). However, this effect disappeared when unadjusted data was analysed. This effect disappeared in longer term follow up seen in the adjusted data. In addition, there was a worsening in quality of life for patients on NPPV. If at first your trials and meta-analyses are negative, do another one…
- Struik, Fransien M., et al. “Nocturnal non-invasive positive pressure ventilation for stable chronic obstructive pulmonary disease.” Cochrane Database Syst Rev 6 (2013).
This Cochrane review, which included seven studies on 245 people, concluded that there was no consistent clinically or statistically significant effect on gas exchange, exercise tolerance, HRQoL, lung function, respiratory muscle strength, or sleep efficiency. Overall the evidence is lacking to justify NPPV in chronic stable hypercapnic COPD. However, all studies thus far are flawed, and there is hope that benefit may be shown if the right patient group is selected, and if the correct settings (higher pressures) are used. An ongoing challenge is that many patients do not like this treatment and may not accept it if the benefit is in mortality rather than QoL. Currently all patients in whom this treatment is considered should be in clinical trials. We await the results of HoT-HMV (UK), RESCUE(Dutch) and NIVOLD(French)….
Lobectomy by VATS – what’s the big deal?
The afternoon featured some of our surgical colleagues. A talk on chest drain management gave an insight into surgical approaches to insertion and management. We then moved on to hear from Mr Kelvin Lau to consider VATS lobectomy for lung cancer, and surgical and interventional options for COPD. Mr Lau began by a review of lung cancer mortality and a consideration of contributing factors including cancer-related, pulmonary complications and other including cardiovascular comorbidity. Surgical procedures have developed with the aim of reducing invasiveness and limiting the amount of lung removed, whilst maintaining best oncological outcomes. Traditional thoracotomy requires a large incision and spreading of the ribs, leading to post-op pain. In a VATS the incision is smaller and, importantly, there is no spreading of the ribs.
- Port, Jeffrey L., et al. “Lobectomy in octogenarians with non-small cell lung cancer: ramifications of increasing life expectancy and the benefits of minimally invasive surgery.” The Annals of thoracic surgery 92.6 (2011): 1951-1957.
Watch a VATS performed by Professor Swanson, director of minimally invasive surgery at Harvard:
This retrospective single-centre study showed that elderly patients (>80 years) did better with VATS than thoracotomy when undergoing resection for stage I NSCLC. This was due to fewer pulmonary complications. Oncological outcomes were noninferior.
- Swanson, Scott J., et al. “Video-assisted thoracoscopic lobectomy is less costly and morbid than open lobectomy: a retrospective multiinstitutional database analysis.” The Annals of thoracic surgery 93.4 (2012): 1027-1032.
This study helped to reassure those who were concerned about the additional costs of VATS eg stapling devices. Such costs are traded off by decreased length of stay and use of HDU beds. The UK, where around 10% of lobectomy is done by VATS, is perhaps behind the US where the rate is 40%. This is changing… A video of a VATS lobectomy provoked gasps from the physicianly audience when the proximity of the surgical instruments to the aorta was appreciated. When a pulmonary artery bleed was then witnessed, and the surgeon opted to control it under VATS rather than open the patient up, the levels of respect for surgical skills increased…
LVRS and EBLVR for severe COPD
Mr Lau moved from lung cancer to COPD, and offered us hope that there is more to treatment than bronchodilators. Initial enthusiasm for lung volume reduction surgery (LVRS) was based on results from a single surgeon, Joel Cooper. As others took up the new technique, concerns were raised about the reproducibility of these early positive results.
- Utz, James P., Rolf D. Hubmayr, and Claude Deschamps. “Lung volume reduction surgery for emphysema: out on a limb without a NETT.” Mayo Clinic Proceedings. Vol. 73. No. 6. Elsevier, 1998
The NETT study is ongoing. Two interesting papers highlighted by @COPDdoc (Prof Nick Hopkinson of Imperial) on Twitter recently include:
- Hopkinson et al. Surgical approaches for lung volume reduction surgery in emphysema. Clinical Medicine April 2014 suggesting that safety in modern practice is better than historical trial data
- Attitudes and access to lung volume reduction surgery for COPD: a survey by the British Thoracic Society BMJ Open Resp Res May 1, 2014 indicating that health professionals often overestimate risk of LVRS in COPD.
We hope to see you at the next training day!
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