We thank Dr Zhang and colleagues for their comments on our paper1. We certainly agree that in this emerging field of extracellular vesicle (EV) research, it is vital that identification and characterisation of different EV populations are as robust as possible. To this end, we very much welcome detailed discussions on methodologies used for each study, to enhance and improve the quality of EV-related work within the lung research community.
In our paper, we specifically chose to examine the role of microvesicles (MVs) in acute lung injury (ALI), and the roles of apoptotic bodies and exosomes are beyond the scope of the study. We do not exclude the presence of apoptotic bodies or surfactant micelles in our in vivo samples, or indeed single or clustered MVs larger than 1µm, however our surface marker analysis of MV subpopulations by flow cytometry was deliberately conservative and limited to only events below the conventional size cut off of 1µm. Hence figure 3 of our paper shows effectively only one EV population, i.e. MVs. For our isolation of MVs for functional studies, we used differential centrifugation to enrich MVs but these technical matters were discussed in some detail in the published manuscript.
Dr Zhang and colleagues have concerns about the dose of LPS (20µg) used in our in vivo ALI model. However, intratracheal (i.t.) instillation of high dose LPS (20µg or more per mouse) is a clinically-relevant, well established model of AL...
We thank Dr Zhang and colleagues for their comments on our paper1. We certainly agree that in this emerging field of extracellular vesicle (EV) research, it is vital that identification and characterisation of different EV populations are as robust as possible. To this end, we very much welcome detailed discussions on methodologies used for each study, to enhance and improve the quality of EV-related work within the lung research community.
In our paper, we specifically chose to examine the role of microvesicles (MVs) in acute lung injury (ALI), and the roles of apoptotic bodies and exosomes are beyond the scope of the study. We do not exclude the presence of apoptotic bodies or surfactant micelles in our in vivo samples, or indeed single or clustered MVs larger than 1µm, however our surface marker analysis of MV subpopulations by flow cytometry was deliberately conservative and limited to only events below the conventional size cut off of 1µm. Hence figure 3 of our paper shows effectively only one EV population, i.e. MVs. For our isolation of MVs for functional studies, we used differential centrifugation to enrich MVs but these technical matters were discussed in some detail in the published manuscript.
Dr Zhang and colleagues have concerns about the dose of LPS (20µg) used in our in vivo ALI model. However, intratracheal (i.t.) instillation of high dose LPS (20µg or more per mouse) is a clinically-relevant, well established model of ALI, used very widely by investigators in ALI research including ourselves2-5. Dr Zhang stated that large doses of LPS often result in release of apoptotic bodies but few MVs from alveolar macrophages, but we wonder if this statement is based on in vitro experiments using non-primary cells, rather than in vivo ALI models? Dr Zhang’s group recently showed6 the production of apoptotic bodies with 1µg LPS treatment, but their results were obtained using an immortalised cell line (MH-S alveolar macrophages) in vitro, rather than primary alveolar macrophages in vivo. Interestingly, they observed that apoptotic body production peaked later (at 6 hours) when primary cells (bone marrow derived macrophages) were treated with LPS in vitro, highlighting a clear difference between primary cells and immortalised cell lines (such as RAW cells, THP-1 and MH-S cells)6. While we cannot entirely exclude the possibility that some apoptotic bodies were produced within our model, it has been shown that i.t. LPS in vivo does not initiate apoptosis of alveolar macrophages until much later time points7,8. Taken together, we believe that concerns regarding apoptotic bodies influencing our conclusions are unsubstantiated for the acute responses investigated in our model. This is of course not to say that the release of apoptotic bodies or other EVs does not play an important role during subsequent phases of ALI pathophysiology.
Sanooj Soni, Michael R Wilson, Kieran P O’Dea, Masao Takata
Section of Anaesthetics, Pain Medicine & Intensive Care, Imperial College London, UK
1. Soni S, Wilson MR, O'dea KP, et al. Alveolar macrophage-derived microvesicles mediate acute lung injury. Thorax 2016;71(11):1020-29.
2. Woods SJ, Waite AA, O'Dea KP, et al. Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation. American Journal of Physiology-Lung Cellular and Molecular Physiology 2015;308(9):L912-L21.
3. Gong J, Wu Zy, Qi H, et al. Maresin 1 mitigates LPS‐induced acute lung injury in mice. British journal of pharmacology 2014;171(14):3539-50.
4. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature medicine 2012;18(5):759-65.
5. Dorr AD, Wilson MR, Wakabayashi K, et al. Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies. Journal of Applied Physiology 2011;111(1):177-84.
6. Zhu Z, Zhang D, Lee H, et al. Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222. Journal of Leukocyte Biology 2017:jlb. 3A1116-483R.
7. Vernooy JH, Dentener MA, Van Suylen RJ, et al. Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-α and infiltrating neutrophils. American journal of respiratory cell and molecular biology 2001;24(5):569-76.
8. Kearns MT, Barthel L, Bednarek JM, et al. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation. American Journal of Physiology-Lung Cellular and Molecular Physiology 2014;307(1):L62-L70.
I enjoyed reading Hodgson et al’s validation study on Early Warning Scores (EWS) in patients admitted with an exacerbation of COPD. The current problem with EWS such as the National Early Warning Score (NEWS) in such patients is that the score is used in two contexts.
The first is in the initial triage of patients on arrival to hospital based on their early risk of death. NEWS is well validated in this context, and I wholeheartedly agree that NEWS is the best tool for this at present; patients at risk of type 2 respiratory failure, with target oxygen saturations of 88-92%, are at a high risk of death in hospital and identifying these patients early to enable senior review is entirely appropriate.
The problem comes with second use of NEWS – as a “track and trigger” tool used to monitor patients during their inpatient stay, with a rising score indicating deterioration, risk of death and the need for intervention. Hodgson et al have confirmed our finding that NEWS lacks specificity for patients with COPD. These patients will often have persistently high NEWS even when stable, well into their admission, and the actions this is supposed to trigger (hourly observations, senior review, etc.) are no longer appropriate. This leads to alarm fatigue, with high scores being ignored, increasing the risk of a true deterioration not being acted upon.
The proposals of Hodgson et al that such patients should have individually assigned observation frequencie...
I enjoyed reading Hodgson et al’s validation study on Early Warning Scores (EWS) in patients admitted with an exacerbation of COPD. The current problem with EWS such as the National Early Warning Score (NEWS) in such patients is that the score is used in two contexts.
The first is in the initial triage of patients on arrival to hospital based on their early risk of death. NEWS is well validated in this context, and I wholeheartedly agree that NEWS is the best tool for this at present; patients at risk of type 2 respiratory failure, with target oxygen saturations of 88-92%, are at a high risk of death in hospital and identifying these patients early to enable senior review is entirely appropriate.
The problem comes with second use of NEWS – as a “track and trigger” tool used to monitor patients during their inpatient stay, with a rising score indicating deterioration, risk of death and the need for intervention. Hodgson et al have confirmed our finding that NEWS lacks specificity for patients with COPD. These patients will often have persistently high NEWS even when stable, well into their admission, and the actions this is supposed to trigger (hourly observations, senior review, etc.) are no longer appropriate. This leads to alarm fatigue, with high scores being ignored, increasing the risk of a true deterioration not being acted upon.
The proposals of Hodgson et al that such patients should have individually assigned observation frequencies undermines the attraction of using EWS: consistency. If each patient has an individualised plan, often dependent on which individual healthcare professional has seen them, the consistency of response is lost. An on-call team member told of a score that has been individually put together cannot know what the urgency of response required is compared to a standardised score. Whilst there will be extreme cases where individualised plans are required, the population of patients with target oxygen saturations of 88-92%, make up a large enough proportion of the inpatient population to justify a standardised alternative score to suit their needs during the middle and latter portions of their admission. I would propose that NEWS is used at the “front door” for all patients to enable early senior review for these patients, but that once a senior clinical decision maker has prescribed target oxygen saturations of 88-92%, a standardised score for patients at risk of type 2 respiratory failure is a better method of monitoring these patients subsequently.
Dear Editors,
We are writing to comment on the work entitled “Alveolar macrophage-derived microvesicles mediate acute lung injury” published by Dr. Soni et al on Thorax 2016; 71:1020-1029[1].
Our group focuses on lung extracellular vesicle (EV) research and also studied the inhaled LPS-induced EVs in mouse models. Based on our experience, we raise the following comments to the work done by Dr. Soni et al and wish to draw attentions to future EV researchers. EV research is a novel field and carries a promising potential for the development of diagnostic and therapeutic agents. However, given the early stage of EV research, particular in the field of lung injury, the consistency of results relies largely on the precise techniques used in the isolation and characterization of these vesicles.
Briefly, EV is currently classified into three major categories per the definition of Society of extracellular vesicle research [2]. Apoptotic bodies (ABs) are the largest sizes of EVs usually larger than 1 µm and often resulted from cell death. Microvesicles (MVs) are the middle sized EVs (200 nm-1 µm) and are generated via plasma membrane budding. Exosomes (Exos) are the smallest EVs (less than 200 nm) and often generated from IVB-ER-Golgi system. Due to the different mechanisms of generation, MVs and Exos usually favor different compositions and subsequently may carry differential downstream biological functions[3 4]. For example, Exos have been reported to carry t...
Dear Editors,
We are writing to comment on the work entitled “Alveolar macrophage-derived microvesicles mediate acute lung injury” published by Dr. Soni et al on Thorax 2016; 71:1020-1029[1].
Our group focuses on lung extracellular vesicle (EV) research and also studied the inhaled LPS-induced EVs in mouse models. Based on our experience, we raise the following comments to the work done by Dr. Soni et al and wish to draw attentions to future EV researchers. EV research is a novel field and carries a promising potential for the development of diagnostic and therapeutic agents. However, given the early stage of EV research, particular in the field of lung injury, the consistency of results relies largely on the precise techniques used in the isolation and characterization of these vesicles.
Briefly, EV is currently classified into three major categories per the definition of Society of extracellular vesicle research [2]. Apoptotic bodies (ABs) are the largest sizes of EVs usually larger than 1 µm and often resulted from cell death. Microvesicles (MVs) are the middle sized EVs (200 nm-1 µm) and are generated via plasma membrane budding. Exosomes (Exos) are the smallest EVs (less than 200 nm) and often generated from IVB-ER-Golgi system. Due to the different mechanisms of generation, MVs and Exos usually favor different compositions and subsequently may carry differential downstream biological functions[3 4]. For example, Exos have been reported to carry the very minimal amount of popular microRNAs (miRNAs). Even for those most promising miRNA markers, less than 1 copy of miRNA can be found in each Exo[5]. This is part of the reason why the classification of EVs may be important.
In the work presented by Dr. Soni et al, a very large dose of LPS (20 μg per mouse) has been delivered to mice via intratracheal instillation. Certainly, different batch of LPS may carry different levels of potency. However, we found that the larger dose of LPS often quickly resulted in the release of ABs but rather than MVs by alveolar macrophages. In our experiences, as little as 1 μg LPS (Sigma-Aldrich, cat #L2630, St. Louis, MO, USA) resulted in the robust amount of MVs (about 50% in total EVs). However, a fair amount of Exos (about 25% in total EVs) is still mixed in the LPS-induced EVs. Additionally, the FACS analysis presented in figure 3 shows only one population of vesicles. This could be due to the overly too large dose of LPS and the detected EVs fall mainly on the range of ABs. In our experience, using a smaller dose of LPS, we often clearly observe two different population of EVs, one belongs to the larger size of ABs, and the other belongs to the smaller MVs.
We recognize that the variability of results could result from different technique, detecting apparatus, different batch of LPS and also different size/age/strain of mice. However, we would like to discuss our findings on this emerging novel topic and our comments may be found interesting and useful by other audience.
Thank you for your time and attention!
REFERENCES
1. Soni S, Wilson MR, O'Dea KP, et al. Alveolar macrophage-derived microvesicles mediate acute lung injury. Thorax 2016;71(11):1020-29. doi: 10.1136/thoraxjnl-2015-208032
2. Gyorgy B, Szabo TG, Pasztoi M, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011;68(16):2667-88. doi: 10.1007/s00018-011-0689-3
3. Yanez-Mo M, Siljander PRM, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015;4 doi: ARTN 27066
10.3402/jev.v4.27066
4. Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol 2013;200(4):373-83. doi: 10.1083/jcb.201211138
5. Alexander M, Hu RZ, Runtsch MC, et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun 2015;6 doi: ARTN 7321
10.1038/ncomms8321
We thank Cardwell et al for their thoughtful comments on our paper.[1] The two alternative scoring systems did not demonstrate improved discrimination or calibration in our large dataset of AECOPD admissions. The authors suggest employing the Salford-NEWS only in patients ‘at risk’ of hypercapnic respiratory failure however, this introduces a subjective element that may negate the benefits of an objective physiological scoring system. As we emphasised in what we believe was a balanced discussion, patients with COPD should be managed in the right place by specialists and on-going education is crucial to avoid potential harms associated with misinterpretation of the NEWS alluded to by Cardwell and colleagues. Our article adds evidence that suggested RCP thresholds would indeed lead to unnecessary callouts in such patients. However, as we proposed, rather than abandon a scoring system that provides the significant advantages of standardisation and familiarity, it is possible to individualise patient management. For example, lowering observation frequency in a patient who is clinically ‘stable’, not increasing oxygen delivery if the prescribed target saturation is achieved, or taking into account prior/baseline physiology when deciding observation frequency and whether a senior review is required. Indeed a senior review may be appropriate to interpret whether the patient is at risk of hypercapnic respiratory failure and be able to advise on appropriate targets and level of mon...
We thank Cardwell et al for their thoughtful comments on our paper.[1] The two alternative scoring systems did not demonstrate improved discrimination or calibration in our large dataset of AECOPD admissions. The authors suggest employing the Salford-NEWS only in patients ‘at risk’ of hypercapnic respiratory failure however, this introduces a subjective element that may negate the benefits of an objective physiological scoring system. As we emphasised in what we believe was a balanced discussion, patients with COPD should be managed in the right place by specialists and on-going education is crucial to avoid potential harms associated with misinterpretation of the NEWS alluded to by Cardwell and colleagues. Our article adds evidence that suggested RCP thresholds would indeed lead to unnecessary callouts in such patients. However, as we proposed, rather than abandon a scoring system that provides the significant advantages of standardisation and familiarity, it is possible to individualise patient management. For example, lowering observation frequency in a patient who is clinically ‘stable’, not increasing oxygen delivery if the prescribed target saturation is achieved, or taking into account prior/baseline physiology when deciding observation frequency and whether a senior review is required. Indeed a senior review may be appropriate to interpret whether the patient is at risk of hypercapnic respiratory failure and be able to advise on appropriate targets and level of monitoring for the individual with subsequent avoidance of alarm fatigue.
1. Hodgson LE, Dimitrov BD, Congleton J, Venn R, Forni LG, Roderick PJ. A validation of the National Early Warning Score to predict outcome in patients with COPD exacerbation. Thorax 2017;72(1):23-30 doi: 10.1136/thoraxjnl-2016-208436.
2. Prytherch DR, Smith GB, Schmidt PE, Featherstone PI. ViEWS--Towards a national early warning score for detecting adult inpatient deterioration. Resuscitation 2010;81(8):932-7 doi: 10.1016/j.resuscitation.2010.04.014.
We read the paper of Hodgson and colleagues with interest.1 Unfortunately, we note that the Salford-NEWS system (observation chart based on target Oxygen saturation prescription) has been applied in this study to all patients with a diagnosis of acute exacerbation of COPD (AECOPD) whereas we proposed applying this system for all patients at risk of type 2 (hypercapnic) respiratory failure, a group which includes many but not all patients with AECOPD and a number of patients with other conditions.2 Around 86% of those prescribed the lower range of Oxygen saturation (88-92%) in Salford are COPD patients judged to be at risk of hypercapnia, the remainder have conditions such as morbid obesity, neuro-muscular disorders, or complex lung diseases.3 Given this key difference in rationale we suggest that the Salford-NEWS system has been inappropriately applied in this study; hence, the conclusions have to be interpreted with extreme caution.
When comparing NEWS with Salford-NEWS, it is clear that none of the systems had acceptable sensitivity at score thresholds of 5 and 7, and the most consistently reliable result from using either of them is the negative predictive value, which was similar. It was also evident that Salford-NEWS had better specificity at 91% and 95% compared to 57% and 80% for NEWS at score thresholds of 5 and 7 respectively. Since the increased sensitivity in NEWS is achieved at the expense of high “callout” rates, and low positive predictive value (8%...
We read the paper of Hodgson and colleagues with interest.1 Unfortunately, we note that the Salford-NEWS system (observation chart based on target Oxygen saturation prescription) has been applied in this study to all patients with a diagnosis of acute exacerbation of COPD (AECOPD) whereas we proposed applying this system for all patients at risk of type 2 (hypercapnic) respiratory failure, a group which includes many but not all patients with AECOPD and a number of patients with other conditions.2 Around 86% of those prescribed the lower range of Oxygen saturation (88-92%) in Salford are COPD patients judged to be at risk of hypercapnia, the remainder have conditions such as morbid obesity, neuro-muscular disorders, or complex lung diseases.3 Given this key difference in rationale we suggest that the Salford-NEWS system has been inappropriately applied in this study; hence, the conclusions have to be interpreted with extreme caution.
When comparing NEWS with Salford-NEWS, it is clear that none of the systems had acceptable sensitivity at score thresholds of 5 and 7, and the most consistently reliable result from using either of them is the negative predictive value, which was similar. It was also evident that Salford-NEWS had better specificity at 91% and 95% compared to 57% and 80% for NEWS at score thresholds of 5 and 7 respectively. Since the increased sensitivity in NEWS is achieved at the expense of high “callout” rates, and low positive predictive value (8%), clinicians would need to adjust the scoring parameters for almost half of patients with AECOPD to avoid repeated un-necessary “callouts”. Since there is no evidence-based system for making such adjustments, it may be worth considering the extension of the Salford-NEWS system to most patients with AECOPD as an interim solution.
This study does, however, demonstrate that the Salford-NEWS system, when applied blindly to all admitted patients with AECOPD (at risk of hypercapnia or not); at a score threshold of >5, generated fewer “alarms” requiring clinical callouts compared with the NEWS system, (the percent reduction is not revealed in the paper) but at the same time maintaining comparable positive and negative predicted values. Our previously published data, reported a “callout” rate of 56% for patients deemed to be at risk of hypercapnia when NEWS was used compared with 18% using the Salford-NEWS system.3 Such high “callout” rate would very quickly lead to “alarm fatigue”, as described by the authors, particularly at a time when hospital rotas are extremely pressurised. We note that similar concerns over NEWS and its tendency to trigger an increased volume of alerts in patients with AECOPD were raised by the authors in 2013. 4
Therefore, we would be concerned over the clinical appropriateness of keeping the NEWS score unadjusted for COPD patients, as suggested by Hodgson and colleagues, when the callout rate is as high as 44% with no evidence of improved outcomes in this cohort, particularly on reducing mortality through better and earlier identification of clinical deterioration leading to step-up in care; which can only be tested in a prospectively designed study. That said, the effort made by the investigators to extract evidence on such an important subject using retrospective data has to be applauded.
Furthermore, as it is known that the risk of death in AECOPD may be at least doubled if too much oxygen is given, 5, 6 we would argue strongly that bedside observation systems should help clinicians to identify patients with iatrogenic hyperoxaemia as well as identifying hypoxaemia. In addition to mortality benefit, evidence on COPD admission bundles demonstrates that when oxygen target ranges are assessed and documented correctly within 1 hour of admission, the mean length of stay is significantly reduced (LOS <5 days; OR 1.84(1.38-2.46)).6 Thus, in promoting more accurate assessments of oxygen target ranges, Salford-NEWS can be viewed as a better care-lower cost model of quality improvement.
The NEWS and CREWS systems do not flag hyperoxaemia although there are increasing safety concerns about this, not just in hypercapnic patients but also in a variety of medical conditions including myocardial infarction where Nehme et al. have reported an increase in infarct size of 17-21% associated with the unnecessary use of supplemental oxygen.7 Apart from patients at risk of hypercapnia, the Salford-NEWS system allocates one point for iatrogenic hyperoxaemia (target saturation is 94-98%, but patient is on Oxygen with measured saturation >98%) prompting nursing staff to titrate down un-necessary Oxygen. Bedside charts should not just predict risk of death but should also guide and facilitate best practice including the avoidance of hyperoxaemia, especially in oxygen sensitive patients.
References
1. Hodgson LE, Dimitrov BD, Congleton j et al . A validation of the National Early Warning Score to predict outcomes in patients with COPD exacerbation. Thorax 2016 In press
2. O’Driscoll BR, Bakerly ND, Murphy P et al. Concerns regarding the design of the bedside monitoring chart for use with the NEWS (National Early Warning System). Clinical Medicine 2013: 13:319-320
3. O’Driscoll BR, Grant K, Green D et al. Clinical and scientific letters: The national early warning score gives misleading scores for oxygen saturation in patients at risk of hypercapnia. Clinical Medicine 2014;14:695–696
4. Hodgson L, Bax S, Montefort M et al. The National Early Warning Score (NEWS) and iatrogenic harm – Could the NEWS for COPD patients be improved. Thorax. 2013;68:A37
5. Austin MA, Wills KE, Blizzard L, et al Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010 Oct 18;341:c5462
6. Turner AM, Lim WS, Rodrigo C, et al. A care-bundles approach to improving standard of care in AECOPD admissions: results of a national project. Thorax. 2015 Oct;70(10):992-4.
7. Nehme Z, Stub D, Bernard S, et al. AVOID Investigators. Effect of supplemental oxygen exposure on myocardial injury in ST-elevation myocardial infarction. Heart. 2016 ;102:444-51
We read the article by Hodgson LE, et al with interest. The authors examined the performance of National Early Warning Score (NEWS) for patients with an acute exacerbation of COPD. A limitation to this study was that the electronic scores (ward-based) were used as first NEWS - as the (paper) observations within the emergency department (ED) could not be included. We have reviewed data from our Hospital Trust of patients admitted with exacerbation of COPD (n=111), to determine whether NEWS scores from the ED department (paper records) differed from the first observation recorded on subsequent transfer to the acute medical wards (Electronic Patient Records). Admissions direct to ICU or HDU were excluded. Wilcoxon rank test was used to compare NEWS scores from ED to ward. Results are median (IQR).
NEWS in ED fell from 6 (4-8) to 4 (3-6) on the acute medical ward (P<0.0001) over a mean time interval of 377 (sd 182) mins. The change in NEWS was due to a reduction in scores for respiratory rate and heart rate. Improvement in score for oxygen saturations was offset by scoring for use of oxygen.
Not including the NEWS at presentation could underestimate risk of mortality, and hence contribute to the reduced sensitivity of NEWS that was observed in patients with COPD. Alternatively, utilising the NEWS at presentation to ED may lead to lower specificity in a patient with rapidly improving physiology.
Harmonisation of data collection between ED and the hospital...
We read the article by Hodgson LE, et al with interest. The authors examined the performance of National Early Warning Score (NEWS) for patients with an acute exacerbation of COPD. A limitation to this study was that the electronic scores (ward-based) were used as first NEWS - as the (paper) observations within the emergency department (ED) could not be included. We have reviewed data from our Hospital Trust of patients admitted with exacerbation of COPD (n=111), to determine whether NEWS scores from the ED department (paper records) differed from the first observation recorded on subsequent transfer to the acute medical wards (Electronic Patient Records). Admissions direct to ICU or HDU were excluded. Wilcoxon rank test was used to compare NEWS scores from ED to ward. Results are median (IQR).
NEWS in ED fell from 6 (4-8) to 4 (3-6) on the acute medical ward (P<0.0001) over a mean time interval of 377 (sd 182) mins. The change in NEWS was due to a reduction in scores for respiratory rate and heart rate. Improvement in score for oxygen saturations was offset by scoring for use of oxygen.
Not including the NEWS at presentation could underestimate risk of mortality, and hence contribute to the reduced sensitivity of NEWS that was observed in patients with COPD. Alternatively, utilising the NEWS at presentation to ED may lead to lower specificity in a patient with rapidly improving physiology.
Harmonisation of data collection between ED and the hospital ward is needed so that these questions may be addressed.
The authors of the UK guidelines on asthma have asked for feedback
based on audit.[1] The latest British guidelines for asthma management
suggest that children with moderate exacerbation of asthma presenting to
the accident and emergency unit (annexure 5) must be treated with beta
agonists: 2 to 10 puffs via a spacer and re-assed after 15 minutes. This
recommendation seems to be observed often in the...
The authors of the UK guidelines on asthma have asked for feedback
based on audit.[1] The latest British guidelines for asthma management
suggest that children with moderate exacerbation of asthma presenting to
the accident and emergency unit (annexure 5) must be treated with beta
agonists: 2 to 10 puffs via a spacer and re-assed after 15 minutes. This
recommendation seems to be observed often in the breach. We report our
experience in a UK university hospital with that component of asthma care
in the local guidelines
We did this retrospective audit of all children with exacerbation of
asthma who presented to A&E at the West Middlesex University Hospital,
between 1/11/04 and 9/1/05. Protocol mandated a prior diagnosis of
asthma. 87 children fulfilled the above criteria for inclusion in the
study. 90% of them had moderate exacerbation of asthma according to the
guideline criteria.[1] Among the 78 children with moderate exacerbation,
90% received nebulised salbutamol rather than beta-agonist via a spacer as
first line treatment.
We can only speculate why the protocol to first try a spacer in the
A&E is not followed. All the children studied here had previously been
diagnosed as asthmatic and so most of them would have beta-agonist and
spacer at home and would have tried this before presenting to the A&E.
Thus there may have been subtle or explicit pressure to scale up treatment
rather than give a further trial to a form of therapy that was tried at
home without success. A previous study has shown that lack of ‘outcome
expectancy’ was a major reason for non-adherence to asthma guidelines.[2]
The guidelines on asthma have been revised previously and the
recommendation of the use of pulsus paradoxus, to determine severity of
asthma, has been rescinded for ‘pragmatic reasons’ in the latest version.
The recommendation to use a spacer in the A&E may also need to be
reconsidered if the findings in our hospital are a reflection of more
widespread practice nationwide. We hope to use your correspondence column
and the electronic responses facility to gauge how widespread this problem
with guideline compliance is.
1. British Thoracic Society, Scottish Intercollegiate Guidelines
Network (SIGN). British guideline on the management of asthma. Thorax
2003;58(suppl)i 1-94.
The British guidelines [1] recommended an aminophylline-loading dose of 5mg/kg for acute
severe asthma in children. We are concerned that this is not based on reliable clinical or
pharmacokinetics evidence.
Aminophylline hydrate contains 80% theophylline base; [2] therefore 5mg
aminophylline provides only 4mg theophylline. The volume of distribution (Vd) of
theophylline is 0.44-0.57L/kg [3,4] this l...
The British guidelines [1] recommended an aminophylline-loading dose of 5mg/kg for acute
severe asthma in children. We are concerned that this is not based on reliable clinical or
pharmacokinetics evidence.
Aminophylline hydrate contains 80% theophylline base; [2] therefore 5mg
aminophylline provides only 4mg theophylline. The volume of distribution (Vd) of
theophylline is 0.44-0.57L/kg [3,4] this loading dose results in a sub-therapeutic plasma
concentration (= dose÷Vd = 4mg/kg÷0.5L/kg), around 8mg/L.
To achieve the therapeutic level 10-20mg/L [5] (=55-110micromol/L (SI unit
conversion factor x5.5)), a loading dose of 5-10mg/kg theophylline, or 6-12.5mg/kg
aminophylline salt is required. Due to the narrow therapeutic index, we should aim at
severity-tailored therapy. While the level 16-20 would be appropriate for life-threatening
attacks, the lower level 10-15mg/L may be sufficient in less severe asthma. The
corresponding doses are 10-12.5 and 6-10 mg/kg respectively. Allowing for Vd variability, a
dose of 10 rather than 12.5 mg/kg is safer.
Yung and South produced a strong evidence for aminophylline dose of 10mg/kg,
which produced a high level (80-110micromol/L) in over 50% of cases. The increase in
vomiting was offset by the clinically more important, reduced ventilation. For every 5-6
children who vomited (in excess of control group), one was saved ventilation.[6,7]
The studies that used a smaller bolus reported no therapeutic benefit. A recent study,
published after the guidelines, used aminophylline 5mg/kg bolus and 0.9mg/kg/hr infusion
produced a post-bolus theophylline level of 9.1mg/L, demonstrated no early response –
before 6 hours, but resulted in shorter oxygen therapy and hospital stay.[8] Maxwell-
Rubin et al. demonstrated that 6mg/kg of aminophylline produced levels <_10 mg="mg" l="l" in="in" _72="_72" of="of" cases.="cases." _9="_9" our="our" opinion="opinion" there="there" is="is" insufficient="insufficient" evidence="evidence" to="to" recommend="recommend" aminophyllinebolus="aminophyllinebolus" _5mg="_5mg" kg.="kg." p="p"/>
When an inadequate loading dose (5mg/kg) is followed by an adequate
maintenance dose (0.9-1.5 mg/kg/hour) the blood level will increase gradually from subtherapeutic
to therapeutic range after 4-6 half-lives (24-36 hours), which is a potentially
hazardous approach to managing a life threatening condition.
Since acute severe asthma is potentially life threatening in developed countries
(where inhaled bronchodilators are available) and more so in the developing world (with
limited access to the un-affordable inhaled or intensive care therapy), we would strongly
argue that we should follow the available evidence [6,7] regarding aminophylline efficacy
and dosing. Utilisation of pharmacokinetic principles helps fine-tuning the dosage on the
basis of individual patient “drug dose-concentration” as well as "concentration-clinical
response". An example of age- and severity-related dosage is illustrated in table 1.
Table 1 Theophylline Clearance [10], Volume of Distribution and Dosages:
Volume of
Distribution (L/kg)
0.55
0.5
0.45
Loading dose (mg/kg) (=Volume of
Distribution x desired concentration):
Severe
attack (e.g. Level 13 mg/L)
8.9
8.1
7.3
Life-threatening (e.g. Level 16 mg/L)
11.0
10.0
9.0
Age band
1-5 year
5-9 year
9-16 year
Theophylline
Clearance [10](L/kg/hr)
0.0949
0.0813
0.066
Maintenance dose (mg/kg/hr) (=Clearance x desired
concentration):
Severe
attack (e.g. Level 13 mg/L)
1.5
1.3
1.1
Life-threatening (e.g. Level 16 mg/L)
1.9
1.6
1.3
References
1 British guideline on the management of asthma. Thorax, 2003. 58 Suppl 1: p. i1-94.
2 Mayo, P.R., Effect of passive smoking on theophylline clearance in children. Ther Drug
Monit, 2001. 23(5): p. 503-5.
3 Odajima, Y., [Examination of theophylline pharmacokinetics during an attack of
bronchial asthma in children]. Arerugi, 1992. 41(1): p. 22-8.
4 el Desoky, E., et al., Disposition of intravenous theophylline in asthmatic children:
Bayesian approach vs direct pharmacokinetic calculations. Jpn J Pharmacol, 1997.
75(1): p. 13-20.
5 Simons, F.E., et al., Pharmacokinetics of theophylline in acute asthma. J Med, 1978.
9(1): p. 81-90.
6 Yung, M. and M. South, Randomised controlled trial of aminophylline for severe acute
asthma. Arch Dis Child, 1998. 79(5): p. 405-10.
7 Mitra, A., D. Bassler, and F.M. Ducharme, Intravenous aminophylline for acute severe
asthma in children over 2 years using inhaled bronchodilators. Cochrane Database Syst
Rev, 2001. 4.
8 Roberts, G., et al., Intravenous salbutamol bolus compared with an aminophylline
infusion in children with severe asthma: a randomised controlled trial. Thorax, 2003.
58(4): p. 306-10.
9 Maxwell-Rubin, M., C.M. Paap, and P.J. Godley, Adequacy of recommended
aminophylline loading doses in children. Am J Hosp Pharm, 1994. 51(13): p. 1667-71.
10 Botha, J.H., et al., Determination of theophylline clearance in South African children.
Eur J Clin Pharmacol, 1993. 44(4): p. 369-75.
Dr. Abul-Anine highlights interesting pharmacokinetic data of relevance to the use of intravenous salbutamol and terbutaline to treat acute asthma in childhood.[1] The Brtitish guidelines for the management of asthma recommend a salbutamol loading dose (LD) of 15mcg/kg derived from that used in clinical studies showing good evidence for efficacy and safety.[2,3] There are no trial data for the safety and ef...
Dr. Abul-Anine highlights interesting pharmacokinetic data of relevance to the use of intravenous salbutamol and terbutaline to treat acute asthma in childhood.[1] The Brtitish guidelines for the management of asthma recommend a salbutamol loading dose (LD) of 15mcg/kg derived from that used in clinical studies showing good evidence for efficacy and safety.[2,3] There are no trial data for the safety and efficacy of higher LD doses of salbutamol or terbutaline as suggested. Recommended maintenance doses (MD) of salbutamol are higher than those used to treat adults. There are little trial data about the optimal MD of intravenous (IV) salbutamol or any other parenteral therapeutic intervention for acute asthma in childhood. Such interventions are not appropriate to treat those with moderate or severe acute asthma in the UK. There is extensive evidence for the safety and efficacy of initial treatment with frequent doses of nebulised salbutamol and ipratropium bromide plus corticosteroids for these cases. It is recommended that IV salbutamol be reserved for the small number of children with life threatening symptoms, poorly responsive to nebuliser therapy. This represents a very small number of children in any one unit and it is unlikely that adequate safety studies will ever be done to address Dr Abul-Anine’s concerns about toxic effects as a result of current practice. Recommended MD doses are based on over 20 years clinical experience in HDU and PICU settings used according to good clinical practice including ECG monitoring, correction of hypokalaemia, close observation for the occurrence of side effects and dose titration according to clinical response.
Salbutamol and terbutaline are very similar molecules differing by one methyl group. Stereoselectivity in the pharmacokinetics of racemic mixes of active and inactive isomers is well known and an active R-salbutamol formulation is available for use as a nebuliser solution in North America.[3] There is limited evidence for improved bronchodilation after R-isomer nebulised salbutamol compared with the routinely used racemic mixture of R- and S-salbutamol but the clinical relevance of this is uncertain.[4] Single active isomer beta-2-agonist formulations are not available for IV use. The clinical significance of differences in the pharmacology of racemic mixes of IV salbutamol and terbutaline is unknown.
(2) Browne GJ. Trieu L. Van Asperen P. Randomized, double-blind, placebo-controlled trial of intravenous salbutamol and nebulized ipratropium bromide in early management of severe acute asthma in children presenting to an emergency department. Critical Care Medicine 2002;30(2):448-53.
(3) Browne GJ, Penna AS, Phung X, Soo M. Randomised trial of intravenous salbutamol in early management of acute severe asthma in children. Lancet 1997; 349: 301–5.
(4) Vakily M, Mehvar R, Brocks D, et al. Stereoselective pharmacokinetics and pharmacodynamics of anti-asthma agents. Annals of Pharmacotherapy 2002;36(4):693-701.
(5) Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. Journal of Allergy and Clinical Immunology 1998;102(61)943-952.
The British asthma guidelines recommended salbutamol loading dose (LD) 15mcg/kg
and maintenance dose (MD) 1-2mcg/kg/min (5mcg/kg/min in intensive care) for children’s
acute severe asthma.[1] Terbutaline is similarly used in some paediatric units.
My concerns are:
(A) this MD can be several-fold the adult dose (e.g. 30-150 mcg/min in 30kg-child versus 3-
20mcg/min in adult!);...
The British asthma guidelines recommended salbutamol loading dose (LD) 15mcg/kg
and maintenance dose (MD) 1-2mcg/kg/min (5mcg/kg/min in intensive care) for children’s
acute severe asthma.[1] Terbutaline is similarly used in some paediatric units.
My concerns are:
(A) this MD can be several-fold the adult dose (e.g. 30-150 mcg/min in 30kg-child versus 3-
20mcg/min in adult!); (B) it is not based on reliable clinical evidence or pharmacokinetics; (C) blood level progressively increases to a very high steady state concentration (Css); and (D) there are no safety studies for the higher range of doses! Similarly, the pharmacokinetics of
terbutaline does not rationalize a higher dose/weight in children than in adults. [2]
Salbutamol is a racemic mixture of an active, rapidly metabolised, R-enantiomer and
the inactive S-enantiomer, which might be antagonistic, pro-inflammatory or exacerbate
airway reactivity. [3,4] Prolonged high-dose infusion results in S-enantiomer preferential
accumulation that may enhance competitive antagonism. Unlike salbutamol, the active
terbutaline enantiomer (+T) preferentially accumulates (Table 1). Therefore, there is a strong
case for the use of terbutaline or R-salbutamol (levalbuterol) whenever prolonged high-dose
intravenous therapy is indicated.
Table 1 Pharmacokinetics of Terbutaline and Salbutamol
Pharmacokinetic parameters
Vd - L/kg
Calculated Loading
Dose (=Vd x C)
Target level 30 mcg/L
Clearance -L/kg/h
Calculated Maintenance
Dose (=CL x Css)
Target level 30 mcg/L
Terbutaline [2]
1.55
±0.28
46.5
mcg/kg
0.25
±0.08
7.5
mcg/kg/hr
Salbutamol (derived
from [7])
2.08 ±0.50
62.4
mcg/kg
0.38
±0.10
11.4
mcg/kg/hr
S-salbutamol* [6]
0.39
±0.12
R-salbutamol* [6]
0.62
±0.18
* Average salbutamol clearance= 0.5L/kg/hour.
Salbutamol suggested therapeutic plasma concentration (PC) is up to 14mcg/L
(=60nmol/L), volume of distribution (Vd) is 2L/kg and clearance is 0.5L/kg/hour (table1). [5-7] Therefore, salbutamol LD should be (14x2=) 28mcg/kg and MD is (14x0.5=) 7mcg/kg/hour
or 0.12mcg/kg/minute. The recommended LD (15mcg/kg) produces PC only 7.5mcg/L, while
the MD (1-5mcg/kg/minute) progressively increase PC 16-80 times to an excessively high Css
(~120–600mcg/L) over 5-6 half-lives (20-24 hours) (Figure 1). If the patient showed signs of
improvement within several hours, it would be difficult to maintain a steady state at the
"response level" since concentration will still be on the rise. The concentration would continue to build-up unnecessarily –with probable development of toxicity. Such dose can only be
recommended after adequate safety studies, which should incorporate myocardial short-term
and long-term safety profiles, since at these levels the beta-2- selectivity cannot be presumed.
Figure 1 Log of plasma concentrations in "Stepped Titration Therapy" as compared to
progressively rising levels produced by the current recommendation.
Because of the pharmacokinetic properties and preferential R/S-enantiomer
accumulation, I strongly argue that terbutaline rather than salbutamol should be used for
prolonged infusion by "stepped titration therapy". Possibly by choosing an initial therapeutic
PC based on severity, and administering the corresponding LD and MD (Table 2). Clinical
response is assessed regularly (e.g. hourly) and treatment is escalated as required by topping-up
(each 15mcg/kg increases PC by 10mcg/L) and upgrading the MD.
Table 2 proposed severity-tailored “Terbutaline Stepped Titration Therapy”: LD (as duration of infusion) and MD based on published
pharmacokinetics [2]
Severity of asthma attack
Approximate Desired Therapeutic
level
mcg/L
Approximate
Loading dose
mcg/kg
Approximate
Maintenance dose
mcg/kg/hr
Loading Infusion
Rate = 3.6ml/kg/hr
(25 mcg/ml)
Maintenance
Infusion ml/hr
(2.5 mg/100ml)
Moderate
10
15
2.5
For
10 minutes
0.1
ml/kg/hr
Severe
20
30
4.9
For
20 minutes
0.2
ml/kg/hr
Life-threatening
30
45
7.4
For
30 minutes
0.3
ml/kg/hr
If
safety is proved higher levels could be achieved as follows:
40
60
9.8
For
40 minutes
0.4
ml/kg/hr
50
75
12.3
For
50 minutes
0.5
ml/kg/hr
References
1. British guideline on the management of asthma. Thorax 2003;58 Suppl 1:i1-94.
2. Hultquist C, Lindberg C, Nyberg L, Kjellman B, Wettrell G. Pharmacokinetics of
intravenous terbutaline in asthmatic children. Dev Pharmacol Ther 1989;13(1):11-20.
3. Bremner P, Siebers R, Crane J, Beasley R, Burgess C. Partial vs full beta-receptor agonism.
A clinical study of inhaled albuterol and fenoterol. Chest 1996;109(4):957-62.
4. Handley D. The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists. J
Allergy Clin Immunol 1999;104(2 Pt 2):S69-76.
5. Janson C, Boe J, Boman G, Mossberg B, Svedmyr N. Bronchodilator intake and plasma
levels on admission for severe acute asthma. Eur Respir J 1992;5(1):80-5.
6. Boulton DW, Fawcett JP. Enantioselective disposition of salbutamol in man following oral
and intravenous administration. Br J Clin Pharmacol 1996;41(1):35-40.
7. Morgan DJ, Paull JD, Richmond BH, Wilson-Evered E, Ziccone SP. Pharmacokinetics of
intravenous and oral salbutamol and its sulphate conjugate. Br J Clin Pharmacol
1986;22(5):587-93.
Dear Editors
We thank Dr Zhang and colleagues for their comments on our paper1. We certainly agree that in this emerging field of extracellular vesicle (EV) research, it is vital that identification and characterisation of different EV populations are as robust as possible. To this end, we very much welcome detailed discussions on methodologies used for each study, to enhance and improve the quality of EV-related work within the lung research community.
In our paper, we specifically chose to examine the role of microvesicles (MVs) in acute lung injury (ALI), and the roles of apoptotic bodies and exosomes are beyond the scope of the study. We do not exclude the presence of apoptotic bodies or surfactant micelles in our in vivo samples, or indeed single or clustered MVs larger than 1µm, however our surface marker analysis of MV subpopulations by flow cytometry was deliberately conservative and limited to only events below the conventional size cut off of 1µm. Hence figure 3 of our paper shows effectively only one EV population, i.e. MVs. For our isolation of MVs for functional studies, we used differential centrifugation to enrich MVs but these technical matters were discussed in some detail in the published manuscript.
Dr Zhang and colleagues have concerns about the dose of LPS (20µg) used in our in vivo ALI model. However, intratracheal (i.t.) instillation of high dose LPS (20µg or more per mouse) is a clinically-relevant, well established model of AL...
Show MoreI enjoyed reading Hodgson et al’s validation study on Early Warning Scores (EWS) in patients admitted with an exacerbation of COPD. The current problem with EWS such as the National Early Warning Score (NEWS) in such patients is that the score is used in two contexts.
The first is in the initial triage of patients on arrival to hospital based on their early risk of death. NEWS is well validated in this context, and I wholeheartedly agree that NEWS is the best tool for this at present; patients at risk of type 2 respiratory failure, with target oxygen saturations of 88-92%, are at a high risk of death in hospital and identifying these patients early to enable senior review is entirely appropriate.
The problem comes with second use of NEWS – as a “track and trigger” tool used to monitor patients during their inpatient stay, with a rising score indicating deterioration, risk of death and the need for intervention. Hodgson et al have confirmed our finding that NEWS lacks specificity for patients with COPD. These patients will often have persistently high NEWS even when stable, well into their admission, and the actions this is supposed to trigger (hourly observations, senior review, etc.) are no longer appropriate. This leads to alarm fatigue, with high scores being ignored, increasing the risk of a true deterioration not being acted upon.
The proposals of Hodgson et al that such patients should have individually assigned observation frequencie...
Show MoreDear Editors,
We are writing to comment on the work entitled “Alveolar macrophage-derived microvesicles mediate acute lung injury” published by Dr. Soni et al on Thorax 2016; 71:1020-1029[1].
Our group focuses on lung extracellular vesicle (EV) research and also studied the inhaled LPS-induced EVs in mouse models. Based on our experience, we raise the following comments to the work done by Dr. Soni et al and wish to draw attentions to future EV researchers. EV research is a novel field and carries a promising potential for the development of diagnostic and therapeutic agents. However, given the early stage of EV research, particular in the field of lung injury, the consistency of results relies largely on the precise techniques used in the isolation and characterization of these vesicles.
Briefly, EV is currently classified into three major categories per the definition of Society of extracellular vesicle research [2]. Apoptotic bodies (ABs) are the largest sizes of EVs usually larger than 1 µm and often resulted from cell death. Microvesicles (MVs) are the middle sized EVs (200 nm-1 µm) and are generated via plasma membrane budding. Exosomes (Exos) are the smallest EVs (less than 200 nm) and often generated from IVB-ER-Golgi system. Due to the different mechanisms of generation, MVs and Exos usually favor different compositions and subsequently may carry differential downstream biological functions[3 4]. For example, Exos have been reported to carry t...
Show MoreWe thank Cardwell et al for their thoughtful comments on our paper.[1] The two alternative scoring systems did not demonstrate improved discrimination or calibration in our large dataset of AECOPD admissions. The authors suggest employing the Salford-NEWS only in patients ‘at risk’ of hypercapnic respiratory failure however, this introduces a subjective element that may negate the benefits of an objective physiological scoring system. As we emphasised in what we believe was a balanced discussion, patients with COPD should be managed in the right place by specialists and on-going education is crucial to avoid potential harms associated with misinterpretation of the NEWS alluded to by Cardwell and colleagues. Our article adds evidence that suggested RCP thresholds would indeed lead to unnecessary callouts in such patients. However, as we proposed, rather than abandon a scoring system that provides the significant advantages of standardisation and familiarity, it is possible to individualise patient management. For example, lowering observation frequency in a patient who is clinically ‘stable’, not increasing oxygen delivery if the prescribed target saturation is achieved, or taking into account prior/baseline physiology when deciding observation frequency and whether a senior review is required. Indeed a senior review may be appropriate to interpret whether the patient is at risk of hypercapnic respiratory failure and be able to advise on appropriate targets and level of mon...
Show MoreWe read the paper of Hodgson and colleagues with interest.1 Unfortunately, we note that the Salford-NEWS system (observation chart based on target Oxygen saturation prescription) has been applied in this study to all patients with a diagnosis of acute exacerbation of COPD (AECOPD) whereas we proposed applying this system for all patients at risk of type 2 (hypercapnic) respiratory failure, a group which includes many but not all patients with AECOPD and a number of patients with other conditions.2 Around 86% of those prescribed the lower range of Oxygen saturation (88-92%) in Salford are COPD patients judged to be at risk of hypercapnia, the remainder have conditions such as morbid obesity, neuro-muscular disorders, or complex lung diseases.3 Given this key difference in rationale we suggest that the Salford-NEWS system has been inappropriately applied in this study; hence, the conclusions have to be interpreted with extreme caution.
When comparing NEWS with Salford-NEWS, it is clear that none of the systems had acceptable sensitivity at score thresholds of 5 and 7, and the most consistently reliable result from using either of them is the negative predictive value, which was similar. It was also evident that Salford-NEWS had better specificity at 91% and 95% compared to 57% and 80% for NEWS at score thresholds of 5 and 7 respectively. Since the increased sensitivity in NEWS is achieved at the expense of high “callout” rates, and low positive predictive value (8%...
Show MoreWe read the article by Hodgson LE, et al with interest. The authors examined the performance of National Early Warning Score (NEWS) for patients with an acute exacerbation of COPD. A limitation to this study was that the electronic scores (ward-based) were used as first NEWS - as the (paper) observations within the emergency department (ED) could not be included. We have reviewed data from our Hospital Trust of patients admitted with exacerbation of COPD (n=111), to determine whether NEWS scores from the ED department (paper records) differed from the first observation recorded on subsequent transfer to the acute medical wards (Electronic Patient Records). Admissions direct to ICU or HDU were excluded. Wilcoxon rank test was used to compare NEWS scores from ED to ward. Results are median (IQR).
Show MoreNEWS in ED fell from 6 (4-8) to 4 (3-6) on the acute medical ward (P<0.0001) over a mean time interval of 377 (sd 182) mins. The change in NEWS was due to a reduction in scores for respiratory rate and heart rate. Improvement in score for oxygen saturations was offset by scoring for use of oxygen.
Not including the NEWS at presentation could underestimate risk of mortality, and hence contribute to the reduced sensitivity of NEWS that was observed in patients with COPD. Alternatively, utilising the NEWS at presentation to ED may lead to lower specificity in a patient with rapidly improving physiology.
Harmonisation of data collection between ED and the hospital...
Dear Editor,
The authors of the UK guidelines on asthma have asked for feedback based on audit.[1] The latest British guidelines for asthma management suggest that children with moderate exacerbation of asthma presenting to the accident and emergency unit (annexure 5) must be treated with beta agonists: 2 to 10 puffs via a spacer and re-assed after 15 minutes. This recommendation seems to be observed often in the...
Dear Editor
The British guidelines [1] recommended an aminophylline-loading dose of 5mg/kg for acute severe asthma in children. We are concerned that this is not based on reliable clinical or pharmacokinetics evidence.
Aminophylline hydrate contains 80% theophylline base; [2] therefore 5mg aminophylline provides only 4mg theophylline. The volume of distribution (Vd) of theophylline is 0.44-0.57L/kg [3,4] this l...
Dear Editor
Dr. Abul-Anine highlights interesting pharmacokinetic data of relevance to the use of intravenous salbutamol and terbutaline to treat acute asthma in childhood.[1] The Brtitish guidelines for the management of asthma recommend a salbutamol loading dose (LD) of 15mcg/kg derived from that used in clinical studies showing good evidence for efficacy and safety.[2,3] There are no trial data for the safety and ef...
Dear Editor
The British asthma guidelines recommended salbutamol loading dose (LD) 15mcg/kg and maintenance dose (MD) 1-2mcg/kg/min (5mcg/kg/min in intensive care) for children’s acute severe asthma.[1] Terbutaline is similarly used in some paediatric units.
My concerns are:
(A) this MD can be several-fold the adult dose (e.g. 30-150 mcg/min in 30kg-child versus 3- 20mcg/min in adult!);...
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