Publications by authors named "Annabel H Nickol"

25 Publications

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Successful awake proning is associated with improved clinical outcomes in patients with COVID-19: single-centre high-dependency unit experience.

BMJ Open Respir Res 2020 09;7(1)

Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.
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http://dx.doi.org/10.1136/bmjresp-2020-000678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490910PMC
September 2020

Intravenous iron and chronic obstructive pulmonary disease: a randomised controlled trial.

BMJ Open Respir Res 2020 06;7(1)

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

Background: Increased iron availability modifies cardiorespiratory function in healthy volunteers and improves exercise capacity and quality of life in patients with heart failure or pulmonary hypertension. We hypothesised that intravenous iron would produce improvements in oxygenation, exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD).

Methods: We performed a randomised, placebo-controlled, double-blind trial in 48 participants with COPD (mean±SD: age 69±8 years, haemoglobin 144.8±13.2 g/L, ferritin 97.1±70.0 µg/L, transferrin saturation 31.3%±15.2%; GOLD grades II-IV), each of whom received a single dose of intravenous ferric carboxymaltose (FCM; 15 mg/kg bodyweight) or saline placebo. The primary endpoint was peripheral oxygen saturation (SpO) at rest after 1 week. The secondary endpoints included daily SpO, overnight SpO, exercise SpO, 6 min walk distance, symptom and quality of life scores, serum iron indices, spirometry, echocardiographic measures, and exacerbation frequency.

Results: SpO was unchanged 1 week after FCM administration (difference between groups 0.8%, 95% CI -0.2% to 1.7%). However, in secondary analyses, exercise capacity increased significantly after FCM administration, compared with placebo, with a mean difference in 6 min walk distance of 12.6 m (95% CI 1.6 to 23.5 m). Improvements of ≥40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after 1 week (p=0.009). Modified MRC Dyspnoea Scale score was also significantly lower after FCM, and fewer participants reported scores ≥2 in the FCM group, compared with placebo (33.3% vs 66.7%, p=0.02). No significant differences were observed in other secondary endpoints. Adverse event rates were similar between groups, except for hypophosphataemia, which occurred more frequently after FCM (91.7% vs 8.3%, p<0.001).

Conclusions: FCM did not improve oxygenation over 8 weeks in patients with COPD. However, this treatment was well tolerated and produced improvements in exercise capacity and functional limitation caused by breathlessness. These effects on secondary endpoints require confirmation in future studies.

Trial Registration Number: ISRCTN09143837.
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http://dx.doi.org/10.1136/bmjresp-2020-000577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311010PMC
June 2020

Continuous positive airway pressure versus standard care for the treatment of people with mild obstructive sleep apnoea (MERGE): a multicentre, randomised controlled trial.

Lancet Respir Med 2020 04 2;8(4):349-358. Epub 2019 Dec 2.

National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK.

Background: The evidence base for the treatment of mild obstructive sleep apnoea is limited and definitions of disease severity vary. The MERGE trial investigated the clinical effectiveness of continuous positive airway pressure in patients with mild obstructive sleep apnoea.

Methods: MERGE, a multicentre, parallel, randomised controlled trial enrolled patients (≥18 years to ≤80 years) with mild obstructive sleep apnoea (apnoea-hypopnoea index [AHI] ≥5 to ≤15 events per h using either AASM 2007 or AASM 2012 scoring criteria) from 11 UK sleep centres. Participants were assigned (1:1) to either 3 months of continuous positive airway pressure plus standard care (sleep counselling), or standard care alone, by computer-generated randomisation; neither participants nor researchers were blinded. The primary outcome was a change in the score on the Short Form-36 questionnaire vitality scale in the intention-to-treat population of patients with mild obstructive sleep apnoea diagnosed using the American Academy of Sleep Medicine 2012 scoring criteria. The study is registered with ClinicalTrials.gov, NCT02699463.

Findings: Between Nov 28, 2016 and Feb 12, 2019, 301 patients were recruited and randomised. 233 had mild obstructive sleep apnoea using AASM 2012 criteria and were included in the intention-to-treat analysis: 115 were allocated to receive continuous positive airway pressure and 118 to receive standard care. 209 (90%) of these participants completed the trial. The vitality score significantly increased with a treatment effect of a mean of 10·0 points (95% CI 7·2-12·8; p<0·0001) after 3 months of continuous positive airway pressure, compared with standard care alone (9·2 points [6·8 to 11·6] vs -0·8 points [-3·2 to 1·5]). Using the ANCOVA last-observation-carried-forward analysis, a more conservative estimate, the vitality score also significantly increased with a treatment effect of a mean of 7·5 points (95% CI 5·3 to 9·6; p<0·0001) after 3 months of continuous positive airway pressure, compared with standard care alone (7·5 points [6·0 to 9·0] vs 0·0 points [-1·5 to 1·5]). Three serious adverse events occurred (one allocated to the continuous positive airway pressure group) and all were unrelated to the intervention.

Interpretation: 3 months of treatment with continuous positive airway pressure improved the quality of life in patients with mild obstructive sleep apnoea. These results highlight the need for health-care professionals and providers to consider treatment for patients with mild obstructive sleep apnoea.

Funding: ResMed Ltd.
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http://dx.doi.org/10.1016/S2213-2600(19)30402-3DOI Listing
April 2020

Tracheostomy in motor neurone disease.

Pract Neurol 2019 Dec 4;19(6):467-475. Epub 2019 Jul 4.

Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.

Tracheostomy-associated ventilation for the respiratory insufficiency caused by amyotrophic lateral sclerosis (motor neurone disease (MND)) is a complex issue with practical, ethical and economic dimensions. This article considers the current prevalence of tracheostomy in MND, the evidence for its benefit both for survival and quality of life, and the practicalities of its implementation. The decision to request invasive ventilatory support is among the most challenging for those living with MND. Neurologists should be prepared to discuss this option openly and objectively: we suggest a framework for discussion, including withdrawal of therapy.
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http://dx.doi.org/10.1136/practneurol-2018-002109DOI Listing
December 2019

Adverse respiratory effects of opioids for chronic breathlessness: learning lessons from chronic pain.

Eur Respir J 2018 03 1;51(3). Epub 2018 Mar 1.

Nuffield Dept of Clinical Neurosciences, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1183/13993003.02531-2017DOI Listing
March 2018

A risk stratifying tool to facilitate safe late-stage percutaneous endoscopic gastrostomy in ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2017 05 19;18(3-4):243-248. Epub 2017 Jan 19.

a Nuffield Department of Clinical Neurosciences , University of Oxford , Oxford , UK.

Background: The safety of percutaneous endoscopic gastrostomy (PEG) insertion in amyotrophic lateral sclerosis (ALS) patients with significant respiratory compromise has been questioned.

Objectives: To review the characteristics of an ALS clinic patient cohort undergoing PEG, and the introduction of a risk stratification tool with procedural adaptations for higher-risk individuals.

Methods: Patients undergoing PEG insertion were analysed (n = 107). Cases stratified as higher-risk underwent insertion in a semi-recumbent position, minimising sedation, with the option of nasal non-invasive ventilation.

Results: All underwent successful PEG. One-third had pre-procedure FVC ≤50% (mean, 64 ± 22%). Of those who underwent PEG insertion after introduction of risk stratification (n = 58), 39 (67%) met criteria for being higher risk, 16 (41%) of whom had FVC ≤50% (p = 0.005). High-risk patients received lower sedative doses vs. the low-risk group (midazolam 2.1 ± 1.1 vs.2.8 ± 0.95mg, p = 0.021; fentanyl 42 ± 16 vs. 60 ± 21μg, p = 0.015). Four deaths occurred within one month of insertion (attributable to the natural disease course).

Conclusions: Risk stratification identified a greater number of patients with evidence of respiratory compromise than using the sole criterion of FVC ≤50%. A modified PEG procedure enabled safe insertion despite respiratory compromise, in those who might not have tolerated attempted insertion by alternative means such as radiologically-inserted gastrostomy.
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http://dx.doi.org/10.1080/21678421.2016.1274330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425625PMC
May 2017

Chronic Obstructive Pulmonary Disease: Lobar Analysis with Hyperpolarized Xe MR Imaging.

Radiology 2017 03 12;282(3):857-868. Epub 2016 Oct 12.

From the Department of Radiology (T.N.M., M.C., X.X., F.V.G.) and Oxford Centre for Respiratory Medicine (N.R., A.H.N.), The Churchill Hospital, Oxford University Hospitals NHS Trust, Old Rd, Headington, OX3 7LE, England; Unit of Academic Radiology, Royal Hallamshire Hospital, University of Sheffield, Sheffield, England (N.J.S., J.M.W.); and Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Headington, England (T.D., V.G.).

Purpose To compare lobar ventilation and apparent diffusion coefficient (ADC) values obtained with hyperpolarized xenon 129 (Xe) magnetic resonance (MR) imaging to quantitative computed tomography (CT) metrics on a lobar basis and pulmonary function test (PFT) results on a whole-lung basis in patients with chronic obstructive pulmonary disease (COPD). Materials and Methods The study was approved by the National Research Ethics Service Committee; written informed consent was obtained from all patients. Twenty-two patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) underwent hyperpolarized Xe MR imaging at 1.5 T, quantitative CT, and PFTs. Whole-lung and lobar Xe MR imaging parameters were obtained by using automated segmentation of multisection hyperpolarized Xe MR ventilation images and hyperpolarized Xe MR diffusion-weighted images after coregistration to CT scans. Whole-lung and lobar quantitative CT-derived metrics for emphysema and bronchial wall thickness were calculated. Pearson correlation coefficients were used to evaluate the relationship between imaging measures and PFT results. Results Percentage ventilated volume and average ADC at lobar Xe MR imaging showed correlation with percentage emphysema at lobar quantitative CT (r = -0.32, P < .001 and r = 0.75, P < .0001, respectively). The average ADC at whole-lung Xe MR imaging showed moderate correlation with PFT results (percentage predicted transfer factor of the lung for carbon monoxide [Tlco]: r = -0.61, P < .005) and percentage predicted functional residual capacity (r = 0.47, P < .05). Whole-lung quantitative CT percentage emphysema also showed statistically significant correlation with percentage predicted Tlco (r = -0.65, P < .005). Conclusion Lobar ventilation and ADC values obtained from hyperpolarized Xe MR imaging demonstrated correlation with quantitative CT percentage emphysema on a lobar basis and with PFT results on a whole-lung basis. RSNA, 2016.
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http://dx.doi.org/10.1148/radiol.2016152299DOI Listing
March 2017

Nutritional pathway for people with motor neurone disease.

Br J Community Nurs 2016 Jul;21(7):360-3

Consultant Neurologist, Oxford University Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford.

This paper provides an overview of the nutritional management and care of people living with motor neurone disease (MND) in a specialist nutrition clinic. A specialist pathway of care has been developed to enable people living with MND to undergo a percutaneous endoscopic gastrostomy (PEG) procedure in a safe way; the pathway incorporates attendance at a dedicated nutrition clinic, a stratification tool to identify patients with a high periprocedural risk and a PEG insertion team with significant experience in the MND population. Since this pathway has been in place, gastrostomies have been successfully placed in patients with a forced vital capacity (FVC) of less than 50%; previously, this would not have been possible.
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http://dx.doi.org/10.12968/bjcn.2016.21.7.360DOI Listing
July 2016

Clinical iron deficiency disturbs normal human responses to hypoxia.

J Clin Invest 2016 06 3;126(6):2139-50. Epub 2016 May 3.

Background: Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia.

Methods: We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography.

Results: Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7-9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, -8.3 to -0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups.

Conclusion: Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health.

Trial Registration: ClinicalTrials.gov (NCT01847352).

Funding: M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and a National Institute for Health Research (NIHR) Programme grant (RP-PG-0310-1004). This research was funded by the NIHR Oxford Biomedical Research Centre Programme.
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http://dx.doi.org/10.1172/JCI85715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887172PMC
June 2016

A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease.

BMJ Open 2015 Jul 6;5(7):e007911. Epub 2015 Jul 6.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Objectives: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Iron deficiency, with or without anaemia, is associated with other chronic conditions, such as congestive heart failure, where it predicts a worse outcome. However, the prevalence of iron deficiency in COPD is unknown. This observational study aimed to determine the prevalence of iron deficiency in COPD and associations with differences in clinical phenotype.

Setting: University hospital outpatient clinic.

Participants: 113 adult patients (65% male) with COPD diagnosed according to GOLD criteria (forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) ratio <0·70 and FEV1 <80% predicted); with age-matched and sex-matched control group consisting of 57 healthy individuals.

Main Outcome Measures: Prevalence of iron deficiency, defined as: any one or more of (1) soluble transferrin receptor >28.1 nmol/L; (2) transferrin saturation <16% and (3) ferritin <12 µg/L. Severity of hypoxaemia, including resting peripheral arterial oxygen saturation (SpO2) and nocturnal oximetry; C reactive protein (CRP); FEV1; self-reported exacerbation rate and Shuttle Walk Test performance.

Results: Iron deficiency was more common in patients with COPD (18%) compared with controls (5%). In the COPD cohort, CRP was higher in patients with iron deficiency (median 10.5 vs 4.0 mg/L, p<0.001), who were also more hypoxaemic than their iron-replete counterparts (median resting SpO2 92% vs 95%, p<0.001), but haemoglobin concentration did not differ. Patients with iron deficiency had more self-reported exacerbations and a trend towards worse exercise tolerance.

Conclusions: Non-anaemic iron deficiency is common in COPD and appears to be driven by inflammation. Iron deficiency associates with hypoxaemia, an excess of exacerbations and, possibly, worse exercise tolerance, all markers of poor prognosis. Given that it has been shown to be beneficial in other chronic diseases, intravenous iron therapy should be explored as a novel therapeutic option in COPD.
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http://dx.doi.org/10.1136/bmjopen-2015-007911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499677PMC
July 2015

Pulmonary artery pressure increases during commercial air travel in healthy passengers.

Aviat Space Environ Med 2012 Jul;83(7):673-6

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.

Background: It is not known whether the mild hypoxia experienced by passengers during commercial air travel triggers hypoxic pulmonary vasoconstriction and increases pulmonary artery pressure in flight. Insidious pulmonary hypertensive responses could endanger susceptible passengers who have cardiopulmonary disease or increased hypoxic pulmonary vascular sensitivity. Understanding these effects may improve pre-flight assessment of fitness-to-fly and reduce in-flight morbidity and mortality.

Methods: Eight healthy volunteers were studied during a scheduled commercial airline flight from London, UK, to Denver, CO. The aircraft was a Boeing 777 and the duration of the flight was 9 h. Systolic pulmonary artery pressure (sPAP) was assessed by portable Doppler echocardiography during the flight and over the following week in Denver, where the altitude (5280 ft/1610 m) simulates a commercial airliner environment.

Results: Cruising cabin altitude ranged between 5840 and 7170 ft (1780 to 2185 m), and mean arterial oxygen saturation was 95 +/- 0.6% during the flight. Mean sPAP increased significantly in flight by 6 +/- 1 mmHg to 33 +/- 1 mmHg, an increase of approximately 20%. After landing in Denver, sPAP was still 3 +/- 1 mmHg higher than baseline and remained elevated at 30 +/- 1 mmHg for a further 12 h.

Conclusions: Pulmonary artery pressure increases during commercial air travel in healthy passengers, raising the possibility that hypoxic pulmonary hypertension could develop in susceptible individuals. A hypoxia altitude simulation test with simultaneous echocardiography ('HAST-echo') may be beneficial in assessing fitness to fly in vulnerable patients.
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http://dx.doi.org/10.3357/asem.3235.2012DOI Listing
July 2012

Preparation and medical outcomes of Nepalese staff and porters compared with foreign nationals on the Annapurna trekking circuit.

High Alt Med Biol 2011 ;12(4):349-56

Warwick Medical School, The University of Warwick, Coventry, United Kingdom.

This cross-sectional study investigates preparedness and medical problems in Nepalese staff and porters compared with foreign nationals trekking at altitude in the Nepal Himalaya. 331 Nepalese and 338 foreign nationals in 61 trekking groups were surveyed over 4 weeks on the Annapurna trekking circuit. Foreign nationals reported that 92% of trekking groups received altitude illness information and carried a medical kit. However, fewer than 30% knew the evacuation insurance status of the Nepalese staff and porters on their trek, 39% would not pay for an ill Nepalese national's helicopter evacuation, and 41% reported insufficient resources to carry an individual. Medical problems occurred in 44% of groups. A significantly higher proportion of Nepalese staff and porters were evacuated compared with foreign nationals. No significant differences in Nepalese and foreign national preparation were found between groups with and without medical problems. Medical problems were commonly encountered, yet many groups lacked resources to evacuate someone dangerously ill. Foreign and Nepalese nationals have a duty of care towards each other; recognizing that preparedness relies not only on a first aid kit, but also on knowledge of acclimatization and individuals' insurance is an important part of health and safety for individuals trekking at altitude.
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http://dx.doi.org/10.1089/ham.2011.1023DOI Listing
May 2012

Regulation of hepcidin expression at high altitude.

Blood 2012 Jan 30;119(3):857-60. Epub 2011 Nov 30.

Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores.
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http://dx.doi.org/10.1182/blood-2011-03-341776DOI Listing
January 2012

Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.

High Alt Med Biol 2011 ;12(3):265-9

Department of Physiology, Anatomy & Genetics, University of Oxford, and Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, United Kingdom.

Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers.
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http://dx.doi.org/10.1089/ham.2011.1005DOI Listing
February 2012

Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials.

JAMA 2009 Oct;302(13):1444-50

Department of Physiology, Anatomy, and Genetics, University of Oxford, Sherrington Bldg, Parks Road, Oxford OX1 3PT, England.

Context: Hypoxia is a major cause of pulmonary hypertension in respiratory disease and at high altitude. Recent work has established that the effect of hypoxia on pulmonary arterial pressure may depend on iron status, possibly acting through the transcription factor hypoxia-inducible factor, but the pathophysiological and clinical importance of this interaction is unknown.

Objective: To determine whether increasing or decreasing iron availability modifies altitude-induced hypoxic pulmonary hypertension.

Design, Setting, And Participants: Two randomized, double-blind, placebo-controlled protocols conducted in October-November 2008. In the first protocol, 22 healthy sea-level resident men (aged 19-60 years) were studied over 1 week of hypoxia at Cerro de Pasco, Peru (altitude 4340 m). In the second protocol, 11 high-altitude resident men (aged 30-59 years) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco, Peru.

Intervention: In the first protocol, participants received intravenous infusions of Fe(III)-hydroxide sucrose (200 mg) or placebo on the third day of hypoxia. In the second protocol, patients underwent staged isovolemic venesection of 2 L of blood. Two weeks later, patients received intravenous infusions of Fe(III)-hydroxide sucrose (400 mg) or placebo, which were subsequently crossed over.

Main Outcome Measure: Effect of varying iron availability on pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography.

Results: In the sea-level resident protocol, approximately 40% of the pulmonary hypertensive response to hypoxia was reversed by infusion of iron, which reduced PASP by 6 mm Hg (95% confidence interval [CI], 4-8 mm Hg), from 37 mm Hg (95% CI, 34-40 mm Hg) to 31 mm Hg (95% CI, 29-33 mm Hg; P = .01). In the chronic mountain sickness protocol, progressive iron deficiency induced by venesection was associated with an approximately 25% increase in PASP of 9 mm Hg (95% CI, 4-14 mm Hg), from 37 mm Hg (95% CI, 30-44 mm Hg) to 46 mm Hg (95% CI, 40-52 mm Hg; P = .003). During the subsequent crossover period, no acute effect of iron replacement on PASP was detected.

Conclusion: Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion.

Trial Registration: clinicaltrials.gov Identifier: NCT00952302.
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http://dx.doi.org/10.1001/jama.2009.1404DOI Listing
October 2009

Mechanisms of improvement of respiratory failure in patients with COPD treated with NIV.

Int J Chron Obstruct Pulmon Dis 2008 ;3(3):453-62

Respiratory Muscle Laboratory, Royal Brompton Hospital, London, UK.

Background: Noninvasive ventilation (NIV) improves gas-exchange and symptoms in selected chronic obstructive pulmonary disease (COPD) patients with hypercapnic respiratory failure. We hypothesized NIV reverses respiratory failure by one or all of increased ventilatory response to carbon-dioxide, reduced respiratory muscle fatigue, or improved pulmonary mechanics.

Methods: Nineteen stable COPD patients (forced expiratory volume in one second 35% predicted) were studied at baseline (DO), 5-8 days (D5) and 3 months (3M) after starting NIV.

Results: Ventilator use was 6.2 (3.7) hours per night at D5 and 3.4 (1.6) at 3M (p = 0.12). Mean (SD) daytime arterial carbon-dioxide tension (PaCO2) was reduced from 7.4 (1.2) kPa to 7.0 (1.1) kPa at D5 and 6.5 (1.1) kPa at 3M (p = 0.001). Total lung capacity decreased from 107 (28) % predicted to 103 (28) at D5 and 103 (27) % predicted at 3M (p = 0.035). At D5 there was an increase in the hypercapnic ventilatory response and some volitional measures of inspiratory and expiratory muscle strength, but not isolated diaphragmatic strength whether assessed by volitional or nonvolitional methods.

Conclusion: These findings suggest decreased gas trapping and increased ventilatory sensitivity to CO2 are the principal mechanism underlying improvements in gas-exchange in patients with COPD following NIV. Changes in some volitional but not nonvolitional muscle strength measures may reflect improved patient effort.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629992PMC
http://dx.doi.org/10.2147/copd.s2705DOI Listing
January 2009

A quick and easy method of measuring the hypercapnic ventilatory response in patients with COPD.

Respir Med 2009 Feb 7;103(2):258-67. Epub 2008 Oct 7.

Clinical and Academic Unit of Sleep and Breathing, National Heart and Lung Institute, Royal Brompton Hospital, Fulham Road, London SW3 6NP, UK.

Background: Hypercapnic ventilatory response (HCVR) techniques have not previously been adequately validated in patients with chronic obstructive pulmonary disease (COPD). We have tested the hypothesis that end-tidal PCO(2) may be used to test the HCVR in COPD during non-steady-state rebreathing, despite the fact that large (arterial-end-tidal) PCO(2) differences (P(a-et)CO(2)) exist during air breathing.

Methods: Eight patients and 11 healthy volunteers underwent steady-state HCVR testing and non-steady-state rebreathing HCVR testing, using Pa and PetCO(2).

Results: In COPD patients, PetCO(2) was lower than PaCO(2) by a constant amount throughout steady-state HCVR, but equalised with PaCO(2) during non-steady-state HCVR. Consequently there were no differences in HCVR slope using either method (steady-state p=0.91; rebreathing p=0.73), or HCVR intercept in rebreathing (p=0.68) whether PaCO(2) or PetCO(2) was used. The steady-state HCVR intercept using PetCO(2) was greater than that using PaCO(2) (p=0.02). In healthy volunteers PetCO(2) equalised with PaCO(2) during steady-state HCVR, but was progressively greater than PaCO(2) during non-steady-state. Consequently, there was no difference in HCVR slope (p=0.21) or intercept (p=0.46) whether PaCO(2) or PetCO(2) was used. During non-steady-state there was a P(a-et)CO(2) difference in slope (p=0.03) and intercept (p=0.04).

Conclusions: In COPD patients non-steady-state HCVR using PetCO(2) is well tolerated, which is as accurate as PaCO(2). HCVR slope may be derived using PetCO(2) during steady-state testing, though there may be errors in intercept compared to use of PaCO(2). In healthy volunteers PetCO(2) may be used to estimate PaCO(2) during steady-state but not rebreathing HCVR.
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http://dx.doi.org/10.1016/j.rmed.2008.08.013DOI Listing
February 2009

Randomised trial of inpatient versus outpatient initiation of home mechanical ventilation in patients with nocturnal hypoventilation.

Respir Med 2008 Nov 7;102(11):1528-35. Epub 2008 Sep 7.

Sleep and Ventilation Unit, Academic and Clinical Department of Sleep and Breathing, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.

Background: Long-term home mechanical ventilation (HMV) is usually initiated in hospital. Admission to hospital has resource implications and may not be reimbursable in some healthcare systems.

Methods: Twenty-eight stable neuromuscular and chest wall disease patients with nocturnal hypoventilation (transcutaneous carbon dioxide (TcCO(2) >6.5 kPa), were randomised to start HMV either as an outpatient (n=14, age range 12-62 years) or inpatient (n=14, age range 14-73 years). We compared effects of HMV on nocturnal and diurnal arterial blood gas tensions, ventilator compliance, healthcare professional (HCP) contact time, and time in hospital.

Results: Improvements in nocturnal arterial oxygen saturation (SaO(2)) and daytime PaO(2) were equivalent in both groups. Peak nocturnal TcCO(2), improved in both groups; % time TcCO(2) >6.5 kPa fell in the inpatient group and daytime PaCO(2) decreased significantly (p<0.05) in the outpatient group. The mean (SD) inpatient stay was 3.8 (1.0) days, and the outpatient attendance sessions 1.2 (0.4). HCP contact time including telephone calls was: inpatient 177 (99) min; outpatient 188 (60) min (p=not significant); 2 month ventilator compliance was: inpatient 4.32 (7); outpatient 3.92 (8) (p=not significant) hours per night.

Conclusion: Outpatient initiation of HMV is feasible with equivalent outcome in the outpatient and the inpatient groups.
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http://dx.doi.org/10.1016/j.rmed.2008.07.019DOI Listing
November 2008

Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study.

J Sleep Res 2006 Dec;15(4):445-54

Oxford Centre for Respiratory Medicine, Churchill Hospital, Headington, Oxford, UK.

The aim of the study was to examine the efficacy and safety of temazepam on nocturnal oxygenation and next-day performance at altitude. A double-blind, randomized, cross-over trial was performed in Thirty-three healthy volunteers. Volunteers took 10 mg of temazepam and placebo in random order on two successive nights soon after arrival at 5000 m, following a 17-day trek from 410 m. Overnight SaO(2) and body movements, and next-day reaction time, maintenance of wakefulness and cognition were assessed. Compared with placebo, temazepam resulted in a reduction in periodic breathing from a median (range) of 16 (0-81.3)% of the night to 9.4 (0-79.6)% (P = 0.016, Wilcoxon's signed-rank test), associated with a small but significant decrease in mean nocturnal SaO(2) from 78 (65-84)% to 76 (64-83)% (P = 0.013). There was no change in sleep latency (P = 0.40) or restlessness (P = 0.30). Temazepam had no adverse effect on next-day reaction time [241 (201-380) ms postplacebo and 242 (204-386) ms post-temazepam], maintenance of wakefulness (seven trekkers failed to maintain 40 min of wakefulness postplacebo, and four post-temazepam), cognition or acute mountain sickness. At high altitude temazepam reduces periodic breathing during sleep without an adverse effect on next-day reaction time, maintenance of wakefulness or cognition. The 2% reduction in mean SaO(2) post-temazepam is likely to be predominantly because of acclimatization, as by chance more trekkers took temazepam on the first night (19 versus 14). We conclude that at high altitude temazepam is effective in reducing periodic breathing, and is safe to use, without any adverse effect upon next-day performance.
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http://dx.doi.org/10.1111/j.1365-2869.2006.00558.xDOI Listing
December 2006

+9/+9 Homozygosity of the bradykinin receptor gene polymorphism is associated with reduced fat-free mass in chronic obstructive pulmonary disease.

Am J Clin Nutr 2006 Apr;83(4):912-7

Respiratory Muscle Laboratory, Royal Brompton Hospital, Fulham Road, London SW3 6NP, United Kingdom.

Background: The etiology of muscle wasting in chronic obstructive pulmonary disease (COPD) is incompletely understood. We previously showed that the D rather than the I polymorphic variant of the angiotensin-converting enzyme (ACE) gene is associated with preserved quadriceps strength in COPD. If the ACE D allele influences skeletal muscle through increased ACE-related kinin degradation [and reduced activity at the bradykinin type 2 receptor (BK(2)R)], we might expect a similar association with the +9 BK(2)R genotype in this population as well.

Objective: The objective was to test the hypothesis that the BK(2)R gene polymorphism is a determinant of fat-free mass and quadriceps strength in patients with COPD.

Design: In a cross-sectional design we determined BK(2)R genotype, fat-free mass, and quadriceps strength in 110 COPD patients with a mean (+/-SD) predicted forced expiratory volume in 1 s of 34.3 +/- 16.4% and in 104 healthy age-matched control subjects.

Results: The mean (+/-SD) fat-free mass index (in kg/m(2)) was significantly lower in 37 patients homozygous for the +9 allele than in carriers of the -9 allele (15.7 +/- 1.8 compared with 16.7 +/- 2.3; P = 0.038); the same pattern was true for quadriceps maximal voluntary force (30.8 +/- 10.4 and 36.4 +/- 12.8 kg; P = 0.02), respectively. No significant effect of BK(2)R genotype on inspiratory muscle strength or on any variable in control subjects was observed. There was no interaction between the effect of the BK(2)R and ACE genotypes on quadriceps strength.

Conclusions: The genotype associated with reduced BK(2)R expression is associated with reduced fat-free mass and quadriceps strength in COPD. However, alterations in the activity at the BK(2)R do not seem to account for the previously identified association of quadriceps strength with ACE genotype.
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http://dx.doi.org/10.1093/ajcn/83.4.912DOI Listing
April 2006

Motor control of the costal and crural diaphragm--insights from transcranial magnetic stimulation in man.

Respir Physiol Neurobiol 2005 Mar;146(1):5-19

Respiratory Muscle Laboratory, Royal Brompton and Harefield NHS Trust, Fulham Road, London, SW3 6NP, UK.

The costal and crural parts of the diaphragm differ in their embryological development and physiological function. It is not known if this is reflected in differences in their motor cortical representation. We compared the response of the costal and crural diaphragms using varying intensities of transcranial magnetic stimulation of the motor cortex at rest and during submaximal and maximal inspiratory efforts. The costal and crural motor evoked potential recruitment curves during submaximal inspiratory efforts were similar. The response to stimulation before, during and at 10 and 30 min after 44 consecutive maximal inspiratory efforts was also the same. Using paired stimulations to investigate intra-cortical facilitatory and inhibitory circuits we found no difference between the costal and crural response with varying interstimulus intervals, or when conditioning and test stimulus intensity were varied. We conclude that supraspinal control of the costal and crural diaphragm is identical during inspiratory tasks.
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http://dx.doi.org/10.1016/j.resp.2004.10.010DOI Listing
March 2005

Corticospinal control of respiratory muscles in chronic obstructive pulmonary disease.

Respir Physiol Neurobiol 2004 Jul;141(1):1-12

Respiratory Muscle Laboratory, Royal Brompton Hospital, London SW3 6NP, UK.

Patients with chronic obstructive pulmonary disease (COPD) face an increased respiratory load and in consequence have an elevated respiratory drive. We used transcranial magnetic stimulation (TMS) to investigate associated changes in corticospinal excitability both at rest and during voluntary facilitation at different levels of inspiratory effort. Diaphragm and abdominal motor thresholds were significantly lower in COPD than healthy controls, but the quadriceps response was the same. In patients there was a significant increase in diaphragm response from rest during 20% inspiratory efforts but no further increase with greater efforts. In controls there was a further stepwise increase at 40% and 60% of inspiratory effort. The cortical silent period was significantly shorter in COPD. Using paired stimulation to study intracortical inhibitory and excitatory circuits we found significantly less excitability of intracortical facilitatory circuits in patients at long (>7 ms) interstimulus intervals. These results suggest that there is a ceiling effect in motor control output to the respiratory muscles of patients with COPD.
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http://dx.doi.org/10.1016/j.resp.2004.04.003DOI Listing
July 2004

Angiotensin converting enzyme genotype and strength in chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2004 Aug 29;170(4):395-9. Epub 2004 Apr 29.

Respiratory Muscle Laboratory, Royal Brompton Hospital, Fulham Road, London, SW3 6NP, United Kingdom.

Quadriceps muscle weakness is an important contributor to exercise limitation in patients with chronic obstructive pulmonary disease. The deletion allele of the angiotensin converting enzyme gene polymorphism has previously been associated with a greater response to strength training in healthy subjects and might, therefore, protect against detraining in these patients. In 103 stable outpatients (mean [SD] FEV(1) 34.4 [16.5] % predicted), the angiotensin deletion allele was associated with greater isometric quadriceps strength; mean (SD) 31.4 (10.8) kg for insertion homozygotes, 34.1 (13.0) kg for heterozygotes, and 38.3 (11.6) kg for deletion homozygotes (p = 0.04 linear trend). Adjusted for fat-free mass, the relationship was stronger (linear trend p = 0.007). There was no correlation between strength and genotype in a group of 101 age-matched healthy control subjects. Twitch quadriceps force in response to magnetic femoral nerve stimulation, measured in 39 patients, was also genotype dependent; 8.3 (2.6) kg for insertion homozygotes, 10.1 (3.6) kg for heterozygotes, and 12.4 (3.5) kg for deletion homozygotes (p = 0.002 linear trend). Body mass index and fat-free mass did not differ significantly between genotypes in either group. There was no association in either patients or control subjects between genotype and inspiratory muscle strength. In chronic obstructive pulmonary disease the deletion allele is associated with greater quadriceps strength independent of confounding factors.
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http://dx.doi.org/10.1164/rccm.200304-578OCDOI Listing
August 2004

Depression of diaphragm motor cortex excitability during mechanical ventilation.

J Appl Physiol (1985) 2004 Jul 12;97(1):3-10. Epub 2004 Mar 12.

Respiratory Muscle Laboratory, Royal Brompton Hospital, Sydney St, London SW3 6NP UK.

The effect of mechanical ventilation on the diaphragm motor cortex remains unknown. We assessed the effect of mechanical ventilation on diaphragm motor cortex excitability by measuring the costal and crural diaphragm motor-evoked potential (MEP) elicited by single and paired transcranial magnetic stimulation. In six healthy subjects, MEP recruitment curves of the costal and crural diaphragms were assessed at relaxed end expiration during spontaneous breathing [baseline tidal volume (Vt(baseline))] and isocapnic volume cycled ventilation delivered noninvasively (NIV) at three different levels of tidal volume (Vt(baseline), Vt(baseline) + 5 ml/kg liters, and Vt(baseline) + 10 ml/kg liters). The costal and crural diaphragm response to peripheral stimulation of the right phrenic nerve was not reduced by NIV. NIV reduced the costal and crural MEP amplitude during NIV (P < 0.0001) with the maximal reduction at Vt(baseline) + 5 ml/kg. Response to paired TMS showed that NIV (Vt(baseline) + 5 ml/kg) significantly increased the sensitivity of the cortical motoneurons to facilitatory (>9 ms) interstimulus intervals (P = 0.002), suggesting that the diaphragm MEP amplitude depression during NIV is related to neuromechanical inhibition at the level of motor cortex. Our results demonstrate that mechanical ventilation directly inhibits central projections to the diaphragm.
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http://dx.doi.org/10.1152/japplphysiol.01099.2003DOI Listing
July 2004

Effect of severe isolated unilateral and bilateral diaphragm weakness on exercise performance.

Am J Respir Crit Care Med 2002 May;165(9):1265-70

Respiratory Muscle Laboratory and Lung Function Unit, Royal Brompton Hospital, London, United Kingdom.

Patients with isolated diaphragm paralysis depend on recruitment of extradiaphragmatic respiratory muscles to increase ventilation, but little is known about exercise performance or the response of the inspiratory muscles to loaded breathing. By convention, unilateral diaphragm paralysis is regarded as a trivial condition whereas bilateral paralysis is considered to be potentially life-threatening. In fact, no data exist concerning exercise performance under these conditions. We studied incremental treadmill exercise performed by eight patients with bilateral diaphragm paralysis, eight patients with unilateral diaphragm paralysis, and eight age-matched control subjects. Respiratory muscle endurance (RME) was also measured by an inspiratory threshold loading method. Exercise time, compared with control subjects (671 seconds), was moderately reduced in unilateral diaphragm paralysis (512 seconds, p = 0.07) and further reduced in bilateral diaphragm paralysis (456 seconds, p = 0.02). Similarly, peak minute ventilation was lower in patients with unilateral diaphragm paralysis (84 L x min(-1), p = 0.01) and in patients with bilateral diaphragm paralysis (69 L x min(-1), p = 0.001) compared with control subjects (114 L x min(-1)). However, patients with unilateral diaphragm paralysis and patients with bilateral diaphragm paralysis had increased ratios of peak oxygen consumption to peak minute ventilation compared with control subjects (p = 0.0007 and p < 0.0001, respectively). Nine patients had normal RME; exercise time was moderately increased in these patients (502 seconds) compared with seven patients with reduced RME (461 seconds). In conclusion, although exercise performance is impaired in bilateral diaphragm paralysis, these patients can sustain a reasonable exercise load, particularly if RME is preserved and compensatory mechanisms have developed. In addition, exercise tolerance is diminished in patients with unilateral diaphragm paralysis.
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http://dx.doi.org/10.1164/rccm.2110016DOI Listing
May 2002