Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations.

BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) generate a right-to-left shunt. Impaired gas exchange results in hypoxaemia and impaired CO2 clearance. Most patients compensate effectively but some are dyspneic, and these are rarely the most hypoxaemic. AIM: To test degrees of concurrent pathology influencing exercise capacity. DESIGN: Replicate, sequential single centre, prospective studies. METHODS: Cardiopulmonary exercise tests (CPETs) were performed in 26 patients with PAVMs, including individuals with and without known airflow obstruction. To replicate, relationships were tested prospectively in an independent cohort where self-reported exercise capacity evaluated by the Veterans Specific Activity Questionnaire (VSAQ) was used to calculate metabolic equivalents (METs) at peak exercise (n = 71). Additional measurements included oxygen saturation (SpO2), forced expiratory volume in 1 s (FEV1), vital capacity (VC), fractional exhaled nitric oxide (FeNO), haemoglobin and iron indices. RESULTS: By CPET, the peak work rate was only minimally associated with low SpO2 or low arterial oxygen content (calculated as CaO2=1.34 × SpO2 × haemoglobin), but was reduced in patients with low FEV1 or VC. Supranormal work rates were seen in patients with severe right-to-left shunting and SpO2 < 90%, but only if FEV1 was >80% predicted. VSAQ-calculated METS also demonstrated little relationship with SpO2, and in crude and CaO2-adjusted regression, were lower in patients with lower FEV1 or VC. Bronchodilation increased airflow even where spirometry was in the normal range: exhaled nitric oxide measurements were normal in 80% of cases, and unrelated to any PAVM-specific variable. CONCLUSIONS: Exercise capacity is reduced by relatively mild airflow limitation (obstructive or restrictive) in the setting of PAVMs.

Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema.

We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC(norm)). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMC(hyp)). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMC(norm) (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMC(hyp) (as assessed by (3)H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating-cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension.

Prognostic factors in pulmonary arterial hypertension: assessing the course of the disease.

The practical management of pulmonary arterial hypertension (PAH) requires an accurate assessment of disease severity and prognosis. A number of prognostic indicators are known to be associated with patient outcome, and recent treatment guidelines advocate using such parameters to guide management decisions. Although PAH is characterised by the presence of pulmonary vasculopathy, it is the response of the right ventricle to an increased afterload that is the greatest determinant of a patient's symptoms and survival; thus, measurements that capture right ventricular function provide the best potential to assess PAH severity. One challenge is to understand how the tests we use in everyday clinical practice relate to right heart function in PAH patients, and how current measures can be improved and developed to optimise assessment of disease status and progress. Future research in the field of PAH should focus on how best to assess right heart function, and which measures or combination of measures provide the most relevant information for the individual patient.

Emergency oxygen use in adult patients: concise guidance.

There is considerable controversy concerning the benefits and risks of oxygen treatment in many situations and healthcare professionals receive conflicting advice about safe oxygen use. The British Thoracic Society (BTS) has published up-to-date, evidence-based guidelines for emergency oxygen use in the UK in order to encourage the safe use of oxygen in emergency situations and improve consistency of clinical practice. The purpose of this concise guideline is to summarise the key recommendations, particularly concerning emergency oxygen use in the hospital setting.

British Thoracic Society emergency oxygen audits.

The British Thoracic Society (BTS) guideline for emergency oxygen use in adult patients was commissioned by the BTS and developed in conjunction with 21 other colleges and societies prior to publication in 2008. One of the specific aims of the Guideline Development Group was to audit the use of oxygen in UK hospitals before the guideline was published and at intervals afterwards.

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points. Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg⁻¹·day⁻¹, 1.25 mg·kg⁻¹ and 2.5 mg·kg⁻¹·48 h⁻¹) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro. Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil.

Pulmonary veno-occlusive disease (PVOD) is a disorder which causes progressive pulmonary hypertension, usually presenting with worsening dyspnoea and right heart failure. Pulmonary oedema induced by pulmonary vasodilator therapy to reduce pulmonary arterial pressure has been well described in PVOD, but here we describe a case of PVOD presenting with recurrent episodes of acute non-cardiogenic pulmonary oedema, in the absence of significant pulmonary hypertension. Concern over the risk of precipitating pulmonary oedema led us to use inhaled nitric oxide to predict the safety and efficacy of sildenafil.

Use of vasopressin after Caesarean section in idiopathic pulmonary arterial hypertension.

We report the successful use of vasopressin in the management of hypotension in association with severe right ventricular (RV) failure in two patients with advanced idiopathic pulmonary arterial hypertension. Both patients were pregnant and developed systemic hypotension after delivery by Caesarean section. Placental autotransfusion and possibly oxytocin use were thought to be the major contributing factors in worsening RV function. After the use of vasopressin in both patients, cardiovascular variables improved without untoward effect on RV function, and provided rescue therapy for systemic hypotension in this setting. Vasopressin, a direct vasopressor acting via V1 receptors on the vascular endothelium, has been shown to cause pulmonary vasodilatation experimentally and in animal models of pulmonary hypertension. Its synthetic analogue, terlipressin, has been shown to reduce pulmonary vascular resistance in humans with cirrhosis. Vasopressin may therefore have differential effects on the pulmonary and systemic circulations, allowing systemic pressure to be supported without detrimental effects on the pulmonary circulation.

Initial oxygen management in patients with an exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: The Norfolk and Norwich University Hospital (NNUH) is situated in rural Norfolk, and ambulance journey times are often >30 min. Longer ambulance journeys could lead to a greater risk of hypercapnia, if inappropriately high concentrations of oxygen are given during an exacerbation of COPD. AIM: To investigate the effect of high concentration oxygen (HCO, FiO(2) > 0.28) on COPD patients, and the outcome of instituting a simple protocol to reduce such exposure. DESIGN: Retrospective audit. METHOD: An audit was conducted of all patients admitted with an exacerbation of COPD to the NNUH during the 2 months from 1 December 2001 to 31 January 2002 (n = 108). Results were shared with paramedics, and guidelines agreed for the initial provision of lower concentrations of oxygen (LCO, FiO(2) < or = 0.28). A second audit was conducted a year later between 1 December 2002 and 31 January 2003 (n = 103). RESULTS: HCO caused significant (p < 0.01) acidosis and inappropriately high PaO(2) and PaCO(2), compared to initial LCO therapy. There was a significantly increased complication rate during admission (p < 0.01) in those COPD patients receiving HCO compared to LCO, particularly when ambulance journeys exceeded 30 min. The second audit demonstrated a significant (p < 0.001) reduction in the number of patients initially receiving HCO, but the complication rate was unaltered. DISCUSSION: A simple intervention, such as providing paramedics with 28% Venturi masks, can reduce the number of COPD patients exposed to HCO. A randomized controlled trial is long overdue to establish whether HCO or LCO as initial management is associated with the most favourable prognosis in different hospital settings.

Microbiological profile of community-acquired pneumonia in adults over the last 20 years.

OBJECTIVES: To assess any change in the microbiological profile of community-acquired pneumonia (CAP) in our region over the last 20 years. METHODS: We compared hospital admissions aged between 15 and 74 (n = 61) in Norfolk (UK) for CAP over a 19-month period in 1982-3 (ST1) with all admissions aged over 16 (n = 99) over a 14-month period in 1999-2000 (ST2). Data were collected for ST1 as part of a prospective multicentred research study, in a period of high Mycoplasma pneumoniae activity. ST2 was a prospective study of clinical practice. Chlamydophila species were differentiated in ST2 using whole-cell immunofluorescence. RESULTS: A microbiological diagnosis was made in 38 (62%) in ST1 compared with 48 (48%) in ST2. Streptococcus pneumoniae remained the most common pathogen (26% in ST1, 25% in ST2). The incidence of M. pneumoniae was 18% in ST1 and 4% in ST2. The proportion of viral pathogens identified was similar: nine (15%) in ST1 and 14 (14%) in ST2. No cases of Chlamydophila pneumoniae were diagnosed in ST2. CONCLUSIONS: The microbiological profile of CAP in Norfolk (UK) has not changed over the last 20 years and C. pneumoniae is not a frequent pathogen.

Changes in respiratory control during and after 48 h of isocapnic and poikilocapnic hypoxia in humans.

Ventilatory acclimatization to hypoxia is associated with an increase in ventilation under conditions of acute hyperoxia (VEhyperoxia) and an increase in acute hypoxic ventilatory response (AHVR). This study compares 48-h exposures to isocapnic hypoxia (protocol I) with 48-h exposures to poikilocapnic hypoxia (protocol P) in 10 subjects to assess the importance of hypocapnic alkalosis in generating the changes observed in ventilatory acclimatization to hypoxia. During both hypoxic exposures, end-tidal PO2 was maintained at 60 Torr, with end-tidal PCO2 held at the subject's prehypoxic level (protocol I) or uncontrolled (protocol P). VEhyperoxia and AHVR were assessed regularly throughout the exposures. VEhyperoxia (P < 0.001, ANOVA) and AHVR (P < 0.001) increased during the hypoxic exposures, with no significant differences between protocols I and P. The increase in VEhyperoxia was associated with an increase in slope of the ventilation-end-tidal PCO2 response (P < 0.001) with no significant change in intercept. These results suggest that changes in respiratory control early in ventilatory acclimatization to hypoxia result from the effects of hypoxia per se and not the alkalosis normally accompanying hypoxia.

A protocol for determining the shape of the ventilatory response to hypoxia in humans.

The ventilatory response to isocapnic hypoxia is biphasic, which makes any experimental assessment of the relationship between the acute (peak) ventilatory response and the level of hypoxia difficult. This study explored whether one particular protocol could be useful for determining this relationship. The protocol consisted of exposing subjects to seven different levels of isocapnic hypoxia, each of which lasted 50 sec. In order to test whether the order of the hypoxic exposure had any effect on the outcome, the steps were performed both in increasing and decreasing severity of hypoxia, and the ventilatory responses compared. Twelve subjects were studied, and each test was repeated four times in each subject. PETCO2 was held at 2 mmHg above resting throughout. The ventilations obtained at the lowest level of PETO2 employed were clearly different between the two protocols. However, provided that these ventilations were excluded, no significant differences were present between the results from the ascending and descending exposures (ANOVA). This finding suggests that the rate of change of PO2 in these protocols was sufficiently slow for a full ventilatory response to develop, but also sufficiently fast to prevent significant ventilatory depression from occurring.

Ventilatory response to 8 h of isocapnic and poikilocapnic hypoxia in humans.

Almost all studies of the effects of prolonged hypoxia on ventilation (VE) in humans have been performed with the end-tidal PCO2 (PETCO2) left uncontrolled. The purpose of this study was to compare the effects of 8 h of hypoxia with PETCO2 held constant with 8 h of hypoxia with PETCO2 left uncontrolled. Ten subjects completed the study. Each was seated inside a chamber in which the inspired gas could be controlled so as to maintain the desired partial pressures of end-tidal gases (sampled via nasal catheter) constant (see L.S.G.E. Howard et al. J. Appl. Physiol. 78:1088-1091, 1995.). Three 8-h protocols were employed: 1) isocapnic hypoxia, at an end-tidal PO2 of 55 Torr with PETCO2 held at the subject's resting value; 2) poikilocapnic hypoxia, at the same end-tidal PO2; and 3) control, where the inspired gas was air. VE was measured (over 3 min) at 0 and 20 min and at hourly intervals between 1.5 and 7.5 h. There was a rise in VE during isocapnic hypoxia [from an initial VE of 16.2 +/- 1.3 (SE) l/min to a final VE of 24.8 +/- 1.6 l/min], which was significant compared with poikilocapnic hypoxia and control values (P < 0.001, analysis of variance). There was no significant progressive rise in VE during poikilocapnic hypoxia compared with control values. These results show that isocapnic hypoxia produces a progressive increase in VE when sustained over an 8-h period. The onset of this response is faster than has been noted in studies of the progressive rise in VE associated with the poikilocapnic hypoxia of altitude.