Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU trial: protocol and statistical analysis plan.

BACKGROUND: Although supplemental oxygen can be lifesaving, liberal oxygen administration causing hyperoxaemia may be harmful. The targets for oxygenation in patients with acute hypoxaemic respiratory failure acutely admitted to the intensive care unit (ICU) are strongly debated, and consensus on which targets to recommend has not been reached. The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2  = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure. In this study, we aim to evaluate the effects of these targets on long-term cognitive and pulmonary function in Danish patients, enrolled in the HOT-ICU trial and surviving to 1-year follow-up. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: All patients enrolled in the HOT-ICU trial at Danish sites and surviving to 1 year after randomisation are eligible to participate. The last patient is expected to be included by November 2021. A Repeatable Battery for the Assessment of Neuropsychological Status and a body plethysmography, including diffusion capacity for carbon monoxide, both pre-planned secondary long-term outcomes of the HOT-ICU trial, will be obtained. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on cognitive and pulmonary function in adult ICU patients with acute hypoxaemic respiratory failure.

Bone turnover biomarkers in COPD patients randomized to either a regular or shortened course of corticosteroids: a substudy of the randomized controlled CORTICO-COP trial.

BACKGROUND: Long-term treatment with corticosteroids causes loss of bone density, but the effects of using short-term high-dose systemic-corticosteroid therapy to treat acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are unclear. Our aim was to determine whether high-dose corticosteroid therapy affected bone turnover markers (BTMs) to a greater extent compared to low-dose corticosteroid therapy. METHODS: The CORTICO-COP trial (NCT02857842) showed that an eosinophil-guided corticosteroid intervention led to approximately 60% lower accumulated corticosteroid dose for hospitalized patients with AECOPD (low-dose group) compared with 5-day standard corticosteroid treatment (high-dose group). We compared the levels of BTMs C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 participants during AECOPD and at 1- and 3-month follow-up visits. RESULTS: CTX decreased and P1NP increased significantly over time in both treatment groups. There were no significant differences between the groups at 1- or 3-months follow-up for P1NP. A significant drop in CTX was seen at 3 months (down Δ24% from the baseline, p = 0.017) for the high dose group. CONCLUSION: Short-term, high-dose systemic corticosteroid treatment caused a rapid suppression of biomarkers of bone resorption. Corticosteroids did not suppress biomarkers of bone formation, regardless of patients receiving low or high doses of corticosteroids. This therapy was, therefore, harmless in terms of bone safety, in our prospective series of COPD patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02857842 . Submitted August 2nd, 2016.

Measuring the administered dose of particles on the facial mucosa of a realistic human model.

Exposure to particulate contaminants can cause serious adverse health effects. Deposition on the facial mucosa is an important path of exposure, but it is difficult to conduct direct dose measurement on real human subjects. In this study, we propose an in vitro method to assess the administered doses of micron-sized particles on the eyes and lips in which computed tomographic scanning and three-dimensional printing were used to create a model that includes a face, oropharynx, trachea, the first five generations of bronchi, and lung volume. This realistic model of a face and airway was exposed to monodispersed fluorescent particles released from an incoming jet. The administered dose of particles deposited upon the eyes and lips, as quantified by fluorescence intensity, was determined via a standard wiping protocol. The results show that, in this scenario, the administered doses normalized by source were 2.15%, 1.02%, 0.88%, 2.13%, and 1.55% for 0.6-, 1.0-, 2.0-, 3.0-, and 5.0-µm particles, respectively. The administered dose of large particles on the mucosa within a given exposure time has great significance. Moreover, the lips suffer a much greater risk of exposure than the eyes and account for more than 80% of total facial mucosa deposition. Our study provides a fast and economical method to assess the administered dose on the facial mucosa on an individual basis.

The effects of oxygen induced pulmonary vasoconstriction on bedside measurement of pulmonary gas exchange.

In patients with respiratory failure measurements of pulmonary gas exchange are of importance. The bedside automatic lung parameter estimator (ALPE) of pulmonary gas exchange is based on changes in inspired oxygen (FiO2) assuming that these changes do not affect pulmonary circulation. This assumption is investigated in this study. Forty-two out of 65 patients undergoing coronary artery bypass grafting (CABG) had measurements of mean pulmonary arterial pressure (MPAP), cardiac output and pulmonary capillary wedge pressure thus enabling the calculation of pulmonary vascular resistance (PVR) at each FiO2 level. The research version of ALPE was used and FiO2 was step-wise reduced a median of 0.20 and ultimately returned towards baseline values, allowing 6-8 min' steady state period at each of 4-6 levels before recording the oxygen saturation (SpO2). FiO2 reduction led to median decrease in SpO2 from 99 to 92 %, an increase in MPAP of 4 mmHg and an increase in PVR of 36 dyn s cm(-5). Changes were immediately reversed on returning FiO2 towards baseline. In this study changes in MPAP and PVR are small and immediately reversible consistent with small changes in pulmonary gas exchange. This indicates that mild deoxygenation induced pulmonary vasoconstriction does not have significant influences on the ALPE parameters in patients after CABG.

Measuring gas exchange with step changes in inspired oxygen: an analysis of the assumption of oxygen steady state in patients suffering from COPD.

Bedside estimation of pulmonary gas exchange efficiency may be possible from step changes in FIO2 and subsequent measurement of arterial oxygenation at steady state conditions. However, a steady state may not be achieved quickly after a change in FIO2, especially in patients with lung disease such as COPD, rendering this approach cumbersome. This paper investigates whether breath by breath measurement of respiratory gas and arterial oxygen levels as FIO2 is changed can be used as a much more rapid alternative to collecting data from steady state conditions for measuring pulmonary gas exchange efficiency. Fourteen patients with COPD were studied using 4-5 step changes in FIO2 in the range of 0.15-0.35. Values of expired respiratory gas and arterial oxygenation were used to calculate and compare the parameters of a mathematical model of pulmonary gas exchange in two cases: from data at steady state; and from breath by breath data prior to achievement of a steady state. For each patient, the breath by breath data were corrected for the delay in arterial oxygen saturation changes following each change in FIO2. Calculated model parameters were shown to be similar for the two data sets, with Bland-Altman bias and limits of agreement of -0.4 and -3.0 to 2.2 % for calculation of pulmonary shunt and 0.17 and -0.47 to 0.81 kPa for alveolar to end-capillary PO2, a measure of oxygen abnormality due to shunting plus regions of low [Formula: see text] A/[Formula: see text] ratio. This study shows that steady state oxygen levels may not be necessary when estimating pulmonary gas exchange using changes in FIO2. As such this technique may be applicable in patients with lung disease such as COPD.

Effects of a lower versus a higher oxygenation target in intensive care unit patients with chronic obstructive pulmonary disease and acute hypoxaemic respiratory failure: a subgroup analysis of a randomised clinical trial.

Background: Oxygen supplementation is ubiquitous in intensive care unit (ICU) patients with chronic obstructive pulmonary disease (COPD) and acute hypoxaemia, but the optimal oxygenation target has not been established. Methods: This was a pre-planned subgroup analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, which allocated patients with acute hypoxaemia to a lower oxygenation target (partial pressure of arterial oxygen [Pao2] of 8 kPa) vs a higher target (Pao2 of 12 kPa) during ICU admission, for up to 90 days; the allocation was stratified for presence or absence of COPD. Here, we report key outcomes for patients with COPD. Results: The HOT-ICU trial enrolled 2928 patients of whom 563 had COPD; 277 were allocated to the lower and 286 to the higher oxygenation group. After allocation, the median Pao2 was 9.1 kPa (inter-quartile range 8.7-9.9) in the lower group vs 12.1 kPa (11.2-12.9) in the higher group. Data for arterial carbon dioxide (Paco2) were available for 497 patients (88%) with no between-group difference in time-weighted average; median Paco2 6.0 kPa (5.2-7.2) in the lower group vs 6.2 kPa (5.4-7.3) in the higher group. At 90 days, 122/277 patients (44%) in the lower oxygenation group had died vs 132/285 patients (46%) in the higher (relative risk 0.98; 95% confidence interval 0.82-1.17; P=0.67). No statistically significant differences were found in any secondary outcome. Conclusions: In ICU patients with COPD and acute hypoxaemia, a lower vs a higher oxygenation target did not reduce mortality. There were no between-group differences in Paco2 or in secondary outcomes. Clinical trial registration: NCT03174002, EudraCT number 2017-000632-34.

Time to steady state after changes in FIO(2) in patients with COPD.

BACKGROUND: International guidelines recommend that when changing FIO2 in patients with COPD receiving Long-Term Oxygen Therapy (LTOT), 30 minutes should be waited for steady state before measurement of arterial blood gasses. This study evaluates whether 30 minutes is really necessary, as a smaller duration might improve the logistics of care, potentially reducing the time spent by patients at the out-patient clinic. METHODS: 12 patients with severe to very severe COPD according to the GOLD guidelines were included. Patients had a median FEV1% of 23% of the predicted value (range 15-64%), median FEV1/FVC 0.43 (range 0.26-0.63), and chronic respiratory failure necessitating LTOT, 1-4 liters/minute, minimum 16 hours/day. Following a FIO2 reduction (wash out), arterial blood gases were measured at 0, 1, 2, 4, 8, 12, 17, 22, 32 and 34 minutes. FIO2 was then increased to baseline levels (wash in) and blood gasses measured at 0, 1, 2, 4, 8, 12, 17, 22, 32, and 34 minutes. Data were analyzed to examine the dynamics of arterial PO2 and saturation (SO2) wash out and wash in by calculating the time constants, tau (ô), and to evaluate the time required to reach values which might be considered clinically stable, defined as PO2 within 0.5 kPa and SO2 within 1% of equilibrium values. RESULTS: For arterial PO2 values of time constants were about 3 minutes and similar for both wash out and wash in. A median of 5 minutes was required to reach clinically stable values of PO2 in both wash out and wash in, with 7-8 minutes sufficient in 75% of patients, and in the worst case 14 minutes. For SO2, values of the time constant were 4.5 and 1.4 minutes for wash out and wash in, respectively. The time required to reach clinically stable values was different in the two phases. For wash out the median time was 7.4 minutes, and in the worst case 15.6 minutes. For wash in the median time was 2.6 minutes and in worst case 6.8 minutes. No significant changes in PCO2 or pH were seen during FIO2 changes. DISCUSSION/CONCLUSION: This study shows that oxygen equilibration relevant for clinical interpretation requires only 10 minutes following an increase and 16 minutes following a decrease in FIO2. over the range studied.

Clinical refinement of the automatic lung parameter estimator (ALPE).

The automatic lung parameter estimator (ALPE) method was developed in 2002 for bedside estimation of pulmonary gas exchange using step changes in inspired oxygen fraction (FIO2). Since then a number of studies have been conducted indicating the potential for clinical application and necessitating systems evolution to match clinical application. This paper describes and evaluates the evolution of the ALPE method from a research implementation (ALPE1) to two commercial implementations (ALPE2 and ALPE3). A need for dedicated implementations of the ALPE method was identified: one for spontaneously breathing (non-mechanically ventilated) patients (ALPE2) and one for mechanically ventilated patients (ALPE3). For these two implementations, design issues relating to usability and automation are described including the mixing of gasses to achieve FIO2 levels, and the automatic selection of FIO2. For ALPE2, these improvements are evaluated against patients studied using the system. The major result is the evolution of the ALPE method into two dedicated implementations, namely ALPE2 and ALPE3. For ALPE2, the usability and automation of FIO2 selection has been evaluated in spontaneously breathing patients showing that variability of gas delivery is 0.3 % (standard deviation) in 1,332 breaths from 20 patients. Also for ALPE2, the automated FIO2 selection method was successfully applied in 287 patient cases, taking 7.2 ± 2.4 min and was shown to be safe with only one patient having SpO2 < 86 % when the clinician disabled the alarms. The ALPE method has evolved into two practical, usable systems targeted at clinical application, namely ALPE2 for spontaneously breathing patients and ALPE3 for mechanically ventilated patients. These systems may promote the exploration of the use of more detailed descriptions of pulmonary gas exchange in clinical practice.

All-cause admissions following a first ever exacerbation-related hospitalisation in COPD.

Background: Hospital admissions are important contributors to the overall burden of chronic obstructive pulmonary disease (COPD). Understanding the patterns and causes of hospital admissions will help to identify targets for preventive interventions. This study aimed to determine the 5-year all-cause hospital admission trajectories of patients with COPD following their first ever exacerbation-related hospitalisation. Methods: Patients with COPD were identified from the Danish national registries. Patients experiencing their first ever exacerbation-related hospitalisation, defined as the index event, between 2000 and 2014 were included. All-cause hospital admissions were examined during a subsequent 5-year follow-up period, and categorised using the International Classification of Diseases, 10th revision. Results: In total, 82 964 patients with COPD were included. The mean±sd age was 72±10 years and 48% were male. Comorbidities were present in 58%, and 65% of the patients collected inhalation medication ≤6 months prior to the index event. In total, 337 066 all-cause hospital admissions were identified, resulting in a 5-year admission rate of 82%. Most admissions were due to nonrespiratory causes (59%), amongst which cardiac events were most common (19%). Conclusion: Hospital admissions following a first exacerbation-related hospitalisation are common; nonrespiratory events constitute the majority of admissions. Besides the respiratory causes, treatment targeting the nonrespiratory causes of hospital admission should be considered to effectively decrease the burden of hospitalisation in COPD.

Calculating acid-base and oxygenation status during COPD exacerbation using mathematically arterialised venous blood.

BACKGROUND: Repeated arterial puncture is painful. A mathematical method exists for transforming peripheral venous pH, PCO 2 and PO 2 to arterial eliminating the need for arterial sampling. This study evaluates this method to monitor acid base and oxygenation during admission for exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Simultaneous arterial and peripheral venous blood was analysed. Venous values were used to calculate arterial pH, PCO 2 and PO 2, with these compared to measured values using Bland-Altman analysis and scatter plots. Calculated values of PO 2 were assessed with previously defi ned rules.Differences between maximal changes of calculated and measured values were compared using a t-test, with trends analysed by inspection of plots. RESULTS: Fifty-four patients, median age 67 years (range 62 ­ 75), were studied on average 3 days. Mean values of pH,PCO 2 and PO 2 were 7.432 } 0.047, 6.8 } 1.7 kPa and 9.2 } 1.5kPa, respectively. Calculated and measured arterial pH and PCO 2 agreed well, differences having small bias and SD(0.000 } 0.022 pH, ­ 0.06 } 0.50 kPa PCO 2 ), significantly better than venous blood alone. Calculated PO 2 obeyed the clinical rules. Calculated values could track patients, with no significant differences in maximal changes in measured and calculated values (pH p = 0.96, PCO 2 p = 0.62, PO 2 p = 0.33), and time-course plots matching quantity and pattern of change in measurements. CONCLUSIONS: This study shows that arterial pH, PCO 2 and PO 2 can be calculated from peripheral venous values so as to characterise changes seen during exacerbation. Application of the method has potential to reduce arterial sampling, decrease discomfort and enable venous sampling as routine practice.

Agreement between arterial and non-arterialised fingertip capillary blood gas and acid-base values.

Background: Arterial puncture is considered the gold standard for obtaining blood gas and acid-base values and facilitates the assessment of acutely and critically ill patients, as well as control of patients in long-term oxygen therapy (LTOT). Substitutional capillary sampling has been proposed, as researchers cite lower complication rates, physician independence, lower degree of invasiveness and higher degree of patient comfort. An arterialised earlobe is considered the method of choice to obtain capillary blood sampling, but in an acute setting, the need for vasodilating pastes may be time-consuming and impractical. The aim of this study is to examine whether accurate blood gas and acid-base measurements can be obtained using non-arterialised fingertip blood. Materials and methods: Consecutive arterial punctures and non-arterialised capillary blood samples were drawn from 62 patients with stable-phase chronic obstructive pulmonary disease (COPD), and subsequently analysed. Agreement between arterial and capillary blood gas values was compared using the method recommended by Bland and Altman. Results: Results show that limits of agreement (LoA) regarding PO2 (LoA: -1.27-4.45 kPa); Base Excess (LoA: -1.35-0.55); lactate (LoA: -0.77-0.20 mmol/l) and SO2 (LoA: -0.02-0.06) are wider than what would be applicable for clinical use. However, clinically acceptable LoA were obtained regarding PCO2 (LoA: -0.64-0.38 kPa); pH (LoA: -0.02-0.03), and HCO3 - (LoA: -1.06-0.55 mmol/l). Conclusion: LoA for PCO2, pH and HCO3 - indicate that measurement of these parameters in non-arterialised capillary blood may be useful in clinical practice/an acute setting. What this paper adds: Capillary blood sampling provides a fast, non-invasive means of obtaining blood gas-values;Traditionally, capillary blood sampling for blood gas analysis is obtained from the earlobe using arterialisation;The present study presents accurate measurements of PCO2, HCO3 - and pH using non-arterialised fingertip capillary blood;The present study is the first to show this in a population of stable-phase COPD patients.

Undiagnosed chronic obstructive pulmonary disease in patients admitted to an acute assessment unit.

Introduction: Chronic obstructive pulmonary disease (COPD) is very prevalent worldwide, yet underdiagnosed. Aim: This study investigates feasibility of performing spirometry in patients in need of acute hospital admission as well as the prevalence of undiagnosed COPD in the same cohort. Methods: During a two-week period, all patients admitted to three large acute assessment units were evaluated. Patients ≥ 18 years, able to perform spirometry, with no surgery to the thorax or abdomen within the last weeks and no known COPD was included. Patients with FEV1/FEV6 ≤ 0.7 or FEV1 < 80% or FEV6 < 80% were offered follow-up visit after 6 weeks. Results: Of the 1145 admitted patients, 46% were eligible: 28% of those had an abnormal spirometry. The offered follow-up visit was attended by 51% and in this group 17% were diagnosed with lung disease. COPD was the most prevalent diagnosis (73%), and 2/3 was in GOLD group A. In total, 75% of the patients with airflow obstruction at the initial examination remained obstructive. Conclusion: Performing spirometry in patients in need of acute hospital admission is feasible, abnormal findings are common, and COPD is the most prevalent diagnosis.

[Pulmonary cystic disease may be a rare complication to recurrent respiratory human papilloma virus infection].

A 19-year-old woman with a history of juvenile laryngeal papillomatosis (JLP), treated since childhood with multiple resections, was admitted with symptoms of pneumonia. A chest X-ray and CAT-scan revealed multiple lung cysts and a bronchoalveolar lavage detected human papilloma virus 11. The patient responded well to antibiotics. A body plethysmography showed small lung volumes and low diffusion capacity for carbon monoxide, but normal volume diffusion capacity divided by alveolar volume. Pulmonary cystic disease should be considered when patients with JLP have symptoms of pneumonia.

Can computed tomography classifications of chronic obstructive pulmonary disease be identified using Bayesian networks and clinical data?

Diagnosis and classification of chronic obstructive pulmonary disease (COPD) may be seen as difficult. Causal reasoning can be used to relate clinical measurements with radiological representation of COPD phenotypes airways disease and emphysema. In this paper a causal probabilistic network was constructed that uses clinically available measurements to classify patients suffering from COPD into the main phenotypes airways disease and emphysema. The network grades the severity of disease and for emphysematous COPD, the type of bullae and its location central or peripheral. In four patient cases the network was shown to reach the same conclusion as was gained from the patients' High Resolution Computed Tomography (HRCT) scans. These were: airways disease, emphysema with central small bullae, emphysema with central large bullae, and emphysema with peripheral bullae. The approach may be promising in targeting HRCT in COPD patients, assessing phenotypes of the disease and monitoring its progression using clinical data.