Stefano Nava

Extracorporeal Co2 removal in hypercapnic patients at risk of noninvasive ventilation failure: a matched cohort study with historical control.

Objectives:To assess efficacy and safety of noninvasive ventilation-plus-extracorporeal Co2 removal in comparison to noninvasive ventilation-only to prevent endotracheal intubation patients with acute hypercapnic respiratory failure at risk of failing noninvasive ventilation. Design:Matched cohort study with historical control. Setting:Two academic Italian ICUs. Patients:Patients treated with noninvasive ventilation for acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease (May 2011 to November 2013). Interventions:Extracorporeal CO2 removal was added to noninvasive ventilation when noninvasive ventilation was at risk of failure (arterial pH ⩽ 7.30 with arterial PCO2 > 20% of baseline, and respiratory rate ≥ 30 breaths/min or use of accessory muscles/paradoxical abdominal movements). The noninvasive ventilation-only group was created applying the genetic matching technique (GenMatch) on a dataset including patients enrolled in two previous studies. Exclusion criteria for both groups were mean arterial pressure less than 60 mm Hg, contraindications to anticoagulation, body weight greater than 120 kg, contraindication to continuation of active treatment, and failure to obtain consent. Measurements and Main Results:Primary endpoint was the cumulative prevalence of endotracheal intubation. Twenty-five patients were included in the noninvasive ventilation-plus-extracorporeal CO2 removal group. The GenMatch identified 21 patients for the noninvasive ventilation-only group. Risk of being intubated was three times higher in patients treated with noninvasive ventilation-only than in patients treated with noninvasive ventilation-plus-extracorporeal CO2 removal (hazard ratio, 0.27; 95% CI, 0.07–0.98; p = 0.047). Intubation rate in noninvasive ventilation-plus-extracorporeal CO2 removal was 12% (95% CI, 2.5–31.2) and in noninvasive ventilation-only was 33% (95% CI, 14.6–57.0), but the difference was not statistically different (p = 0.1495). Thirteen patients (52%) experienced adverse events related to extracorporeal CO2 removal. Bleeding episodes were observed in three patients, and one patient experienced vein perforation. Malfunctioning of the system caused all other adverse events. Conclusions:These data provide the rationale for future randomized clinical trials that are required to validate extracorporeal CO2 removal in patients with hypercapnic respiratory failure and respiratory acidosis nonresponsive to noninvasive ventilation.

Use of high-flow nasal cannula oxygenation in ICU adults: a narrative review

Oxygen therapy can be delivered using low-flow, intermediate-flow (air entrainment mask), or high-flow devices. Low/intermediate-flow oxygen devices have several drawbacks that cause critically ill patients discomfort and translate into suboptimal clinical results. These include limitation of the FiO2 (due to the high inspiratory flow often observed in patients with respiratory failure), and insufficient humidification and warming of the inspired gas. High-flow nasal cannula oxygenation (HFNCO) delivers oxygen flow rates of up to 60xa0L/min and over the last decade its effect on clinical outcomes has widely been evaluated, such as in the improvement of respiratory distress, the need for intubation, and mortality. Mechanisms of action of HFNCO are complex and not limited to the increased oxygen flow rate. The main aim of this review is to guide clinicians towards evidence-based clinical practice guidelines. It summarizes current knowledge about HFNCO use in ICU patients and the potential areas of uncertainties. For instance, it has been recently suggested that HFNCO could improve the outcome of patients with hypoxemic acute respiratory failure. In other settings, research is ongoing and additional evidence is needed. For instance, if intubation is required, studies suggest that HFNCO may help to improve preoxygenation and can be used after extubation. Likewise, HFNCO might be used in obese patients, or to prevent respiratory deterioration in hypoxemic patients requiring bronchoscopy, or for the delivery of aerosol therapy. However, areas for which conclusive data exist are limited and interventions using standardized HFNCO protocols, comparators, and relevant clinical outcomes are warranted.

Oronasal mask versus helmet in acute hypercapnic respiratory failure

The choice of the interface for noninvasive ventilation (NIV) is a key factor in NIV success. We hypothesised that a new helmet specifically design to improve performance in hypercapnic patients would be clinically equivalent to a standard oronasal mask. In a multicentre, short-term, physiological, randomised trial in chronic obstructive pulmonary disease patients facing an acute hypercapnic respiratory failure episode, we compared the changes in arterial blood gases (ABGs) and tolerance score obtained using the helmet or mask, and, as secondary end-points, dyspnoea, vital signs, early NIV discontinuation and rate of intubation. 80 patients were randomly assigned to receive NIV either with the helmet (n=39) or mask (n=41), using an intensive care unit ventilator. Compared with baseline, in the first 6u2005h, NIV improved ABGs, dyspnoea and respiratory rate (p<0.05) in both groups. Changes in ABGs and discomfort were similar with the two groups, while dyspnoea decreased more (p<0.005) using the mask. The rate of intubation and the need for interface change during the whole period of NIV were very low and not different between groups. The new helmet may be a valid alternative to a mask in improving ABGs and achieving a good tolerance during an episode of acute hypercapnic respiratory failure. In COPD patients undergoing NIV, an oronasal mask and a helmet equally improved ABGs and tolerance score http://ow.ly/DMVIg

Effects of Extracorporeal CO2 Removal on Inspiratory Effort and Respiratory Pattern in Patients Who Fail Weaning from Mechanical Ventilation.

Gene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy. Adv Drug Deliv Rev 2009;61:128–139. 3. Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, et al.; UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, doubleblind, placebo-controlled, phase 2b trial. Lancet Respir Med [online ahead of print] 3 Jun 2015; DOI: 10.1016/S2213-2600(15)00245-3. 4. Davies JC, Gill D, Griesenbach U, Voase N, Davies G, Higgins T, Innes JA, Boyd C, Porteous D, Hyde S, et al. Evaluation of safety and gene expression with single dose of pGM169/GL67A administered to the nose and lung of individuals with CF: the UK CF Gene Therapy Consortium Pilot Study [abstract]. Pediatr Pulmonol 2009;(Suppl 32):305. 5. Davies JC, Gill D, Griesenbach U, Voase N, Davies G, Higgins T, Innes JA, Boyd C, Porteous D, Hyde S, et al. Evaluation of safety and gene expression with single dose of pGM169/GL67A administered to the nose and lung of individuals with CF: the UK CF Gene Therapy Consortium Pilot Study [abstract]. Thorax 2009;64:A70. 6. Hyde SC, Pringle IA, Abdullah S, Lawton AE, Davies LA, Varathalingam A, Nunez-Alonso G, Green AM, Bazzani RP, Sumner-Jones SG, et al. CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat Biotechnol 2008;26:549–551. 7. Gill DR, Smyth SE, Goddard CA, Pringle IA, Higgins CF, Colledge WH, Hyde SC. Increased persistence of lung gene expression using plasmids containing the ubiquitin C or elongation factor 1alpha promoter. Gene Ther 2001;8:1539–1546. 8. McLachlan G, Davidson H, Holder E, Davies LA, Pringle IA, SumnerJones SG, Baker A, Tennant P, Gordon C, Vrettou C, et al. Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung. Gene Ther 2011;18:996–1005. 9. Davies LA, Nunez-Alonso GA, McLachlan G, Hyde SC, Gill DR. Aerosol delivery of DNA/liposomes to the lung for cystic fibrosis gene therapy. Hum Gene Ther Clin Dev 2014;25:97–107. 10. Kent L, Reix P, Innes JA, Zielen S, Le Bourgeois M, Braggion C, Lever S, Arets HG, Brownlee K, Bradley JM, et al.; European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) Standardisation Committee. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros 2014;13:123–138. 11. Rose AC, Goddard CA, Colledge WH, Cheng SH, Gill DR, Hyde SC. Optimisation of real-time quantitative RT-PCR for the evaluation of nonviral mediated gene transfer to the airways.Gene Ther 2002;9:1312–1320.

Physiotherapy for Patients on Awake Extracorporeal Membrane Oxygenation: A Systematic Review

BACKGROUND AND PURPOSEnExtracorporeal membrane oxygenation (ECMO) is used as temporary life support in subjects with potentially reversible respiratory/cardiac failure. The principal purpose of this review was to assess the characteristics and potential advantages of physiotherapeutic interventions in subjects on awake ECMO support.nnnMETHODSnSeven databases were interrogated: we searched titles, abstracts and keywords using the Medical Subject Headings terms extracorporeal membrane oxygenation and rehabilitation linked with the Boolean operator AND.nnnRESULTS AND CONCLUSIONnIn total, 216 citations were retrieved. Nine citations satisfied our inclusion criteria and were subjected to full-text analysis. The numbers of patients enrolled in the included studies (most of which were case series) were low (nu2009=u200952). We found no prospective studies or randomized controlled trials. Overall, subjects on awake ECMO usually received a combination of passive and active physiotherapy, and most achieved an acceptable degree of autonomy after treatment. Emerging research in the field affords preliminary evidence supporting the safety of early mobilization and ambulation in patients on awake veno-venous ECMO support. Copyright

Efficacy of non-invasive mechanical ventilation in the general ward in patients with chronic obstructive pulmonary disease admitted for hypercapnic acute respiratory failure and pH < 7.35: a feasibility pilot study.

To date non‐invasive (NIV) mechanical ventilation use is not recommended in chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF) and pH < 7.30 outside a ‘protected environment’. We assessed NIV efficacy and feasibility in improving arterial blood gases (ABG) and in‐hospital outcome in patients with ARF and severe respiratory acidosis (RA) admitted to an experienced rural medical ward.

Regular versus as-needed budesonide and formoterol combination treatment for moderate asthma: a non-inferiority, randomised, double-blind clinical trial

BACKGROUNDnTreatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma.nnnMETHODSnIn this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095.nnnFINDINGSnBetween April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated.nnnINTERPRETATIONnIn patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small.nnnFUNDINGnItalian Medicines Agency.

Evaluation of a systematic approach to weaning of tracheotomized neurological patients: an early interrupted randomized controlled trial.

BackgroundWhile a systematic approach to weaning reduces the rate of extubation failure in intubated brain-injured patients, no data are available on the weaning outcome of these patients after tracheotomy. We aimed to assess whether a systematic approach to disconnect tracheotomized neurological and neurosurgical patients off the ventilator (intervention) is superior to the sole physician’s judgment (control). Based on previous work in intubated patients, we hypothesized a reduction of the rate of failure within 48xa0h from 15 to 5xa0%. Secondary endpoints were duration of mechanical ventilation, ICU length of stay and mortality.MethodsWe designed a single center randomized controlled study. Since no data are available on tracheotomized patients, we based our a priori power analysis on results derived from intubated patients and calculated an overall sample size of 280 patients.ResultsAfter inclusion of 168 consecutive patients, the trial was interrupted because the attending physicians judged the observed rate of reconnection to be much greater than expected. The overall rate of failure was 29xa0%, confirming the physicians’ judgment. Twenty-one patients (24xa0%) in the intervention group and 27 (33xa0%) controls were reconnected to the ventilator within 48xa0h (pxa0=xa00.222). The main reasons for failure were respiratory distress (80 and 88xa0% in the treatment and control group, respectively), hemodynamic impairment (15 and 4xa0% in the treatment and control group, respectively), neurological deterioration (4xa0% in the control group only). The duration of mechanical ventilation was of 412xa0±xa0202xa0h and 402xa0±xa0189xa0h, in the control and intervention group, respectively. ICU length of stay was on average of 23xa0days for both groups. ICU mortality was 6xa0% in the control and 2xa0% in the intervention group without significant differences.ConclusionWe found no difference between the two groups under evaluation, with a rate of failure much higher than expected. Consequent to the early interruption, our study results to be underpowered. Based on the results of the present study, a further trial should overall enroll 790 patients.Trial registration: ACTRN12612000372886

Ventilator associated pneumonia following liver transplantation: Etiology, risk factors and outcome

AIMnTo determine the incidence, etiology, risk factors and outcome of ventilator-associated pneumonia (VAP) in patients undergoing orthotopic liver transplantation (OLT).nnnMETHODSnThis retrospective study considered 242 patients undergoing deceased donor OLT. VAP was diagnosed according to clinical and microbiological criteria.nnnRESULTSnVAP occurred in 18 (7.4%) patients, with an incidence of 10 per 1000 d of mechanical ventilation (MV). Isolated bacterial etiologic agents were mainly Enterobacteriaceae (79%). Univariate logistic analysis showed that model for end-stage liver disease (MELD) score, pre-operative hospitalization, treatment with terlipressin, Child-Turcotte-Pugh score, days of MV and red cell transfusion were risk factors for VAP. Multivariate analysis, considering significant risk factors in univariate analysis, demonstrated that pneumonia was strongly associated with terlipressin usage, pre-operative hospitalization, days of MV and red cell transfusion. Mortality rate was 22% in the VAP group vs 4% in the group without VAP.nnnCONCLUSIONnOur data suggest that VAP is an important cause of nosocomial infection during postoperative period in OLT patients. MELD score was a significant risk factor in univariate analysis. Multiple transfusions, treatment with terlipressin, preoperative hospitalization rather than called to the hospital while at home and days of MV constitute important risk factors for VAP development.

Is sedation safe and beneficial in patients receiving NIV? No

Sedation and analgesia are commonly used in the ICU to improve patient comfort and tolerance, to minimize reactions to painful stimuli and the physiologic stress response, and to modulate patient respiratory effort, drive, or timing. Although intolerance is commonly perceived as an important reason for NIV failure that should respond to sedation and analgesia, recent studies suggest that they are not used very often for that indication. Muriel et al. [1] found that sedation and analgesia were used in ‘‘only’’ about 20 % of patients using NIV, confirming the results of an earlier web-survey performed in North America and Europe [2]. Therefore, the large majority of patients (approximately 80 %) treated with NIV for acute respiratory failure do not receive any form of sedation and yet tolerate NIV and usually succeed with it [1].