Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children (Review)

Abstract
Background: Automated closed loop systems may improve adaptation of the mechanical support to a patient's ventilatory needs and
facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of
ventilation.

Objectives: To compare the duration of weaning from mechanical ventilation for critically ill ventilated adults and children when managed
with automated closed loop systems versus non-automated strategies. Secondary objectives were to determine differences
in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1948 to August 2011); EMBASE (OvidSP) (1980 to August 2011); CINAHL (EBSCOhost) (1982 to August 2011); and the Latin American and Caribbean Health Sciences Literature (LILACS). In addition we received and reviewed auto-alerts for our search strategy in MEDLINE, EMBASE, and CINAHL up to August 2012. Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles.

Selection criteria: We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning
strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an intensive care unit (ICU).

Data collection and analysis: Two authors independently extracted study data and assessed risk of bias. We combined data into forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria.

Main results: Pooled data from 15 eligible trials (14 adult, one paediatric) totalling 1173 participants (1143 adults, 30 children) indicated that automated closed loop systems reduced the geometric mean duration of weaning by 32% (95% CI 19% to 46%, P =0.002), however heterogeneity was substantial (I2 = 89%, P < 0.00001). Reduced weaning duration was found with mixed or
medical ICU populations (43%, 95% CI 8% to 65%, P = 0.02) and Smartcare/PS™ (31%, 95% CI 7% to 49%, P = 0.02) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (17%, 95% CI 8% to 26%) and ICU length of stay (LOS) (11%, 95% CI 0% to 21%). There was no difference in mortality rates or hospital LOS. Overall the quality of evidence was high with the majority of trials rated as low risk.

Authors' conclusions: Automated closed loop systems may result in reduced duration of weaning, ventilation, and ICU stay. Reductions are more
likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized
controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.

Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine

Objective of the study: To determine the extent and nature of unlicensed/off-label prescribing patterns in hospitalised children in Palestine. Setting: Four paediatric wards in two public health system hospitals in Palestine [Caritas children’s hospital (Medical and neonatal intensive care units) and Rafidia general hospital (Medical and surgical units)]. Method: A prospective survey of drugs administered to infants and children <18 years old was carried out over a five-week period in the four paediatric wards. Main outcome measure: Drug-licensing status of all prescriptions was determined according to the Palestinian Registered Product List and the Physician’s Desk Reference. Results: Overall, 917 drug prescriptions were administered to 387 children. Of all drug prescriptions, 528 (57.5%) were licensed for use in children; 65 (7.1%) were unlicensed; and 324 (35.3%) were used off-label. Of all children, 49.6% received off-label prescriptions, 10.1% received unlicensed medications and 8.2% received both. Seventy-two percent of off-label drugs and 66% of unlicensed drugs were prescribed for children <2 years. Multivariate analysis showed that patients who were admitted to the neonatal intensive care unit and infants aged 0–1 years were most likely to receive a greater number of off-label or unlicensed medications (OR 1.80; 95% CI 1.03–3.59 and OR 1.99; 95% CI 0.88–3.73, respectively). Conclusion: The present findings confirmed the elevated prevalence of unlicensed and off-label paediatric drugs use in Palestine and strongly support the need to perform well designed clinical studies in children.

A national clinical scenario-based survey of clinicians' attitudes towards fresh frozen plasma transfusion for critically ill patients

Background: It is known that 20-30% of fresh frozen plasma (FFP) is used in intensive care units (ICUs), but little is known about variations in decision making between clinicians in relation to coagulopathy management. Our aim was to describe ICU clinicians' beliefs and practice in relation to FFP treatment of non-bleeding coagulopathic critically ill patients.

General and Respiratory Health Outcomes in Adult Survivors of Bronchopulmonary Dysplasia: A Systematic Review

Background: The purpose of this systematic literature review was to examine current empirical research on general and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia (BPD).

Methods: We searched seven databases up to the end of November 2010 (MEDLINE, PubMed, EMBASE, PsycINFO, Maternity and Infant Care, Cumulative Index of Nursing and Allied Health Literature, and Web of Knowledge). We independently screened and included only those studies concerning the assessment of outcome measures in adult survivors of BPD. Data on methodologic design and findings were extracted from each included study; in addition, the methodologic quality of each study was assessed using the Critical Appraisal Skills Programme checklist.

Results: Fourteen cohort studies met the review criteria. Of those, a total of eight studies were considered to be of high quality (score 9-12), five of moderate quality (score 5-8), and only one was of low quality (score 0-4). In all studies of adult survivors of BPD, differences were found between the index and control groups, suggesting that many adults survivors of BPD who were born preterm or with very low birth weight had more respiratory symptoms and pulmonary function abnormalities compared with their peers. Five studies concerning radiologic findings reported structural changes persisting into adulthood. Findings from three studies suggested impairment in exercise capacity, although firm conclusions were limited by the small sample size in the studies reviewed.

Conclusions: Compared with adults born at term, adult survivors of BPD have more impairment in general and respiratory health, which does not seem to diminish over time.

Decisional responsibility for mechanical ventilation and weaning: an international survey

Introduction: Optimal management of mechanical ventilation and weaning requires dynamic and collaborative decision making to minimize complications and avoid delays in the transition to extubation. In the absence of collaboration, ventilation decision making may be fragmented, inconsistent, and delayed. Our objective was to describe the professional group with responsibility for key ventilation and weaning decisions and to examine organizational characteristics associated with nurse involvement.

Methods: A multi-center, cross-sectional, self-administered survey was sent to nurse managers of adult intensive care units (ICUs) in Denmark, Germany, Greece, Italy, Norway, Switzerland, Netherlands and United Kingdom (UK). We summarized data as proportions (95% confidence intervals (CIs)) and calculated odds ratios (OR) to examine ICU organizational variables associated with collaborative decision making.

Results: Response rates ranged from 39% (UK) to 92% (Switzerland), providing surveys from 586 ICUs. Interprofessional collaboration (nurses and physicians) was the most common approach to initial selection of ventilator settings (63% (95% CI 59 to 66)), determination of extubation readiness (71% (67 to 75)), weaning method (73% (69 to 76)), recognition of weaning failure (84% (81 to 87)) and weaning readiness (85% (82 to 87)), and titration of ventilator settings (88% (86 to 91)). A nurse-to-patient ratio other than 1:1 was associated with decreased interprofessional collaboration during titration of ventilator settings (OR 0.2, 95% CI 0.1 to 0.6), weaning method (0.4 (0.2 to 0.9)), determination of extubation readiness (0.5 (0.2 to 0.9)) and weaning failure (0.4 (0.1 to 1.0)). Use of a weaning protocol was associated with increased collaborative decision making for determining weaning (1.8 (1.0 to 3.3)) and extubation readiness (1.9 (1.2 to 3.0)), and weaning method (1.8 (1.1 to 3.0)). Country of ICU location influenced the profile of responsibility for all decisions. Automated weaning modes were used in 55% of ICUs.

Conclusions: Collaborative decision making for ventilation and weaning was employed in most ICUs in all countries although this was influenced by nurse-to-patient ratio, presence of a protocol, and varied across countries. Potential clinical implications of a lack of collaboration include delayed adaptation of ventilation to changing physiological parameters, and delayed recognition of weaning and extubation readiness resulting in unnecessary prolongation of ventilation.

Eating as a neurodevelopment process for high risk newborns

Many high-risk and preterm infants have difficulty with successful feeding and subsequent optimal growth during their stay in the neonatal intensive care unit as well as in the months after discharge. Environmental, procedural, and medical issues necessary for treatment of the hospitalized infant present challenges for the development of successful eating skills. Emerging data describe eating as a predictable neurodevelopmental process that depends on the infant’s organization of physiologic processes, motor tone and movement, level of arousal, and ability to simultaneously regulate these processes.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

Objectives: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate in paediatric patients. Patients and Methods: Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analysed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. Results: A one-compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (L/hr) = 11.4 × (WT /70.0)(0.75) and V/F (L) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 L/hr and 21.4 L, respectively, resulting in an elimination half-life of 11.2 hr. Conclusions: The range of estimated CL/F in the study population was 0.67-7.38 L/hr. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients

Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial

BACKGROUND:
In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
METHODS:
We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged =16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 µg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
FINDINGS:
We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).
INTERPRETATION:
Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of ß-2 agonist treatment in ventilated patients with this disorder cannot be recommended.

The impact of nonadherence to inhaled long-acting β - adrenoceptor agonist/corticosteroid combination therapy on healthcare costs in difficult-to-control asthma

Background: Asthma is a leading, preventable cause of morbidity, mortality and cost. A disproportionate amount of the cost is generated by the 5-10%of patients with difficult-to-control asthma, who are prescribed treatment at step 4/5 of the Global Initiative for Asthma (GINA) guidelines. We have previously demonstrated a high prevalence of nonadherence to inhaled combination therapy (i.e. long-acting ß -adrenoceptor agonist [ß - agonist] and corticosteroid) in this population. The aim of this study was to examine the costs of healthcare utilization in a nonadherent group of patients with difficult-to-control asthma compared with adherent subjects. We also wished to examine potential savings if nonadherence to inhaled combination therapy could be addressed. All costs were measured from the perspective of a publicly funded health service Methods: Adherence was determined through examination of patient prescription refill behaviour and validated with a medical concordance interview. Data on healthcare use were collected from a patient survey and hospital records that included prescribed medicines, hospital admissions, intensive care unit (ICU) admissions and other unscheduled healthcare visits associated with asthma care. Activity was monetized using standard UK references and between-group comparisons based on a series of univariate and multivariate regression analyses. Results: Cost differences were identified for inhaled combination therapy, nebulizer, short acting b2-agonists and hospital costs excluding and including ICU admissions between adherent and nonadherent subjects. Compared with a group who have refractory asthma and who are adherent with medication, additional healthcare costs in nonadherent subjects are offset by the reduction in costs associated with reduced medication utilization. However, if nonadherence can be successfully targeted and hospital admissions avoided in this population, there is a potential $475 ($843-$368) saving per patient, per annum. Conclusion: Nonadherence is an important cause of difficult-to-control asthma. A uniform cost for subjects with difficult-to-control disease can be applied to economic analyses, independent of adherence, as increased healthcare utilization costs are offset by the reduced medication cost due to poor adherence. However, there are substantial potential savings in subjects with difficult-to-control asthma, who are nonadherent to inhaled combination therapy, if cost effective strategies for nonadherence are developed. © 2011 Adis Data Information BV. All rights reserved.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia

ABSTRACT BACKGROUND: Acute exposure to high-altitude stimulates free radical formation in lowlanders yet whether this persists during chronic exposure in healthy well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress [ascorbate radical (A•-), electron paramagnetic resonance spectroscopy and nitrite (NO2-), ozone-based chemiluminescence] was assessed in venous blood of 25 male highlanders living at 3,600 m with (n = 13, CMS+) and without (n = 12, CMS-) CMS. Twelve age and activity-matched healthy male lowlanders were examined at sea-level and during acute hypoxia. We also measured flow-mediated dilatation (FMD), arterial stiffness (AIx-75) and carotid intima-media thickness (IMT). RESULTS: Compared to normoxic lowlanders, oxidative-nitrosative stress was moderately increased in CMS- (P < 0.05) as indicated by elevated A•- (3,191 ± 457 vs. 2,640 ± 445 arbitrary units (AU)] and lower NO2- (206 ± 55 vs. 420 ± 128 nmol/L) whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS+ (A•-: 3,765 ± 429 AU and NO2- : 148 ± 50 nmol/L) compared to both CMS- and lowlanders (P < 0.05). This was associated with systemic vascular dysfunction as indicated by lower (P < 0.05 vs. CMS-) FMD (4.2 ± 0.7 vs. 7.6 ± 1.7 %) and increased AIx-75 (23 ± 8 vs. 12 ± 7 %) and carotid IMT (714 ± 127 vs. 588 ± 94 µM). CONCLUSIONS: Healthy highlanders display a moderate sustained elevation in oxidative-nitrosative stress that unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.Clinical Trials Gov Registration # NCT011827921Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, Wales, UK;2Sondes Moléculaires en Biologie et Stress Oxydant, Institut de Chimie Radicalaire, CNRS UMR 7273, Aix-Marseille University, France;3Department of Cardiology, University Hospital of Bern, Bern, Switzerland;4Institute of Clinical Physiology, CNR, Pisa, Italy;5Instituto Bolivano de Biologia de Altura, La Paz, Bolivia;6Centre for Clinical and Population Sciences, Queen's University Belfast, Belfast, Northern Ireland,7Botnar Center for Clinical Research, Hirslanden Group, Lausanne, Switzerland;8Facultad de Ciencias, Departamento de Biología, Universidad de Tarapacá, Arica, Chile and9Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland*Drs Bailey, Rimoldi, Scherrer and Sartori contributed equally to this workCorrespondence: Damian Miles Bailey, Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, UK CF37 4AT email: dbailey1@glam.ac.uk.

Cord blood erythropoietin, pH, PaO2 and haematocrit following caesarean section before labour

We have investigated the relationship between erythropoietin (Epo) and pH, PaO2 and haematocrit in 100 cord blood samples obtained at Caesarean section prior to labour. Of 82 term (> 37 weeks) infants, 64 were appropriately grown (10th-90th centiles), and their mean cord serum Epo and cord blood Epo was 23 +/- 8 mU/ml (mean +/- SD). Strong inverse correlations were found between cord serum Epo and cord blood pH (r = -0.74; p <0.0001), and between cord serum Epo and cord blood PaO2 (r = -0.55; p <0.0001), but not between cord serum Epo and cord haematocrit (r = 0.02; p <0.9). For the 18 preterm babies (gestation 32.4 +/- 4.1 weeks, birth weight 1,820 +/- 476 g), the Epo level was 36 +/- 8 mU/ml, which was not significantly greater than for the term babies. Strong inverse correlations were again found between Epo and pH (r = -0.87; p <0.0001) and Epo and PaO2 (r = -0.69; p <0.002). Babies from complicated pregnancies (intra-uterine growth retardation, pre-eclampsia, antepartum haemorrhage, diabetes mellitus and fetal distress) tended to have higher Epo levels. Thirteen babies had Epo levels > 40 mU/ml, and 11 (85%) of these required neonatal intensive care. Cord serum Epo correlates better with oxygen tension and pH at birth than with fetal growth and haematocrit, which are measures of chronic stress to the fetus.