Trial Of Mechanical Ventilation Research Articles

Virtual patient with temporal evolution for mechanical ventilation trial studies: A stochastic model approach

Background and objectiveHealthcare datasets are plagued by issues of data scarcity and class imbalance. Clinically validated virtual patient (VP) models can provide accurate in-silico representations of real patients and thus a means for synthetic data generation in hospital critical care settings. This research presents a realistic, time-varying mechanically ventilated respiratory failure VP profile synthesised using a stochastic model. MethodsA stochastic model was developed using respiratory elastance (Ers) data from two clinical cohorts and averaged over 30-minute time intervals. The stochastic model was used to generate future Ers data based on current Ers values with added normally distributed random noise. Self-validation of the VPs was performed via Monte Carlo simulation and retrospective Ers profile fitting. A stochastic VP cohort of temporal Ers evolution was synthesised and then compared to an independent retrospective patient cohort data in a virtual trial across several measured patient responses, where similarity of profiles validates the realism of stochastic model generated VP profiles. ResultsA total of 120,000 3-hour VPs for pressure control (PC) and volume control (VC) ventilation modes are generated using stochastic simulation. Optimisation of the stochastic simulation process yields an ideal noise percentage of 5–10% and simulation iteration of 200,000 iterations, allowing the simulation of a realistic and diverse set of Ers profiles. Results of self-validation show the retrospective Ers profiles were able to be recreated accurately with a mean squared error of only 0.099 [0.009–0.790]% for the PC cohort and 0.051 [0.030–0.126]% for the VC cohort. A virtual trial demonstrates the ability of the stochastic VP cohort to capture Ers trends within and beyond the retrospective patient cohort providing cohort-level validation. ConclusionVPs capable of temporal evolution demonstrate feasibility for use in designing, developing, and optimising bedside MV guidance protocols through in-silico simulation and validation. Overall, the temporal VPs developed using stochastic simulation alleviate the need for lengthy, resource intensive, high cost clinical trials, while facilitating statistically robust virtual trials, ultimately leading to improved patient care and outcomes in mechanical ventilation.

The Basics of ARDS Mechanical Ventilatory Care for Cardiovascular Specialists

The ongoing COVID-19 pandemic has placed pressure on health care systems and intensive care unit capacity worldwide. Respiratory insufficiency is the most common reason for hospital admission in patients with COVID-19. The most severe form of respiratory failure is acute respiratory distress syndrome (ARDS), which is associated with significant morbidity and mortality. Patients with ARDS are often treated with invasive mechanical ventilation according to established evidence-based and guideline recommended management strategies. With growing strain on critical care capacity, clinicians from diverse backgrounds, including cardiovascular specialists, might be required to help care for the growing number of patients with severe respiratory failure and ARDS. The aim of this article is to outline the fundamentals of ARDS diagnosis and management, including mechanical ventilation, for the nonintensivist. In the absence of mechanical ventilation trials specifically in patients with COVID-19-associated ARDS, the information presented is on the basis of general ARDS trials.

Disassociating Lung Mechanics and Oxygenation in Pediatric Acute Respiratory Distress Syndrome.

Both oxygenation and peak inspiratory pressure are associated with mortality in pediatric acute respiratory distress syndrome. Since oxygenation and respiratory mechanics are linked, it is difficult to identify which variables, pressure or oxygenation, are independently associated with outcome. We aimed to determine whether respiratory mechanics (peak inspiratory pressure, positive end-expiratory pressure, ΔP [PIP minus PEEP], tidal volume, dynamic compliance [Cdyn]) or oxygenation (PaO2/FIO2) was associated with mortality. Prospective, observational, cohort study. University affiliated PICU. Mechanically ventilated children with acute respiratory distress syndrome (Berlin). None. Peak inspiratory pressure, positive end-expiratory pressure, ΔP, tidal volume, Cdyn, and PaO2/FIO2 were collected at acute respiratory distress syndrome onset and at 24 hours in 352 children between 2011 and 2016. At acute respiratory distress syndrome onset, neither mechanical variables nor PaO2/FIO2 were associated with mortality. At 24 hours, peak inspiratory pressure, positive end-expiratory pressure, ΔP were higher, and Cdyn and PaO2/FIO2 lower, in nonsurvivors. In multivariable logistic regression, PaO2/FIO2 at 24 hours and ΔPaO2/FIO2 (change in PaO2/FIO2 over the first 24 hr) were associated with mortality, whereas pressure variables were not. Both oxygenation and pressure variables were associated with duration of ventilation in multivariable competing risk regression. Improvements in oxygenation, but not in respiratory mechanics, were associated with lower mortality in pediatric acute respiratory distress syndrome. Future trials of mechanical ventilation in children should focus on oxygenation (higher PaO2/FIO2) rather than lower peak inspiratory pressure or ΔP, as oxygenation was more consistently associated with outcome.

ECMO in major burn patients: feasibility and considerations when multiple modes of mechanical ventilation fail

BackgroundWe report two cases of acute respiratory distress syndrome in burn patients who were successfully managed with good outcomes with extra corporeal membrane oxygenation (ECMO) after failing multiple conventional modes of ventilation, and review the relevant literature.Case presentationThe two patients were a 39-year-old male and 53-year-old male with modified Baux Scores of 79 and 78, respectively, with no known inhalation injury. After the initial modified Parkland-based fluid resuscitation and partial escharotomy, both patients developed worsening hypoxemia and acute respiratory distress syndrome.The hypoxemia continued to worsen on multiple modes of ventilation including volume control, pressure regulated volume control, pressure control, airway pressure release ventilation and volumetric diffusive ventilation. In both cases, the PaO2 ≤ 50 mm Hg on a FiO2 100% during the trial of mechanical ventilation. The deterioration was rapid (<12 h since onset of worsening oxygenation) in both cases.A decision was made to trial the patients on ECMO. Veno-Venous ECMO (V-V ECMO) was successfully initiated following cannulation-under transesophgeal echo guidance—with the dual lumen Avalon® (Maquet, NJ, USA) cannula. ECMO support was maintained for 4 and 24 days, respectively. Both patients were successfully weaned off ECMO and were discharged to rehabilitation following their complex hospital course.ConclusionEarly ECMO for isolated respiratory failure in the setting on maintained hemodynamics resulted in a positive outcome in our two burn patients suffered from acute respiratory distress syndrome.

Effective sample size estimation for a mechanical ventilation trial through Monte-Carlo simulation: Length of mechanical ventilation and Ventilator Free Days

Randomised control trials have sought to seek to improve mechanical ventilation treatment. However, few trials to date have shown clinical significance. It is hypothesised that aside from effective treatment, the outcome metrics and sample sizes of the trial also affect the significance, and thus impact trial design.In this study, a Monte-Carlo simulation method was developed and used to investigate several outcome metrics of ventilation treatment, including 1) length of mechanical ventilation (LoMV); 2) Ventilator Free Days (VFD); and 3) LoMV-28, a combination of the other metrics. As these metrics have highly skewed distributions, it also investigated the impact of imposing clinically relevant exclusion criteria on study power to enable better design for significance. Data from invasively ventilated patients from a single intensive care unit were used in this analysis to demonstrate the method.Use of LoMV as an outcome metric required 160 patients/arm to reach 80% power with a clinically expected intervention difference of 25% LoMV if clinically relevant exclusion criteria were applied to the cohort, but 400 patients/arm if they were not. However, only 130 patients/arm would be required for the same statistical significance at the same intervention difference if VFD was used.A Monte-Carlo simulation approach using local cohort data combined with objective patient selection criteria can yield better design of ventilation studies to desired power and significance, with fewer patients per arm than traditional trial design methods, which in turn reduces patient risk. Outcome metrics, such as VFD, should be used when a difference in mortality is also expected between the two cohorts. Finally, the non-parametric approach taken is readily generalisable to a range of trial types where outcome data is similarly skewed.

Characteristics and Outcomes of Eligible Nonenrolled Patients in a Mechanical Ventilation Trial of Acute Respiratory Distress Syndrome.

Patients eligible for randomized controlled trials may not be enrolled for various reasons. Nonenrollment may affect study generalizability and lengthen the time required for trial completion. To describe characteristics and outcomes of eligible nonenrolled (ENE) patients in a multicenter trial of mechanical ventilation strategies. Within the OSCILLATE trial of high-frequency oscillation (HFO) versus conventional ventilation (CV) in adults with adult respiratory distress syndrome, and with approval from research ethics boards, we collected a minimal dataset on patients who satisfied eligibility criteria but were not enrolled. We categorized ENE patients as ENE-HFO and ENE-CV based on receipt of HFO at any time. We used multivariable logistic regression to assess the association between ENE status and mortality. A total of 548 patients were randomized, and 546 were ENE. The most common reasons for ENE were no consent (42%), physician refusal (24%), missed randomization window (15%), and current HFO use (14%). Compared with randomized patients in respective arms of the trial, ENE-HFO patients were younger and had worse lung injury, whereas ENE-CV patients had lower illness severity. ENE status was independently associated with mortality (adjusted odds ratio, 1.39; 95% confidence interval, 1.06-1.84; P = 0.02), with no significant interaction with ventilation treatment group. Nonenrollment was common, with approximately one ENE patient for every randomized patient. Our study suggests that enrollment in trials of mechanical ventilation may be associated with improved outcomes compared with standard care and highlights the need for prospective tracking and transparent reporting of ENE patients as part of trial management.

The COVenT study: developing a core outcome set for mechanical ventilation trials

Background Inconsistency in trial outcomes reporting is a widely recognised problem in clinical research and critical care research is no exception. Our 2014 review of 66 trials evaluating reporting of ventilation outcomes, revealed a significant heterogeneity in both the outcomes selected and their definitions, particularly in terms of start and end points [1]. The purpose of our study is to establish a core outcome set (COS) for trials of interventions which aim to modify the duration of mechanical ventilation. We will actively promote the use of this set and follow its uptake in the academic press for ten years post publication.

Confronting the frustrations of negative clinical trials in acute respiratory distress syndrome.

Despite robust successes in trials of mechanical ventilation, pharmacologic interventions in acute respiratory distress syndrome have been disappointing. Although ineffective therapy remains the compelling explanation for these negative trials, other possible explanations exist. These negative trials, better termed "statistically negative trials" or "indeterminate trials," cannot prove that a therapy is ineffective. It is important for clinicians and investigators to appreciate the alternative explanations for negative trials of potentially effective therapies because these indicate options for improving clinical trials in acute respiratory distress syndrome. These options can be organized into strategies that increase sample size, increase the signal from the therapy, and reduce the noise or variation in the study. Each of the strategies to improve the likelihood of a positive clinical trial poses a potential tradeoff in generalizability, cost, sample size, signal, or noise.

The Esophageal Pressure-Guided Ventilation 2 (EPVent2) trial protocol: a multicentre, randomised clinical trial of mechanical ventilation guided by transpulmonary pressure

IntroductionOptimal ventilator management for patients with acute respiratory distress syndrome (ARDS) remains uncertain. Lower tidal volume ventilation appears to be beneficial, but optimal management of positive end-expiratory pressure (PEEP) remains...

A Peek at PEEP in Patients With AIDS

PEEP was described to improve oxygenation in ventilated patients with ARDS in 1967,[1][1] although the mechanism of action was not clear. The potential benefits of lung volume recruitment maneuvers became apparent from results of a randomized controlled trial of mechanical ventilation of patients

Prone or PEEP, PEEP and prone

Dear Editor, Recently in your journal, Sud et al. [1] reported on a meta-analysis of randomized controlled trials of mechanical ventilation in the prone position. They found a 16% reduction in relative risk of mortality among patients with baseline PaO2/FiO2 <100 mmHg, which was consistent with their a priori hypothesis that improved oxygenation during prone ventilation would be clinically important in patients at high risk of death from profound hypoxemia. Furthermore, post hoc analysis showed that the statistically significant difference between the relative risks of mortality in the more severely hypoxemic patients versus the less severely hypoxemic patients was robust across several PaO2/FiO2 thresholds up to 140 mmHg. This meta-analysis could help bedside clinicians in their decisions to mechanically ventilate patients in the prone position, or not. The investigators chose a threshold PaO2/FiO2 of 100 mmHg because this value was used to stratify patients in a recent randomized controlled trial of mechanical ventilation in prone position [2], and because bedside clinicians can readily determine whether a patient’s PaO2/FiO2 is above or below this threshold. However, a practical question facing bedside clinicians when deciding to use or forego mechanical ventilation in the prone position is interpretation of the effects of the level of positive end-expiratory pressure (PEEP). Higher levels of PEEP recruit collapsed alveoli, and as such improve oxygenation. Thus, higher levels of PEEP could erroneously give the impression that acute respiratory distress syndrome (ARDS) is not present or resolving, causing bedside clinicians to forego the use of mechanical ventilation in the prone position. Of course, it should be noted that the investigators chose to use the baseline PaO2/FiO2 as a threshold in their analysis. Frequently the baseline PaO2/FiO2 is not greatly influenced by PEEP, since the level of PEEP usually is low at the moment it is calculated (i.e., directly after initiation of mechanical ventilation). However, this may not always be true, especially not in intensive care units familiar with use of higher levels of PEEP (i.e., where PEEP is titrated on peripheral oxygenation, frequently before any arterial blood sample is obtained). In addition, patients may develop ARDS during the course of mechanical ventilation [3]. In these patients, higher levels of PEEP are used even more regularly. Probably it was not possible to obtain sufficient data to calculate the Lung Injury Score [4] or the Oxygenation Index [5] from the trials that were meta-analyzed. Both the Lung Injury Score and the Oxygenation Index take into account the level of PEEP (or mean airway pressure). It can be questioned, however, whether bedside clinicians can readily determine these scores, and thus adequately use them in their decisions to use or forego mechanical ventilation in the prone position. We developed a more practical approach in our intensive care unit (Fig. 1). In case of acute respiratory distress syndrome with profound hypoxemia (defined as PaO2/FiO2 <125 mmHg) we first raise the level of PEEP stepwise to 15 cmH2O. Each step may or may not be preceded by recruitment maneuvers by using sustained inflation. From then, the prone position is used, irrespective of PaO2/FiO2, with the knowledge that PaO2/FiO2 would decline if the level of PEEP would be reduced. Prone ventilation is continued as long as the level of PEEP to be used is ≥15 cmH2O. If PaO2/FiO2 remains <125 mmHg with prone ventilation, the level of PEEP is further increased and inversed ratio ventilation is used. This approach is not evidence based, though it is practical and in harmony with the findings of the meta-analysis by Sud et al. [1]. In our center, neither extracorporeal membrane oxygenation nor high-frequency oscillation nor ventilation with nitric oxide is used. Fig. 1 Schematic presentation of the local mechanical ventilation guideline; mechanical ventilation in the prone position is used when the level of PEEP is >15 cmH2O, aiming for PaO2/FiO2 >125 mmHg (below the dotted line); prone ...

The Design of Future Pediatric Mechanical Ventilation Trials for Acute Lung Injury

Pediatric practitioners face unique challenges when attempting to translate or adapt adult-derived evidence regarding ventilation practices for acute lung injury or acute respiratory distress syndrome into pediatric practice. Fortunately or unfortunately, there appears to be selective adoption of adult practices for pediatric mechanical ventilation, many of which pose considerable challenges or uncertainty when translated to pediatrics. These differences, combined with heterogeneous management strategies within pediatric critical care, can complicate clinical practice and make designing robust clinical trials in pediatric acute respiratory failure particularly difficult. These issues surround the lack of explicit ventilator protocols in pediatrics, either computer or paper based; differences in modes of conventional ventilation and perceived marked differences in the approach to high-frequency oscillatory ventilation; challenges with patient recruitment; the shortcomings of the definition of acute lung injury and acute respiratory distress syndrome; the more reliable yet still somewhat unpredictable relationship between lung injury severity and outcome; and the reliance on potentially biased surrogate outcome measures, such as ventilator-free days, for all pediatric trials. The purpose of this review is to highlight these challenges, discuss pertinent work that has begun to address them, and propose potential solutions or future investigations that may help facilitate comprehensive trials on pediatric mechanical ventilation and define clinical practice standards.

Sustained hyperoxia stabilizes breathing in healthy individuals during NREM sleep.

The present study was designed to determine whether hyperoxia would lower the hypocapnic apneic threshold (AT) during non-rapid eye movement (NREM) sleep. Nasal noninvasive mechanical ventilation was used to induce hypocapnia and subsequent central apnea in healthy subjects during stable NREM sleep. Mechanical ventilation trials were conducted under normoxic (room air) and hyperoxic conditions (inspired PO(2) > 250 Torr) in a random order. The CO(2) reserve was defined as the minimal change in end-tidal PCO(2) (PET(CO(2))) between eupnea and hypocapnic central apnea. The PET(CO(2)) of the apnea closest to eupnea was designated as the AT. The hypocapnic ventilatory response was calculated as the change in ventilation below eupnea for a given change in PET(CO(2)). In nine participants, compared with room air, exposure to hyperoxia was associated with a significant decrease in eupneic PET(CO(2)) (37.5 ± 0.6 vs. 41.1 ± 0.6 Torr, P = 0.001), widening of the CO(2) reserve (-3.8 ± 0.8 vs. -2.0 ± 0.3 Torr, P = 0.03), and a subsequent decline in AT (33.3 ± 1.2 vs. 39.0 ± 0.7 Torr; P = 001). The hypocapnic ventilatory response was also decreased with hyperoxia. In conclusion, 1) hyperoxia was associated with a decreased AT and an increase in the magnitude of hypocapnia required for the development of central apnea. 2) Thus hyperoxia may mitigate the effects of hypocapnia on ventilatory motor output by lowering the hypocapnic ventilatory response and lowering the resting eupneic PET(CO(2)), thereby decreasing plant gain.

Long term follow-up of very low birthweight infants from a neonatal volume versus pressure mechanical ventilation trial

Long term follow-up of very low birthweight infants from a neonatal volume versus pressure mechanical ventilation trial

Long term follow-up of very low birthweight infants from a neonatal volume versus pressure mechanical ventilation trial

Background:A previous randomised trial showed volume controlled ventilation (VCV) was efficacious in ventilating very preterm and extremely low birthweight babies.Objective:To compare long term survival, pulmonary morbidities and gross neurodevelopmental outcomes...

Neuromechanical regulation of respiratory motor output in ventilator-dependent C1-C3 quadriplegics.

To evaluate the role of phrenic and sternocleidomastoid afferents as alternate sources of inhibitory feedback during mechanical ventilation, we studied five C2-C3 quadriplegics with sensory denervation of the rib cage and diaphragm, six C1-C2 quadriplegics with additional loss of sensory feedback from the neck muscles, and seven normal subjects. We compared the return of inspiratory muscle activity [the recruitment threshold (PCO2RT)] during mechanical ventilation between subject groups after stepwise increases in end-tidal PCO2 (PETCO2) either by increasing the inspired fraction of CO2 (FICO2), decreasing tidal volume (VT; 50 ml/min), or decreasing frequency (f; 1 breath/2 min). Normal subjects were mechanically hyperventilated via a nasal mask until inspiratory activity was undetectable. Efferent input to the sternocleidomastoid was intact at both levels of spinal cord injury, but phasic activity was not evident at the quadriplegics' baseline resting ventilation. The PCO2RT was defined as the level of PETCO2 at which phasic activity of the diaphragm in normal subjects and of the sternocleidomastoid in C1-C2 and C2-C3 quadriplegics recurred. The mean PCO2RT (in response to raising PETCO2 via increased FICO2 while maintaining a high VT and f) was not significantly different (P = 0.6) between normal subjects (43 +/- 3 Torr) and C2-C3 quadriplegics (38 +/- 5 Torr). Both subject groups demonstrated a frequency- and volume-related inhibition, as evidenced by a substantially lower PCO2RT when PETCO2 was raised by reducing either VT or f. In contrast to the C2-C3 quadriplegics, the C1-C2 quadriplegics responded with a similar PCO2RT among the three different mechanical ventilation trials, independent of whether PETCO2 was raised with high VT and f, with reduced VT, or with reduced f. We conclude that feedback from at least some part of the chest wall is required to produce a volume- and frequency-dependent inhibition of inspiratory muscle activity observed during mechanical ventilation.