Article

Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

To evaluate the effects of neuromuscular blocking agents (NMBAs) on pulmonary and systemic inflammation in patients with acute respiratory distress syndrome ventilated with a lung-protective strategy. Multiple-center, prospective, controlled, and randomized trial. One medical and two medical-surgical intensive care units. A total of 36 patients with acute respiratory distress syndrome (Pao2/Fio2 ratio of < or =200 at a positive end-expiratory pressure of > or =5 cm H2O) were included within 48 hrs of acute respiratory distress syndrome onset. Patients were randomized to receive conventional therapy plus placebo (n = 18) or conventional therapy plus NMBAs (n = 18) for 48 hrs. Both groups were ventilated with a lung-protective strategy (tidal volume between 4 and 8 mL/kg ideal body weight, plateau pressure of < or =30 cm H2O). Bronchoalveolar lavages and blood samples were performed, before randomization and at 48 hrs, to determine the concentrations of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-8. Pao2/Fio2 ratio was evaluated before randomization and at 24, 48, 72, 96, and 120 hrs. A decrease over time in IL-8 concentrations (p = .034) was observed in the pulmonary compartment of the NMBA group. At 48 hrs after randomization, pulmonary concentrations of IL-1beta (p = .005), IL-6 (p = .038), and IL-8 (p = .017) were lower in the NMBA group as compared with the control group. A decrease over time in IL-6 (p = .05) and IL-8 (p = .003) serum concentrations was observed in the NMBA group. At 48 hrs after randomization, serum concentrations of IL-1beta (p = .037) and IL-6 (p = .041) were lower in the NMBA group as compared with the control group. A sustained improvement in Pao2/Fio2 ratio was observed and was reinforced in the NMBA group (p < .001). Early use of NMBAs decrease the proinflammatory response associated with acute respiratory distress syndrome and mechanical ventilation.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Regarding the bias of the individual trials, three trials were judged to have an unclear risk of bias. 9 11 13 The remaining trials were assessed as having a high risk of bias because of deficits in the blinding methods 12 ...
... (figure 8). Different inclusion criteria (ARDS patients with PaO 2 / FiO 2 <150 mm Hg, 9 11 13 21 PaO 2 /FiO 2 <200 mm Hg, 12 and PaO 2 /FiO 2 <300 mm Hg 28 and whether prone position was used among patients were not the source of heterogeneity (see online supplemental figure 7A,B. Further details are shown in table 4. ...
... 39 40 NMBAs may restrain the release of inflammatory factors (eg, interleukin (IL)-1β, IL-6 and IL-8) and block nicotinic acetylcholine receptor α1 to achieve their anti-inflammatory effect and improve the clinical outcomes of respiratory patients in critical condition. 12 41 42 After the inflammatory stage, NMBAs may be reduced due to side effects, such as ICU-acquired muscle weakness, which may explain why NMBAs could only relieve short-term mortality among patients with ARDS. 16 In clinical practice, NMBAs are used only when patients with ARDS cannot be treated successfully with a ventilator and are not recommended for mild patients wih ARDS. ...
Article
Full-text available
Objective To determine whether neuromuscular blocking agents (NMBAs) can decrease the mortality of patients with acute respiratory distress syndrome (ARDS) and improve their clinical outcomes. Design Systematic review, meta-analysis and meta-regression. Data sources PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov. Methods Randomised controlled trials (RCTs) comparing the treatment effect of NMBAs with that of placebo (or traditional treatment) in patients with ARDS were carefully selected. The primary outcome was 90-day mortality. The secondary outcomes were 21–28 days mortality, NMBA-related complications (barotrauma, pneumothorax and intensive care unit (ICU)-acquired muscle weakness), days free of ventilation and days not in the ICU by day 28, Medical Research Council score, Acute Physiology and Chronic Health Evaluation II score and arterial oxygen tension (PaO 2 )/fractional inspired oxygen (FiO 2 ) (at 48 hours and 72 hours). Random-effects meta-regression was used to explore models involving potential moderators. Trial sequential analysis was performed to estimate the cumulative effect on mortality across RCTs. Results NMBAs were not associated with reduced 90-day mortality (risk ratio (RR) 0.85; 95% CI 0.66 to 1.09; p=0.20). However, they decreased the 21–28 days mortality (RR 0.71; 95% CI 0.53 to 0.96; p=0.02) and the rates of pneumothorax (RR 0.46; 95% CI 0.28 to 0.77; p=0.003) and barotrauma (RR 0.56; 95% CI 0.37 to 0.86; p=0.008). In addition, NMBAs increased PaO 2 /FiO 2 at 48 hours (mean difference (MD) 18.91; 95% CI 4.29 to 33.53; p=0.01) and 72 hours (MD 12.27; 95% CI 4.65 to 19.89; p=0.002). Meta-regression revealed an association between sample size (p=0.042) and short-term mortality. Publication year (p=0.050), sedation strategy (p=0.047) and sample size (p=0.046) were independently associated with PaO 2 /FiO 2 at 48 hours. Conclusions In summary, the results suggested that use of NMBAs might reduce 21–28 days mortality, NMBA-related complications and oxygenation. However, NMBAs did not reduce the 90-day mortality of patients with ARDS, which contradicts a previous meta-analysis. PROSPERO registration number CRD42019139440.
... After screening 1247 titles and abstracts, reviewers assessed 43 full-texts for eligibility. Four new trials were eligible for this review (Fig. 1), resulting in a total of 7 trials (1598 patients) [9,12,[19][20][21][22][23]. Of the new trials, the largest was conducted in the USA (N = 1006), with one in France (N = 24), and the other two in China (N = 41 and N = 96). ...
... All seven studies were specifically designed to investigate the effects of a continuous NMBA infusion on gas exchange, inflammatory markers, and/or clinical outcomes in patients with ARDS. Four studies used a 48-h infusion of cisatracurium [9,12,19,20], whereas the other three studies did not pre-specify a duration for NMBA infusions. Weight-based dosing of cisatracurium was used in two of the studies [19,20], and a fixed high dose was used in another three studies (15 mg bolus, followed by a continuous infusion of 37.5 mg per hour) [9,12,22]. ...
... Four studies used a 48-h infusion of cisatracurium [9,12,19,20], whereas the other three studies did not pre-specify a duration for NMBA infusions. Weight-based dosing of cisatracurium was used in two of the studies [19,20], and a fixed high dose was used in another three studies (15 mg bolus, followed by a continuous infusion of 37.5 mg per hour) [9,12,22]. The two studies of vecuronium used the following maintenance doses, without boluses being reported: 0.05 mg/kg/h and 1 μg/ kg/min [21,23]. ...
Article
Full-text available
Purpose Existing clinical practice guidelines support the use of neuromuscular blocking agents (NMBA) in acute respiratory distress syndrome (ARDS); however, a recent large randomized clinical trial (RCT) has questioned this practice. Therefore, we updated a previous systematic review to determine the efficacy and safety of NMBAs in ARDS. Methods We searched MEDLINE, EMBASE (October 2012 to July 2019), the Cochrane (Central) database, and clinical trial registries ( ClinicalTrials.gov , ISRCTN Register, and WHO ICTRP) for RCTs comparing the effects of NMBA as a continuous infusion versus placebo or no NMBA infusion (but allowing intermittent NMBA boluses) on patient-important outcomes for adults with ARDS. Two independent reviewers assessed the methodologic quality of the primary studies and abstracted data. Results Seven RCTs, including four new RCTs, met eligibility criteria for this review. These trials enrolled 1598 patients with moderate to severe ARDS at centers in the USA, France, and China. All trials assessed short-term continuous infusions of cisatracurium or vecuronium. The pooled estimate for mortality outcomes showed significant statistical heterogeneity, which was only explained by a subgroup analysis by depth of sedation in the control arm. A continuous NMBA infusion did not improve mortality when compared to a light sedation strategy with no NMBA infusion (relative risk [RR] 0.99; 95% CI 0.86–1.15; moderate certainty; P = 0.93). On the other hand, continuous NMBA infusion reduced mortality when compared to deep sedation with as needed NMBA boluses (RR 0.71; 95% CI 0.57–0.89; low certainty; P = 0.003). Continuous NMBA infusion reduced the rate of barotrauma (RR 0.55; 95% CI 0.35–0.85, moderate certainty; P = 0.008) across eligible trials, but the effect on ventilator-free days, duration of mechanical ventilation, and ICU-acquired weakness was uncertain. Conclusions Inconsistency in study methods and findings precluded the pooling of all trials for mortality. In a pre-planned sensitivity analysis, the impact of NMBA infusion on mortality depends on the strategy used in the control arm, showing reduced mortality when compared to deep sedation, but no effect on mortality when compared to lighter sedation. In both situations, a continuous NMBA infusion may reduce the risk of barotrauma, but the effects on other patient-important outcomes remain unclear. Future research, including an individual patient data meta-analysis, could help clarify some of the observed findings in this updated systematic review.
... There were 5 RCTs [258][259][260][261][262] that were in line with PICO. As for the effect estimates, survival (5 RCTs: N = 1461) [258][259][260][261][262] had a risk difference of 84 more/1000 patients (95% CI: 39 fewer-236 more/1000 patients), QOL (EQ-5D, etc.) (1 RCT: N = 246) [259] had a mean of 0.02 points lower (95% CI: 0.09 less-0.05 ...
... There were 5 RCTs [258][259][260][261][262] that were in line with PICO. As for the effect estimates, survival (5 RCTs: N = 1461) [258][259][260][261][262] had a risk difference of 84 more/1000 patients (95% CI: 39 fewer-236 more/1000 patients), QOL (EQ-5D, etc.) (1 RCT: N = 246) [259] had a mean of 0.02 points lower (95% CI: 0.09 less-0.05 more points), and barotrauma (4 RCTs: N = 1,437) [258][259][260][261] had a risk difference of 31 fewer/1000 patients (95% CI: 46 fewer-9 fewer/1000 patients). ...
... As for the effect estimates, survival (5 RCTs: N = 1461) [258][259][260][261][262] had a risk difference of 84 more/1000 patients (95% CI: 39 fewer-236 more/1000 patients), QOL (EQ-5D, etc.) (1 RCT: N = 246) [259] had a mean of 0.02 points lower (95% CI: 0.09 less-0.05 more points), and barotrauma (4 RCTs: N = 1,437) [258][259][260][261] had a risk difference of 31 fewer/1000 patients (95% CI: 46 fewer-9 fewer/1000 patients). The desirable effect due to intervention was judged as "moderate". ...
Article
Full-text available
Background The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4–8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO 2 (PaO 2 ) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html ). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.
... The lower production of proinflammatory cytokines in the lung and the blood reported in patients receiving cisatracurium [24] has suggested an "anti-inflammatory" role for NMBAs. Two mechanisms could be involved: first, a reduced inflammation through the reduction of ventilator-induced lung injury (VILI). ...
... NMBAs have multiple, potentially positive, biological effects in humans [25]. In patients with moderateto-severe ARDS, NMBAs administration has been associated with lower local and systemic release of inflammation, epithelial dysfunction, and endothelial injury biomarkers, such as IL-8, surfactant protein-D, and von Willebrand factor [24,26]. ...
... Seven randomized controlled trials (RCT) [13,24,37,54,[73][74][75] have studied NMBA infusions in patients with moderate-severe ARDS ( Table 2). Conflicting results from the two largest randomized controlled trials (RCTs) [37,54] evaluating the role of NMBAs in ARDS have further tempered the enthusiasm for their use as a front-line adjunctive therapy [76]. ...
Article
Neuromuscular blocking agents (NMBAs) inhibit patient-initiated active breath and the risk of high tidal volumes and consequent high transpulmonary pressure swings, and minimize patient/ ventilator asynchrony in acute respiratory distress syndrome (ARDS). Minimization of volutrauma and ventilator-induced lung injury (VILI) results in a lower incidence of barotrauma, improved oxygenation and a decrease in circulating proinflammatory markers. Recent randomized clinical trials did not reveal harmful muscular effects during a short course of NMBAs. The use of NMBAs should be considered during the early phase of severe ARDS for patients to facilitate lung protective ventilation or prone positioning only after optimising mechanical ventilation and sedation. The use of NMBAs should be integrated in a global strategy including the reduction of tidal volume, the rational use of PEEP, prone positioning and the use of a ventilatory mode allowing spontaneous ventilation as soon as possible. Partial neuromuscular blockade should be evaluated in future trials.
... A systematic review team, with input from the panel and the methods team, conducted the systematic review and meta-analysis for this ICM-RPG. We identified 7 RCTs enrolling 1598 patients with ARDS [8,[14][15][16][17]; we present a summary of the studies in the Supplement. ...
... The hospital mortality for this subgroup did not favour either the intervention or control [relative risk (RR) 0.99; 95% confidence interval (CI) 0.86-1.15]. The remaining subgroup included 3 trials that aimed to use a deeper sedation strategy for patients in the control arm [14,15,19]. In this subgroup, an NMBA infusion reduced hospital mortality (RR 0.72; 95% CI 0.58-0.91) ...
... As the relationships between dose of cisatracurium and clinical and adverse effects are unclear, clinicians may titrate the dose to clinical paralytic effect. While it is plausible to assume that the beneficial effect of cisatracurium is related to its neuromuscular blockade effect; some evidence suggest that it may have a direct anti-inflammatory effect as well [14,25]. Therefore, it is unclear if clinicians should use a fixed high-dose of cisatracurium or titrate the dose of cisatracurium administered to paralytic effect. ...
Article
The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) is to formulate an evidence-based guidance for the use of neuromuscular blocking agents (NMBA) in adults with acute respiratory distress syndrome (ARDS). The panel comprised 20 international clinical experts from 12 countries, and 2 patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines and followed a strict conflict of interest policy. We convened panelists through teleconferences and web-based discussions. Guideline experts from the guidelines in intensive care, development, and evaluation Group provided methodological support. Two content experts provided input and shared their expertise with the panel but did not participate in drafting the final recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence and grade recommendations and suggestions. We used the evidence to decision framework to generate recommendations. The panel provided input on guideline implementation and monitoring, and suggested future research priorities. The overall certainty in the evidence was low. The ICM-RPG panel issued one recommendation and two suggestions regarding the use of NMBAs in adults with ARDS. Current evidence does not support the early routine use of an NMBA infusion in adults with ARDS of any severity. It favours avoiding a continuous infusion of NMBA for patients who are ventilated using a lighter sedation strategy. However, for patients who require deep sedation to facilitate lung protective ventilation or prone positioning, and require neuromuscular blockade, an infusion of an NMBA for 48 h is a reasonable option.
... The term critical illness-associated diaphragm weakness (CIADW) is now preferred over VIDD to describe respiratory muscle weakness in critically ill patients [90]. Remarkably, clinical studies have shown that neuromuscular blockers administered in the first 48 hours of moderate to severe ARDS improves outcome without the development of clinically relevant muscle weakness [4,[91][92][93]. Recently, it was observed that patients on assist-control ventilation regularly exhibited contractions of the diaphragm, a type of asynchrony called reversed triggering [94]. ...
... If the Ppl is higher than alveolar pressure (Palv) the alveoli have a tendency to collapse, promoting atelectasis and possibly cyclic recruitment of alveoli (atelectrauma) [99,104]. It is possible that the beneficial effects of muscle relaxants during the early course of ARDS can be attributed to the prevention of excessive muscle effort [4,92,93], although effort was not measured in these studies. ...
... Based on certain patient characteristics and targets set by the clinician, automated weaning involves adaptations in the PSV level, followed by an automatic gradual reduction of the PSV level and weaning tests when the level of support is sufficiently low [91]. Compared to non-automated weaning strategies, reductions in weaning time with SmartCare TM were demonstrated in some studies; adequately powered randomized clinical studies are warranted [92,93]. ...
Book
Full-text available
PhD thesis "Towards respiratory muscle-protective mechanical ventilation in the critically ill: technology to monitor and assist physiology"
... [1] Research demonstrates that a trial of continuous infusion cisatracurium (CIS) leads to improved PaO 2 /FiO 2 (P/F) ratios potentially by decreasing serum inflammatory markers, oxygen consumption, patient-ventilator asynchronies, and ventilator-induced lung injury. [2][3][4][5][6][7] While data on the impact of neuromuscular blockade on mortality are conflicting, guidelines recommend a trial of neuromuscular blocking agents (NMBA) in life-threatening situations. [8,9] However, optimal continuous infusion dosing strategies remain undefined. ...
... [13][14][15] Three continuous dosing strategies have been described in the literature and employed in clinical practice: a fixed dosing approach (37.5 mg/h), weight-based dosing with titration guided exclusively by Train-of-Four (TOF) assessments, and weight-based dosing using ventilator synchrony to guide adjustments. [4,5,10,11,[16][17][18][19][20] Despite the two largest randomized controlled trials in ARDS utilizing a fixed-dosing approach, earlier studies report experiences with titrating neuromuscular blockade to target zero twitches on TOF stimulation. [4,5] Several studies support utilizing TOF to reduce NMBA exposure, however, data suggest TOF measurements do not correlate to clinical assessment nor depth of paralysis. ...
... [4,5,10,11,[16][17][18][19][20] Despite the two largest randomized controlled trials in ARDS utilizing a fixed-dosing approach, earlier studies report experiences with titrating neuromuscular blockade to target zero twitches on TOF stimulation. [4,5] Several studies support utilizing TOF to reduce NMBA exposure, however, data suggest TOF measurements do not correlate to clinical assessment nor depth of paralysis. [17][18][19][21][22][23][24][25] A protocolized dosing strategy targeting ventilator synchrony allows for titration of NMBA based on a more physiologic and clinically relevant target and therefore potentially limit excessive drug use and potential complications. ...
Article
Purpose: Three continuous dosing strategies of cisatracurium (CIS) for acute respiratory distress syndrome (ARDS) have been described in the literature. After implementation of a ventilator synchrony protocol (VSP), we sought to determine which continuous CIS dosing strategy utilized the least amount of drug without compromising efficacy. Methods: We retrospectively reviewed patients with ARDS receiving continuous CIS from January 1, 2013 to December 31, 2018. We categorized patients into one of three dosing strategies: fixed dose (FD), titration based solely on train-of-four (TOF), or the VSP. We documented drug consumption and determined efficacy by comparing the change in PaO2/FiO2 ratio (P/F) and oxygenation index (OI) from baseline up to 48 h. Results: A total of 1047 patients were screened, and 189 met inclusion criteria (VSP = 69, TOF = 99, FD = 21). Drug consumption (mg) was significantly lower in the VSP arm: 415 [IQR 318-528] compared to both the TOF: 665 [IQR 472-927] and the FD arms: 1730 [IQR 1695-1800], p < 0.001 for each. The change in P/F and OI from baseline were statistically equivalent at all time points. Conclusion: Without impacting efficacy of gas exchange, a protocol using ventilator synchrony for CIS titration required significantly less drug compared to TOF-based titration and a fixed dosing regimen.
... ARDS can lead to a reduction in lung compliance and severe hypoxemia, along with insults to other organs. The Berlin criteria further define ARDS into three stages based on a patient's Pao 2 /Fio 2 on positive endexpiratory pressure (PEEP) greater than or equal to 5 Hg < Pao 2 /Fio 2 ≤ 200 mm Hg), or severe (Pao 2 /Fio 2 ≤ 100 mm Hg) (3). ...
... Optimal management of ARDS is complex and centers around strategies that improve the efficacy and safety of mechanical ventilation, such utilization of lower tidal volumes and higher PEEP, prone-positioning, and use of neuromuscular blocking agents (1,(4)(5)(6)(7). Inhaled pulmonary vasodilators, such as inhaled epoprostenol (iEPO) and inhaled nitric oxide (iNO), have been shown to improve hypoxemia by increasing blood flow to well-ventilated portions of the lung, leading to improvements in ventilation and perfusion matching (8)(9)(10). ...
Article
Full-text available
Objectives: The objectives of this study were to evaluate the efficacy and safety of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019. Design: Retrospective single-center study. Setting: ICUs at a large academic medical center in the United States. Patients: Thirty-eight adult critically ill patients with coronavirus disease 2019 and refractory hypoxemia treated with either inhaled epoprostenol or inhaled nitric oxide for at least 1 hour between March 1, 2020, and June 30, 2020. Interventions: Electronic chart review. Measurements and main results: Of 93 patients screened, 38 were included in the analysis, with mild (4, 10.5%), moderate (24, 63.2%), or severe (10, 26.3%), with acute respiratory distress syndrome. All patients were initiated on inhaled epoprostenol as the initial pulmonary vasodilator and the median time from intubation to initiation was 137 hours (68-228 h). The median change in Pao2/Fio2 was 0 (-12.8 to 31.6) immediately following administration of inhaled epoprostenol. Sixteen patients were classified as responders (increase Pao2/Fio2 > 10%) to inhaled epoprostenol, with a median increase in Pao2/Fio2 of 34.1 (24.3-53.9). The mean change in Pao2 and Spo2 was -0.55 ± 41.8 and -0.6 ± 4.7, respectively. Eleven patients transitioned to inhaled nitric oxide with a median change of 11 (3.6-24.8) in Pao2/Fio2. A logistic regression analysis did not identify any differences in outcomes or characteristics between the responders and the nonresponders. Minimal adverse events were seen in patients who received either inhaled epoprostenol or inhaled nitric oxide. Conclusions: We found that the initiation of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019, on average, did not produce significant increases in oxygenation metrics. However, a group of patients had significant improvement with inhaled epoprostenol and inhaled nitric oxide. Administration of inhaled epoprostenol or inhaled nitric oxide may be considered in patients with severe respiratory failure secondary to coronavirus disease 2019.
... NMBAs provide a pharmacologic intervention to combat spontaneous effort, lung stress and ventilator dyssynchrony [20][21][22]. Therefore, early administration of NMBAs might also play an important role in decreasing devastating pulmonary outcomes. ...
... In a cohort of 56 patients with ARDS comparing conventional therapy vs conventional therapy plus NMBA, Gainner et al. [20] reported improvement in PaO 2 /FIO 2 ratio at 48, 96, and 120 hrs after establishing an adequate neuromuscular blockade (P < 0.001). Also, the early administration of NMBA in patients with ARDS with a lung-protective ventilation strategy has brought benefits in terms of inflammatory marker reduction, demonstrating a decrease in IL-8, IL-1beta, IL-6, and IL-8 [21]. Additionally, in those patients with severe ARDS (PaO 2 /FIO 2 < 150 mmHg), the hazard ratio (HR) for death at 90 days using cisatracurium compared with placebo was 0.68 (95% CI, 0.48-0.98, ...
Article
This narrative review evaluates the evidence for using neuromuscular blocking agents (NMBA) in patients being treated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While large prospective randomized-controlled trials (RCTs) are lacking at this point in time, smaller observational studies and case series are reviewed to ascertain the indications and utility of NMBAs. Additionally, large RCTs that address similar clinical scenarios are reviewed and the authors translate these findings to patients with COVID-19. Specifically, NMBAs can be helpful during endotracheal intubation to minimize the risk of patient coughing and possibly infecting healthcare personnel. NMBAs can also be used in patients to promote patient-ventilator synchrony while reducing the driving pressure needed with mechanical ventilation, particularly in patients with the severe clinical presentation (Type H phenotype). Prone positioning has also become a cornerstone in managing refractory hypoxemia in patients with SARS-CoV-2 acute respiratory distress syndrome (ARDS), and NMB can be useful in facilitating this maneuver. In the perioperative setting, deep levels of neuromuscular blockade can improve patient outcomes during laparoscopic operations and may theoretically reduce the risk of aerosolization as lower insufflation pressures may be utilized. Regardless of the indication, quantitative neuromuscular monitoring remains the only reliable method to confirm adequate recovery following cessation of neuromuscular blockade. Such monitors may serve a unique purpose in patients with COVID-19 as automation of measurements can reduce healthcare personnel - patient contact that would occur during periodic subjective evaluation with a peripheral nerve stimulator.
... Patients may-in an attempt to maintain homeostasis-initiate a vicious cycle through vigorous breathing efforts, exacerbating their lungs pathology by means of extremely elevated transpulmonary forces, leading to excessive stress and increased pulmonary inflammation [36,37]. In our study, this patient-induced biotrauma might be one of the factors explaining the pronounced CRP dynamics in the noninvasively supported groups as opposed to those receiving early IMV [38]. Consequently, the prolonged use of noninvasive ventilation, delaying intubation in patients who ultimate fail and thus require IMV, has been associated with higher mortality rates in ARDS [39][40][41][42][43], as well as in critically ill COVID-19 patients [44][45][46]. ...
Article
Full-text available
Background Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. Methods Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. Results Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). Conclusion In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.
... In the 2016 SSC guidelines we issued a weak recommendation for using NMBA infusion for 48 hours in sepsis-induced moderate to severe ARDS (12,13). This recommendation was based on a meta-analysis of three trials that examined the role of NMBAs in ARDS (465)(466)(467), showing reduced risks of death (RR, 0.72; 95% CI, 0.58−0.91) and barotrauma (RR, 0.43; 95% CI, 0.20−0.90) ...
... Cisatracurium is a newer nondepolarizing agent that is metabolized via Hoffman degradation to metabolites without neuromuscular blocking activity. It is also associated with a decrease in both pulmonary and systemic inflammatory cytokines, 9 which may be a result not only of minimizing VALI, but also a direct effect of the cisatracurium itself. 10 It is not associated with intensive care unit (ICU)-acquired weakness 11 and, in comparison with vecuronium, cisatracurium is associated with fewer ICU and ventilator days, 12 suggesting that it may be a preferable neuromuscular blocking agent for patients with ARDS. ...
Article
Acute respiratory distress syndrome is a heterogenous syndrome with many etiologies for which there are no definitive pharmacologic treatments, despite decades of research. We explore some adjunctive pharmacologic therapies, including neuromuscular blockade, corticosteroids, and inhaled pulmonary vasodilators. Additionally, we explore some investigative therapies, including Vitamin C, beta-agonists, statins, mesenchymal stromal cells, and granulocyte-macrophage colony stimulating factor. We do discuss the potential role of steroids in acute respiratory distress syndrome with severe acute respiratory syndrome coronavirus 2 as a trigger. The standard of care, however, remains supportive care.
... Furthermore, patients receiving routine intraoperative thermal care exhibited a lower core temperature (34.7 • C), delayed wound healing, and a 3-fold higher incidence of surgical wound infections compared with patients who were warmed to a core temperature of 36.6 • C [13]. However, effectors such as immune-defensesuppressing neuromuscular blocking agents [14] and fentanyl anesthesia [15], which are used in clinical settings, as well as limited systemic (e.g., impact of stress hormones), temperature (e.g., equalization from low to control values), and diurnal effects on isolated cells in vitro [3] may not reveal the natural temperature, immune, and stresshormone response kinetics of healthy individuals when considering the natural recovery from acute cold exposure. ...
Article
A poor outcome of whole-body hypothermia often results from a late complication, rather than from acute effects of hypothermia. A low body (cell) temperature or the increase in the concentrations of the stress hormones cortisol, epinephrine, and norepinephrine in response to acute cold stress have been proposed as potent proinflammatory cytokine suppressant. In the current study, we tested the hypothesis that the recovery of body temperature from a whole-body intermittent cold-water immersion (CWI, at 13–14oC for a total 170 min) is associated with a delayed response of proinflammatory cytokines in young healthy men. Our results revealed a delay in the increase in the proinflammatory interleukin 6 and interleukin 1 cytokines after the CWI, which paralleled the changes in cortisol, epinephrine, norepinephrine, and body temperature. CWI downregulated tumor necrosis factor α (TNF-α) expression immediately and 1 h after the CWI. Although TNF-α had recovered to the pre-immersion level at 2 h after CWI, its natural circadian cycle kinetics was disrupted until 12 h after the CWI. Furthermore, we showed that CWI strongly modified the white blood cell counts, with changes reaching a peak between 1 and 2 h after the CWI.
... In the present study, the calculated sample size estimated at 22 is satisfactory compared to several studies including samples ranging from 6 to 37 patients [15,23,24,[28][29][30][31][32] (Table 3). All patients presenting an indication for paralysis within the study period were included. ...
Article
Full-text available
Introduction: use of generic drugs is common. However, there is still concern among patients and physicians that brand name drugs are more efficient. The aim of the study was to compare efficacy and tolerance between two forms of cisatracurium: brand name versus generic name. Methods: it´s a crossover, randomized, double-blind physiological trial. Patients admitted for hypoxemic acute respiratory failure with PaO2/FIO2 < 200mmHg despite optimized ventilation and sedation thus requiring non-depolarizing neuromuscular blocking agents (NMBAs), were enrolled. Patients received consecutively, in a random order, cisatracurium brand name (Nimbex®) and generic (Cisatrex®) over two-hour period separated by one-hour washout period. Neuromuscular function was monitored by a calibrated train-of-four (TOF) stimulation device. Paralysis time delay to reach TOF of 2/4, recovery kinetics and tolerance were monitored. The number needed to demonstrate a significant difference in time delays to reach a TOF of 2/4 between the two forms of cisatracurium was estimated at 22 patients. Results: twenty-two patients were included. Eight (36.4%) had acute respiratory distress syndrome; 8(36.4%), acute exacerbation of chronic obstructive pulmonary disease and 3(13.6%), status asthmaticus. Median [IQR] SAPS II at admission, 28.5 [22, 41]. PaO2/FIO2, 121 [81, 156] mmHg. Paralysis time delays were respectively, 80 [50, 112] vs. 87 [65, 115] minutes, in Nimbex® group and Cisatrex® group; (p=0.579). Within the recovery period, the between two-studied drugs´ difference in TOF was at 0.25±0.96; p=0.64. There were no significant hemodynamic differences. Conclusion: the present study revealed no significant differences in efficacy nor in tolerance between cisatracurium brand name Nimbex® and generic name Cisatrex® in hypoxemic ventilated patients.
... In our paper, the average RSBI among patients with successful weaning was Until now, no empirical evidence has been found of studies investigating the impact of the V T /IBW ratio on the success in weaning from PMV. That said, the recommended values of the V T /IBW ratio in cases of lung-protective mechanical ventilation in patients with severe lung disease, such as ARDS, was in the range of between 4 and 8 mL/kg [30]. The average V T /IW ratio in the population with successful weaning in the current study was within this range. ...
Article
Introduction: For patients on prolonged mechanical ventilation (PMV; > 21 days), successful weaning has been attributed to various factors. The aim of this study is to determine the usefulness of the rapid shallow breathing index(RSBI) and other potential predictors of successful weaning in patients unable to wean and requiring extreme PMV at a hospital-based long-term ventilator facility in Israel. Material and ethods: Retrospective analysis of prospectively collected data over 5 years. Results: A total of 150 subjects on PMV, ready to undergo a weaning process, were included in the study. Of them, 60 (40.0%) were males. The mean age of the whole study population was 76.5 years (SD = 13.6; range 22.0-96.0 years). The subjects were on MV for a mean period of 170.1 days (SD = 237.6; range 25.0-1624.0 days). Sixty patients (40%) were successfully weaned. The mean RSBI in the successfully weaned population was 41.9 breaths/min/L (SD = 12.3; range 13.0-80.4 breaths/min/L), in the population where weaning failed, it was 114.8 breaths/min/L (SD = 69.2; range 47.5-450.0 breaths/min/L). By univariate logistic regression analysis, younger age (p < 0.007), female gender (p < 0.001), decreased duration of MV (p < 0.023), re-spiratory rate (p < 0.001) and RSBI (p < 0.001), increased tidal volume/ideal body weight (p < 0.001) and minute ventilation (p < 0.01) were found to be factors that significantly predict successful weaning. By multivariate analysis, increased tidal volume/ /ideal body weight (p < 0.007) and decreased RSBI (p < 0.046) were found to be independent predictors of successful weaning (p < 0.001; R2 Nagelkerke = 0.90). Conclusions: Factors independently predicting successful weaning in patients requiring extreme PMV included increased tidal volume/ideal body weight and decreased RSBI.
... T en percent to 15% of patients requiring mechanical ventilation in the ICU suffer from acute respiratory distress syndrome (ARDS), and one third to half of these patients die in the hospital (1)(2)(3). In patients with ARDS, adjunctive treatment with neuromuscular blocking agent (NMBA) infusions can help reduce patient-ventilator dyssynchrony and associated lung injury (4)(5)(6)(7). However, NMBA infusions carry the risks associated with immobilization (8,9). ...
Article
Objectives: Two previously published trials (ARDS et Curarisation Systematique [ACURASYS] and Reevaluation of Systemic Early Neuromuscular Blockade [ROSE]) presented equivocal evidence on the effect of neuromuscular blocking agent infusions in patients with acute respiratory distress syndrome (acute respiratory distress syndrome). The sedation regimen differed between these trials and also within the ROSE trial between treatment and control groups. We hypothesized that the proportion of deeper sedation is a mediator of the effect of neuromuscular blocking agent infusions on mortality. Design: Retrospective cohort study. Setting: Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA). Patients: Intubated and mechanically ventilated ICU patients with acute respiratory distress syndrome (Berlin definition) admitted between January 2008 until June 2019. Interventions: None. Measurements and main results: The proportion of deeper sedation was defined as days with nonlight sedation as a fraction of mechanical ventilation days in the ICU after acute respiratory distress syndrome diagnosis. Using clinical data obtained from a hospital network registry, 3,419 patients with acute respiratory distress syndrome were included, of whom 577 (16.9%) were treated with neuromuscular blocking agent infusions, for a mean (SD) duration of 1.8 (±1.9) days. The duration of deeper sedation was prolonged in patients receiving neuromuscular blocking agent infusions (4.6 ± 2.2 d) compared with patients without neuromuscular blocking agent infusions (2.4 ± 2.2 d; p < 0.001). The proportion of deeper sedation completely mediated the negative effect of neuromuscular blocking agent infusions on in-hospital mortality (p < 0.001). Exploratory analysis in patients who received deeper sedation revealed a beneficial effect of neuromuscular blocking agent infusions on mortality (49% vs 51%; adjusted odds ratio, 0.80; 95% CI, 0.63-0.99, adjusted absolute risk difference, -0.05; p = 0.048). Conclusions: In acute respiratory distress syndrome patients who receive neuromuscular blocking agent infusions, a prolonged, high proportion of deeper sedation is associated with increased mortality. Our data support the view that clinicians should minimize the duration of deeper sedation after recovery from neuromuscular blocking agent infusion.
... The drug was used at a dose of 0.64 µM since it resulted in a significant increase in protein expression on Western blot analysis ( Figure 3). As anticipated, we observed disruption of VE-cadherin distribution in on the results of the ACURASYS study, which showed reduced 90-day mortality (6,7,(25)(26)(27). In 2019, the efficacy of NMBA in ARDS was called into question by the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial, which evaluated cisatracurium versus no cisatracurium in moderate-to-severe ARDS and observed no difference in 90-day mortality (6). ...
Article
Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI) associated with hypoxemic lung damage and inflammation. Matrix metalloproteinase protein-3 (MMP3 or Stromelysin-1) is known to promote vascular injury in ALI/ARDS. Cisatracurium, a nicotinic neuromuscular blocker, is used in ARDS patients to decrease mechanical ventilator dyssynchrony, increase oxygenation, and improve mortality. However, the magnitude and the underlying mechanisms of these potential benefits of cisatracurium remains unclear. We investigated the effect of cisatracurium on lipopolysaccharide-induced MMP3 expression in human microvascular endothelial cells. In our results, cisatracurium treatment significantly decreased LPS-induced MMP3 expression and increased expression of cell junction proteins such as vascular endothelial cadherin (VE-cadherin) and claudin-5.
... In the 2016 SSC guidelines we issued a weak recommendation for using NMBA infusion for 48 hours in sepsis-induced moderate to severe ARDS (12,13). This recommendation was based on a meta-analysis of three trials that examined the role of NMBAs in ARDS (465)(466)(467), showing reduced risks of death (RR, 0.72; 95% CI, 0.58−0.91) and barotrauma (RR, 0.43; 95% CI, 0.20−0.90) ...
... Dugodelujući i srednjedelujući relaksanti imaju veliku ulogu u mehaničkoj ventilaciji. Oni smanjuju asinhroniju između pacijenta i ventilatora, smanjuju disajni rad, poboljšavaju oksigenaciju, čak i smanjuju koncentraciju inflamatornih biomarkera (34,35,36). Relaksaciju treba održavati kontinuirano do 48 časova, a zatim po potrebi bolusno, da bi se sprečila atrofija respiratorne muskulature. ...
Article
Full-text available
The coronavirus disease pandemic (2019) has burdened health systems around the world with a large number of severe patients in a short period of time. According to the law of large numbers, a significant number of critically ill COVID-19 patients appear in such conditions which require treatment in the intensive care unit. That percentage of those patients is around 3 - 5% in different countries. It is similar in Serbia; however, every rule has its exceptions. KBC "Dr Dragiša Mišović-Dedinje" in Belgrade has been determined to take care of the most difficult COVID-19 patients since the beginning of the epidemic due to its space, organizational and personnel possibilities. Out of the total number of patients treated in KBC "Dr Dragiša Mišović-Dedinje", about 25% of patients were treated in the intensive care unit for the above mentioned reasons. Guided by valid treatment protocols, Anesthesiology and Intensive Care clinic of the KBC "Dr Dragiša Mišović-Dedinje" has developed its own work protocols for rapid diagnosis, isolation and clinical management of such difficult patients. These protocols are important not only for the treatment of the most severe COVID-19 patients, but also for the best utilization of hospital resources, as well as for the prevention of the spread of the infection to the medical staff. Extensive experience in the treatment of critically ill patients was gained from the entire engagement during the epidemic, experienced doctors, anesthesiologists-intensivists with great knowledge in the field of work in the intensive care unit, but also managers of clinics and institutions, who can share their experience with health care policy makers. It is clear that in the future, the capacities and organization of work in the field of intensive care medicine should be redefined, as well as health workers should be trained to work in the most demanding field of medicine. Expert experience in the form of practical guidelines, derived from over fourteen months of continuous work in the red zone of COVID-19, where they fought for every breath of the patient, in this review are translated into simplified guidelines for orientation of those who find themselves in a similar situation.
... In addition, deep NMB may improve intraoperative safety by fully preventing any unexpected gross movement (i.e., bucking, coughing, or contraction of abdominal muscles) to occur, which could result in surgical instruments to inflict harm to intra-abdominal organs of the patient. Finally, various studies have noted beneficial immune effects of muscle relaxants [9,30]. Muscle relaxants block various (sub-)types of the nicotinic acetylcholine receptor. ...
Article
Full-text available
Background Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of neuromuscular block (NMB) needed for optimal surgical working conditions and how this relates to other outcomes. For instance, a deep neuromuscular block yields superior surgical working conditions compared to a standard NMB in laparoscopic surgery, however, a robust association to other (safety) outcomes has not yet been established. Methods Trial design: an international multicenter randomized controlled double-blind strategy trial. Trial population: 922 patients planned for elective, laparoscopic or robotic, abdominal surgery. Intervention: Patients will be randomized to a deep NMB (post-tetanic count 1–2 twitches) or standard care (single-dose muscle relaxant administration at induction and repeated only if warranted by surgical team). Main trial endpoints: Primary endpoint is the difference in incidence of intraoperative adverse events during laparoscopic surgery graded according to ClassIntra® classification (i.e., ClassIntra® grade ≥ 2) between both groups. Secondary endpoints include the surgical working conditions, 30-day postoperative complications, and patients’ quality of recovery. Discussion This trial was designed to analyze the effect of deep neuromuscular block compared to standard neuromuscular block on intra- and postoperative adverse events in patients undergoing laparoscopic surgery. Trial registration ClinicalTrials.gov NCT04124757 (EURO-RELAX); registration URL: https://clinicaltrials.gov/ct2/show/NCT04124757 , registered on October 11th, 2019.
... In a multicentre study (ACURASIS trial), early administration of an NMB agent, namely, cisatracurium, improved the outcome by decreasing biotrauma in ARDS 13 . It may be attributed to the anti-inflammatory properties of cisatracurium rather than to a consequence of the reduction in patient-ventilator asynchrony 30 . Although a new multicentre study (ROSE trial) detected no significant decrease on long-term mortality 31 , cisatracurium may reduce biotrauma and short-term mortality 32 . ...
Article
Full-text available
We hypothesized that deep neuromuscular blockade (NMB) with low-pressure pneumoperitoneum (PP) would improve respiratory mechanics and reduce biotrauma compared to moderate NMB with high-pressure PP in a steep Trendelenburg position. Seventy-four women undergoing robotic gynecologic surgery were randomly assigned to two equal groups. Moderate NMB group was maintained with a train of four count of 1–2 and PP at 12 mmHg. Deep NMB group was maintained with a post-tetanic count of 1–2 and PP at 8 mmHg. Inflammatory cytokines were measured at baseline, at the end of PP, and 24 h after surgery. Interleukin-6 increased significantly from baseline at the end of PP and 24 h after the surgery in moderate NMB group but not in deep NMB group ( P group*time = 0.036). The peak inspiratory, driving, and mean airway pressures were significantly higher in moderate NMB group than in deep NMB group at 15 min and 60 min after PP ( P group*time = 0.002, 0.003, and 0.048, respectively). In conclusion, deep NMB with low-pressure PP significantly suppressed the increase in interleukin-6 developed after PP, by significantly improving the respiratory mechanics compared to moderate NMB with high-pressure PP during robotic surgery.
... The rationale for restoring early spontaneous breathing was further strengthened by demonstrating the long-term benefits of daily awakening and spontaneous breathing trials [4]. On the other hand, clinical research in patients with moderate-to-severe ARDS demonstrated that preventing spontaneous breathing through the use of neuromuscular blocking agents may reduce biotrauma [5] and lead to improved clinical outcomes [6]. These findings were supported by experimental studies demonstrating that high transpulmonary pressure swings associated with strong spontaneous breathing efforts may lead to worsening of lung injury [7] and produce local overstretch in inhomogeneously injured lungs [8]. ...
... Most patients were receiving corticosteroids, which may modulate the cellular immune response and could affect the behavior or activation status of lymphocytes and neutrophils; the effect on DEspR expression in vivo is unknown. Critically ill patients also received sedatives, analgesics, and sometimes neuromuscular blocking agents, all of which may affect the inflammatory response 58,59 . Because the study was conducted over 5 months of intensive COVID-19 research and evolving clinical standards, care of early and later patients may have varied somewhat, potentially affecting the immunoinflammatory response. ...
Article
Full-text available
SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.
... 110 A related study found significantly reduced proinflammatory mediators both in pulmonary edema fluid and serum. 111 Thus, combining evidence that P DR < 15 cmH 2 O reduces mortality risk in ARDS, 112 However, the negative impact of spontaneous breathing may depend upon the underlying severity of acute lung injury. 119 In the aforementioned preclinical model, spontaneous breathing during mild lung injury occurred at both a lower P plat and lower effort causing dorsal lung recruitment with improved oxygenation and little histological impact (compared to passive ventilation). ...
Article
Full-text available
Contemplating the future should be grounded in history. The rise of post-Polio intensive care units was inextricably related to mechanical ventilation. Critically-ill patients who developed acute respiratory failure often had "congestive atelectasis" (ie. a term used to describe ARDS prior to 1967). Initial mechanical ventilation strategies for treating this condition and others inadvertently led to ventilator-induced lung injury. Both injurious ventilation and later use of overly cautious weaning practices resulted from both limited technology and understanding of ARDS and other aspects of critical illness. The resulting misperceptions, misconceptions and missed opportunities took decades to rectify, and in some instances still persist. This suggests a reluctance to acknowledge that all therapeutic strategies reflect the historical period in which they were developed and the corresponding limited understanding of ARDS pathophysiology at that time. We are at the threshold of a revolutionary moment in critical care. The confluence of enormous clinical data production, massive computing power, advances in understanding the biomolecular and genetic aspects of critical illness and the emergence of neural networks will have enormous impact on how critical care is practiced in the decades to come. Therefore, it is imperative we understand the long-crooked path needed to reach the era of protective ventilation in order to avoid similar mistakes moving forward. The emerging era is as difficult to fathom as our current practices and technologies were to those practicing 60 years ago. This review explores the history of mechanical ventilation in treating ARDS, describes current protective ventilation strategies and speculates how ARDS management might look 20 years from now.
... 93 In ARDS patients, the use of NMB lowers the proinflammatory cytokines and improves the PaO 2 / FiO 2 ratio. 94 A clinical trial (NCT00299650) evaluated that early administration of cisatracurium besylate in patients with severe ARDS enhances the time off the ventilator and improves survival without increasing muscle weakness. 95 A meta-analysis of 3 RCTs piloted on critically ill adult patients suggested that cisatracurium besylate when given in continuous infusion, increases the survival rate consistently at 28 days, but does not affect the length of mechanical ventilation. ...
Article
Full-text available
Acute respiratory distress syndrome (ARDS) is an overwhelming inflammatory disorder of the lung due to direct and indirect insults to the lungs. ARDS is characterized by increased vascular permeability, protein-rich edema, diffuse alveolar infiltrate, and loss of aerated lung tissue, leading to decreased lung compliance, tachypnea, and severe hypoxemia. COVID-19 is generally associated with ARDS, and it has gained prime importance since it started. The mortality rate is alarmingly high in COVID-19-related ARDS patients regardless of advances in mechanical ventilation. Several pharmacological agents, including corticos-teroids, nitric oxide, neuromuscular blocker, anti-TNF, statins, and exogenous surfactant, have been studied and some are under investigation, like ketoconazole, lisofylline, N-acetylcysteine, prostaglandins, prostacyclin, and fish oil. The purpose of this review is to appraise the understanding of the pathophysiology of ARDS, biomarkers, and clinical trials of pharmacological therapies of ARDS and COVID-19-related ARDS.
... Such increase is expected to vary among patients, as lung elastance is related with the number of ventilated units, being higher with increasing alveolar flooding. Neuromuscular blockers obviously contrast this phenomenon (Forel et al., 2006;Papazian et al., 2010). External (inspiratory) intercostal muscles do exhibit proprioceptors innervation: accordingly, they might increase their contraction on adding external elastance ("load compensating reflex") but would be silent on increasing alveolar pressure (thus, the decrease in elastance remains unopposed). ...
Article
Full-text available
This review analyses the mechanisms by which lung fluid balance is strictly controlled in the air-blood barrier (ABB). Relatively large trans-endothelial and trans-epithelial Starling pressure gradients result in a minimal flow across the ABB thanks to low microvascular permeability aided by the macromolecular structure of the interstitial matrix. These edema safety factors are lost when the integrity of the interstitial matrix is damaged. The result is that small Starling pressure gradients, acting on a progressively expanding alveolar barrier with high permeability, generate a high transvascular flow that causes alveolar flooding in minutes. We modeled the trans-endothelial and trans-epithelial Starling pressure gradients under control conditions, as well as under increasing alveolar pressure (Palv) conditions of up to 25 cmH 2 O. We referred to the wet-to-dry weight (W/D) ratio, a specific index of lung water balance, to be correlated with the functional state of the interstitial structure. W/D averages ∼5 in control and might increase by up to ∼9 in severe edema, corresponding to ∼70% loss in the integrity of the native matrix. Factors buffering edemagenic conditions include: (i) an interstitial capacity for fluid accumulation located in the thick portion of ABB, (ii) the increase in interstitial pressure due to water binding by hyaluronan (the “safety factor” opposing the filtration gradient), and (iii) increased lymphatic flow. Inflammatory factors causing lung tissue damage include those of bacterial/viral and those of sterile nature. Production of reactive oxygen species (ROS) during hypoxia or hyperoxia, or excessive parenchymal stress/strain [lung overdistension caused by patient self-induced lung injury (P-SILI)] can all cause excessive inflammation. We discuss the heterogeneity of intrapulmonary distribution of W/D ratios. A W/D ∼6.5 has been identified as being critical for the transition to severe edema formation. Increasing Palv for W/D > 6.5, both trans-endothelial and trans-epithelial gradients favor filtration leading to alveolar flooding. Neither CT scan nor ultrasound can identify this initial level of lung fluid balance perturbation. A suggestion is put forward to identify a non-invasive tool to detect the earliest stages of perturbation of lung fluid balance before the condition becomes life-threatening.
... Neuromuscular blocking agents (NMBAs) are indicated for management in patients with respiratory failure to improve patient-ventilator synchrony and to prevent ventilator-induced lung injury. Cisatracurium, a stereoisomer of atracurium, is a nondepolarizing NMBA that is commonly used in intensive care unit (ICU) patients due to the proven efficacy from several high-quality published studies and favorable safety profiles [1][2][3][4]. Cisatracurium was used in conjunction with mechanical ventilation strategies to improve oxygenation and to reduce the inflammatory response in respiratory failure patients with acute respiratory distress syndrome (ARDS) [5,6]. ...
Article
Full-text available
Background Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. Methods A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient’characteristics and other factors. Results The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. Conclusion The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. Trial registration ClinicalTrials.gov, NCT03337373. Registered on 9 November 2017
... (19) Three randomized controlled trials demonstrated the positive impact of early neuromuscular blockade in ARDS on functional parameters and mortality. (12,21,22) Little attention has been given to the influences of inspiratory and expiratory muscle efforts, ventilatory modes -either volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV) -or the number of mandatory respiratory cycles (set respiratory rate -RR), all of which are combined, on VT and distending alveolar pressures during assisted MV. The main differences between VCV and PCV during assisted MV are the amount and type of flow delivered to the lungs, which may be higher with greater patient effort and exponential deceleration in the latter. ...
Article
Objective: To evaluate the influences of respiratory muscle efforts and respiratory rate setting in the ventilator on tidal volume and alveolar distending pressures at end inspiration and expiration in volume-controlled ventilation and pressure-controlled ventilation modes in acute respiratory distress syndrome. Methods: An active test lung (ASL 5000™) connected to five intensive care unit ventilators was used in a model of acute respiratory distress syndrome. Respiratory muscle efforts (muscle pressure) were configured in three different ways: no effort (muscle pressure: 0cmH2O); inspiratory efforts only (muscle pressure:-5cmH2O, neural inspiratory time of 0.6s); and both inspiratory and expiratory muscle efforts (muscle pressure:-5/+5cmH2O). Volume-controlled and pressure-controlled ventilation modes were set to deliver a target tidal volume of 420mL and positive end-expiratory pressure of 10cmH2O. The tidal volume delivered to the lungs, alveolar pressures at the end of inspiration, and alveolar pressures at end expiration were evaluated. Results: When triggered by the simulated patient, the median tidal volume was 27mL lower than the set tidal volume (range-63 to +79mL), and there was variation in alveolar pressures with a median of 25.4cmH2O (range 20.5 to 30cmH2O). In the simulated scenarios with both spontaneous inspiratory and expiratory muscle efforts and with a mandatory respiratory rate lower than the simulated patient's efforts, the median tidal volume was higher than controlled breathing. Conclusion: Adjusting respiratory muscle effort and pulmonary ventilator respiratory rate to a value above the patient's respiratory rate in assisted/controlled modes generated large variations in tidal volume and pulmonary pressures, while the controlled mode showed no variations in these outcomes.
... These findings remained consistent when combined in a meta-analysis with earlier, smaller studies from the same group of investigators [7]. Additional beneficial effects of NMBAs observed included sustained improvement in oxygenation, less organ dysfunction, and a lower proinflammatory response [8][9][10]. However, the practice change that followed this trial came under scrutiny after the publication of the Re-evaluation Of Systemic Early Neuromuscular Blockade (ROSE) trial in 2019 [11]. ...
Article
Full-text available
Background Paediatric acute respiratory distress syndrome (PARDS) is a manifestation of severe, life-threatening lung injury necessitating mechanical ventilation with mortality rates ranging up to 40–50%. Neuromuscular blockade agents (NMBAs) may be considered to prevent patient self-inflicted lung injury in PARDS patients, but two trials in adults with severe ARDS yielded conflicting results. To date, randomised controlled trials (RCT) examining the effectiveness and efficacy of NMBAs for PARDS are lacking. We hypothesise that using NMBAs for 48 h in paediatric patients younger than 5 years of age with early moderate-to-severe PARDS will lead to at least a 20% reduction in cumulative respiratory morbidity score 12 months after discharge from the paediatric intensive care unit (PICU). Methods This is a phase IV, multicentre, randomised, double-blind, placebo-controlled trial performed in level-3 PICUs in the Netherlands. Eligible for inclusion are children younger than 5 years of age requiring invasive mechanical ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H 2 O for moderate-to-severe PARDS occurring within the first 96 h of PICU admission. Patients are randomised to continuous infusion of rocuronium bromide or placebo for 48 h. The primary endpoint is the cumulative respiratory morbidity score 12 months after PICU discharge, adjusted for confounding by age, gestational age, family history of asthma and/or allergy, season in which questionnaire was filled out, day-care and parental smoking. Secondary outcomes include respiratory mechanics, oxygenation and ventilation metrics, pulmonary and systemic inflammation markers, prevalence of critical illness polyneuropathy and myopathy and metrics for patient outcome including ventilator free days at day 28, length of PICU and hospital stay, and mortality Discussion This is the first paediatric trial evaluating the effects of muscular paralysis in moderate-to-severe PARDS. The proposed study addresses a huge research gap identified by the Paediatric Acute Lung Injury Consensus Collaborative by evaluating practical needs regarding the treatment of PARDS. Paediatric critical care practitioners are inclined to use interventions such as NMBAs in the most critically ill. This liberal use must be weighed against potential side effects. The proposed study will provide much needed scientific support in the decision-making to start NMBAs in moderate-to-severe PARDS. Trial registration ClinicalTrials.gov NCT02902055 . Registered on September 15, 2016.
... six studies reported P:F ratios after 24 hours, [41][42][43][44][45][46] and NMB was associated with an improvement in P:F ratio (MD 29.77 [5.15-54.40]; P=0.02; Table II). ...
Article
Introduction: Acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality. We undertook a meta-analysis of randomized controlled trials (RCTs) to determine the mortality benefit of non-specialist therapeutic interventions for ARDS available to general critical care units. Evidence acquisition: A systematic search of MEDLINE, Embase, and the Cochrane Central Register for RCTs investigating therapeutic interventions in ARDS including corticosteroids, fluid management strategy, high PEEP, low tidal volume ventilation, neuromuscular blockade, prone position ventilation, or recruitment maneuvers. Data was collected on demographic information, treatment strategy, duration and dose of treatment, and primary (28 or 30-day mortality) and secondary (PaO2:FiO2 ratio at 24-48 hours) outcomes. Evidence synthesis: No improvement in 28-day mortality could be demonstrated in three RCTs investigating high PEEP (28.0% vs. 30.2% control; risk ratio [confidence interval] 0.93 [0.82-1.06]; eight assessing prone position ventilation (39.3% vs. 44.5%; RR 0.83 [0.68-1.01]; seven investigating neuromuscular blockade (37.8% vs. 42.0%; RR 0.91 [0.81-1.03]); ten investigating recruitment maneuvers (42.4% vs. 42.1%; RR 1.01 [0.91-1.12]); eight investigating steroids (34.8% vs. 41.1%; RR 0.81 [0.59-1.12]); and one investigating conservative fluid strategies (25.5% vs. 28.4%; RR 0.90 [0.73-1.10]). Three studies assessing low tidal volume ventilation (33.1% vs. 41.9 %; RR 0.79 (0.68-0.91); p=0.001), and subgroup analyses within studies investigating prone position ventilation greater than 12 hours (33.1% vs. 44.4%; RR 0.75 [0.59-0.95), p=0.02) did reveal outcome benefit. Conclusions: Among non-specialist therapeutic strategies available to general critical care units, low tidal volumes and prone position ventilation for greater than 12 hours improve mortality in ARDS.
Chapter
Mechanical ventilation is a central component of the management of patients with acute respiratory distress syndrome (ARDS). However, if it is used improperly, it can lead to further lung injury and worsen clinical outcomes. In this chapter, we present the clinical evidence for lung-protective and open lung ventilation, driving pressure, modes of ventilation, neuromuscular blockade, and prone positioning. We frame our discussion around when and how these strategies can improve outcomes by considering the mechanisms by which they might mitigate ventilator-induced lung injury.
Chapter
Akut respiratuar distres sendromu (ARDS) çeşitli nedenlere bağlı, akut olarak gelişen, artmış inflamatuar yanıta ve akciğerlerde alveolokapiller membran geçirgenliğinde artışa ikincil pulmoner ödem ve ağır hipoksemi ile karakterize hayatı tehdit edici akciğer hasarıdır
Article
Background While emergency physicians are familiar with the management of hypoxemic respiratory failure, management of mechanical ventilation and advanced therapies for oxygenation in the emergency department (ED) have become essential with the pandemic of COVID-19. Objective of the Review: To review current evidence on hypoxemia in COVID-19 and place it in the context of known evidence-based management of hypoxemic respiratory failure in the ED. Discussion COVID-19 causes mortality primarily through the development of acute respiratory distress syndrome (ARDS), with hypoxemia arising from shunt, a mismatch of ventilation and perfusion. Management of patients developing ARDS should focus on mitigating derecruitment and avoiding volutrauma or barotrauma. Conclusions High flow nasal cannula (HFNC) and non-invasive positive pressure ventilation (NIPPV) have a more limited role in COVID-19 due to risk of aerosolization and minimal benefit in severe cases but can be considered. Stable patients who can tolerate repositioning should be placed in prone position while awake. Once intubated, patients should be managed with ventilation strategies appropriate for ARDS, including targeting lung-protective volumes and low pressures. Increasing positive end-expiratory pressure (PEEP) can be beneficial. Inhaled pulmonary vasodilators do not decrease mortality but may be given to improve refractory hypoxemia. Prone positioning of intubated patients is associated with a mortality reduction in ARDS and can be considered for patients with persistent hypoxemia. Neuromuscular blockade should also be administered in patients who remain dyssynchronous with the ventilator despite adequate sedation. Finally, patients with refractory severe hypoxemic respiratory failure in COVID-19 should be considered for veno-venous extracorporeal membrane oxygenation (VV-ECMO).
Article
Introduction: With the latest addition from Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial result, the question of mortality benefit from neuromuscular blocking agents (NMBAs) in different studies, remained unanswered. We hypothesize that NMBAs use in moderate to severe acute respiratory distress syndrome (ARDS) does not influence intensive care unit (ICU) mortality. Evidence acquisition: Pubmed, Embase and the Cochrane Library were searched for randomized controlled trials (RCTs) related to NMBAs infusion in patients with ARDS. The primary outcome was ICU mortality. Secondary outcomes were mortality at day 28 and day 90, oxygenation response to NMBA, ICU length of stay (LOS), ICU Acquired weakness (ICU-AW) and ventilator-free days (VFDs). Meta-analysis was conducted to re-evaluate the effect of NMBAs on patients with ARDS with all randomised controlled trials available. Evidence synthesis: NMBAs infusion was associated with reduced ICU mortality [relative ratio (RR) : 0.69; 95% confidence-interval (CI): 0.55-0.88; I2 = 0 %], but not 28 days mortality (RR: 0.76; 95% CI: 0.57-1.0; I2 = 49%) and 90-day mortality (RR: 0.87; 95% CI: 0.70-1.08; I2 = 46%). NMBA use was not associated with increased risk of ICU-AW (RR, 1.21; 95% CI, 0.84 to 1.76; I2 = 34%). Conclusions: Early 48-hour NMBAs infusion in patients with moderate to severe ARDS was associated with reduced ICU mortality without improvement in oxygenation, VFDs, 28-day and 90-day mortality. It did not contribute significantly to ICU-AW. Based on these results, NMBAs infusion is recommended for moderate to severe ARDS for its short-term benefit in early phase of disease. Prolonged use of NMBAs beyond 48 hours requires further study.
Article
Purpose The aim of the present article is to briefly summarize current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19. Methods The PubMed, Scopus, and Google Scholar databases were comprehensively searched for relevant studies. Findings The novel coronavirus causes a wide spectrum of clinical manifestations, with large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome and multiple organ failure. In these patients, the equilibrium of the inflammatory response is a major determinant of survival. The impact of anesthetics on immune system modulation may vary and include both pro-inflammatory and anti-inflammatory effects. Implications Inhibition of the development of severe inflammation and/or the enhancement of inflammation resolution by anesthetics may limit organ damage and improve outcomes in COVID-19 patients.
Article
Full-text available
PurposeMost randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome.MethodsA systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity.ResultsIn total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001).Conclusion Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics.
Article
Full-text available
Background Control-arm mortality varies between acute respiratory distress syndrome (ARDS) RCTs. Methods We systematically reviewed ARDS RCTs that commenced recruitment after publication of the American–European Consensus (AECC) definition (MEDLINE, Embase, and Cochrane central register of controlled trials; January 1994 to October 2020). We assessed concordance of RCT inclusion criteria to ARDS consensus definitions and whether exclusion criteria are strongly or poorly justified. We estimated the proportion of between-trial difference in control-arm 28-day mortality explained by the inclusion criteria and RCT design characteristics using meta-regression. Results A literature search identified 43 709 records. One hundred and fifty ARDS RCTs were included; 146/150 (97.3%) RCTs defined ARDS inclusion criteria using AECC/Berlin definitions. Deviations from consensus definitions, primarily aimed at improving ARDS diagnostic certainty, frequently related to duration of hypoxaemia (117/146; 80.1%). Exclusion criteria could be grouped by rationale for selection into strongly or poorly justified criteria. Common poorly justified exclusions included pregnancy related, age, and comorbidities (infectious/immunosuppression, hepatic, renal, and human immunodeficiency virus/acquired immunodeficiency syndrome). Control-arm 28-day mortality varied between ARDS RCTs (mean: 29.8% [95% confidence interval: 27.0–32.7%; I²=88.8%; τ²=0.02; P<0.01]), and differed significantly between RCTs with different Pao2:FiO2 ratio inclusion thresholds (26.6–39.9 kPa vs <26.6 kPa; P<0.01). In a meta-regression model, inclusion criteria and RCT design characteristics accounted for 30.6% of between-trial difference (P<0.01). Conclusions In most ARDS RCTs, consensus definitions are modified to use as inclusion criteria. Between-RCT mortality differences are mostly explained by the Pao2:FiO2 ratio threshold within the consensus definitions. An exclusion criteria framework can be applied when designing and reporting exclusion criteria in future ARDS RCTs.
Chapter
Acute respiratory distress syndrome (ARDS) is a prevalent and important cause of respiratory failure. Underlying causes include pulmonary and non-pulmonary aetiologies. ARDS is acute hypoxaemic respiratory failure associated with non-cardiogenic pulmonary oedema, reduced pulmonary compliance, and can lead to lung fibrosis. In addition to treating the underlying cause, often the mainstay of the management of ARDS is invasive mechanical ventilation. This can perpetuate lung injury—ventilator-associated lung injury (VALI). Despite recent advances in our understanding of this, ARDS-associated morbidity and mortality remains high. This chapter discusses the pathophysiology of ARDS and its management, including mechanical ventilation, adjunctive therapies, and some recently trialed pharmacotherapies.
Article
Purpose of review: The aim of this review was to describe the risk factors for developing diaphragm dysfunction, discuss the monitoring techniques for diaphragm activity and function, and introduce potential strategies to incorporate diaphragm protection into conventional lung-protective mechanical ventilation strategies. Recent findings: It is increasingly apparent that an approach that addresses diaphragm-protective ventilations goals is needed to optimize ventilator management and improve patient outcomes. Ventilator-induced diaphragm dysfunction (VIDD) is common and is associated with increased ICU length of stay, prolonged weaning and increased mortality. Over-assistance, under-assistance and patient-ventilator dyssynchrony may have important downstream clinical consequences related to VIDD. Numerous monitoring techniques are available to assess diaphragm function, including respiratory system pressures, oesophageal manometry, diaphragm ultrasound and electromyography. Novel techniques including phrenic nerve stimulation may facilitate the achievement of lung and diaphragm-protective goals for mechanical ventilation. Summary: Diaphragm protection is an important consideration in optimizing ventilator management in patients with acute respiratory failure. The delicate balance between lung and diaphragm-protective goals is challenging. Phrenic nerve stimulation may be uniquely situated to achieve and balance these two commonly conflicting goals.
Article
Introduction: Ventilatory management and general supportive care of acute respiratory distress syndrome (ARDS) in the adult population have led to significant clinical improvements, but morbidity and mortality remain high. Pharmacologic strategies acting on the coagulation cascade, inflammation, oxidative stress, and endothelial cell injury have been targeted in the last decade for patients with ARDS, but only a few of these have shown potential benefits with a meaningful clinical response and improved patient outcomes. The lack of availability of specific pharmacologic treatments for ARDS can be attributed to its complex pathophysiology, different risk factors, huge heterogeneity, and difficult classification into specific biological phenotypes and genotypes. Areas covered: In this narrative review, we briefly discuss the relevance and current advances in pharmacologic treatments for ARDS in adults and the need for the development of new pharmacological strategies. Expert opinion: Identification of ARDS phenotypes, risk factors, heterogeneity, and pathophysiology may help to design clinical trials personalized according to ARDS-specific features, thus hopefully decreasing the rate of failed clinical pharmacologic trials. This concept is still under clinical investigation and needs further development.
Article
Purpose To compare the ventilatory and clinical outcomes associated with a fixed-dose cisatracurium infusion versus a titrated infusion strategy in patients with Acute Respiratory Distress Syndrome (ARDS). Materials and methods Single-center, retrospective, cohort study in a medical ICU of a tertiary care academic medical center. Adult patients ≥18 years old with a continuous infusion of cisatracurium for ≥12 h for treatment of ARDS were included. The primary outcome was the PaO2 /FiO2 ratio assessed at 24 and 48 h following cisatracurium initiation. Secondary outcomes included amount of average dose of drug administered, 28-day ventilator-free days, LOS, and hospital mortality. Results 167 patients were included; median baseline PaO2/FiO2 was 97 (76–146), median SOFA score of 9 (7–11), and ICU mortality was 71/167 (43%). In a mixed-effects model, fixed dose and titrated cisatracurium associated with similar changes in PaO2/FiO2 assessed at 24 and 48 h (p = 0.316). Fixed-dose was associated with a >3-fold increase in drug exposure (average dose 6.4 (5.4–8.0) vs. 2.0 (1.5–2.8) mcg/kg/min; p < 0.001, respectively). No differences were observed in secondary clinical endpoints. Conclusion Fixed-dose cisatracurium was associated with similar ventilatory and clinical outcomes compared to titrated strategy, yet it was associated with a 3-fold increase in dose administered.
Article
Résumé L’usage des curares en réanimation répond essentiellement a deux objectifs : améliorer les conditions d’intubation et faciliter la ventilation des patients en SDRA. Les conditions de l’intubation qui sont souvent celles de l’urgence imposent l’administration d’un curare d’action rapide : succinylcholine ou rocuronium. Le cisatracurium est le curare de référence pour la curarisation continue. La curarisation diminue les pressions intra-thoraciques et améliore les échanges gazeux mais pas la survie des patients ayant un ARDS. La relation entre neuromyopathie de réanimation et curarisation reste discutée.
Article
Neuromuscular blocking agents (NMBAs) and prone position (PP) are two major adjunctive therapies that can improve outcome in moderate-to-severe acute respiratory distress syndrome. NMBA should be used once lung-protective mechanical ventilation has been set, for 48 hours or less and as a continuous intravenous infusion. PP should be used as early as possible for long sessions; in COVID-19 its use has exploded. In nonintubated patients, PP might reduce the rate of intubation but not mortality. The goal of this article is to perform a narrative review on the pathophysiological rationale, the clinical effects, and the clinical use and recommendations of both NMBA and PP.
Chapter
Acute respiratory distress syndrome (ARDS) is a life-threatening cause of hypoxemic respiratory failure characterized by noncardiogenic pulmonary edema and poor lung compliance in the setting of inflammatory alveolar damage. A myriad of direct and indirect pulmonary insults can precipitate its development, and it remains a common cause of respiratory failure in the intensive care unit (ICU). Ten percent of critically ill patients and 23% of mechanically ventilated patients meet diagnostic criteria for ARDS, and the syndrome remains underrecognized by clinicians.¹ Despite the evolution of therapeutic options in the 50 years since it was first recognized, mortality for ARDS remains 35% to 46%.¹ Treatment strategies with demonstrated benefit are primarily supportive and include lung protective ventilation, prone positioning, and extracorporeal membrane oxygenation for refractory, life-threatening hypoxemia.
Article
Acute respiratory distress syndrome (ARDS) presents as an acute inflammatory lung injury characterized by refractory hypoxemia and non-cardiac pulmonary edema. An estimated 10% of patients in the intensive care unit and 25% of those who are mechanically ventilated are diagnosed with ARDS. Increased awareness is warranted as mortality rates remain high and delays in diagnosing ARDS are common. The COVID-19 pandemic highlights the importance of understanding ARDS management. Treatment of ARDS can be challenging due to the complexity of the disease state and conflicting existing evidence. Therefore, it is imperative that pharmacists understand both pharmacologic and non-pharmacologic treatment strategies to optimize patient care. This narrative review provides a critical evaluation of current literature describing management practices for ARDS. A review of treatment modalities and supportive care strategies will be presented.
Article
Full-text available
Background: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D); we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D); we suggest against routinely implementing NO inhalation therapy (GRADE 2C); and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jrs.or.jp/publication/jrs_guidelines/). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.
Article
Veno‐venous extracorporeal membrane oxygenation is indicated in patients with acute respiratory distress syndrome and severely impaired gas exchange despite evidence‐based lung protective ventilation, prone positioning and other parts of the standard algorithm for treating such patients. Extracorporeal support can facilitate ultra‐lung‐protective ventilation, meaning even lower volumes and pressures than standard lung‐protective ventilation, by directly removing carbon dioxide in patients needing injurious ventilator settings to maintain sufficient gas exchange. Injurious ventilation results in ventilator‐induced lung injury, which is one of the main determinants of mortality in acute respiratory distress syndrome. Marked reductions in the intensity of ventilation to the lowest tolerable levels under extracorporeal support may be achieved and could thereby potentially mitigate ventilator‐induced lung injury and theoretically patient self‐inflicted lung injury in spontaneously breathing patients with high respiratory drive. However, the benefits of this strategy may be counterbalanced by the use of continuous deep sedation and even neuromuscular blocking drugs, which may impair physical rehabilitation and impact long‐term outcomes. There are currently a lack of large‐scale prospective data to inform optimal invasive ventilation practices and how to best apply a holistic approach to patients receiving veno‐venous extracorporeal membrane oxygenation, while minimising ventilator‐induced and patient self‐inflicted lung injury. We aimed to review the literature relating to invasive ventilation strategies in patients with acute respiratory distress syndrome receiving extracorporeal support and discuss personalised ventilation approaches and the potential role of adjunctive therapies in facilitating lung protection.
Article
Full-text available
The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality (10 to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged, and it may be different in Europe. Part of the reason for these uncertainties are the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The American-European Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.
Article
Full-text available
The acute respiratory distress syndrome (ARDS) continues as a contributor to the morbidity and mortality of patients in intensive care units throughout the world, imparting tremendous human and financial costs. During the last ten years there has been a decline in ARDS mortality without a clear explanation. The American-European Consensus Committee on ARDS was formed to re-evaluate the standards for the ICU care of patients with acute lung injury (ALI), with regard to ventilatory strategies, the more promising pharmacologic agents, and the definition and quantification of pathological features of ALI that require resolution. It was felt that the definition of strategies for the clinical design and coordination of studies between centers and continents was becoming increasingly important to facilitate the study of various new therapies for ARDS.
Article
Full-text available
The respective roles of high pressure and high tidal volume to promote high airway pressure pulmonary edema are unclear. Positive end-expiratory pressure (PEEP) was shown to reduce lung water content in this type of edema, but its possible effects on cellular lesions were not documented. We compared the consequences of normal tidal volume ventilation in mechanically ventilated rats at a high airway pressure (HiP-LoV) with those of high tidal volume ventilation at a high (HiP-HiV) or low (LoP-HiV) airway pressure and the effects of PEEP (10 cm H2O) on both edema and lung ultrastructure. Pulmonary edema was assessed by extravascular lung water content and microvascular permeability by the drug lung weight and the distribution space of 125I-labeled albumin. HiP-LoV rat lungs were not different from those of controls (7 cm H2O peak pressure ventilation). By contrast, the lungs from the groups submitted to high volume ventilation had significant permeability type edema. This edema was more pronounced in LoP-HiV rats. It was markedly reduced by PEEP, which, in addition, preserved the normal ultrastructural aspect of the alveolar epithelium. This was in striking contrast to the diffuse alveolar damage usually encountered in this type of edema. To our knowledge, this constitutes the first example of a protective effect of PEEP during permeability edema.
Article
Full-text available
Alphaxalone-alphadolone (Althesin), diluted and administered as a controlled infusion, was used as a sedative for 30 patients in an intensive therapy unit. This technique allowed rapid and accurate control of the level of sedation. It had three particularly useful applications: it provided "light sleep," allowed rapid variation in the level of sedation, and enabled repeated assessment of the central nervous system.Sedation was satisfactory for 86% of the total time, and no serious complications were attributed to the use of the drug. Furthermore, though alphaxalone-alphadolone was given for periods up to 20 days there was no evidence of tachyphylaxis or delay in recovery time.
Article
Full-text available
The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies carries a high morbidity, mortality (10-90%) and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those whose wish to know the true incidence and outcome on this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.
Article
Full-text available
Intermittent positive pressure ventilation with large tidal volumes and high peak airway pressures can result in pulmonary barotrauma. In the present study, we examined the hypothesis that ventilation at very low lung volumes can also worsen lung injury by repeated opening and closing of airway and alveolar duct units as ventilation occurs from below to above the infection point (Pinf) as determined from the inspiratory pressure-volume curve. We ventilated isolated, nonperfused, lavaged rat lungs with physiologic tidal volumes (5 to 6 ml/kg) at different end-expiratory pressures (above and below Pinf) and studied the effect on compliance and lung injury. In the groups ventilated with positive end-expiratory pressure (PEEP) below Pinf compliance fell dramatically after ventilation. It did not change in either the control group or the group ventilated with PEEP above Pinf. Lung injury assessed morphologically was significantly greater in the groups ventilated with a PEEP below Pinf, and in these groups the site of injury was dependent on the level of PEEP. The group ventilated without PEEP had significantly greater respiratory and membranous injury to bronchioles, while the group ventilated with PEEP of 4 cm H2O had significantly greater alveolar duct injury. In conclusion, ventilation at lung volumes below those found at Pinf caused a significant decrease in lung compliance and progression of lung injury. Therefore, in addition to high airway pressures, end-expiratory lung volume is an important determinant of the degree and site of lung injury during positive-pressure ventilation.
Article
Full-text available
Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1) have been found to be elevated in bronchoalveolar lavage (BAL) fluid and in plasma from patients with acute respiratory distress syndrome (ARDS). In order to measure the balance of proinflammatory cytokines and their inhibitors, we quantified the upregulation of intercellular adhesion molecules (ICAM-1) induced by ARDS BAL fluids in human alveolar type II-like (A459) cells, and defined proinflammatory activity as the amount of ICAM-1 induced by the SAL fluids. Proinflammatory activity was detected in 77% of the SAL fluids sampled during the first week of ARDS, was found maximal during the 3 first days after onset of ARDS, and was significantly greater than in BAL specimens from at risk patients. Blocking experiments with specific inhibitors of TNF and IL-1 added to the BAL fluids indicated that the bioactivity measured was mainly due to IL-1. In contrast, proinflammatory activity of conditioned supernates from endotoxin-treated alveolar macrophages was mostly due to TNF. Using a bioassay that measures balance of cytokines with their inhibitors, our results indicate that the net proinflammatory activity in ARDS BAL fluids is attributable to IL-1 and not to TNF.
Article
Full-text available
Regional ventilation and perfusion were studied in 10 anesthetized paralyzed supine patients by single-photon emission computerized tomography. Atelectasis was estimated from two transaxial computerized tomography scans. The ventilation-perfusion (V/Q) distribution was also evaluated by multiple inert gas elimination. While the patients were awake, inert gas V/Q ration was normal, and shunt did not exceed 1% in any patient. Computerized tomography showed no atelectasis. During anesthesia, shunt ranged from 0.4 to 12.2. Nine patients displayed atelectasis (0.6-7.2% of the intrathoracic area), and shunt correlated with the atelectasis (r = 0.91, P < 0.001). Shunt was located in dependent lung regions corresponding to the atelectatic area. There was considerable V/Q mismatch, with ventilation mainly of ventral lung regions and perfusion of dorsal regions. Little perfusion was seen in the most ventral parts (zone 1) of caudal (diaphragmatic) lung regions. In summary, shunt during anesthesia is due to atelectasis in dependent lung regions. The V/Q distributions differ from those shown earlier in awake subjects.
Article
Full-text available
We examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a preexisting inflammatory stimulus. 55 Sprague-Dawley rats were randomized to either intravenous saline or lipopolysaccharide (LPS). After 50 min of spontaneous respiration, the lungs were excised and randomized to 2 h of ventilation with one of four strategies: (a) control (C), tidal volume (Vt) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H2O; (b) moderate volume, high PEEP (MVHP), Vt = 15 cc/kg; PEEP = 10 cm H2O; (c) moderate volume, zero PEEP (MVZP), Vt = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), Vt = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFalpha, IL-1beta, IL-6, IL-10, MIP-2, and IFNgamma were measured by ELISA. Zero PEEP in combination with high volume ventilation (HVZP) had a synergistic effect on cytokine levels (e.g., 56-fold increase of TNFalpha versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three-fold increase in TNFalpha, whereas MVZP produced a six-fold increase in lavage TNFalpha. Northern blot analysis revealed a similar pattern (C, MVHP < MVZP < HVZP) for induction of c-fos mRNA. These data support the concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus may play a role in initiating or propagating a local, and possibly systemic inflammatory response.
Article
Full-text available
Artificial mechanical ventilation represents a major cause of iatrogenic lung damage in intensive care. It is largely unknown which mediators, if any, contribute to the onset of such complications. We investigated whether stress caused by artificial mechanical ventilation leads to induction, synthesis, and release of cytokines or eicosanoids from lung tissue. We used the isolated perfused and ventilated mouse lung where frequent perfusate sampling allows determination of mediator release into the perfusate. Hyperventilation was executed with either negative (NPV) or positive pressure ventilation (PPV) at a transpulmonary pressure that was increased 2.5-fold above normal. Both modes of hyperventilation resulted in an approximately 1.75-fold increased expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) mRNA, but not of cyclooxygenase-2 mRNA. After switching to hyperventilation, prostacyclin release into the perfusate increased almost instantaneously from 19 +/- 17 pg/min to 230 +/- 160 pg/min (PPV) or 115 +/- 87 pg/min (NPV). The enhancement in TNFalpha and IL-6 production developed more slowly. In control lungs after 150 min of perfusion and ventilation, TNFalpha and IL-6 production was 23 +/- 20 pg/min and 330 +/- 210 pg/min, respectively. In lungs hyperventilated for 150 min, TNFalpha and IL-6 production were increased to 287 +/- 180 pg/min and more than 1,000 pg/min, respectively. We conclude that artificial ventilation might cause pulmonary and systemic adverse reactions by inducing the release of mediators into the circulation.
Article
Full-text available
The acute respiratory distress syndrome (ARDS) continues as a contributor to the morbidity and mortality of patients in intensive care units throughout the world, imparting tremendous human and financial costs. During the last ten years there has been a decline in ARDS mortality without a clear explanation. The American-European Consensus Committee on ARDS was formed to re-evaluate the standards for the ICU care of patients with acute lung injury (ALI), with regard to ventilatory strategies, the more promising pharmacologic agents, and the definition and quantification of pathological features of ALI that require resolution. It was felt that the definition of strategies for the clinical design and coordination of studies between centers and continents was becoming increasingly important to facilitate the study of various new therapies for ARDS.
Article
Full-text available
Few problems facing the intensivist are as frustrating or as difficult to manage as multiple system organ failure (MSOF). While the precise etiology remains unknown, an integral feature is the development of a rampant systemic inflammatory response that persists unabated by host control mechanisms. Either a single massive insult, or a series of less intense insults (i.e., "two-hits") appear to be necessary to overwhelm the individuals innate regulatory mechanisms. Often the lung is the first organ to fail, leading to initiation (or continuation) of ventilatory support. Although in some patients a precipitating nidus of infection or inflammation is identifiable, and lung injury is simply the first clinically evident manifestation of a systemic process, there remain a large number of patients in whom the explanation for progression from respiratory failure to multiple system organ failure is unclear. In this Perspective, we explore the hypothesis that mechanical ventilation may play a pivotal (and hereto unrecognized) role in the initiation and/or propagation of a systemic inflammatory response leading to MSOF in certain patients. We address this issue by examining the following questions: Can mechanical ventilation initiate or exacerbate lung injury/inflammation? Can lung injury/inflammation lead to systemic inflammation? Is there evidence of MSOF secondary to mechanical ventilation?.
Article
Objective: To present guidelines for hemodynamic support of adult patients with sepsis. Participants: An international task force of nine experts in disciplines related to critical care medicine was convened from the membership of the Society of Critical Care Medicine. Evidence: Review of published literature and expertise and personal experience of task force. The strength of evidence of human studies was classified according to study design and scientific value. Consensus process: The task force met several times in person and communicated by electronic mail to identify the pertinent literature and arrive at consensus recommendations. Consideration was given to the relationship between the weight of scientific evidence and the experts'opinions. Draft documents were composed and debated by the task force until consensus was reached. The strength of recommendations was graded according to evidenced-based guidelines. Conclusions: The panel formulated an underlying approach to the hemodynamic support of sepsis. Hemodynamic therapies should be titrated to specific and definable endpoints. The effects of therapy should be assessed by monitoring a combination of parameters of global and regional perfusion. Using this approach, the panel made specific recommendations for fluid resuscitation, vasopressor therapy, and inotropic therapy of septic patients.
Article
Objective. —To develop and validate a new Simplified Acute Physiology Score, the SAPS II, from a large sample of surgical and medical patients, and to provide a method to convert the score to a probability of hospital mortality.Design and Setting. —The SAPS II and the probability of hospital mortality were developed and validated using data from consecutive admissions to 137 adult medical and/or surgical intensive care units in 12 countries.Patients. —The 13 152 patients were randomly divided into developmental (65%) and validation (35%) samples. Patients younger than 18 years, burn patients, coronary care patients, and cardiac surgery patients were excluded.Outcome Measure. —Vital status at hospital discharge.Results. —The SAPS II includes only 17 variables: 12 physiology variables, age, type of admission (scheduled surgical, unscheduled surgical, or medical), and three underlying disease variables (acquired immunodeficiency syndrome, metastatic cancer, and hematologic malignancy). Goodness-of-fit tests indicated that the model performed well in the developmental sample and validated well in an independent sample of patients (P=.883 and P=.104 in the developmental and validation samples, respectively). The area under the receiver operating characteristic curve was 0.88 in the developmental sample and 0.86 in the validation sample.Conclusion. —The SAPS II, based on a large international sample of patients, provides an estimate of the risk of death without having to specify a primary diagnosis. This is a starting point for future evaluation of the efficiency of intensive care units.(JAMA. 1993;270:2957-2963)
Article
• Arterial blood oxygenation improved repeatedly after sedation and paralysis in a 27-year-old woman requiring mechanical ventilation for the adult respiratory distress syndrome. Oxygen consumption and cardiac output decreased proportionately after paralysis so that the partial pressure of oxygen in mixed venous blood remained unchanged. Paralysis eliminated inspiratory distortion of the airway pressure waveform and prevented forceful use of expiratory musculature. A flow-related reduction of venous admixture or recruitment of lung volume may best explain the beneficial effect of muscle relaxation on arterial saturation. (Arch Intern Med 1985;145:1718-1720)
Article
Carlos, FerrandoMarina, SoroJaume, CanetMa Carmen, UnzuetaFernando, SuárezJulián, LibreroSalvador, PeiróAlicia, LlombartCarlos, DelgadoIrene, LeónLucas, RoviraFernando, RamascoManuel, GranellCésar, AldecoaOscar, DiazJaume, BalustIgnacio, GaruttiManuel, de la MattaAlberto, PensadoRafael, GonzalezMª Eugenia, DuránLucia, GallegoSantiago García, del ValleFrancisco J, RedondoPedro, DiazDavid, PestañaAurelio, RodríguezJavier, AguirreJose M, GarcíaJavier, GarcíaElena, EspinosaPedro, CharcoJose, NavarroClara, RodríguezGerardo, TusmanFrancisco Javier, Belda. (2015) Rationale and study design for an individualized perioperative open lung ventilatory strategy (iPROVE): study protocol for a randomized controlled trial. Trials 16 CrossRef Andrés, EstebanFernando, Frutos-VivarAlfonso, MurielNiall D., FergusonOscar, PeñuelasVictor, AbrairaKonstantinos, RaymondosFernando, RiosNicolas, NinCarlos, ApezteguíaDamian A., VioliArnaud W., ThilleLaurent, BrochardMarco, GonzálezAsisclo J., VillagomezJavier, HurtadoAndrew R., DaviesBin, DuSalvatore M., MaggiorePaolo, PelosiLuis, SotoVinko, TomicicGabriel, D’EmpaireDimitrios, MatamisFekri, AbrougRui P., MorenoMarco Antonio, SoaresYaseen, ArabiFreddy, SandiManuel, JibajaPravin, AminYounsuck, KohMichael A., KuiperHans-Henrik, BülowAmine Ali, ZeggwaghAntonio, Anzueto. (2013) Evolution of Mortality over Time in Patients Receiving Mechanical Ventilation. American Journal of Respiratory and Critical Care Medicine 188, 220-230 CrossRef L. Y., ZhaoJ. K., LuY., XuX. S., LiuE. M., QingC., LiuS., MinK., WeiD., LiuJ., LuoP., LiJ., DongX.- b., LiuC., LiuS., MinK., WeiD., LiuJ., LuoP., LiJ., DongX.- b., LiuK., XieY., YuH., ChenH., HanX., SunG., WangY. L., LiZ. H., HuangD. M., QuX. S., XueB. W., YuH. Y., WangZ. T., WenC. X., WangY., WeiG. L., WangW., YangZ., YueX., CuiY., GuoL., ZhangH., ZhouW., LiY., ZhangK. X., LiuT., YuL., LiuS., MinW., LiK., WeiJ., CaoJ., LuoB., WangJ., CaoQ. S., LiL., LiuK., WeiP., LiJ., DongS., MinY., LuJ., YuC., DongH., ChenK., XieH., HanG., WangW., WangY., YuY., MaoE., GuX., SuZ.- y., GengY.- l., ZhengX., FangL., HouW., LiJ., DengZ. P., FangQ. Z., YangC., LeiY., ChenX., ChenX., LiS., ChenH. L., DongL., XiongD. X., LeiH., TianL., YueX. L., JiangX. R., Song. (2013) Abstracts of a joint meeting of the Anaesthetic Research Society and the Chinese Society of Anesthesiologists. British Journal of Anaesthesia 110, 146-160 CrossRef
Article
Formation of atelectasis is one mechanism of impaired gas exchange during general anaesthesia. We have studied manoeuvres to re-expand such atelectasis in 16 consecutive, anaesthetized adults with healthy lungs. In group 1 (10 patients), the lungs were inflated stepwise to an airway pressure (Paw) of 10, 20, 30 and 40 cm H2O. In group 2 (six patients), three repeated inflations up to Paw = 30 cm H2O were followed by one inflation to 40 cm H2O. Atelectasis was assessed by analysis of computed x-ray tomography (CT). In group 1 the mean area of atelectasis in the CT scan at the level of the right diaphragm was 6.4 cm2 at Paw = 0 cm H2O, 5.9 cm2 at 20 cm H2O, 3.5 cm2 at 30 cm H2O and 0.8 cm2 at 40 cm H2O. A Paw of 20 cm H2O corresponds approximately to inflation with twice the tidal volume. In group 2 the mean area of atelectasis was 9.0 cm2 at Paw = 0 cm H2O and 4.2 cm2 after the first inflation to 30 cm H2O. Repeated inflations did not add to re-expansion of atelectasis. The final inflation (Paw = 40 cm H2O) virtually eliminated the atelectasis. We conclude that, after induction of anaesthesia, the amount of atelectasis was not reduced by inflation of the lungs with a conventional tidal volume or with a double tidal volume ("sigg"). An inflation to vital capacity (Paw = 40 cm H2O), however, re-expanded virtually all atelectatic lung tissue.
When normal lungs are ventilated with large tidal volumes (VT) and end-inspired pressures (Pei), surfactant is depleted and pulmonary edema develops. Both effects are diminished by positive end-expiratory pressure (PEEP). We reasoned that ventilatory with large VT-low PEEP would similarly increase edema following acute lung injury. To test this hypothesis, we ventilated dogs 1 h after hydrochloric acid (HCl) induced pulmonary edema with a large VT (30 ml/kg) and low PEEP (3 cm H2O) (large VT-low PEEP) and compared their results with dogs ventilated with a smaller VT (15 ml/kg) and 12 cm H2O PEEP (small VT-high PEEP). The small VT was the smallest that maintained eucapnia in our preparation; the large VT was chosen to match Pei and end-inspired lung volume. Pulmonary capillary wedge transmural pressure (Ppwtm) was kept at 8 mm Hg in both groups. Five hours after injury, the median lung wet weight to body weight ratio (WW/BW) was 25 g/kg higher in the large VT-low PEEP group than in the small VT-high PEEP group (p less than 0.05). Venous admixture (Qva/Qt) was similarly greater in the large VT-low PEEP group (49.8 versus 23.5%) (p less than 0.05). We conclude that small VT-high PEEP is a better mode of ventilating acute lung injury than large VT-low PEEP because edema accumulation is less and venous admixture is less. These advantages did not result from differences in Pei, end-inspiratory lung volume, or preload (Ppwtm).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
An understanding of ventilator management must be predicated on physiologic principles. There is a considerable array of equipment, permitting an almost limitless number of permutations in ventilator therapy, to support patients with respiratory failure. The physician who understands patient-ventilator interactions and their effects on cardiopulmonary function will be best equipped to individualize therapy. We believe that further refinements in supportive equipment probably will not improve outcome significantly. Thus, more emphasis should be placed on elucidating the underlying disease process and its effects on respiratory structure and function.
Definitions are an essential component of medical progress. But they are not immutable and they need to be continuously refined as new knowledge accrues. The term ARDS has been useful in attracting considerable attention to a group of disorders that all cause diffuse pulmonary parenchymal injury and, accordingly, have several manifestations in common. Since first identified, much has been learned about the factors that predispose to ARDS, its pathologic features, and the spectrum of lung injuries that may occur. However, we lack definitive information about the basic mechanisms of different types of parenchymal lung injury and, without these data, treatment is largely empirical except in infectious causes of the disorder. For these reasons, now is the time to move forward with a more comprehensive definition that utilizes the important clinical, physiologic, and pathologic observations that have been made since the valuable contributions of Ashbaugh and Petty more than 20 years ago.
Article
Twenty patients (23-76 yr) were studied with regard to lung tissue changes prior to and following induction of general anesthesia with muscular relaxation, and another four subjects were studied for a longer period awake. The transverse thoracic area and the structure of the lung tissue were determined by computerized tomography. No abnormalities in the lung tissue were noted before anesthesia. Within 5 min after induction, including muscular relaxation, all subjects had developed crest-shaped changes of increased density in the dependent regions of both lungs. They were largest in the most caudal segment (4.8 +/- 0.8% of the transverse lung area, mean +/- SE) and smaller in the cephalad exposures (3.4 +/- 0.7% of the transverse area). The size of the densities showed no correlation to age. The densities did not increase after a further 20 min of anesthesia and were not affected by the inspiratory oxygen fraction. When the subjects were moved from the supine to the lateral position, the crest-shaped densities disappeared in the nondependent lung and remained in the dorsal part of the dependent lung. The application of positive end-expiratory pressure of 10 cmH2O eliminated or reduced the densities. The four awake subjects showed no lung densities after 90 min in the supine position. It is suggested that these crest-shaped densities represent atelectases, which develop by compression of lung tissue rather than by resorption of gas.
Article
Functional residual capacity (FRC), rib cage and abdominal dimensions (rc-ab), central blood volume (CBV), and extra vascular lung water (EVLW) were measured in six lung-healthy subjects awake and during halothane anesthesia, muscle paralysis, and mechanical ventilation. FRC was assessed by multiple breath nitrogen washout, rc-ab dimensions by computerized tomography, and CBV and EVLW by a double-indicator dilution technique (thermo-dye). During anesthesia, FRC decreased by 0.5 1 (17%). The cross-sectional chest area was reduced by 12-20 cm2, causing an approximate reduction in thoracic volume by 0.3 1. Concomitantly, the diaphragm was moved cranially by an average of 1.9 cm, diminishing the thoracic volume a further 0.5 1. The abdominal cross-sectional area did not alter significantly, despite the shift of the diaphragm. CBV decreased by 0.3 1. EVLW did not change significantly. It is concluded that the thoracic volume is reduced during halothane anesthesia, muscle paralysis, and mechanical ventilation as a result of cranial shift of the diaphragm and reduction in transverse area. The decrease in thoracic volume is accompanied by a reduction in FRC and a displacement of blood from the thorax to the abdomen, the transverse area of the latter thus being maintained despite the shift of the diaphragm.
Article
Arterial blood oxygenation improved repeatedly after sedation and paralysis in a 27-year-old woman requiring mechanical ventilation for the adult respiratory distress syndrome. Oxygen consumption and cardiac output decreased proportionately after paralysis so that the partial pressure of oxygen in mixed venous blood remained unchanged. Paralysis eliminated inspiratory distortion of the airway pressure waveform and prevented forceful use of expiratory musculature. A flow-related reduction of venous admixture or recruitment of lung volume may best explain the beneficial effect of muscle relaxation on arterial saturation.
Article
The effect of peak airway pressure (Paw) on vascular permeability and the "safety factor" against edema formation was determined in isolated blood-perfused lower lobes of dog lungs. Microvascular permeability was evaluated using the measured filtration coefficient (Kf,C), isogravimetric capillary pressure (Pc,i), and critical capillary pressure (Pcrit) for exhaustion of tissue safety factors. Airway pressure was maintained constant at -3 cmH2O except for the test period of 20 min when the lungs were ventilated at 6/min with sufficient volume to generate a peak inflation pressure ranging from 5 to 60 cmH2O. Mean Kf,C (in ml X min-1 X cmH2O X 100 g-1) were measured before and immediately after the period of peak airway pressures. Kf,C was significantly increased in all lungs where Paw exceeded 42 cmH2O, but in only two experiments at a lower Paw. Mean Pc,i was significantly reduced from control in the 45-55 and 55-65 cmH2O Paw groups, and both Pc,i and Pcrit were found to be inversely related to Kf,C measured after Paw ventilation. These data indicate that ventilation with Paw above 42 cmH2O (30.9 Torr) and in some cases lower pressures for 20 min significantly increased capillary hydraulic conductivity, reduced the effective osmotic effect of plasma proteins at the capillary wall, and reduced the total tissue safety factor against edema formation.
Article
Tissue injury that occurs as a result of ischemia and subsequent reperfusion is characterized by endothelial cell injury, edema formation, and the influx of inflammatory leukocytes. Two macrophage-derived proinflammatory cytokines which may play a critical role in cellular injury and leukocyte recruitment/activation that occurs in the setting of ischemia-reperfusion injury are tumor necrosis factor alpha (TNF) and macrophage inflammatory protein-1 alpha (MIP-1 alpha). To determine if modulation of ambient oxygen tensions in vitro alters the expression of proinflammatory cytokines from activated macrophages, murine alveolar macrophages (AMO) were cultured in various combinations of ambient oxygen concentrations, then the supernatant fluid and cell pellet assayed for the presence of TNF and MIP-1 alpha messenger RNA (mRNA) and protein. We demonstrated that conditions of anoxia (95% nitrogen/5% CO2) or hyperoxia (95% oxygen/5% CO2) independently resulted in the increased expression of both TNF and MIP-1 alpha mRNA and protein from lipopolysaccharide (LPS)-stimulated AMO, as compared with cells cultured in room air. The specific culture condition of anoxia (x 6 h) followed by hyperoxia (x 18 h) produced the gr