Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome.

The Cooling to Help Injured Lungs (CHILL) trial is an open label, two group, parallel design multicenter, randomized phase IIB clinical trial assessing the efficacy and safety of targeted temperature management with combined external cooling and neuromuscular blockade to block shivering in patients with early moderate-severe acute respiratory distress syndrome (ARDS). This report provides the background and rationale for the clinical trial and outlines the methods using the Consolidated Standards of Reporting Trials guidelines. Key design challenges include: [1] protocolizing important co-interventions; [2] incorporation of patients with COVID-19 as the cause of ARDS; [3] inability to blind the investigators; and [4] ability to obtain timely informed consent from patients or legally authorized representatives early in the disease process. Results of the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial informed the decision to mandate sedation and neuromuscular blockade only in the group assigned to therapeutic hypothermia and proceed without this mandate in the control group assigned to a usual temperature management protocol. Previous trials conducted in National Heart, Lung, and Blood Institute ARDS Clinical Trials (ARDSNet) and Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks informed ventilator management, ventilation liberation and fluid management protocols. Since ARDS due to COVID-19 is a common cause of ARDS during pandemic surges and shares many features with ARDS from other causes, patients with ARDS due to COVID-19 are included. Finally, a stepwise approach to obtaining informed consent prior to documenting critical hypoxemia was adopted to facilitate enrollment and reduce the number of candidates excluded because eligibility time window expiration.

Proning in COVID-19 Acute Respiratory Distress Syndrome: Role of Paralytics.

Although proning is beneficial to acute respiratory distress syndrome, impressions vary about its efficacy. Some providers believe that paralysis is required to facilitate proning. We studied impact of paralysis on prone-induced gas exchange improvements and provider attitudes regarding paralytics. DESIGN: Observational. SETTING: University of California San Diego. PATIENTS: Intubated COVID acute respiratory distress syndrome patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 1) Changes in Pao2:Fio2 and Spo2:Fio2 ratios before and after proning with and without paralytics, 2) adverse events during proning with and without paralytics, and 3) nurse and physician attitudes about efficacy/safety of proning with and without paralytics. Gas-exchange improvement with proning was similar with and without paralytics (with no serious adverse events). Survey results showed similar attitudes between nurses and physicians about proning efficacy but differing attitudes about the need for paralytics with proning. CONCLUSIONS: Findings support use of proning and may help in design of randomized trials to assess paralytics in acute respiratory distress syndrome management.

Critical Care Pharmacist Attitudes and Perceptions of Neuromuscular Blocker Infusions in ARDS.

BACKGROUND: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. OBJECTIVE: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. METHODS: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. RESULTS: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). CONCLUSIONS AND RELEVANCE: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Usefulness of Inhaled Sedation in Patients With Severe ARDS Due to COVID-19.

BACKGROUND: Sedation in intensive care is fundamental for optimizing clinical outcomes. For many years the world has been facing high rates of opioid use, and to combat the increasing opioid addiction plans at both national and international level have been implemented.1 The COVID-19 pandemic posed a major challenge for health systems and also increased the use of sedatives and opioid analgesia for prolonged periods of time, and at high doses, in a significant proportion of patients. In our institutions, the shortage of many drugs for intravenous (IV) analgosedation forces us to alternatives to replace out-of-stock drugs or to seek sedation goals, which are difficult to obtain with traditional drugs at high doses.2 METHODS: This was an analytical retrospective cohort study evaluating the follow-up of subjects with inclusion criteria from ICU admission to discharge (alive or dead). Five end points were measured: need for high-dose opioids (≥ 200 µg/h), comparison of inhaled versus IV sedation of opioid analgesic doses, midazolam dose, need for muscle relaxant, and risk of delirium. RESULTS: A total of 283 subjects were included in the study, of whom 230 were administered IV sedation and 53 inhaled sedation. In the inhaled sedation group, the relative risks (RRs) were 0.5 (95% CI 0.4-0.8, P = .045) for need of high-dose fentanyl, 0.3 (95% CI 0.20-0.45, P < .001) for need of muscle relaxant, and 0.8 (95% CI 0.61-1.15, P = .25) for risk of delirium. The median difference of fentanyl dose between the inhaled sedation and IV sedation groups was 61 µg/h or 1,200 µg/d (2.2 ampules/d, P < .001), and that of midazolam dose was 5.7 mg/h. CONCLUSIONS: Inhaled sedation was associated with lower doses of opioids, benzodiazepines, and muscle relaxants compared to IV sedation. This therapy should be considered as an alternative in critically ill patients requiring prolonged ventilatory support and where IV sedation is not possible, always under adequate supervision of ICU staff.

Enteral nutrition tolerance in patients receiving neuromuscular blockade.

BACKGROUND: Nutrition support is an essential part of critical care medicine. It is commonly accepted that for the critically ill patient, enteral nutrition (EN) is favored. For the patient who receives neuromuscular blockades, EN may be held, or initiation delayed, because of concerns for EN intolerance. We hypothesized there would be no difference in EN tolerance between groups receiving cisatracurium while receiving EN compared with those not receiving cisatracurium. METHODS: This was a retrospective study that included 459 patients from a combined medical and surgical intensive care unit. There were 44 patients who received cisatracurium with EN and 415 who received EN alone. Data collected included gastric residual volume (GRV) and emesis occurrences, new-onset abdominal pain, new or worsening abdominal distention, and bowel ischemia. RESULTS: There were more patients with new or worsening abdominal distention in the group receiving cisatracurium (31.82% vs 14.94%; P < 0.01) as well as occurrences of GRV > 300 ml (P < 0.01). There was no statistically significant difference between the groups regarding emesis, new-onset abdominal pain, or bowel ischemia. CONCLUSION: Our findings suggest that it is acceptable to provide patients with EN who are receiving cisatracurium.

Sugammadex in Emergency Situations.

Sugammadex may be required or used in multiple emergency situations. Moderate and high doses of this compound can be used inside and outside the operating room setting. In this communication, recent developments in the use of sugammadex for the immediate reversal of rocuronium-induced neuromuscular blockade were assessed. In emergency surgery and other clinical situations necessitating rapid sequence intubation, the tendency to use rocuronium followed by sugammadex instead of succinylcholine has been increasing. In other emergency situations such as anaphylactic shock caused by rocuronium or if intubation or ventilation is not possible, priority should be given to resuming ventilation maintaining hemodynamic stability, in accordance with the traditional guidelines. If necessary for the purpose of resuming ventilation, reversal of neuromuscular blockade should be done in a timely fashion.

Physicians' attitudes and perceptions of neuromuscular blocker infusions in ARDS.

PURPOSE: The perceptions and practices of ICU physicians regarding initiating neuromuscular blocker infusions (NMBI) in acute respiratory distress syndrome (ARDS) may not be evidence-based amidst the surge of severe ARDS during the SARS-CoV-2 pandemic and new practice guidelines. We identified ICU physicians' perspectives and practices regarding NMBI use in adults with moderate-severe ARDS. MATERIALS AND METHODS: After extensive development and testing, an electronic survey was distributed to 342 ICU physicians from three geographically-diverse U.S. health systems(n = 12 hospitals). RESULTS: The 173/342 (50.5%) respondents (75% medical) somewhat/strongly agreed a NMBI should be reserved until: after a trial of deep sedation (142, 82%) or proning (59, 34%) and be dose-titrated based on train-of-four monitoring (107, 62%). Of 14 potential NMBI risks, 2 were frequently reported to be of high/very high concern: prolonged muscle weakness with steroid use (135, 79%) and paralysis awareness due to inadequate sedation (114, 67%). Absence of dyssychrony (93, 56%) and use ≥48 h (87, 53%) were preferred NMBI stopping criteria. COVID-19 + ARDS patients were twice as likely to receive a NMBI (56 ± 37 vs. 28 ± 19%, p < 0.01). CONCLUSIONS: Most intensivists agreed NMBI in ARDS should be reserved until after a deep sedation trial. Stopping criteria remain poorly defined. Unique considerations exist regarding the role of paralysis in COVID-19+ ARDS.

The effect of age on ventilation management and clinical outcomes in critically ill COVID-19 patients-insights from the PRoVENT-COVID study

Introduction: We analyzed the association of age with ventilation practice and outcomes in critically ill COVID-19 patients requiring invasive ventilation. Methods: Posthoc analysis of the PRoVENT-COVID study, an observational study performed in 22 ICUs in the first 3 months of the national outbreak in the Netherlands. The coprimary endpoint was a set of ventilator parameters, including tidal volume normalized for predicted bodyweight, positive end-expiratory pressure, driving pressure, and respiratory system compliance in the first 4 days of invasive ventilation. Secondary endpoints were other ventilation parameters, the use of rescue therapies, pulmonary and extrapulmonary complications in the first 28 days in the ICU, hospital- and ICU stay, and mortality. Results: 1122 patients were divided into four groups based on age quartiles. No meaningful differences were found in ventilation parameters and in the use of rescue therapies for refractory hypoxemia in the first 4 days of invasive ventilation. Older patients received more often a tracheostomy, developed more frequently acute kidney injury and myocardial infarction, stayed longer in hospital and ICU, and had a higher mortality. Conclusions: In this cohort of invasively ventilated critically ill COVID-19 patients, age had no effect on ventilator management. Higher age was associated with more complications, longer length of stay in ICU and hospital and a higher mortality.

Lower Driving Pressure and Neuromuscular Blocker Use Are Associated With Decreased Mortality in Patients With COVID-19 ARDS.

BACKGROUND: The impact of mechanical ventilation parameters and management on outcomes of patients with coronavirus disease 2019 (COVID-19) ARDS is unclear. METHODS: This multi-center observational study enrolled consecutive mechanically ventilated patients with COVID-19 ARDS admitted to one of 7 Korean ICUs between February 1, 2020-February 28, 2021. Patients who were age < 17 y or had missing ventilation parameters for the first 4 d of mechanical ventilation were excluded. Multivariate logistic regression was used to identify which strategies or ventilation parameters that were independently associated with ICU mortality. RESULTS: Overall, 129 subjects (males, 60%) with a median (interquartile range) age of 69 (62-78) y were included. Neuromuscular blocker (NMB) use and prone positioning were applied to 76% and 16% of subjects, respectively. The ICU mortality rate was 37%. In the multivariate analysis, higher dynamic driving pressure (ΔP) values during the first 4 d of mechanical ventilation were associated with increased mortality (adjusted odds ratio 1.16 [95% CI 1.00-1.33], P = .046). NMB use was associated with decreased mortality (adjusted odds ratio 0.27 [95% CI 0.09-0.81], P = .02). The median tidal volume values during the first 4 d of mechanical ventilation and the ICU mortality rate were significantly lower in the NMB group than in the no NMB group. However, subjects who received NMB for ≥ 6 d (vs < 6 d) had higher ICU mortality rate. CONCLUSIONS: In subjects with COVID-19 ARDS receiving mechanical ventilation, ΔP during the first 4 d of mechanical ventilation was independently associated with mortality. The short-term use of NMB facilitated lung-protective ventilation and was independently associated with decreased mortality.

Pharmacologic Treatments for Acute Respiratory Distress Syndrome.

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.

Neuromuscular blockade administration is associated with altered energy expenditure in critically ill intubated patients with COVID-19.

BACKGROUND & AIMS: ESPEN guidelines advocate that energy needs of critically ill patients with COVID 19 should be assessed using indirect calorimetry, if safely available. This study described energy needs of intubated patients with COVID-19 and explores whether neuromuscular blockade administration (NMBAs) is associated with altered energy expenditure. METHODS: Resting energy expenditure (REE) and respiratory exchange rate (RER) evaluated among critically ill intubated COVID-19 patients until 28th day of intensive care unit stay (ICU-S) by indirect calorimetry. Paralysed patients were defined as those with drug induced paralysis using cicatracurium, for at least 3 days during their ICU-S. RESULTS: 34 adult COVID 19 patients (59.8% male, 35.2% obese) requiring mechanical ventilation were assessed prospectively. REE measurements suggest a gradual increase of energy needs post 3rd day of ICU-S in both patients without obesity (non ob) ((from 17.8 kcal/kgr up to 29.3 kcal/kgr actual body weight (AcBW) during 28th day of ICU-S, p = 0.011)) and patients with obesity (ob) ((from 18.1 kcal/kgr up to 30.1 kcal/kgr adjusted body weight (AjBW) during 28th day of ICU-S, p = 0.021)). NMBAs use was accompanied by a significant drop in REE, especially during first 7 days of hospitalization, both in non ob (22.9 vs 17.9 kcal/kgr AcBW, p = 0.014) and ob patients (22.5 vs 19.5 kcal/kgr ABW, p = 0.027). CONCLUSION: We identified the energy needs of COVID-19 intubated patients and highlighted a significant increase beyond the 1st week in the ICU. Administration of NMBAs should be considered, as it may impact resting energy expenditure.

Neuromuscular blockade management in patients with COVID-19.

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 (MV), 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, and NMBAs 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.