Effect of non-sedation on physical function in survivors of critical illness – A substudy of the NONSEDA randomized trial

This article by Nedeergard and colleagues was first published in the Journal of Critical Care in December 2020.
Purpose:  Critical illness impairs physical function. The NONSEDA trial was a multicenter randomized trial, assessing non-sedation versus sedation during mechanical ventilation. The aim of this sub-study was to assess the effect of non-sedation on physical function.
Methods:  All patients from one NONSEDA trial site were included. At ICU discharge and three months thereafter, survivors were assessed for physical function.
Results:  205 patients were included, 118 survived to follow-up, 116 participated (98%). Primary outcome: Three months after ICU-discharge, health-related quality of life (SF-36, physical component score) was similar (non-sedated 38.3 vs sedated 36.6, mean difference 1.7, 95% CI -1.7 to 5.1), as was function in activities of daily living (Barthel Index, non-sedated 19.5 vs sedated 18, median difference 1.5, 95% CI -0.2 to 3.2). Secondary outcomes: Non-sedated patients had a better Barthel Index at ICU-discharge (median 9 vs 4, median difference 5, 95% CI 2.5 to 7.5). At three months post-ICU discharge, the two groups did not differ regarding handgrip strength, walking distance, muscle size or biomechanical data.
Conclusion:  Non-sedation did not lead to improved quality of life regarding physical function or better function in activities of everyday living. Non-sedated patients had a better physical recovery at ICU discharge.
The full text of this article is available to subscribers via this link to the journal’s homepage.  The full text of articles from issues older than sixty days is available via this link to an archive of issues of Journal of Critical Care.  A Rotherham NHS Athens password is required.  Eligible staff can register for an Athens password via this link.  Please speak to the library staff for more details.

Critical Care Reviews Newsletter 456 6th September 2020

The Critical Care Reviews Newsletter lists the best critical care research and open access articles from across the medical literature over the past week.
The highlights of this week’s edition are several fascinating randomised controlled trials on intraoperative low tidal volume vs conventional tidal volume, azithromycin for severe COVID-19, midodrine for persistent hypotension in the ICU, NAVA in acute respiratory failure and preoperative intravenous iron to treat anaemia before major abdominal surgery.
The full text of the issue is available via this link

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

This article by the Writing Committee for the REMAP-CAP Investigators was first published online in JAMA in September 2020.
Importance:  Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.
Objective:  To determine whether hydrocortisone improves outcome for patients with severe COVID-19.
Design, Setting, and Participants:  An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.InterventionsThe corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).
Main Outcomes and Measures:  The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).
Results:  After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.
Conclusions and Relevance:  Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.
The print copy of this issue JAMA is available in the Healthcare Library on D Level of Rotherham General Hospital.

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients with Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.

This article by the COALITION COVID-19 Brazil III Investigators was first published in JAMA online in September 2020.
Importance:  Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.
Objective:  To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS.
Design, Setting, and Participants:  Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.
Interventions:  Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).
Main Outcomes and Measures:  The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.
Results:  A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.
Conclusions and Relevance:  Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.
The full text of this article is freely available via this link.  The paper copy of the article is available in the Healthcare Library on D Level of Rotherham Hospital.

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

This article by participants in the CAPE COVID Trial Group and the CRICS-TriGGERSep Network was published in JAMA in September 2020.
Importance:  Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.
Objective:  To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure.
Design, Setting, and Participants:  Multi-centre randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board.
Interventions:  Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73).
Main Outcomes and Measures:  The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.
Results:  The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment.
Conclusions and Relevance:  In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.
The print copy of this issue JAMA is available in the Healthcare Library on D Level of Rotherham General Hospital.

Effect of Intraoperative Low Tidal Volume vs Conventional Tidal Volume on Postoperative Pulmonary Complications in Patients Undergoing Major Surgery: A Randomized Clinical Trial.

This article by Karalapillai and colleagues was published in JAMA in September 2020
Importance:  In patients who undergo mechanical ventilation during surgery, the ideal tidal volume is unclear.
Objective:  To determine whether low-tidal-volume ventilation compared with conventional ventilation during major surgery decreases postoperative pulmonary complications.
Design, Setting, and Participants:  Single-center, assessor-blinded, randomized clinical trial of 1236 patients older than 40 years undergoing major noncardiothoracic, nonintracranial surgery under general anesthesia lasting more than 2 hours in a tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. The last date of follow-up was February 17, 2019.
Interventions: Patients were randomized to receive a tidal volume of 6 mL/kg predicted body weight (n = 614; low tidal volume group) or a tidal volume of 10 mL/kg predicted body weight (n = 592; conventional tidal volume group). All patients received positive end-expiratory pressure (PEEP) at 5 cm H2O.
Main Outcomes and Measures:  The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days, including pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, or unplanned requirement for postoperative invasive or non-invasive ventilation. Secondary outcomes were postoperative pulmonary complications including development of pulmonary embolism, acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis, acute kidney injury, wound infection (superficial and deep), rate of intraoperative need for vasopressor, incidence of unplanned intensive care unit admission, rate of need for rapid response team call, intensive care unit length of stay, hospital length of stay, and in-hospital mortality.
Results:  Among 1236 patients who were randomized, 1206 (98.9%) completed the trial (mean age, 63.5 years; 494 [40.9%] women; 681 [56.4%] undergoing abdominal surgery). The primary outcome occurred in 231 of 608 patients (38%) in the low tidal volume group compared with 232 of 590 patients (39%) in the conventional tidal volume group (difference, -1.3% [95% CI, -6.8% to 4.2%]; risk ratio, 0.97 [95% CI, 0.84-1.11]; P = .64). There were no significant differences in any of the secondary outcomes.
Conclusions and Relevance:  Among adult patients undergoing major surgery, intraoperative ventilation with low tidal volume compared with conventional tidal volume, with PEEP applied equally between groups, did not significantly reduce pulmonary complications within the first 7 postoperative days.
The print copy of this issue JAMA is available in the Healthcare Library on D Level of Rotherham General Hospital.

Effect of in-bed cycling on sarcopenia in critically ill adults: A randomised clinical trial

This article by Nickels and colleagues from the Journal of Critical Care was first published online in June 2020 in pre proofing format.
Purpose:  To examine whether in-bed cycling assists critically ill adults to reduce acute muscle wasting, improve function and improve quality of life following a period of critical illness.
Materials and methods:  A single-centre, two-group, randomised controlled trial with blinded assessment of the primary outcome was conducted in a tertiary ICU. Critically ill patients expected to be mechanically ventilated for 48 h were randomised to 30 min daily in-bed cycling in addition to usual-care physiotherapy (n = 37) or usual-care physiotherapy (n = 37). The primary outcome was muscle atrophy of rectus femoris cross-sectional area (RF_CSA) measured by ultrasound at Day 10 following study enrolment. Secondary outcomes included manual muscle strength, handgrip strength, ICU mobility score, six-minute walk test distance and health-related quality of life up to six-months following hospital admission.
Results:  Analysis included the 72 participants (mean age, 56-years; male, 68%) who completed the study. There were no significant between-group differences in muscle atrophy of RF_CSA at Day 10 (mean difference 3.4, 95% CI -6.9% to 13.6%; p = .52), or for secondary outcomes (p-values ranged p = .11 to p = .95).
Conclusions and relevance:  In-bed cycling did not reduce muscle wasting in critically ill adults, but this study provides useful effect estimates for large-scale clinical trials.
The full text of this article when fully published will be available to subscribers via this link.

Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

This research by Ranieri and colleagues from the INTEREST Study Group was published during February 2020 in JAMA.
Importance:  Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) β-1a may prevent the underlying event of vascular leakage.
Objective:  To determine the efficacy and adverse events of IFN-β-1a in patients with moderate to severe ARDS.
Design, Setting, and Participants:  Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018.InterventionsPatients were randomized to receive an intravenous injection of 10 μg of IFN-β-1a (144 patients) or placebo (152 patients) once daily for 6 days.
Main Outcomes and Measures:  The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error.
Results:  Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-β-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-β-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group).
Conclusions and Relevance:  Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS.
The print copy of this issue JAMA is available in the Healthcare Library on D Level of Rotherham General Hospital.

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial.

This article by Lamontagne and others first appeared in JAMA during February 2020.
Importance:  Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.
Objective:  To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.
Design, Setting, and Participants:  A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.InterventionsPatients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).
Main Outcome and Measures:  The primary clinical outcome was all-cause mortality at 90 days.
Results:  Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for pre-specified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).
Conclusions and Relevance:  Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.
The print copy of this issue JAMA is available in the Healthcare Library on D Level of Rotherham General Hospital.

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.

This article by the PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group was published in JAMA.
Importance:  Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown.
Objective:  To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis.
Design, Setting, and Participants:  Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital.
Interventions:  Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs).
Main Outcomes and Measures:  The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay.
Results:  Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group.
Conclusions and Relevance:  Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication.
The print copy of this issue of JAMA is available in the Healthcare Library on D Level of Rotherham General Hospital.