Article

The critical care literature 2018

Critical care literature 2018″>American Journal of Emergency Medicine 38 (2020) 670-680

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American Journal of Emergency Medicine

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Review

The critical care literature 2018

Michael E. Winters a,?, Kami Hu a, Joseph P. Martinez a, Haney Mallemat b, William J. Brady c

a Departments of Emergency Medicine and Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

b Cooper Medical School of Rowan University, Camden, NJ, USA

c Departments of Emergency Medicine and Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

a r t i c l e i n f o

Article history:

Received 24 July 2019

Received in revised form 16 November 2019

Accepted 18 November 2019

a b s t r a c t

An emergency physician is often the first health care provider to evaluate, resuscitate, and manage a criti- cally ill patient. In recent years, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased more than 200% (Herring et al., 2013). In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the Initial resuscitation period. In fact, more than 50% of ED patients that require admission to the intensive care unit (ICU) remain in the ED for more than 6 h (Rose et al., 2016). Longer ED boarding times for critically ill patients is associated with a negative impact on in- patient morbidity and mortality (Mathews et al., 2018). It is during these early hours of critical illness, while the patient is in the ED, where lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2018 pertaining to the resuscitation and care of select critically ill patients. We chose these articles based on our opinion of the importance of the study findings and their application to clinical care in the ED. The following topics are covered: cardiac arrest, post-arrest care, septic shock, rapid sequence intubation, mechanical ventila- tion, fluid resuscitation, and metabolic acidosis.

(C) 2019

Introduction

An Emergency physician is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. In recent years, the annual hours of critical care delivered in emergency depart- ments (EDs) across the United States increased more than 200% [1]. From 2001 to 2009, annual intensive care unit admissions from United States EDs exceeded 2 million patients, an increase of almost 80% over that time period [1]. In addition to seeing more critically ill pa- tients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, more than 50% of ED patients that re- quire admission to the ICU remain in the ED for more than 6 h [2]. Lon- ger ED Boarding times for critically ill patients is associated with a negative impact on inpatient morbidity and mortality [3]. It is during these early hours of critical illness, while the patient is in the ED, where lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in resuscitation and critical care medicine. This review summarizes important articles pub- lished in 2018 pertaining to the resuscitation and care of select critically ill patients. We chose these articles based on our opinion of the impor- tance of the study findings and their application to emergency medi- cine. The following topics are covered: cardiac arrest, post-arrest care,

* Corresponding author.

E-mail address: [email protected] (M.E. Winters).

septic shock, rapid sequence intubation, mechanical ventilation, fluid resuscitation, and metabolic acidosis. A summary of articles and key findings are provided in Table 1.

Cardiac arrest

Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest. N Engl J Med. 2018; 379:71121.

Epinephrine has been used by clinicians, and recommended by spe-

cialty societies, in the management of patients with cardiac arrest for decades. The alpha adrenergic effects of epinephrine increase aortic di- astolic blood pressure during cardiopulmonary resuscitation (CPR) and may augment Coronary blood flow. These effects may result in an in- crease in the return of spontaneous circulation (ROSC). In contrast to the alpha adrenergic effects, the beta adrenergic effects of epinephrine can increase myocardial oxygen demand and increase the Incidence of arrhythmias [5-7].

Current advanced life support guidelines from the American Heart Association (AHA) state that epinephrine may be administered every three to five minutes in cardiac arrest resuscitation [4]. However, recent literature has questioned the use of epinephrine in cardiac arrest. In large observational studies, the prehospital administration of epineph- rine to patients with cardiac arrest was associated with increased rates of ROSC but worse neurologic outcomes at hospital discharge [5,

https://doi.org/10.1016/j.ajem.2019.11.032

0735-6757/(C) 2019

Table 1

Summary of articles and key findings.

Article Clinical topic Study type Key findings

Perkins GD, et al. A randomized trial of epinephrine in

out-of-hospital cardiac arrest. N Engl J Med. 2018; 379:711-21

Jabre P, et al. Effect of Bag-mask ventilation vs endotracheal intubation during cardiopulmonary resuscitation on neurological outcome after out-of-hospital cardiopulmonary arrest. A randomized clinical trial. JAMA. 2018; 319:779-87.

Benger JR, et al. Effect of a strategy of a supraglottic airway device vs tracheal intubation during out-of-hospital cardiac arrest on functional outcome: The AIRWAYS-2 randomized clinical trial. JAMA. 2018; 320:779-91

Roberts BW, et al. Association between elevated mean arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest: results from a multicenter prospective cohort study. Crit Care Med. 2018;47(1):93-100.

Roberts BW, et al. Association between early hyperoxia exposure after resuscitation from cardiac arrest and neurological disability: a prospective multi-center protocol-directed cohort study. Circulation 2018;137(20):2114-2124.

Cardiac Arrest

Cardiac Arrest

Cardiac Arrest

Post-Arrest Care

Post-Arrest Care

Multicenter, randomized,

placebo-controlled trial

Multicenter, randomized,

non-inferiority trial

Multicenter,

cluster-randomized, controlled trial

Preplanned analysis of a prospective cohort study

Prospective, observational, cohort trial

  • 30-day survival occurred in 3.2% of patients who received epi- nephrine compared to 2.4% of patients who received placebo.
  • In survivors, severe neurologic impairment occurred in 31% of patients who received epinephrine compared to 17.8% of patients who received placebo.
  • 28-day survival with Favorable neurologic outcome occurred in 4.3% of patients in the BMV group and in 4.2% of patients in the ETI group.
  • There was no difference in the secondary outcomes of Survival to hospital admission and 28-day survival between the two groups.
  • The primary outcome of neurologic outcome at hospital dis- charge or 30-days after OHCA occurred in 6.4% of patients ran- domized to an SGA and 6.8% of patients randomized to ETI.
  • Initial successful insertion rates were greater in the SGA group without any increase in complications.
  • Patients in the higher MAP group (MAP greater than

90 mmHg) had a higher incidence of Good neurologic outcome when compared patients with a MAP between 70 and

90 mmHg.

  • A MAP greater than 90 mmHg was found to be an independent predictor of good neurologic function at hospital discharge.
  • The benefit of a higher MAP was greater in patients with a history of hypertension compared with those with no history of hypertension.
  • Patients exposed to hyperoxia had a higher incidence of poor Neurologic outcome at hospital discharge compared to patients not exposed to hyperoxia.
  • Hyperoxia was found to be an independent predictor of Poor neurologic outcome at hospital discharge.

Venkatesh B, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797-808.

Annane D, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378: 809-18.

Septic Shock Multicenter, pragmatic,

double-blind, randomized, controlled trial

Septic Shock Multicenter,

placebo-controlled trial

  • No significant difference in the primary outcome of 90-day all-cause mortality in patients who received hydrocortisone compared to those who received placebo.
  • Time to shock resolution, time to ICU discharge, and the dura- tion of the initial episode of mechanical ventilation were all shorter in patients who received hydrocortisone.
  • The primary outcome of 90-day all-cause mortality occurred 43% of the hydrocortisone-fludrocortisone group compared with 49.1% in the placebo group.
  • Those in the hydrocortisone-fludrocortisone group had a sta- tistically significant difference in all-cause mortality at ICU dis- charge.
  • Patients in the hydrocortisone-fludrocortisone group had a shorter time to cessation of mechanical ventilation and cessa- tion of vasopressor therapy.

Driver BE, et al. Effect of use of a bougie vs endotracheal tube and stylet on first-attempt intubation success among patients with Difficult airways undergoing emergency intubation: A randomized clinical trial. JAMA 2018; 319:2179-2189.

De Jong Audrey, et al. Cardiac arrest and mortality related to intubation procedure in critically ill adult patients: A Multicenter cohort study. Crit Care Med. 2018; 46:532.

Simonis FD, et al. Effect of a low vs intermediate Tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS. The PReVENT Trial. JAMA 2018; 320 (18):1872-1880.

Stephens RJ, et al. Practice patterns and outcomes associated with early sedation depth in Mechanically ventilated patients: A systematic review and meta-analysis. Crit Care Med 2018; 46 (3):471-479.

Semler MW, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378(9): 829-39.

Jaber S, et al. Sodium bicarbonate therapy for patients with severe metabolic acidemia in the intensive care unit (BICAR-ICU): a multicenter, open-label, randomized controlled, phase 3 trial. Lancet. 2018; 392:31-40

Rapid Sequence Intubation

Rapid Sequence Intubation

Mechanical Ventilation

Mechanical Ventilation

Fluid Resuscitation

Metabolic Acidosis

Randomized clinical trial

retrospective cohort analysis

Multicenter, randomized, controlled trial

Systematic review and meta-analysis

Pragmatic, unblinded, cluster-randomized, multiple crossover trial Multicenter, open-label, randomized, controlled, phase three trial

  • The primary outcome of first attempt success in those with at least one characteristic of a difficult airway occurred in 96% of patients randomized to the bougie and 82% of patients ran- domized to the ETT plus stylet.
  • Patients who suffered an Intubation-related CArdiac arrest had a higher 28-day mortality rate compared with patients who did not have an intubation-related cardiac arrest.
  • A systolic blood pressure b 90 mm Hg prior to intubation, hypoxemia prior to intubation, the absence of preoxygenation, obesity, and age N 75 years were associated with intubation– related cardiac arrest.
  • There was no significant difference in the primary outcome of ventilator free days and alive at day 28 between the Low tidal volume ventilation group and the intermediate tidal volume ventilation group.
  • A statistically significant decrease in mortality was found for patients who received an early, lighter level of sedation com- pared with patients who received early, deep sedation.
  • Lighter sedation was also associated with significantly fewer days of mechanical ventilation and shorter ICU lengths of stay.
  • The primary outcome of MAKE at 30 days occurred in 14.3% of the balanced crystalloid group compared with 15.4% of the 0.9% sodium chloride group.
  • There was no significant difference in the primary outcome of all-cause 28-day mortality and failure of at least one organ system at seven days after randomization between patients in the intervention group and those in the control group.

8,9]. Given the current controversies on epinephrine in cardiac arrest, the authors of the current study sought to determine whether epineph- rine is beneficial or harmful in the treatment of patients with out-of- hospital cardiac arrest (OHCA).

The PARAMEDIC-2 Trial was a multicenter, randomized, double- blind, placebo-controlled trial conducted in five National Health Service ambulance services in the United Kingdom. Investigators included adult patients with OHCA for which advanced life support interventions were provided by trial-trained paramedics during the period from December 2014 to October 2017. Patients less than 16 years of age, those who were pregnant, those in whom anaphylaxis or asthma was considered the primary etiology of OHCA, or those in whom the administration of epi- nephrine occurred prior to the arrival of trial-trained paramedics were excluded from enrollment. Once enrolled, patients were randomized in a 1:1 ratio to receive either epinephrine (1 mg) or saline placebo. Sin- gle doses of the study medication were administered every three to five minutes until ROSC was achieved, care was transferred to hospital clini- cians, or the resuscitation was discontinued. The primary outcome of the study was 30-day survival. Secondary outcomes included the rate of survival to hospital admission, ICU and hospital lengths of stay, sur- vival at hospital discharge and at three months, and neurologic outcome at hospital discharge and three months. Neurologic outcome was mea- sured by the Modified Rankin scale.

A total of 8014 patients were enrolled in the PARAMEDIC-2 Trial, with 4015 patients randomized to receive epinephrine and 3999 pa- tients randomized to receive placebo. The prehospital rate of ROSC was higher in patients who received epinephrine when compared to those who received placebo (36.3% vs. 11.7%). The primary outcome of 30-day survival occurred in 130 patients (3.2%) who received epineph- rine and in 94 patients (2.4%) who received placebo (unadjusted OR 1.39; 95% CI, 1.06-1.82; p = 0.02). The secondary outcome of survival to hospital discharge with favorable neurologic outcome occurred in 2.2% of patients who received epinephrine compared with 1.9% of pa- tients who receive placebo (unadjusted OR 1.18; 95% CI, 0.8-1.61). Im- portantly, severe neurologic impairment occurred in 39 out of 126 survivors who received epinephrine (31%) compared to 16 out of 90 survivors who received placebo (17.8%). There was no statistical differ- ence in survival at three months, hospital or ICU lengths of stay, or neu- rologic outcome at three months. Furthermore, there was no difference in treatment effect based on initial rhythm, patient age, whether the OHCA was witnessed, or whether the patient received bystander CPR.

Limitations of the PARAMEDIC-2 Trial are important to note. The

median time from activation of emergency medical services to study agent administration was approximately 21 min. As such, the results of this trial may not be applicable to the earlier administration of epi- nephrine in OHCA patients. Additional limitations include the lack of in- formation on patients baseline neurologic status, Quality of CPR beyond the first five minutes of resuscitation, and hospital care. Important com- ponents of hospital care known to affect survival (e.g., targeted temper- ature management, optimization of hemodynamics, optimization of oxygenation, cardiac catheterization) were not specified or standard- ized in the trial.

The PARAMEDIC-2 Trial is the largest randomized, placebo- controlled studies on the use of epinephrine for patients with OHCA. Though the administration of epinephrine was found to have a higher 30-day survival rate, there was no statistical difference in the important patient-centered outcome of favorable neurologic status at hospital dis- charge. In fact, those who did survive to hospital discharge and received epinephrine more often had severe neurologic impairment. Though the PARAMEDIC-2 trial is a prehospital study, the results are important and pertinent to the EP. Emergency physicians routinely receive patients with OHCA and often resuscitate patients who develop cardiac arrest within the ED. The results of this trial suggest a limited role for epineph- rine in OHCA resuscitation. Further studies are needed to clarify whether earlier administration, or alternative doses, of epinephrine are beneficial for patients with OHCA.

Jabre P, Penaloza A, Pinero D, Duchateau FX, Borron SW, et al. Effect of bag-mask ventilation vs endotracheal intubation during cardiopulmonary resuscitation on neurological outcome after out-of-hospital cardiopulmo- nary arrest. A randomized clinical trial. JAMA. 2018; 319:77987.

Airway management is an important component in the resuscitation and management of cardiac arrest patients. Despite its importance, the appropriate method and time for airway management in the resuscita- tion of cardiac arrest patients remains controversial. In recent years, several studies have demonstrated an association with endotracheal in- tubation (ETI) and worse outcome in patients with OHCA [10-13]. As a result, many providers advocate the use of bag-mask ventilation , instead of ETI, during the resuscitation of cardiac arrest patients. Impor- tantly, much of the current studies on airway management in cardiac ar- rest are retrospective studies of large cardiac arrest databases. While informative, these studies have limitations that affect the interpretation and application of their conclusions. Given the controversies on airway management in cardiac arrest, the authors of the current study sought to compare ETI with BMV in the treatment of patients with OHCA.

The current study was a multicenter, randomized, parallel-group, non-inferiority trial conducted in 20 prehospital emergency medical service (EMS) centers in France and Belgium. Investigators included adult patients greater than or equal to 18 years of age who had OHCA and received treatment by clinicians from one of the 20 EMS centers. Once enrolled, patients were randomized to receive either ETI or BMV as the method of airway management during CPR. For patients random- ized to receive ETI, video-assisted laryngoscopy or a bougie could be used if standard laryngoscopy was difficult or could not be performed. In addition, a laryngeal mask airway (LMA) could also be placed if stan- dard laryngoscopy was unsuccessful. Patients in both groups received standard advanced life support measures. The primary outcome of the study was 28-day survival with favorable neurologic outcome, as mea- sured by a Cerebral performance category score of one or two. Second- ary endpoints included survival to hospital admission, survival to hospital discharge, 28-day survival, rate of ROSC, and rate of BMV or ETI failure.

A total of 2043 patients were enrolled in the current study, with 1020 patients randomized to receive BMV and 1023 patients random- ized to receive ETI. Ultimately, 1018 patients in the BMV group and 1022 patients in the ETI group were included in the intention-to-treat analysis. The primary outcome of 28-day survival with favorable neuro- logic outcome occurred in 4.3% of patients in the BMV group and in 4.2% of patients in the ETI group (1-sided 97.5% CI, -1.64% to infinity; p for non-inferiority = 0.11). Non-inferiority of BMV to ETI with respect to 28-day survival with favorable neurologic survival was not demon- strated. Furthermore, there was no difference in the secondary out- comes of survival to hospital admission and 28-day survival between the two groups. Significant differences between the groups were noted in the incidence of difficult airway management (18.1% in the BMV group vs. 13.4% in the ETI group [95% CI, 1.5-7.9%; p = 0.04]) and in the frequency of gastric content regurgitation (15.2% in the BMV group vs. 7.5% in the ETI group [95% CI, 4.9-10.4%; p b 0.001]).

The authors of the current study concluded that the use of BMV failed to demonstrate non-inferiority with ETI for 28-day survival with favorable neurologic outcome in OHCA patients. Several limi- tations of the current study should be noted. Perhaps the most im- portant limitation is the lack of generalizability. The presence of a physician and nurse on the ambulance of the 20 participating EMS centers is unlike many EMS centers in the United States and worldwide. This is likely reflected in the high rate of successful ETI (96%), a rate higher than what is commonly reported by para- medic providers in OHCA patients. In addition to limited generaliz- ability, the current study did not achieve the statistical power to definitively compare BMV with ETI in OHCA patients. The authors based their study calculations on the hypothesis that BMV was not inferior to ETI for 28-day survival with favorable neurologic outcome. Finally, the results of the current study are only

applicable to patients with OHCA. The authors did not include pa- tients with in-hospital cardiac arrest in the evaluation of ETI and BMV.

The current study contributes to the literature on airway manage- ment in cardiac arrest resuscitation. Similar to the PARAMEDIC-2 trial, the current trial is a prehospital study with important findings pertinent to the EP. Emergency physicians must decide on the timing of airway in- tervention for non-intubated patients they receive in OHCA or in pa- tients who sustain cardiac arrest within the ED. Though the results of the study did not meet the non-inferiority threshold set by the authors, there was no indication of worse neurologic outcome in OHCA patients managed with BMV as the method of airway management. Until addi- tional research clearly defines the ideal method of airway management in OHCA, it reasonable to use BMV in the prehospital and initial ED re- suscitation of OHCA patients.

Benger JR, Kirby K, Black S, Brett SJ, Clout M, et al. Effect of a strategy of a supraglottic airway device vs tracheal intubation during out-of-hospital cardiac arrest on functional outcome: The AIRWAYS-2 randomized clinical trial. JAMA. 2018; 320:77991.

As previously highlighted, the optimal method of airway manage- ment in patients with OHCA remains uncertain. Current observational studies suggest that basic airway management may be better than ETI in the prehospital resuscitation of OHCA patients [12,14,15]. In recent years, Supraglottic airway \(SGA\) devices have been promoted as an al- ternative, faster, and easier method of airway management in patients with OHCA [14,16,17]. At present, there are no large randomized con- trolled trials that compare SGA devices with ETI in OHCA patients. The authors of the current study sought to assess between-group differences in neurologic outcome at hospital discharge or 30 days after OHCA, in OHCA patients treated with either an SGA or ETI as the initial method of advanced airway management.

The AIRWAYS-2 trial was a multicenter, cluster-randomized, con- trolled trial performed in four large EMS organizations in England. Pa- tients included in this trial were greater than or equal to 18 years of age who sustained a non-traumatic OHCA and were treated by a trialed-trained paramedic. Patients who had an advanced airway al- ready in place, those whose mouth would not open more than two cm, prisoners, and those in whom resuscitation was deemed inappro- priate were excluded. Enrolled patients were randomized in a 1:1 ratio to ETI or the insertion of an SGA. The use of BMV and other simple airway adjuncts prior to airway management was permitted. All other aspects of cardiac arrest care were provided in accordance with stan- dard Resuscitation guidelines. The primary outcome of the study was neurologic outcome, as measured by the modified Rankin Scale (mRS), at hospital discharge or 30-days after OHCA, whichever occurred first. The authors defined a good outcome as a mRS of zero to three. Sec- ondary outcomes included initial ventilation success, ROSC, complica- tions (e.g., regurgitation, aspiration), the sequence of airway interventions delivered, and the unintended loss of previously established airway.

A total of 9296 patients were enrolled in the AIRWAYS-2 trial, with 4886 patients were randomized to receive an SGA and 4410 were ran- domized to receive ETI. The primary outcome occurred in 6.4% of pa- tients randomized to an SGA and 6.8% of patients randomized to ETI (adjusted OR, 0.92; 95% CI, 0.77-1.09). In an exploratory analysis of the primary outcome, more patients randomized to an SGA had a good neurologic outcome compared to those randomized to ETI (3.9% vs. 2.6%; adjusted OR, 1.57; 95% CI, 1.18-2.07). Initial successful ventila- tion after up to two attempts occurred in 87.4% of patients randomized to an SGA and in 79.0% of patients randomized to ETI (adjusted OR, 1.92; 95% CI, 1.66-2.22). There was no statistical difference in the rates of re- gurgitation and aspiration between the two groups.

Similar to the previous studies on cardiac arrest, the AIRWAYS-2 trial is prehospital study that is an important contribution to the literature pertaining to airway management in patients with OHCA. Though the use of an SGA for advanced airway management did not result in a

more favorable neurologic outcome at hospital discharge, initial suc- cessful insertion rates were greater in the SGA group without any in- crease in complications. Limitations of the current study include an unblinded trial design, the use of a single, second-generation SGA de- vice, a greater use of advanced airway management among paramedics in the SGA group, and an imbalance between the two groups with re- spect to initial randomized airway intervention. Patients initially ran- domized to ETI less often received the intervention and were more likely to crossover to the SGA group. Notwithstanding these limitations, the use of an SGA for advanced airway management in OHCA patients was not associated with a worse neurologic outcome when compared to ETI. Given the priorities of high-quality CPR and Early defibrillation in the management of OHCA patients, the use of an SGA for initial ad- vanced airway management in the ED is reasonable.

Post-arrest care

Roberts BW, Kilgannon JH, Hunter BR, Puskarich MA, Shea L, et al. Asso- ciation between elevated mean arterial blood pressure and neurologic out- come after resuscitation from cardiac arrest: results from a multicenter prospective cohort study. Crit Care Med. 2018;47(1):93100.

Hemodynamic optimization is a critical component in the manage-

ment of patients resuscitated from cardiac arrest. Current AHA guide- lines for post-cardiac arrest care recommend the immediate correction of hypotension, defined as a systolic blood pressure less than 90 mm Hg or a mean arterial pressure (MAP) less than 65 mmHg [18]. However, current guidelines do not make any recommendation on an optimal MAP goal for post-cardiac arrest patients, other than to target what is traditionally used for critically ill patients (i.e., 65 mmHg) [18]. In recent years, studies have demonstrated an as- sociation between higher MAPs and improved outcome in patients re- suscitated from cardiac arrest [19-21]. Higher MAPs may increase cerebral perfusion and mitigate the adverse effects of post-cardiac arrest cerebral dysautoregulation. Given the uncertainty on the optimal MAP for post-cardiac arrest patients, the authors of the current study sought to test the association between elevated post-cardiac arrest MAP and neurologic outcome in adult patients resuscitated from cardiac arrest.

The current study was a preplanned analysis of a prospective cohort study conducted in ICUs at six US hospitals. Patients included in the study were greater than or equal to 18 years of age who sustained either in-hospital cardiac arrest or OHCA, achieved ROSC for at least 20 min, remained unresponsive, were initiated on mechanical ventilation, and were candidates for Targeted temperature management (TTM). Patients excluded from the current study were those in whom the presumed eti- ology of cardiac arrest was secondary to trauma, hemorrhage, or sepsis, residents of a nursing home or long-term care facility, prisoners, preg- nant patients, and those with persistent hypotension during the initial six hours following ROSC. MAP was measured immediately after ROSC and then hourly for the first six hours. Vasopressor medication adminis- tration and data required to calculate the Sequential Organ Failure As- sessment (SOFA) score were also prospectively collected. The primary outcome of the study was good neurologic function at the time of hos- pital discharge, defined by the authors as a mRS of three or less. Second- ary outcomes included survival to hospital discharge and good early neurologic response, defined by the authors as a Full Outline of Unre- sponsiveness (FOUR) score greater than six at 72 h after ROSC. A priori, the authors grouped subjects into two categories: those with a MAP be- tween 70 and 90 mmHg, and those with a MAP greater than 90 mmHg. A total of 269 patients were included in the final analysis of this study. The primary outcome of good neurologic function occurred in 30% of patients. Patients in the higher MAP group (MAP greater than 90 mmHg) had a higher incidence of good neurologic outcome when compared patients with a MAP between 70 and 90 mmHg (42% vs. 15%, p b 0.001). In addition, patients with a MAP greater than 90 mmHg had a higher rate of survival at 72 h (86% vs. 74%, p = 0.01) and a higher median FOUR score (11 vs. 6, p b 0.001) compared with

those who had a MAP between 70 and 90 mmHg. A MAP greater than 90 mmHg was associated with an increased survival to hospital dis- charge (57% vs. 28%, p b 0.001). In fact, a MAP greater than 90 mmHg was found to be an independent predictor of good neurologic function at hospital discharge (RR 2.46; 95% CI, 2.09-2.88; p b 0.01). Not surpris- ingly, the benefit of a higher MAP was greater in patients with a history of hypertension compared with those with no history of hypertension. Lastly, the authors report that for every additional hour the MAP was greater than 90 mmHg, the probability of good neurologic outcome in- creased by 15%.

Limitations of the current study are important to note. Perhaps most important is the Observational study design. As such, a definitive link between higher MAP and good neurologic outcome cannot be reached. In addition, the authors excluded patients with a MAP less than 70 mmHg and there was a higher incidence of Shockable rhythms in the study population. These factors may limit the validity and generaliz- ability of study findings by removing patients that may be at risk of worse neurologic outcome. Further limitations include the lack of a standardized MAP target, lack of Invasive blood pressure monitoring, and the findings that patients with a MAP between 70 and 90 mmHg had a longer duration of CPR and higher incidence of withdrawal of care. Despite these limitations, the current study is an important contri- bution to the literature on post-cardiac arrest care. Until further re- search identifies the optimal MAP, it may be reasonable for the EP to target a higher MAP in the immediate post-ROSC period, especially in patients with a history of hypertension.

Roberts BW, Kilgannon JH, Hunter BR, Puskarich MA, Pierce L, et al. As- sociation between early hyperoxia exposure after resuscitation from car- diac arrest and neurological disability: a prospective multi-center protocol-directed cohort study. Circulation 2018;137(20):21142124.

Optimization of hemodynamics, oxygenation, and ventilation, in combination with TTM and early cardiac catheterization for appropriate patients, form the foundation of post-cardiac arrest care. With respect to oxygenation, current guidelines recommend the titration of supple- mental oxygen to avoid hypoxia and prolonged exposure to hyperoxia, commonly defined as a partial pressure of oxygen (PaO2) greater than 300 mmHg [18]. In recent years, several studies have demonstrated an association of hyperoxia and worse neurologic outcome in post- cardiac arrest patients [22-24]. Importantly, many of these studies use arterial blood gas measurements over the first 24 to 48 h after ICU admission to detect hyperoxia. It is uncertain if exposure to hyperoxia within the first few hours following ROSC impacts neurologic outcome. The authors of the current study sought to test the association between early post-resuscitation hyperoxia and poor neurologic out- come in patients resuscitated from cardiac arrest.

The current study is a prospective, observational, cohort trial con- ducted in six US hospitals. Patients included in the study were greater than or equal to 18 years of age who sustained either in-hospital cardiac arrest or OHCA, achieved ROSC for at least 20 min, remained un- responsive, were initiated on mechanical ventilation, and were candi- dates for TTM. All patients received standard post-cardiac arrest care, which included TTM, goal-directed hemodynamic support, cardiac catheterization, and continuous electroencephalographic monitoring. To evaluate the effects of early hyperoxia, investigators measured ABGs at one hour and six hours after ROSC. Arterial oxygen saturations (SpO2) and the fraction of inspired oxygen (FiO2) were also recorded every 15 min for the first six hours. The authors defined hyperoxia as a PaO2 greater than 300 mm Hg on one or more ABGs. The primary out- come of the study was poor neurologic outcome or death at hospital dis- charge. Similar to the preceding study by Roberts and colleagues, poor neurologic outcome was defined as a mRS greater than three. Secondary outcomes included in-hospital mortality and early neurologic injury, defined as a FOUR score less than or equal to six at 72 h after ROSC.

A total of 280 patients were included in the final analysis of this trial. Approximately 70% of the study population met the primary outcome of poor neurologic outcome or death at hospital discharge. During the first

6 h after ROSC, 38% of patients were exposed to hyperoxia. Patients ex- posed to hyperoxia had a higher incidence of poor neurologic outcome at hospital discharge compared to patients not exposed to hyperoxia (77% vs. 65%; absolute Risk difference 12%; 95% CI, 1-23%, p = 0.035). There was no significant difference between the groups with respect to mortality rate at hospital discharge. There was also no significant dif- ference in secondary outcomes between the two groups. After multivar- iate analysis, hyperoxia was found to be an independent predictor of poor neurologic outcome at hospital discharge (RR 1.23; 95% CI, 1.11-1.35; p b 0.001). The authors report a 3% increase in poor neuro- logic outcome for every hour increase in the duration of hyperoxia. Fi- nally, the authors report a poor correlation between SpO2 and PaO2. In fact, SpO2 was not a reliable predictor of exposure to hyperoxia.

The current study has several notable limitations. Similar to other studies on the effects of hyperoxia in critical illness, it is an observational study. Therefore, only an association between early exposure to hyperoxia and poor neurologic outcome in post-cardiac arrest patients can be made. In addition, the authors included patients who sustained an IHCA. These patients generally have different characteristics and eti- ologies of cardiac arrest compared with patients who suffer an OHCA. It is also important to note that more than 320 patients screened for this study were not enrolled due to lack of consent. Furthermore, the au- thors did not measure the Physiologic effects of hyperoxia via bio- markers for brain injury and oxidative stress. Finally, only 26% of patients with OHCA and an Initial shockable rhythm went for cardiac catheterization within the first 36 h following ROSC. This may have im- pacted cerebral perfusion, neurologic outcome, and mortality for a large number of patients in this trial.

Notwithstanding these limitations, the current study is an important contribution to the literature on post-cardiac arrest care. Exposure to hyperoxia soon after ROSC may be associated with increased mortality and poor neurologic outcome in post-cardiac arrest patients. Until addi- tional research clarifies the time and duration of exposure to hyperoxia that results in poor neurologic outcome, the EP should continue to fol- low current guidelines and decrease FiO2 when oxyhemoglobin satura- tion (SaO2) is 100% and can be followed and maintained greater than or equal to 94% [18].

Septic shock

Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378 (9):797808.

Sepsis is one of the most common Critical illnesses encountered by

EPs. Early identification, prompt administration of appropriate antibi- otics, intravenous fluid resuscitation, source control, and vaso- pressor therapy for patients who do not maintain an adequate MAP with IVFs alone form the foundation of ED sepsis management. Despite appropriate therapy with IVFs and Vasopressor medications, a portion of patients’ progress to develop septic shock and remain hemodynamically unstable. The short-term mortality for patients with septic shock can be as high as 50% [25]. Corticosteroids have been used in the treatment of patients with septic shock for decades. Current international guidelines for the management of patients with sepsis and septic shock recom- mend the administration of hydrocortisone in patients with septic shock if adequate fluid resuscitation and vasopressor medications fail to restore hemodynamic stability [26]. Despite current guideline recom- mendations, there remains significant controversy on the benefit of cor- ticosteroids in the management of patients with septic shock. As such, the authors of the current study sought to test the hypothesis that hy- drocortisone results in decreased mortality when compared with pla- cebo in the treatment of patients with septic shock.

The Adjunctive CorticoSteroid treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial was a multicenter, pragmatic, double-blind, randomized, controlled trial conducted in 69 medical- surgical ICUs in Australia, New Zealand, Saudi Arabia, Denmark, and

the United Kingdom. Patients enrolled in the ADRENAL trial were geater than or equal to 18 years of age, had a documented or strong suspicion of infection, had greater than or equal to two systemic inflammatory re- sponse syndrome (SIRS) criteria, were intubated and mechanically ven- tilated, and were treated with vasopressor or inotropic medications for at least four hours. Patients excluded from this trial included those who received Systemic corticosteroids for a condition other than septic shock, received etomidate for Rapid Sequence Intubation , or were likely to die from a pre-existing illness within 90 days of randomization. Patients randomized to the intervention group received a continuous 24-hour infusion of hydrocortisone, at a dose of 200 mg per day, for seven consecutive days or until death or ICU discharge. Patients ran- domized to the control group received a placebo infusion for the same duration. The primary outcome of the trial was 90-day all-cause mortal- ity. Secondary outcomes included 28-day mortality, time to resolution of shock, recurrence of shock, ICU length of stay, hospital length of stay, frequency and duration of mechanical ventilation, and the inci- dence of new bacteremia or fungemia between two to fourteen days.

A total of 3800 patients were enrolled in the ADRENAL trial. Ulti- mately, 3686 patients were included in the final analysis, with 1832 assigned to the intervention group and 1825 assigned to the control group. There was no significant difference in the primary outcome of 90-day all-cause mortality in patients who received hydrocortisone compared to those who received placebo (27.9% vs. 28.8%; p = 0.50). Though there was no difference in the secondary outcome of 28-day mortality, though time to shock resolution, time to ICU discharge, and the duration of the initial episode of mechanical ventilation were all shorter in patients who received hydrocortisone. In addition, there were fewer patients who received a blood transfusion in the interven- tion group compared with the control group. There were 33 adverse events reported in the ADRENAL trial, the most common of which was hyperglycemia. Four out of the six serious adverse events occurred in patients who received hydrocortisone.

The ADRENAL trial has several important limitations. First, investiga- tors enrolled only ventilated patients who received vasoactive agents for at least four consecutive hours. These results may not be generaliz- able to non-intubated patients with septic shock who have received fewer that four hours of vasopressor therapy. In addition, patients in the intervention group received a 24-h continuous infusion of hydrocor- tisone. While a continuous infusion is a reasonable approach to admin- istration, the majority of patients who receive corticosteroids for septic shock receive them at intermittent doses. It is uncertain if these results are generalizable to patients who receive intermittent doses of cortico- steroids. Furthermore, the authors did not assess other important as- pects of sepsis care (e.g., appropriateness of antibiotic therapy). Despite these limitations, the ADRENAL trial is an important study on the management of patients with septic shock. Though time to shock resolution was shorter, the use of a continuous infusion of hydrocorti- sone did not improve 90-day mortality in patients with septic shock.

Annane D, renault A, Brun-Buisson C, megarbane B, quenot JP, et al. Hy- drocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378: 80918.

As aforementioned, corticosteroids have been used in the treatment of patients with septic shock for decades. Corticosteroids may decrease inflammation in select organs and improve Cardiovascular function in patients with sepsis [27,28]. At present, approximately one-third of physicians believe corticosteroids are beneficial for patients with septic shock, one-third believe corticosteroids are not beneficial, and one-third are unsure of their clinical benefit [27,29]. Given the heterogeneity in clinical practice and the inconclusive results of current studies, the au- thors of this trial sought to test the hypothesis that hydrocortisone plus fludrocortisone or drotrecogin alfa would improve the clinical out- comes of patients with septic shock.

The Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial was a multicenter, placebo-controlled trial con- ducted in 34 ICUs in France. The initial trial contained four parallel

groups organized in a 2 x 2 factorial design to compare the benefits and risks of corticosteroids and drotrecogin alfa (activated) given alone or in combination. When drotrecogin alfa was withdrawn from the market in 2011, the trial continued with two parallel groups to eval- uate the effects of hydrocortisone and fludrocortisone in patients with septic shock. Patients enrolled in the trial were admitted to the ICU, had indisputable or probable septic shock for less than 24 h, had a Se- quential Organ Failure Assessment (SOFA) score of three or four for at least two organs for at least six hours, and required the need for vaso- pressor therapy for at least six hours to maintain an SBP of at least 90 mmHg or a MAP of at least 65 mmHg. Patients excluded from the study were those who had septic shock for greater than 24 h prior to randomization, pregnant or lactating, where at high-risk of bleeding, or had an underlying condition that might affect short-term mortality. Once enrolled, patients were randomized in permuted blocks of eight to receive hydrocortisone plus fludrocortisone, drotrecogin alfa (acti- vated), the combination of all three, or placebo for a total of seven days. Hydrocortisone was given as an Intravenous bolus of 50 mg every six hours. Fludrocortisone was administered at 50 mcg per day via a nasogastric tube. The primary outcome of the APROCCHSS trial was 90-day all-cause mortality. Secondary outcomes of the trial in- cluded all-cause mortality at ICU and hospital discharge, day 28, and day 30. Additional secondary outcomes included the percentage of pa- tients weaned from vasopressors at days 28 and 90, the time to cessa- tion of vasopressors, the percentage of patients weaned from mechanical ventilation at days 28 and 90, and the time to cessation of mechanical ventilation. Finally, the investigators reported safety out- comes of superinfection, gastrointestinal bleeding, and hyperglycemia for both groups.

A total of 1241 patients were included in the trial, with 614 patients in the hydrocortisone-fludrocortisone group and 627 in the placebo group. The primary outcome of 90-day all-cause mortality occurred 43% of the hydrocortisone-fludrocortisone group compared with 49.1% in the placebo group (RR 0.88; 95% CI, 0.78-0.99; p = 0.03). Those in the hydrocortisone-fludrocortisone group also had a statistically signif- icant difference in all-cause mortality at ICU discharge (35.4% vs. 41%, p = 0.04), all-cause mortality at hospital discharge (39% vs. 45.3%, p = 0.02), and 180-day mortality (46.6% vs. 52.5%, p = 0.04). Further- more, patients in the hydrocortisone-fludrocortisone group had a shorter time to cessation of mechanical ventilation and cessation of va- sopressor therapy. Not surprisingly, there was a higher incidence of hy- perglycemia noted in the hydrocortisone-fludrocortisone group compared with placebo (RR 1.07, 95% CI, 1.03-1.12; p = 0.002). There was no difference in the incidence of gastrointestinal bleeding or super- infection between the groups.

The APROCCHSS trial has several important limitations. The trial took approximately six and a half years to complete. As the study began enrollment in 2008, investigators based patient treatment on the 2008 Surviving sepsis campaign guidelines for the management of patients with severe sepsis and septic shock. Over the course of the study, the trial was suspended twice and finally terminated by the spon- sor when the expiration dates of the medications were reached. The first trial suspension occurred when drotrecogin alfa (activated) was re- moved from the market, and the second trial suspension was requested by the data and safety monitoring board. In addition, the removal of drotrecogin alfa (activated) from the market adversely impacted the in- vestigators statistical Power calculations. Finally, there was minor im- balances noted in patients between the study groups.

Taken together, the ADRENAL and APROCCHSS trials provide impor- tant contributions to the literature on the management of patients with septic shock. Both studies demonstrate that patients with septic shock who receive corticosteroids have a faster time to shock resolution and shorter duration of mechanical ventilation. However, the APROCCHSS trial demonstrated improved 90-day all-cause mortality, whereas the ADRENAL trial did not demonstrate improved mortality. Variation in mortality results between these studies can likely be explained by the

populations enrolled in each study. Patients in the current APROCCHSS trial were more critically ill than those enrolled in the ADRENAL trial. Patients in the ADRENAL trial were more often surgical ICU admissions, had higher rates of Abdominal infections, and had lower rates of pulmo- nary, genitourinary, and Bloodstream infections. An additional signifi- cant difference in these trials is the addition of fludrocortisone to hydrocortisone in the APROCCHSS trial. While additional studies are needed to determine if corticosteroids truly impact mortality for pa- tients with septic shock, it is worth noting that neither the ADRENAL or APROCCHSS trials demonstrated an increase in mortality with the ad- ministration of corticosteroids. Given the shorter time to shock resolu- tion and the lack of patient harm in these two large studies, it is reasonable for the EP to continue to consider the administration of hy- drocortisone to ED patients with persistent septic shock.

Rapid sequence intubation

Driver BE, Prekker ME, Klein LR, Reardon RF, Miner JR, et al. Effect of use of a bougie vs endotracheal tube and stylet on first-attempt intubation suc- cess among patients with difficult airways undergoing emergency intuba- tion: A randomized clinical trial. JAMA 2018; 319:21792189.

EPs perform approximately 350,000 ETIs each year in the United States [30,31]. In approximately 15% of cases, the first attempt at ETI is unsuccessful, which may place the patient at higher risk of adverse events and outcome [30,32,33]. When the initial attempt at ETI with di- rect or video laryngoscopy is unsuccessful, the EP often relies on a res- cue airway device to intubate the patient. In recent years, the bougie has become a popular Rescue device for EPs. Despite its popularity as a rescue device, the bougie is rarely used during the initial attempt at ETI [30,32]. It is unknown whether the use of a bougie during the initial attempt at ETI would improve the First-pass success rate. As such, the authors of the current study sought to compare the bougie with a stan- dard endotracheal tube and stylet for ETI in ED patients with at least one characteristic of a difficult laryngoscopy or intubation.

The Bougie Use in Emergency airway management (BEAM) trial was

a randomized trial performed in a single, urban, academic, level one trauma center in the United States between September 2016 and Au- gust 2017. Patients included in the study were 18 years of age or older, who underwent ETI in the ED, and in whom the attending EP planned to use a Macintosh Laryngoscope blade during the first attempt. Prisoners, pregnant patients, and patients with a known distortion of the upper airway were excluded. All ETIs were performed by an emer- gency medicine resident or attending. Both direct and video laryngos- copy were permitted. Once enrolled, patients were randomized in a 1:1 ratio to ETI using the bougie or an ETT plus stylet for the first at- tempt. The ETT was configured in a straight-to-cuff shape with a bend angle of 25-35 degrees. Characteristics of a difficult airway were de- fined by the investigators as follows: body fluid that obscured the laryn- geal view, airway obstruction or edema, obesity, short neck, small mandible, large tongue, facial trauma, or cervical spine immobilization. Importantly, these characteristics were subjectively determined by the physicians after they completed ETI. The primary outcome of the study was first attempt ETI success in patients with at least 1 character- istic of a difficult airway. Secondary outcomes included first attempt du- ration, Esophageal intubation, and hypoxemia.

A total of 757 patients were enrolled in the BEAM trial, with 381 pa-

tients randomized to the bougie and 376 patients randomized to the ETT plus stylet. Three hundred eighty patients possessed at least one characteristic of a difficulty airway. The primary outcome of first at- tempt success in those with at least one characteristic of a difficult air- way occurred in 96% of patients randomized to the bougie and 82% of patients randomized to the ETT plus stylet (absolute difference 14%; 95% CI, 8-20%). In fact, for the entire study population, first attempt suc- cess was higher for those intubated with the bougie compared with those intubated with the ETT plus stylet (98% vs. 87%; absolute differ- ence 11%, 95% CI, 7-14%). In an exploratory analysis, the authors

reported greater first attempt success with the bougie in obese patients (96% vs. 75%) and in those with cervical spine immobilization (100% vs. 78%) compared to the ETT plus stylet. There was no difference in the in- cidence of hypoxemia or esophageal intubations between the groups.

Several limitations of the BEAM trial are important to highlight. First, the results of this single center trial may not be generalizable to other clinical settings or patient populations. In fact, the majority of ETIs at this center before the study were performed with video laryngoscopy and the bougie for the initial attempt. This suggests that these EPs were likely skilled in the use of the bougie compared to other sites that primarily use the bougie as a rescue device. In addition to the lack of generalizability, it is important to also highlight that the characteris- tics of a difficult airway were based on the subjective assessment of the EP and recorded after ETI was performed. Therefore, randomization was not based on the presence of difficult airway characteristics. Finally, the EP could not be blinded to the intervention of either the ETT plus stylet or bougie. Notwithstanding these limitations, the BEAM trial provides a valuable contribution to the literature on ED airway management. Based on these results, it is reasonable for the EP to consider the use of a bougie during the first attempt at ETI, especially in patients who are anticipated to have a difficulty airway.

De Jong Audrey, Rolle A, Molinari N, Paugam-Burtz C, Constantin JM,

et al. Cardiac arrest and mortality related to intubation procedure in criti- cally ill adult patients: A multicenter cohort study. Crit Care Med. 2018; 46:532.

Critically ill patients who require ETI are at high risk for adverse events, including an intubation-related cardiac arrest. To date, the liter- ature on intubation-related cardiac arrest in critically ill adults is limited [34]. In fact, very few studies have prospectively evaluated risk factors for intubation-related cardiac arrest in ICU patients. As such, the authors of the current study sought to establish the prevalence of cardiac arrest during ETI, the mortality rate of patients who sustain an intubation- related cardiac arrest, and to identify risk factors for intubation-related cardiac arrest among a cohort of ICU patients.

The current study is a retrospective cohort analysis of ETIs per- formed in six prospective randomized and observational studies that used five databases in 64 ICUs. Patients included in this study were greater than or equal to 18 years of age and underwent ETI in one of the 64 ICUs. Patients excluded from the study were those admitted to the ICU as a result of cardiac arrest or those intubated during cardiac ar- rest resuscitation. The primary outcome of the study was intubation- related cardiac arrest, defined by the authors as occurring during, or within, five minutes of ETI. Secondary outcomes included 28-day mor- tality, length of ICU stay, cardiac arrest without ROSC, and intubation- related complications (e.g., hypoxemia, hypotension, esophageal intubation).

A total of 1847 intubations were included in the current study. The primary outcome of intubation-related cardiac arrest occurred in 2.7% of patients. Not surprisingly, patients who suffered an intubation- related cardiac arrest had a higher 28-day mortality rate compared with patients who did not have an intubation-related cardiac arrest (73.5% vs. 30.1%; p b 0.0001). In fact, the authors found that intubation-related cardiac arrest was an independent risk factor for 28-day mortality (HR 3.9; 95% CI, 2.4-6.3; p b 0.0001). In addition to these results, the authors also identified five risk factors for intubation-related cardiac arrest: a systolic blood pressure b 90 mm Hg prior to intubation (OR 3.406; 95% CI, 1.797-6.454; p = 0.0002),

hypoxemia prior to intubation (OR 3.991; 95% CI, 2.101-7.583; p b 0.0001), the absence of preoxygenation (OR 3.584; 95% CI, 1.287-9.985; p = 0.0146), obesity (OR 2.005; 95% CI, 1.017-3.951;

p = 0.0445), and age greater than 75 years (OR 2.251; 95% CI, 1.080-4.678; p = 0.0297). Of these, the strongest risk factor associated with intubation-related cardiac arrest was hypoxemia prior to intubation.

The study is limited by the retrospective cohort design and is subject to the biases and confounders contained in the randomized and

observational studies included in the study. Furthermore, the databases used for these studies were not specifically focused on the authors pri- mary outcome and may have contained incomplete data. Nevertheless, the current study by De Jong and colleagues provides important infor- mation to EPs and critical care physicians that routinely perform ETI. Specifically, the risk factors associated with intubation-related cardiac arrest are critical to note. Three of these risk factors (hypotension prior to intubation, hypoxemia prior to intubation, absence of preoxygenation) should be identified and addressed, when possible, prior to ETI.

Mechanical ventilation

Simonis FD, Serpa Neto A, Binnekade JM, Braber A, Bruin KCM, et al. Ef- fect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS. The PReVENT Trial. JAMA 2018; 320(18):18721880.

Critically ill ED patients are often intubated and initiated on mechan- ical ventilation. Like any therapy, mechanical ventilation can cause harm if not properly set and closely monitored. For patients with Acute respiratory distress syndrome , the use of low tidal vol- umes (six to eight ml/kg ideal body weight) has been shown to improve mortality when compared to higher tidal volumes (greater than 12 ml/ kg ideal body weight) [35]. Unfortunately, a low tidal volume ventila- tion strategy can have also have adverse effects, which include patient-ventilator asynchrony, increased doses of sedatives, increased risk of delirium, and increased risk of barotrauma secondary to higher respiratory rates that result from air-hunger caused by low tidal vol- umes [36-39]. Whether a low tidal volume ventilation strategy is bene- ficial for patients without ARDS is uncertain. Given this uncertainty, the authors of the current study sought to determine whether the use of low tidal volumes was superior to intermediate tidal volumes in venti- lated patients without ARDS.

The PreVENT study was a multicenter, randomized, controlled trial performed in six ICUs in the Netherlands. Patients included in the study were greater than or equal to 18 years of age, intubated shortly before or after admission to the ICU, were expected to be intubated for at least 24 h after randomization, and did not have evidence of ARDS. Patients less than 18 years of age, those with ARDS, a history of pulmo- nary disease, a new diagnosis of pulmonary embolism, increased or un- controllable intracranial pressure, pregnancy, and those ventilated longer than 12 h before ICU admission were excluded. Once enrolled, patients were randomized in a 1:1 ratio to either a low tidal volume ventilation strategy or an intermediate tidal volume strategy. Patients in the low tidal volume ventilation strategy group received an initial tidal volume of 6 ml/kg predicted body weight, whereas those in the in- termediate tidal volume group received an initial tidal volume of 10 ml/ kg predicted body weight. Investigators allowed the treating clinician to decide whether to use a volume-controlled (VC) or pressure-support (PS) mode of mechanical ventilation. For patients placed on VC ventila- tion, the Plateau pressure was measured. If the plateau pressure was greater than 25 mm Hg, tidal volume could be decreased one ml/kg pre- dicted body weight every hour to a minimum of four ml/kg predicted body weight. For patients placed on PS ventilation, the maximum air- way pressure was measured. pressure support was then adjusted to tar- get a maximum airway pressure less than 25 cm H2O. The primary outcome of this study was the number of ventilator-free days and alive at day 28. Secondary outcomes included ICU and hospital length of stay, ICU mortality, hospital mortality, 28-day and 90-day mortality, the use of analgesics and Neuromuscular blocking agents, and the occur- rence of pulmonary complications (new ARDS, ventilator-associated pneumonia, severe atelectasis, pneumothorax).

A total of 961 patients were included in the current study, with 477

assigned to the low tidal volume ventilation group and 484 assigned to the intermediate tidal volume ventilation group. Baseline characteristics between the two groups were well balanced. The most frequent reason

for mechanical ventilation was cardiac arrest. With respect to the pri- mary outcome of ventilator free days and alive at day 28, there was no significant difference between the low tidal volume ventilation group and the intermediate tidal volume ventilation group (21 days vs. 21 days; mean difference, -0.27 [95% CI, -1.74 to 1.19]; p = 0.71)). There was also no significant difference in the secondary outcomes of ICU and hospital length of stay, ICU and hospital mortality, 28-day and 90-day mortality, and the occurrence of pulmonary complications. The only difference noted between the groups was a higher incidence of re- spiratory acidosis in patients randomized to the low tidal volume group. The PreVENT trial is an important contribution to the literature on mechanical ventilation in patients without ARDS. The trial was well de- signed with patient-centered outcomes. Notwithstanding, there are several important limitations of the study that should be noted. The trial was not blinded and included a heterogeneous group of patients without ARDS. In addition, a significant number of patients were eligible for randomization were missed and not enrolled. Perhaps most notably, a significant number of patients in the low tidal volume ventilation group did not achieve the trial targets. By day one, approximately 60% of patients in the low tidal volume ventilation group received tidal vol- umes in excess of six ml/kg predicted body weight. Despite these limita- tions, the PreVENT trial demonstrated that a low tidal volume ventilation strategy was not more effective with respect to ventilator free days at day 28 compared with a ventilation strategy that used inter- mediate tidal volumes. As the majority of patients intubated and venti- lated in the ED do not have evidence of ARDS, it may be reasonable for the EP to select an initial tidal volume higher than six ml/kg of predicted body weight. If a higher initial tidal volume is selected, it is imperative to continue to follow serial plateau Pressure measurements with the goal

of maintain less than 30 cm H2O.

Stephens RJ, Dettmer MR, Roberts BW, Ablordeppey E, Fowler SA, et al. Practice patterns and outcomes associated with early sedation depth in me- chanically ventilated patients: A systematic review and meta-analysis. Crit Care Med 2018; 46(3):471479.

The administration of appropriate amounts of analgesic and sedative medications is a critical component in the care of me- chanically ventilated patients. Current guidelines for the manage- ment of pain and agitation in critically ill adult patients recommend the titration of these medications to achieve lighter levels of sedation [40]. This recommendation stems from recent studies that demonstrated an association of deep levels of sedation with increased rates of delirium, ICU length of stay, and mortality [41,42]. Unfortunately, these studies did not examine the impact of sedation depth in the period immediately following intubation and initial ICU admission. As such, the authors of the current study sought to investigate the effects of deep sedation within the first 48 h of initiation of mechanical ventilation.

The current study is systematic review and meta-analysis performed

in accordance with the Preferred Reporting Items for Systematic Re- views and Meta-Analysis Protocol (PRISMA-P). A literature search was conducted using the following databases: 1) MEDLINE, 2) EMBASE,

3) Scopus, 4) Cochrane Central Register of Controlled Trials, 5) Database of Abstracts of Reviews and Effects, and 6) Cochrane Database of Sys- tematic Reviews. A search was also performed of abstracts from the sev- eral clinical meetings from 2010 to 2017. Abstracts were screened by two independent reviewers. Studies that included mechanically venti- lated adult patients were eligible for inclusion. Randomized controlled trials, prospective and retrospective cohort analyses, cross-sectional studies, and before-and-after studies were included. Patient-centered outcomes were compared in patients who had light versus deep seda- tion during the first 48 h after initiation of mechanical ventilation. The primary outcome was hospital mortality, with secondary outcomes of hospital length of stay, ICU length of stay, duration of mechanical venti- lation, delirium, and frequency of tracheostomy. Patients who were intubated in the operating room were only included in the analysis if they were immediately admitted to the ICU.

Out of 946 studies identified by the authors searches, nine were in- cluded in the final analysis. These studies were published between 2012 and 2017 and included 4521 patients. Two of the nine studies were randomized controlled trials and seven were observational stud- ies. Two of the studies included data from ED patients, with the remain- ing seven studies including data only from ICU patients. The authors found a statistically significant decrease in mortality for patients titrated to an early, lighter level of sedation compared with patients who re- ceived early, deep sedation [9.2% vs. 27.6%; OR 0.34; (0.21-0.54)]. Ligh- ter sedation was also associated with significantly fewer days of mechanical ventilation and shorter ICU lengths of stay. The rate of delir- ium and the rate of tracheostomy were not significantly different be- tween the light and deep sedation groups.

The current systematic review and meta-analysis suggests that the level of sedation shortly after initiation of mechanical ventilation may make a difference in the patient-centered outcome of mortality. This di- rectly impacts EPs, as patients are initiated on mechanical ventilation and often board in the ED for an extended period of time until transfer to the ICU. Importantly, the current study has several limitations. First, the authors were able to identify only nine studies for their analysis. There is the possibility that additional studies on the level of early seda- tion were not identified by their search methodology, and therefore may affect the conclusions of this study. Second, the authors identified a high level of statistical heterogeneity due to the lack of randomized controlled trials and the different definitions of deep sedation within the studies. Finally, the results of observational studies can only be viewed as associated with the outcomes of interest, rather than causa- tive. Despite these limitations, the current study provides important in- formation on the level of sedation soon after initiation of mechanical ventilation. When possible and clinically feasible, the EP should target lighter levels of sedation in intubated ED patients awaiting ICU admission.

Fluid resuscitation

Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378(9): 82939.

intravenous fluid administration is one of the most common

interventions in the resuscitation of critically ill ED patients. Though there are numerous crystalloid and colloid solutions, 0.9% sodium chlo- ride is the most common IVF administered to critically ill patients [42-45]. Often referred to as “normal” saline, 0.9% sodium chloride can produce a Hyperchloremic metabolic acidosis and has been associ- ated with Acute kidney injury and increased mortality [42, 46-49]. As a result of the potential harmful effects of 0.9% sodium chlo- ride, many clinicians have turned to balanced crystalloid solutions for IVF resuscitation in critically ill patients. Balanced crystalloid solutions (e.g., Plasmalyte, lactated Ringer‘s) have lower Chloride levels and or- ganic anions (e.g., acetate, lactate, gluconate) and cations (e.g., potassium, calcium, magnesium) compared to 0.9% sodium chlo- ride. Several recent studies have demonstrated lower rates of AKI, renal-replacement therapy (RRT), and mortality in patients who re- ceived a balanced solution for resuscitation [42,47,48,50,51] These stud- ies, however, have significant limitations that limit the ability to determine if balanced solutions are superior to 0.9% sodium chloride for IVF resuscitation in critically ill patients. The authors of the current study sought to compare balanced crystalloids with 0.9% sodium chlo- ride to determine if IVF composition affected clinical outcomes in criti- cally ill adult patients.

The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) was a pragmatic, unblinded, cluster-randomized, multiple crossover trial conducted in five ICUs is a single, urban, academic med- ical center. Patients included in the study were 18 years of age or older who were admitted to one of the participating ICUs and enrolled in the trial at the time of ICU admission. The participating ICUs were randomly

assigned to use 0.9% sodium chloride during even-numbered months and balanced crystalloids during odd-numbered months. The two bal- anced solutions used in this trial were Lactated Ringer’s (LR) and Plasma-Lyte A. Choice of which balanced solution to use for fluid resus- citation was left to physician preference. The primary outcome of this trial was the proportion of patients who met one or more of the authors criteria for major adverse kidney event (MAKE) within 30 days. These MAKE criteria were death, new receipt of RRT, or persistent renal dys- function. Secondary outcomes included in-hospital death before ICU discharge or at 30 or 60 days, number of ventilator free days, number of vasopressor free days, and the number of ICU free days.

A total of 15,802 patients were enrolled in the current trial. The me- dian volume of balanced fluid administered between ICU admission and hospital discharge or 30 days was 1000 ml; whereas, the median vol- ume of 0.9% sodium chloride administered during the same time frame was 1020 ml. The primary outcome of MAKE at 30 days occurred in 14.3% of the balanced crystalloid group compared with 15.4% of the 0.9% sodium chloride group (marginal odds ratio 0.91; 95% CI, 0.82-0.99; p = 0.04). The difference in the primary outcome between patients who received a balanced solution and those who received 0.9% sodium chloride was greater among those who received larger vol- umes of fluid and those with sepsis. The secondary outcome of death be- fore hospital discharge or within 30 days of ICU admission occurred in 10.3% of patients in the balanced solution group compared with 11.1% of those in the 0.9% sodium chloride group (p = 0.06).

The SMART trial is the largest randomized trial to compare the use of 0.9% sodium chloride with balanced crystalloid solutions for IVF resusci- tation in critically ill adult patients. The authors report an absolute dif- ference in MAKE at 30 days of 1.1% in favor of balanced crystalloid solutions. Though the absolute difference is small, the authors empha- size that the potential impact of this difference may be significant when applied to the millions of patients admitted to ICUs each year. Im- portantly, the current trial has several limitations. First, the trial was conducted at a single, urban, academic center in the United States. As such, these results may not be generalizable to patients in different set- tings and populations. Second, clinicians were not blinded to the com- position of IVFs each patient received. Perhaps most importantly, the authors used a Composite outcome of death, RRT, and persistent renal dysfunction. When individually analyzed, the difference between bal- anced crystalloids and 0.9% normal saline for each outcome was no lon- ger statistically significant. It was only when the authors combined these three outcomes into a composite outcome that a statistical differ- ence was found. Despite these limitations, the SMART study is a signifi- cant contribution to the literature on fluid resuscitation in the critically ill. Until further studies are published, the EP should consider the use of a balanced crystalloid solution, rather than 0.9% sodium chloride, in the resuscitation of critically ill adult patients.

Metabolic acidosis

Jaber S, Paugam C, Futier E, Lefrant JY, Lasocki S, et al. Sodium bicarbon- ate therapy for patients with severe metabolic acidemia in the intensive care unit (BICAR-ICU): a multicenter, open-label, randomized controlled, phase 3 trial. Lancet. 2018; 392:3140.

Metabolic acidosis is common among critically ill patients. Severe acidosis can adversely affect the cardiovascular system and lead to poor patient outcomes [52]. Unfortunately, mortality rates can reach al- most 60% in patients whose pH remains below 7.20 despite resuscita- tive therapies [53]. The administration of sodium bicarbonate to treat ICU patients with severe acidosis is common practice [52,54]. Despite the frequent administration of sodium bicarbonate for severe acidosis, there is an overall lack of high-quality data that consistently demon- strates the benefit of this therapy in critical illness. Given the controver- sies on the use of sodium bicarbonate in critically ill patients, the authors of the current study sought to evaluate whether a sodium

bicarbonate infusion would improve clinical outcome in critically ill pa- tients with severe metabolic acidemia.

The BICAR-ICU study is a multicenter, open-label, randomized, con- trolled, phase three trial performed in 26 ICUs in France. Patients in- cluded in the trial were greater than or equal to 18 years of age with severe acidemia (pH less than or equal to 7.2, PaCO2 less than or equal to 45 mmHg, sodium Bicarbonate concentration less than or equal to 20 mmol/L), a total SOFA score greater than or equal to four, an arterial lactate concentration greater than or equal to 2 mmol/L, and were within 48 h of ICU admission. Patients with a respiratory acidosis, diges- tive or urinary disorder with loss of sodium bicarbonate, stage IV chronic kidney disease, ketoacidosis, or receipt of a sodium bicarbonate infusion or RRT therapy within 24 h prior to screening were excluded. Once enrolled, patients were randomized to an intervention group or control group. Patients in the intervention group received an infusion of 4.2% sodium bicarbonate, with the goal to achieve a pH of 7.30 during the 28-day ICU admission or until ICU discharge. Those in the control group did not receive a sodium bicarbonate infusion. The primary out- come of the study was the composite of all-cause 28-day mortality and failure of at least one organ system at seven days after randomiza- tion. Secondary outcomes included the need for and duration of life- support interventions (RRT, vasopressors, mechanical ventilation), SOFA score on days one, two, and seven, total fluid intake by day two, the incidence of ICU-acquired infections, and the ICU length of stay. A priori patients were stratified by site, age, presence or absence of sepsis, and the presence or absence of the Acute Kidney Injury Network (AKIN) score of two or three.

A total of 389 patients were include in the intention-to-treat analy- sis. Overall, there was no significant difference in the primary outcome between patients in the intervention group and those in the control group (71% vs. 66%, p = 0.24). However, in patients with AKIN scores of two or three, treatment with sodium bicarbonate was associated with a decrease in the primary outcome (70% vs. 82%, p = 0.046), a de- crease in mortality (46% vs. 63%, p = 0.017), and a decrease in single organ failure (66% vs. 82%, p = 0.014) by day 28. More patients in the control group received RRT (52% vs. 25%, p = 0.0009) and more patients were dialysis-dependent at ICU discharge (48% vs. 20%, p = 0.047). There was no significant difference between the groups in the amount of fluid intake by day two, the days free of mechanical ventilation, or the ICU length of stay. Not surprisingly, there was a higher number of electrolyte disturbances (e.g., hypernatremia, hypocalcemia) in patients who received sodium bicarbonate.

The current study did not demonstrate a Mortality benefit to the ad-

ministration of a sodium bicarbonate infusion for severe acidemia in all critically ill patients. However, there may be benefit to a bicarbonate in- fusion in critically ill patients with severe acidemia and AKIN scores of two or three. Limitations of the current study include the lack of blinding between the groups, the lack of stratification based on the eti- ology of acidosis, the use of a hypertonic sodium bicarbonate solution (4.2%), the lack of a standard control fluid, and the observation that as many as 24% of patients in the control group actually received sodium bicarbonate. Finally, only 60% of patients in the intervention group achieved and maintained the target pH of 7.3. Notwithstanding these limitations, the BICAR-ICU adds to the literature on the use of sodium bi- carbonate in critically ill patients with severe acidemia. Based on the re- sults of this trial, it is reasonable for the EP to consider the administration of sodium bicarbonate to critically ill patients with se- vere acidemia and evidence of acute kidney injury.

Funding

None.

Declaration of Competing Interest

The authors do not have any financial conflicts of interest.

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