Good afternoon. My name is Dr. Adwoa Boateng-Evans, and I will be presenting the year in review, which will chronicle the top 10 articles of anesthesiology critical care throughout 2021. I'm a clinical assistant professor at Stanford University Medical Center and work as an anesthesiologist intensivist. I have no disclosures to report. Our itinerary for the session is as follows. We will begin by discussing seminal literature relating to the treatment of COVID-19, which will bring us to high-yield papers surrounding hypoxia therapies. We will then transition to a core tenet of critical care, that is sedation, analgesia, resuscitation, and end with a key discussion of articles on traumatic brain injury and neurocritical care management. The HOT-ICU trial published in the New England Journal of Medicine looks to answer the key question, what is the ideal oxygenation target in patients with acute hypoxic respiratory failure? That balances not only the risk of hypoxia, but also hyperoxia, which we know can include sequelae such as resorption atelectasis, lung injury, and oxidative stress. Clinical practice guidelines give great recommendations for patients who are suffering from ARDS and have recommended a conservative range with a PaO2 from 55 to 80 millimeters of mercury. However, for those outside of the setting of ARDS, there aren't clear recommendations as to an optimal oxygenation target. To do so, the study enrolled about 2,900 patients across 35 ICUs in Denmark, Switzerland, Finland, the Netherlands, and Norway. About 60% of the patients were admitted with pneumonia, about 60% requiring mechanical ventilation, and about 12% of the participants actually had ARDS. They were randomized to receive a lower oxygen target of about a PaO2 of 60 millimeters of mercury, or a higher oxygen target of about a PaO2 of 90 millimeters of mercury. There was no significant difference found in 90-day all-cause mortality, days alive without life support, median percentage days alive after hospital discharge, or serious adverse events as prior data had indicated. Thus, targeting a PaO2 of about 60 to 90 continues to be appropriate with undue harm or risk for critically ill patients with acute hypoxic respiratory failure. Number two, the pre-oxygenation using high-flow nasal cannula versus tight face mask during rapid sequence induction was published in February 2021 in Anesthesia and sought to identify which method of oxygenation really mitigates the risk of hypoxia in this setting. So the study enrolled about 300 patients across six centers in Sweden and Switzerland who were undergoing elective surgery requiring rapid sequence induction. The patients were randomized to high-flow nasal cannula at about 100% or a tight-fitting face mask and monitored for an outcome of 93% or less from the time of induction to one minute post-intubation. There was no difference in the lowest mean oxygen saturation from the start of pre-oxygenation until one minute post-intubation. There was also no significant difference in the end-tidal CO2 levels in the first breath after intubation between the two groups. However, a subtle difference that was noticed was that the oxygen concentration in the first breath after intubation was higher in the face mask group than in the high-flow nasal cannula group. And the thought process behind this is likely due to some patients inspiring with their mouth open and diluting the 100% oxygen with room air, thus lowering the end-tidal oxygen concentration after that first breath. Similarly, because end-tidal oxygen has been used as a surrogate for the efficacy of pre-oxygenation, that variable was not able to be ascertained accurately during high-flow nasal oxygenation and thus does not take into effect the apneic pre-oxygenation period. Similarly, the study did not include obese patients, pregnant women, and populations who we know are at risk for desaturation during apnea due to low FRCs, low functional residual capacities, and concomitant high metabolic demand. However, the study overall shows that high-flow nasal cannula is a suitable method for pre- and perioxygenation to maintain adequate oxygen levels during rapid sequence induction and is an alternative to traditional face mask pre-oxygenation. Number three, the recovery trial. As a society of critical care medicine, we'd be entirely remiss if we did not discuss one of the most seminal pieces of critical care literature throughout 2021 and thus not discuss recovery. Recovery, for those who are unfamiliar, is the randomized evaluation of COVID-19 therapy trial, which actually began in 2021, and is an umbrella trial design that simultaneously looks at various treatment modalities for patients with SARS-CoV-2. We are specifically going to discuss the dexamethasone arm of that trial. The premise of the study being that steroids have been used favorably in disease states that mirror COVID-19, such as SARS, MERS, influenza, and even community-acquired pneumonia. And so the question remained if and how corticosteroids could be used in syndromes similar to COVID. And so the authors were able to erect an unblinded, adapted, randomized controlled trial that took place amidst 176 NHS hospitals in the UK. And patients were randomized to dexamethasone 6 milligrams once per day for 10 days or less if they were discharged from the hospital and compared to patients randomized to usual care alone. What was found was that the dexamethasone group reduced mortality, particularly in patients with ARDS, requiring mechanical ventilation, with a number needed to treat of 8. The age-adjusted mortality was about 21% in the dexamethasone group as compared to 24% in the placebo group. Similarly, the length of hospital stay was also reduced in the dexamethasone group from 13 days to 12 days. However, for patients not receiving respiratory support, there was no significant difference. Notably, the trial was unblinded, and usual care was actually not standardized given the time period by which this took place, which was about March to May 2020. And because ventilation methods, as well as treatment modalities, were evolving rapidly during that time period. Nonetheless, overall, the trial has led to a mainstay of COVID-19 therapy, and that is the use of dexamethasone for those with respiratory failure. Number 4. The Co-Barrier Study, funded by Eli Lilly, was a double-blinded, placebo-controlled parallel group phase 3 randomized control trial that investigated the efficacy and safety of baricitinib in patients hospitalized with COVID-19. For those who are unfamiliar, baricitinib is a JAK2 inhibitor known to have anti-cytokine properties used in disease states such as rheumatoid arthritis and postulated to have some antiviral properties. And thus, included patients had to have serologies consistent with SARS-CoV-2 and at least one elevated inflammatory marker. This study took place in about 101 centers across 12 countries, with about a quarter of the study participants being located in Brazil. Baricitinib was studied in combination with remdesivir in a prior study called the ACT-II trial, and this demonstrated a reduction in the time to recovery compared with those receiving remdesivir alone. However, it was not powered to detect a mortality difference. Thus, this study utilized a National Institute of Allergy and Infectious Disease ordinal scale and enrolled those who scored a 5 or higher, meaning that the patients were hospitalized and continuing to require medical care with or without supplemental respiratory support. As participants were given 4 milligrams of baricitinib daily versus placebo and as an intention to treat analysis, the study ultimately found no difference in the primary endpoint, which was progression of the previously mentioned scale, which reflects essentially worsening critical illness requiring the increased need for supplemental oxygen. However, there was a significant difference in one of the secondary outcomes, which looked at all-cause mortality at day 28 and day 60, with a number needed to treat of 20. Adverse events occurred with equal prevalence across the placebo and intervention groups, and in terms of the generalizability, notably, this difference was actually more pronounced in the subgroup of patients who were sicker at baseline. So overall, the study demonstrates that baricitinib appears to be safe and effective for critically ill patients with COVID-19. We've come to use it at my center as well as other centers throughout the United States. The MEMS-II trial asked the question, can we mitigate the risk of delirium and coma by using dexmedetomidine in lieu of propofol? Much of the impetus for the study arose from its precursor, the MEMS study, which demonstrated that the use of dexmedetomidine resulted in more days alive without delirium and coma as compared to lorazepam. Thus, the MEMS-II study was a double-blind, placebo-controlled, randomized trial that enrolled about 400 patients in medical and surgical ICUs with suspected or confirmed infection, essentially sepsis, and respiratory failure requiring mechanical ventilation. The participants received anywhere from 0.1 to 1.5 mics per kilo per hour of dexmedetomidine with an average dose, excuse me, a median dose of 0.27, and a propofol infusion at between 5 to 50 mics per kilo per minute with a median dose of about 10, both chitrated to actual body weight. The primary endpoint elucidated that there was no significant difference in days alive without delirium or coma during the 14-day study period. The secondary endpoint similarly showed no difference in ventilator-free days between the two groups at day 28, nor a death at day 90 or global cognition at six months. And lastly, there was no difference in safety endpoints, significant organ dysfunction between the two groups. There was one reported incidence of propofol infusion syndrome, but that was later dismissed after further analysis of the study participant. So overall, the study demonstrates near equivalence of two commonly used sedatives among critically ill patients for neurologic-related outcomes. The BASICS trial is a randomized control trial that was conducted across 75 ICUs in Brazil, which enrolled about 11,000 patients looking to see if there was a mortality benefit with the use of a balanced crystalloid solution as compared to isotonic saline. Thus, they enrolled patients who were requiring fluid resuscitation due to hyperperfusion, but also demonstrating fluid responsiveness and had at least one factor for acute kidney injury. They additionally wanted to assess whether there was a mortality benefit in FAS, which was defined by about a liter per hour versus slow infusion rates. So they assessed both the type of fluid as well as the speed of infusion. And the study builds off of prior data published in the SPLIT and SMART trials, which some of us are familiar with. Those trials actually demonstrated opposite outcomes, the former showing no difference in 90-day AKI, while the latter showed a significant increase in some of the incidence of 30-day mortality events, such as AKI. Thus, in the BASICS trial, the fluid that the patient was randomized to was used for the entirety of their ICU stay, with the exception of certain pathophysiologic states that would require alternative IV infusions, such as hypernatremia. However, once safely feasible to do so, the study fluid was resumed. Assessing the primary outcome, there was no difference in 90-day mortality. However, there was a statistically significant difference in one of the secondary outcomes, including the SOFID score at day 7 in the balanced solution group. There were no significant differences in the additional 17 secondary outcomes, which also included renal replacement therapy during admission, ventilator-free days, and CADECO scores above 2 at days 3 and 7. However, the subgroup analysis did reveal an interesting, statistically significant interaction between the presence of traumatic brain injury, fluid type, and 90-day mortality. As for the rapid versus slow rate of infusion, there was no difference in the primary outcome 90-day mortality. As for the secondary outcomes, we did see differences in the cardiovascular, respiratory, and coagulation SOFA scores, and these were actually statistically significant. However, they were not found by day 7, and the SOFA scores had also dissipated by that time. The differences in the SOFA scores had dissipated by that time. So overall, the study neither demonstrates a mortality benefit with the selection of balanced versus isotonic saline, nor with the rate of infusion. However, the subgroup analysis among TBI patients cannot be overlooked, suggesting the role for isotonic saline in that demographic. The VAM-IHCA trial sought to answer the question, in patients who suffer in-hospital cardiac arrest, does vasopressin plus methylprednisolone increase the likelihood of achieving ROSC? Part of the impetus for this study was previous literature that demonstrates that endogenous vasopressin levels are actually lower in non-survivals of cardiac arrest. So here are 10 hospitals across Denmark, randomized about 500 patients to the intervention arm, or placebo, the intervention including 40 milligrams of methylprednisolone and 20 international units of vasopressin. The SOFA scores were collected at 24, 48, and 72 hours post-arrest, and neurologic outcomes were assessed at 30, 90, 180, and one year post-arrest. Final participants were about age 70, with a male predominance, and about equal rates of comorbidities between the two groups. The primary rhythm identified in the arrest were PEA. The primary outcome showed a statistically significant higher rate of ROSC in the intervention vasopressin-methylprednisolone group. However, there was no significant difference at 30 or 90 days of survival, demonstrating favorable neurologic outcome. So while the study demonstrates a favorable outcome in terms of ROSC, it remains to be demonstrated if this correlates to long-term survival benefit. And we see that exemplified here with a risk ratio of 1.3 for ROSC, however, a risk ratio of about 0.8 for 30-day survival. Number eight. The COBE trial looked to assess, can a continuous infusion of 20% hypertonic saline improve neurologic outcomes at six months in traumatic brain injury patients by essentially staving off intracranial hypertension? However, hypertonic solutions, as we know, are wrought with myriad side effects, and so does the benefit outweigh the risk in this patient population? The study design here was a multicenter, parallel group, open-labeled, randomized control trial conducted across nine French hospitals with high-volume traumatic brain injury patients. Participants had to have moderate to severe TBI, as documented by a GCS equal to or less than 12 in positive CAT scan findings. After patients were randomized, a one-hour infusion of either the intervention or placebo therapy was given within 24 hours and modified for the patient's baseline sodium so as not to exceed a sodium of 155, which was the author's threshold for hyperneutremia. Notably, those administering the intervention were not blinded. The control arm had a standard therapy of intracranial hypertension, which include boluses of sedative drugs and hyperosmolar therapy as needed. The primary outcome showed no significant difference in the six-month Glasgow outcome scale between the two groups at six months, with an adjusted odds ratio of about 1.02. As for the secondary outcomes, there were also no differences in ICH, nor with median length of ICU stay. Note that rates of severe hypernatremia were about 12% in the intervention group and about 6% in the control group. The intervention was also associated with reduction of the risk of intracranial hypertension. However, more patients in the intervention group did develop delayed intracranial hypertension, suggesting something like a rebound effect with therapy cessation. So overall, the findings do not support the use of 20% hypertonic saline toward better neurologic status at six months. The ULTRA study sought to answer the question, does early treatment with TXA improve outcomes at six months in patients with subarachnoid hemorrhage? The study was conducted across 24 sites in the Netherlands, enrolling about 1,000 patients with admission-documented subarachnoid hemorrhage on a non-contrast CT scan. The intervention arm were randomized to receive either placebo or a 1-gram bolus of trans-oxemic acid plus 1-gram QA hours as compared to the standard treatment. The primary outcome found no difference in the modified Rankin scale at six months, which was assessed via a standard telephone interview. The secondary outcome was actually notable for a difference in quote-unquote excellent outcomes, which was denoted by a modified Rankin scale of 0 to 2 at six months. And that was significantly lower in the TXA group. However, there was no difference in thromboembolic events during endovascular treatment, all-cause mortality at six months, serious adverse events, re-bleeding before securing the aneurysm, or delayed cerebral ischemia. Thus, overall, the study does not show any clear clinical benefit from trans-oxemic acid use in subarachnoid hemorrhage, particularly given the risk for delayed cerebral ischemia. And last but not least, we will finish with another seminal trial in a series looking at targeted temperature management, TTM2. Temperature management after cardiac arrest is a very well-studied area of literature within critical care, though with very disparate findings. Unanimously, we understand that fever and certainly hyperthermia have been demonstrated to be deleterious and affiliated with worse outcomes. However, the ideal temperature after arrest in patients who are unconscious remains to be elucidated. And so here, the authors compared targeted hypothermia versus targeted normalthermia and their impact on all-cause mortality. They did this by conducting an international, multi-centered, randomized superior trial that was non-blinded across 14 countries and 61 institutions, predominantly in Europe, with specific inclusion criteria being out-of-hospital cardiac arrest in a state of unconsciousness after ROSC. Participants had similar baseline characteristics. For the hypothermia group, rapid cooling was achieved by cool fluids or physical cooling devices, either surface or intravascular, and patients were re-warmed after 28 hours. In the normalthermia arm, participants who developed a temperature over 37.8, which was the trigger, were cooled similarly with surface cooling devices or intravascular cooling, which were set at 37.5 degrees centigrade. Of those, about 46% of patients actually did require that cooling device to achieve the target temperature. The primary outcome found no difference in all-cause mortality at six months. Neither was there a difference appreciated in the secondary outcomes, which included functional status and health-related quality of life. And that concludes our talk for this session. Thank you all for attending, and I wish you an enjoyable rest of the conference.

anesthesiology critical care

HOT-ICU trial

PRE-OX trial

RECOVERY trial

COV-BARRIER trial