Reversal of Factor Xa Inhibitor-Related Intracranial Hemorrhage: A Multicenter, Retrospective, Observational Study Comparing the Efficacy and Safety of Andexanet and PCCs
This study compared patients with a wide variety of intracranial hemorrhage types taking direct oral anticoagulants (e.g. apixaban or rivaroxaban) who then received andexanet versus prothrombin complex concentrates (PCCs)
Patients receiving andexanet (87.8%) had higher odds of achieving excellent/good hemostasis (odds ratio [OR] 1.60; 95% CI, 1.00-2.56; p = 0.048) compared with PCCs (81.8%). Patients treated with andexanet (7.9%) had higher odds of a thrombotic event (OR 1.91; 95% CI, 1.13-3.20; p = 0.014) compared to those treated with PCCs (4.2%).
This study found similar results to the previous ANNEXA-1 trial but included GCS < 7 or Neurosurgery within 12 hours of enrollment, which ANNEXA did not. This study was not designed to prove non-inferiority and should not change practice, especially given the eye-watering cost of Andexanet ($25,000+) versus PCCs (~$4000-6000)…. but betting they are working on one that will.
Duan et al recently published in Intensive Care Medicine the results of a trial looking at a PEEP of 5 cm H2O vs 10 cm H2O and impact on failure rate (progression to intubation) when using non-invasive ventilation (NIV). In their trial, the high PEEP group had a lower rate of intubation (32% vs 43%), and this was statistically significant. It is important to note that they excluded patients whose indication for NIV was heart failure, asthma, or COPD exacerbation.
Ultimately, how to choose the right PEEP is a very complex question and requires tailoring to your patient's physiology and clinical circumstances. For example, hypercarbic patients may benefit more from a maximization of their driving pressure (Pplat - PEEP), which can involve lowering their PEEPs, especially when trying to avoid gastric insufflation (remember, pressures of 30 cm of H2O or higher are very likely to open the LES).
Bottom Line: PEEP and other vent settings should be tailored to the patient's pathophysiology, but this trial suggests that in hypoxemic patients not getting NIV for heart failure, asthma, or COPD exacerbation, a higher PEEP (10 vs 5) may reduce the risk of intubation.
Sedation for the Mechanically Ventilated Adult ICU Patient
This large RCT compared High-Flow Nasal Oxygen (HFNO) against Noninvasive Ventilation (NIV) via face mask in 5 types of Acute Respiratory Failure (ARF): non-immunocompromised hypoxemia, immunocompromised hypoxemia, COPD with acidosis, acute cardiogenic pulmonary edema (ACPE), and COVID-19.
Bottom Line:
RENOVATE suggests HFNO might be a reasonable, more comfortable initial choice for non-immunocompromised hypoxemic ARF or COVID-19 ARF. However, exercise caution using HFNO first-line for COPD exacerbations with acidosis or immunocompromised hypoxemic ARF due to conflicting analyses and potential harm signals. The signal for HFNO benefit in ACPE is intriguing but needs confirmation before changing practice. Close monitoring for failure and timely escalation are essential regardless of the initial noninvasive strategy.
Background:
Acetaminophen can reduce hemoprotein induced oxidative damage. There has been growing discussion about its benefits in critically ill patients with sepsis. Multiple observational studies have found conflicting results on mortality in critically ill patients with sepsis. The ASTER trial found no difference in number of days alive and free of organ support. Interestingly their secondary outcomes found significantly less development of ARDS in the acetaminophen group 2.2% vs 8.5%, p = .01. There was also a non-statistically significant difference in mortality between the groups in favor of the acetaminophen group, 17% vs 22% p = 0.19. This study looked to further evaluate if acetaminophen used in critically ill patients with sepsis would have a decrease in mortality and increase in ventilator free days.
Study:
- Retrospective analysis of the Ibuprofen in Sepsis Study (ISS)
- The ISS was a randomized clinical trial comparing ibuprofen with placebo in critically ill patients with sepsis. Careful documentation of Acetaminophen use was recorded for the trial
- Critically-ill adults across 7 ICU’s in the US and Canada with known or suspected infection and severe organ dysfunction
- Acetaminophen use within 48 hours of enrollment = Acetaminophen exposed
- Primary outcome: 30-day mortality
- Secondary outcome: Renal failure and ventilator free days up to day 28
- 455 patients. 172 Acetaminophen unexposed, 235 Acetaminophen exposed.
Results:
- Propensity-matched analysis showed a lower mortality risk at 30 days in patients exposed to acetaminophen compared to unexposed, 32% vs 49% (HR 0.58, p .004)
- Secondary outcomes found acetaminophen exposed group had more ventilator free days (p .02) but there was no difference in renal failure among the groups.
Limitations:
- Major risk for confounding variables
- Retrospective and the data used was from decades ago (1989 -1995). Sepsis care has evolved and improved since this time
- Dose and frequency of acetaminophen administration was not standardized
Take Home Points:
- Interesting research that provides further support on the possible benefit to using acetaminophen in the management of critically ill patients with sepsis.
- With the ASTER trial showing a signal for the decrease in development of ARDS and this study showing improvement in mortality one could make a case for starting acetaminophen early in the course for these patients. However, the data is conflicting and more prospective, RCT’s are needed to confirm these findings before making this a staple for sepsis care in critically ill patients.
Flow rates are, in theory, determined by Poiseuille’s Law, which states that the flow rate depends on fluid viscosity, pipe length, and the pressure difference between the ends of the pipe .
Of course we won’t be calculating this during a resuscitation! Nor would it be useful if we did: the equation assumes laminar flow, whereas turbulent flow is more likely. Nor is it practical to look up the viscosity of crystalloid/blood/plasma, which also dramatically impacts flow rates.
Instead, remember this equation: Larger + shorter = faster
And keep in mind the following:
In practice, our friends in Australia actually put common catheters to the test, and provided these helpful results:
Or, as a picture:
Note, these flow rates were achieved using crystalloid. Blood will be slower due to higher viscosity.
A 2023 retrospective cohort study comparing amiodarone to lidocaine for in-hospital cardiac arrests (IHCA) with refractory VT/VF found that use of lidocaine was associated with increased chance of ROSC, 24 hour survival, survival to discharge, and favorable neurologic outcome at hospital discharge.[1]
Now, a recent study comparing amiodarone to lidocaine in the pre-hospital setting for OHCA has found similar results. [2] Another retrospective cohort study using propensity score matching, they evaluated 23,263 adult patients with OHCA and defibrillation refractory VT/VF managed by 1700 EMS agencies.
Use of lidocaine was associated with greater odds of prehospital ROSC, fewer post-drug administration defibrillations, and greater odds of survival to discharge.
In comparison to earlier trials, these studies are some of the first demonstrating benefits to lidocaine use over amiodarone that reach statistical significance, but of course have all the limitations that come with retrospective studies and are not further analyzed in the context of etiologies for cardiac arrest or application of post-ROSC care.
Bottom Line: If you happen to be someone who reaches for amiodarone as your go-to, it may be time to start considering lidocaine.
If you watch those medical drama (House MD, ER, Grey’s Anatomy, Resident…), the doctors and residents are always faced with a dilemma – is it a rare autoimmune disorder or is it an infection? They are worried that if they give steroid to a patient with infections, that would kill the patients.
Well, it might not be the case for Community acquired pneumonia.
A meta-analysis of randomized control trials involving 3224 patients to look into the efficacy of adjuvant corticosteroids for CAP. The authors assessed the heterogeneity of treatment effect (different groups should have different response to treatment).
For patients who were anticipated to benefit (those who had CRP > 240 mg/L), corticosteroids were associated with lower odds of 30-day mortality (OR 0·43 [0·25–0·76], p=0·026).
When stratifying by risk, there was no significant effect between those with Pneumonia Severity Index (PSI) I-III versus those with PSI IV-V.
However, corticosteroids increased odds of hyperglycemia (OR 2·50 [95% CI 1·63–3·83], p<0·0001), odds of hospital readmissions (1·95 [1·24–3·07], p=0·0038)
Discussion:
There were different regiments for corticosteroids in the included studies. However, hydrocortisone appeared to be more effective than other corticosteroids.
Furthermore, the time intervals for treatment is still debatable. The data suggested that the ideal treatment is within 24 hours of hospital admission, but patients can still benefit from treatment in up to 48 hours.
A response-dependent treatment is also recommended: 8 days or 14 days, depending on how patients respond to treatment by day 4.
Conclusion:
Adjuvant treatment with corticosteroids among hospitalized patients with CAP was significantly associated with reduction of 30-day mortality. The treatment effect, however, varied according to patients CRP concentrations at baseline.
Intubation and mechanical ventilation of brain injured patients, which is extremely common in the Emergency Department, can be very challenging and subject to significant practice variation. It is often said that brain injured patients “can't take a joke”, meaning that they are less tolerant to hemodynamic and metabolic perturbations, and these perturbations tend to be associated with very large swings in their clinical outcomes. For example, hypo/hyperglycemia, hypo/hypernatremia, hypo/hypertension, hypo/hyperoxia, hypo/hypercapnea, etc are all extremely important to avoid. This is probably the one patient population where “euboxia” (the notion that we obsess too much about making all the numbers pretty in the EMR) is probably not as applicable. As such, there is at least good physiologic rationale, and now increasing empirical evidence, that ventilating these patients very thoughtfully is extremely important and likely to have meaningful impact on patient-oriented outcomes (mortality, neurologic outcome, etc).
The VENTIBRAIN study was a prospective observation trial of 2,095 intubated patients in 26 countries who had TBI, ICH (including SAH), or acute ischemic stroke. Interestingly, they found that patients with lower tidal volume (TV) per predicted body weight had higher mortality (although the majority of their TVs were well controlled and in a fairly tight range), which is contrary to conventional thinking in pulmonary pathologies like ARDS. They also found that higher driving pressure (DP) was associated with higher mortality, which agrees with data from other conditions. PEEP and FiO2 had U-shaped curves, but FiO2 in particular tended to favor lower FIO2, also similar to current thinking for ICU patients in general.
Take Home Points:
Non-Pharmacologic Measures to Prevent VAP
Arterial lines are essential tools in managing critically ill patients, but it is frustrating when they are not working as expected. It can be hard to tell when an unexpected waveform or pressure reflects the patient's physiology versus a problem with the line. Recognizing common issues and systematic troubleshooting will optimize your hemodynamic monitoring.
Types of arterial line problems
Troubleshooting Steps
By following these steps, you can systematically identify whether waveform or pressure abnormalities are due to technical issues or true patient physiology.
Background
Diagnosed by continuous seizure activity that lasts for 5 minutes or more and/or multiple seizures that occur without returning to baseline in-between each. Further classified as being convulsive or non-convulsive. Refractory status epilepticus can be defined as status epilepticus that does not respond to an adequately dosed benzodiazepine and another anti-seizure medication. The primary objective in management is to stop both clinical and electrographic seizures which can become an important point for those patients who require intubation and receive neuromuscular blockade. Essential to evaluate early for reversible causes (electrolytes, liver function, glucose, ammonia, medications) and for other precipitating causes with toxicology screening and CT head imaging with consideration for angiography and venography.
Management:
First-Line/Initial Therapy:
Lorazepam IV 0.1 mg/kg up to 4 mg per dose is the preferred agent, can be repeated after 5 minutes if seizures persist
Diazepam 0.15 mg/kg IV/0.2 mg/kg PR up to 10 mg, or midazolam IM 0.2 mg/kg up to 10 mg are also alternatives
Second-line/Urgent control: (Provided to all patients with SE after initial therapy)
- Levetiracetam 60 mg/kg, Valproate 40 mg/kg, and fosphenytoin 20 mgPE/kg were studied by Kapur et al., and they found similar rates of resolution of status epilepticus with similar rates of adverse events.
- Phenobarbital 15-20 mg/kg is another agent that has good efficacy and is remerging as an effective agent. Can cause respiratory depression at high doses.
- Keppra may have the best side-effect profile to consider.
- Valproate can cause hepatotoxicity, elevated ammonia and thrombocytopenia.
- Fosphenytoin can cause hypotension and arrhythmias.
Third-line:
Midazolam 0.2 mg/kg load followed by 0.05 – 2 mg/kg/hr infusion
Propofol 1-2 mg/kg load followed by 20-200 mcg/kg/min infusion
Ketamine 0.5 – 3 mg/kg load followed by 1.5-10 mg/kg/hr infusion
Pentobarbital 5 mg/kg load followed by 0.5-5 mg/kg/hr infusion
- Propofol carries the risk of propofol infusion syndrome with high doses or prolonged infusions, some favor midazolam because of this.
No conclusive data to support one over another.
Important Considerations
- A common mistake is to under-dose benzodiazepines for initial therapy, give the full weight-based dose as described above.
- Following initial management it is important to monitor patients with continuous EEG if they have not returned to their neurologic baseline
- Propofol, midazolam or ketamine are good options for induction for intubation.
- Consider against using etomidate for induction of intubation since it can cause myoclonus which can complicate the picture if you are already worried about seizures, can be hard to differentiate.
- If intubation is required and EEG is not readily available consider reversal of neuromuscular blockade after intubation to better monitor for continued seizures.
- If in refractory status epilepticus despite using a second-line agent and a third line agent then consider adding a second agent from the second-line/urgent control that was not previously started (fosphenytoin, valproate, levetiracetam, or phenobarbital).
For those of us living in a world where ED boarding is a reality and ICU beds are in short supply, a re-up on the basic tenets of post-arrest care to optimize survival and neurologic outcomes in patients with sustained ROSC after OHCA:
Two recent studies (see “Additional Information” for more study details) published in the New England Journal of Medicine evaluated the outcomes of OHCA, comparing drug administration via intraosseous devices versus intravenous access, neither demonstrating benefit to one strategy over the other in terms of sustained ROSC or 30-day survival. [1,2] While there were a few limitations, these results are generally in line with existing literature. Although it is worth noting that some studies signal improved outcomes with IV access, the time to intervention seems to be the more important metric related to outcome. [3-5]
Bottom Line: Intraosseous devices remain rapid and easy to place devices that can provide access for drug administration when IV access is unable to be obtained. In patients with difficult access, use an IO to administer meds, fluids, or blood products as indicated while you and your team work on more definitive IV access and focus on high-quality CPR.
Delirium in the ICU means badness as delirious ICU patients are associated with longer stay and higher mortality. While medications are not proven to prevent delirium, certain environmental interventions such as window access, light and sound levels have been recognized as legit interventions to prevent ICU delirium.
Settings: This is a retrospective study at Massachusetts General Hospital
Participants: 3527 patients admitted to a surgical ICU between 2020 and 2023.
Outcome measurement: This study hypothesized that patients in a windowed ICU room will have lower rates of delirium, decreased ICU length of stay, hospital LOS. Multivariable logistic regressions were performed for the association of clinical variables and the presence of delirium.
Study Results:
Delirium was observed in 460 patients (21%) of the windowed rooms group and 206 patients (16%) of the nonwindowed rooms group. Multivariable logistic regression showed that patients in windowed rooms were associated with higher odds of delirium (aOR, 1.29; 95% CI, 1.07–1.56; p = 0.008), although they were not associated with longer ICU LOS or longer HLOS
Discussion:
The study’s findings added to the literature that natural lighting might not be the effective prevention of delirium. The presence of windows might not be the answer.
In this study, all the windows were facing another building, and there was no view of other natural scenes, with a limited view of the sky. Therefore, the authors suggested that the overall quality of the windows would be more important.
Conclusion:
The ICU environment is more important for patients’ delirium than just the presence of windows.
These 2 papers challenge management dogmas in critical care that have persisted despite low-quality/absent evidence.
In particular, one explores the dogma, “bicarbonate improves ventricular contractility in severe metabolic acidosis,” with the following points:
-intracellular pH (which has a large impact on myocardial contractility) correlates poorly with blood gas pH
-many of the studies regarding bicarbonate in severe metabolic acidosis and hemodynamics are done on animal shock models
-two studies in patients with lactic acidosis showed increase in pH with bicarb administration without beneficial impact on hemodynamics (even in pts with pH < 7.1)
-bicarb administration is associated with hypernatremia, hypokalemia, and decreased ionized calcium levels
Extracorporeal cardiopulmonary resuscitation (ECPR) is a type of extracorporeal support following cardiac arrest available at a small, but growing number of ECMO centers around the world. After some initial promising results, more recent data have been mixed. There is a nice narrative review in JACEP Open recently which summarizes the most recent evidence. Implementation considerations and patient selection seemingly drive the variance seen in the studies reviewed.
To this point, a new article from Critical Care Medicine was just published looking at the outcomes of eCPR with respect to age using 5 years of ELSO patient data. Unsurprisingly, advancing age is associated with worse outcomes, with significantly reduced odds of survival above the age of 65.
The level of fitness/health a patient has entering the marathon of recovery from critical illness or trauma has a major impact on morbidity and mortality. Frailty is a measure of this fitness level. The clinical frailty scale can be used to assess your patients ability to survive critical illness. Age is a number. Frailty is more useful.
Post-Intensive Care Syndrome (PICS) is an increasingly recognized phenomenon of impairment of physical, cognitive, and/or mental health after intensive care admission. Even more recently, similar deficits in caregivers of patients admitted to the ICU, often called Post-Intensive Care Syndrome Family (PICS-F) is increasingly recognized. A study recently published by Watland et al in Critical Care Medicine looking at reducing PICS-F through a “caregiver pathway” got me wondering if there's any literature out there about reducing PICS-F via interventions in the emergency department. Patients' treatment course in the ED is a highly stressful and uncertain time for both the patient and family members, so it stands to reason this is an impactful period where intervention may help, and even in patients where their condition is too advanced for us to make a medical difference, our actions could have a positive impact on long term outcomes for the family members.
The short answer is no, to this author's knowledge and based on my review of the literature, there is no good evidence for reducing PICS-F by ED interventions (hint, hint: if anyone's looking for a good area to study…) Based on evidence from the critical care realm, the following are probably reasonable approaches that would translate well to the ED:
In a fascinating perspective piece, Matt Bivens and colleagues explain that the combination of struggle and restraint leads to death not because of hypoxia, but because of acidosis.
The sequence is something like this: exertion or struggle results in an acidotic state -> restraint reduces respiratory ability, especially when held prone or weight is applied to back or chest -> acidosis worsens with the potential for cardiac arrhythmia and arrest.
In this setting, “I can’t breathe” does not mean that there is no air movement over the vocal cords but that respiration is impaired, much as it is in asthma or obstructive lung disease.
Use of sedation in this setting reduces respiration even further, worsening acidosis and risking death. It’s not hypoxia that kills; it’s acidosis.
See the complete perspective here: https://www.nejm.org/doi/full/10.1056/NEJMp2407162.
