UMEM Educational Pearls - By William Teeter

Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME)

Current guidelines recommend normocapnia for out-of-hospital cardiac arrest (OHCA), the TAME Study asked is mild hypercapnia better?

• Smaller previous studies have shown some benefits for hypercapnia including some improved outcomes:
  • Increased likelihood of discharge home and better 12 month neurologic outcomes
• The TAME study enrolled adults with OHCA with presumed cardiac or unknown cause within 3 hours of ROSC who were unconcious
• Unwitnessed, asystolic, hypothermic, pregnant, or ICH patients were excluded.
  • ECMO and Severe COPD patients on home O2 also excluded
• Randomization to either 24 hours of PaCO2:
  • Intervention arm:  50-55 mmHg
  • Control: 35-45 mmHg
• Strong design with strong methodology, adequate power, and good protocol adherence (>65% of measurements in group limitations) 
• Protocol violations in 8% of hypercapnia and 3% of normocapnia groups
• Missing primary outcome data in 7% of patients.
• Note: concurrent TTM trial (TTM2) was allowed to cross-enroll. Addressed with adequate statistical methodology

• Primary outcome (Favorable neurological outcome (GOSE ≥ 5)
  • 43.5% (mild hypercapnia) vs 44.6% (normocapnia)
    • ARR 0.98 (95% CI 0.87 to 1.11)
• Secondary outcomes: no differences

Conclusion: "In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia."

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CCM recently published Stanford's experience with their Emergency Critical Care Program (ECCP), an ED based intensivist consultation/management model staffed by EM/CC during peak hours with the "goals of improving care of the critically ill in the ED, offloading the ED team, and optimizing ICU bed utilization without the need for a dedicated physical space." 

Conclusions:

This is the third group to document decrease in overall mortality utilizing an early or dedicated critical care consult model. EC3 and the CCRU here at UMMC have also both shown improvements in patient transfer and resource utilization metrics. As with all studies in this space, there are many limitations to these studies in both design and generalizability, even amongst each other. However, the literature is replete with data that increased boarding time in the ED for critically ill patients is associated with worse outcomes and these studies are now a body of complementary and growing evidence that teams such as this can perhaps bridge that gap. Hopefully come to an ED near you soon...

Study Details:

Objectives: To determine whether implementation of an Emergency Critical Care Program (ECCP) is associated with improved survival and early downgrade of critically ill medical patients in the emergency department (ED).

Design: Single-center, retrospective cohort study from a tertiary academic medical center using ED-visit data between 2015 and 2019 for adult medical patients presenting to the ED with a critical care admission order within 12 hours of arrival.

Pre and post intervention (2017) cohort analysis of patients when facility implemented dedicated bedside critical care by an ED-based intensivist "following initial resuscitation by the ED team". A difference-in-differences (DiD) analysis compared the change in outcomes for patients arriving during ECCP hours (2 pm to midnight, weekdays) between the preintervention period (2015–2017) and the intervention period (2017–2019) to the change in outcomes for patients arriving during non-ECCP hours (all other hours).

Primary outcomes: In-hospital mortality and proportion of patients downgraded to non-ICU status while in the ED within 6 hours

Results:

• The primary cohort included 2,250 patients
• emergency critical care Sequential Organ Failure Assessment (eccSOFA) score. The DiDs for the eccSOFA-adjusted inhospital mortality decreased by 6.0% (95% CI, –11.9 to –0.1)
  • Largest difference in the intermediate illness severity group (DiD, –12.2%; 95% CI, –23.1 to –1.3)
• The increase in ED downgrade less than 6 hours was not statistically significant (DiD, 4.8%; 95% CI, –0.7 to 10.3%) for all patients
  • The intermediate group was statistically significant (DiD, 8.8%; 95% CI, 0.2–17.4).

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Given my previous post on APRV (11/6/2022) and while I take issue with many of the author's statements, I wanted to share a very well referenced article with an excellent discussion on the current gaps in the knowledge around APRV and its use.

One statement I do agree with is the need for a well-designed and adequately powered trial of this mode in an admittedly difficult-to-study population.

Fortunately, this article has an invited rebuttal pending from Dr. Habashi which I am sure will appear in the Educational Pearls in short order. 

Good luck to the residents on the ITE!

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Airway Pressure Release Ventilation (APRV) is an "advanced" mode of mechanical ventilation that has long been considered a "rescue" mode of ventilation and has recently garnered much more attention during the COVID pandemic.  Given the long boarding times of critical care patients in the ED with widespread improvement in sight, I wanted to send out some great resources that have come out recently delineating the difference in thought process between APRV as a "rescue" mode and as a "primary" mode.

Rory Spiegel of EMNerd and former UMMC CCM fellow has recently given a great talk on APRV and its use as a rescue mode of ventilation. See also Phil Rola's recent paper listed on that webpage.

https://emcrit.org/emcrit/aprv-for-lung-rescue/

APRV as a primary mode of ventilation has been used in the STC for years and is often referred to in the literature according to the basic ventilatory philsophy called Time Controlled Adaptive Ventilation. I realize this may be heresy to some and perhaps a curiousity to others. I recommend you take some time to peruse the following resources:

1. Dr. Habashi has done a great deal of work in the basic and translation literature on APRV and TCAV. His recent review dispels many myths and concerns surrounding APRV

Myths and Misconceptions of Airway Pressure Release Ventilation: Getting Past the Noise and on to the Signal - https://www.frontiersin.org/articles/10.3389/fphys.2022.928562/full

2. The TCAV Network has great resources for those who want to do a deeper dive into this topic. 

https://www.tcavnetwork.org/

(Can also find their recommended protocols at the Multi Trauma Critical Care education website: https://stcmtcc.com/handouts/)

Attachments

fphys-13-928562_(2).pdf (5,575 Kb)

Standard_Settings_for_APRV_using_the_TCAV_Method.pdf (1,525 Kb)

APRV_TCAV_Rescue_Strategy_Strategy_Guidelines_2020.pdf (1,614 Kb)

Take Home:

This is essentially a secondary analysis of a previous prospective observational cohort study with high quality methods. The authors have an excellent discussion of the previous studies on this topic (which for those with an interest I highly recommend you read). They conclude that this study supports previous literature which I would think would be seemingly obvious, which is that those who are more ill to begin with have less tolerance of propofol (in a dose-independent relationship) in this and previous studies. Their use of IPTW extends the analysis on this large international population by addressing confounders in a novel way.

Their overall conclusion is that propofol is bad for the critically ill, and especially bad for those with pre-existing risk factors for intubation complications. I agree: This study suggests in even stronger terms that propofol should be used carefully and probably only in unhealthy patients when other options are unavailable.

Study Background and Characteristics

• INTUBE study¹ was a prospective cohort study conducted from October 1, 2018, to July 31, 2019
• Enrolled consecutive “critically ill” patients over 8 week period at 197 clinical sites from all over the world. Critically ill was defined as those with “an underlying life-threatening condition causing cardio–respiratory failure or neurologic impairment”.
• Outcome of “cardiovascular instability/collapse” as one or more of the following events within 30 minutes of intubation start: (1199 of 2760 enrolled patients; 43.4%)
  • systolic arterial pressure <65 mm Hg recorded at least once (collapse criteria) – 12.8%
  • cardiac arrest (collapse criteria) – 7.8%
  • systolic arterial pressure <90 mm Hg for >30 minutes – 24%
  • new requirement or increase of vasopressors – 87.8%
  • fluid bolus >15 ml/kg to maintain the target blood pressure – 13.2%
• STROBE Compliant

Findings

• CV-instability group were significantly older, high SOFA scores, and higher rates of ischemic heart disase, NYHA 3/4 heart failure, poor oxygenation (SPO2/FIO2 ration), pressors, fluid bolus/total, systolic/diastolic BP, and more commonly respiratory failure and cardiovascular instability as the reason for intubation.
• CV-stability group was less likely to receive propofol and at lower doses and more likely receive ketamine.
• Notably, CV-instability patients were less likely to be intubated by emergency physicians versus anesthesiology.
• Anesthesiologists were more likely to use propofol and more emergency medicine physicians using ketamine.
• Higher incidence of CV-instability in ischemic heart disease and heart failure, noninvasive ventilation and apneic oxygenation, and in the 30–45° head-up position.
• ICU mortality associated with:
  • vasopressors/fluids without hypotension (OR, 1.47; 95% CI, 1.21–1.79)
  • systolic blood pressure <90 mm Hg for >30 min despite vasopressors (OR, 2.65; 95% CI, 1.87–3.75)
  • systolic blood pressure <65 mm Hg (OR, 1.89; 95% CI, 1.31–2.71)
  • cardiac arrest (OR, 8.79; 95% CI, 5.46–14.7)
• Inverse Probability Treatment Weighting² (IPTW) analysis found that the only treatment effect with significance associate with the entire CV-instability group was propofol usage (OR, 1.23; 95% CI, 1.02–1.49).
  • No treatment effect, including propofol use or dosage, was associated with those meeting cardiovascular collapse criteria.

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Balanced crystalloids:  So Hot Right Now

Brief Read:

The use of balanced crystalloids has been the subject of several RCTs with conflicting results. However, recent post-hoc and meta-analyses of these same trials suggest that balanced crystalloids may be the best choice initially. See nice summary at: https://www.atsjournals.org/doi/full/10.1164/rccm.202203-0611ED.

Long Read:

While I had thought about summarizing the recently published data on EPR from the CRITICAL trial in Japan, JournalFeed today covered the recent post-hoc analysis of the BaSICS trial originally seen on CC Pearls back in August 31, 2021 by Dr. Sjelocha. This subject is as important as it is confusing. There are large and relatively well done RCTs that point in opposite and sometimes strange directions. However, as the authors of the SMART trial summarized, even an NNT of 94 in this population could be a huge number of patients!

The use of balanced crystalloids (e.g. Plasmalyte) has been the subject of several previous RCTs (SMART and SALT-ED) with conflicting results. Recently the PLUS RCT and BaSICS trials seemed to push the literature towards to concluding there was no difference, but there are caveats for both trials now in the literature:

• While the PLUS RCT found no difference, a concurrently published meta-analysis seemed to conclude the opposite (https://doi.org/10.1056/EVIDoa2100010).
• Further confusing the issue, apost-hoc analysis of the similarly negative BaSICS RCTcame out in March 2022 suggesting that overall there was a benefit for patients who received balanced crystalloid when they hit the door, but that those who arrived with sepsis and were unplanned admissions benefited most!
  • The authors note that their original analysis is likely affected by the fact that 68% of the original BaSICS study population had already received balanced fluid, saline, or both before randomization.

This paper makes a nice point which I think is important for us in the ED: the evidence is suggesting a commonality in many critical care concepts, which is that decisions made in early resuscitation may have an outsized impact on patient outcomes. However, this will not be the last we hear on this subject, but for the time being, I agree with Dr. Lacy that “It might not matter as much what fluids you choose when patients are on their third, fourth, or fifth liter of fluid – but especially for the sickest patients, it sure seems like the initial resuscitation fluid makes a difference.”

BaSICS post hoc: https://www.atsjournals.org/doi/full/10.1164/rccm.202111-2484OC (See JournalFeed post from today and the accompanying editorial)

• 68% (10,520) of enrolled patients had balanced crystalloids (3,202), saline (2,096), or both (1,862) prior to enrollment
• “There was a high probability that balanced solution use was associated with lower 90-day mortality in patients who exclusively received balanced solutions before study enrollment.”

BASICS: https://jamanetwork.com/journals/jama/fullarticle/2783039 (summary stolen from Dr. Sjeklocha’s  August 31, 2022 CC Pearl)

• No difference in 90 days mortality (P-Lyte 26.4% v NS 27.2, aHR p=0.47), AKI or RRT out to 7-days, or in duration of MV, ICU LOS or hospital LOS
• Signal for possible harm in TBI population with balanced crystalloids compared to normal saline

PLUS: https://www.nejm.org/doi/10.1056/NEJMoa2114464

• 5,037 critically ill patients
• No statistically significant difference in the primary outcome of death within 90 days of randomization in the BMES group compared to the saline group (21.8% vs 22.0%, 95% CI -3.6 to 3.3; P=0.90).
• Subgroup analyses were conducted based on illness severity before randomization, presence of sepsis, kidney injury, age, sex, and ICU admission after surgery, and did not show a significant difference between the two groups.

SMART: https://www.nejm.org/doi/full/10.1056/nejmoa1711584

• 7942 patients in the balanced-crystalloids group,
• Balanced: 1139 (14.3%) versus Saline: 1211 of 7860 patients (15.4%) had a major adverse kidney event in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04).
• “Our results suggest that the use of balanced crystalloids rather than saline might prevent 1 patient among every 94 patients admitted to an ICU from the need for new renal-replacement therapy, from persistent renal dysfunction, or from death.”

SALT-ED: https://www.nejm.org/doi/full/10.1056/nejmoa1711586

• 13,347 patients
• The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adj. OR, 0.98; 95% CI, 0.92 to 1.04; P=0.41).
• Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).

https://journalfeed.org/article-a-day/2022/back-to-basics-first-fluid-choice-matters-a-reanalysis-of-the-basics-rct/

Encountered a situation in CCRU where we needed to prepare for a patient exsanguinating from gastric varices, and found a great summary of the different types of gastroesophageal balloons from EMRAP.

Summary: https://www.youtube.com/watch?v=Yv4muh0hX7Y

More in depth video on the Minnesota tube: https://www.youtube.com/watch?v=4FHIiA_doWU

Nice review article: https://www.sciencedirect.com/science/article/abs/pii/S0736467921009136

The use of catecholamines following OHCA has been a mainstay option for management for decades. Epinephrine is the most commonly used drug for cardiovascular support, but norepinephrine and dobutamine are also used. There is relatively poor data in their use in the out of hospital cardiac arrest (OHCA). This observational multicenter trial in France enrolled 766 patients with persistent requirement for catecholamine infusion post ROSC for 6 hours despite adequate fluid resuscitation. 285 (37%) received epinephrine and 481 (63%) norepinephrine.

Findings

• Deaths from refractory shock (35% vs. 9%, P<0.001) and Recurrent cardiac arrest (9% vs. 3%, P<0.001) were higher in the epinephrine group
• In both univariate/multivariate analyses, use of epinephrine was significantly associated with:
  • All-cause mortality during the hospital stay (83% vs. 61%, P<0.001) / (OR 2.6, 95%CI 1.4–4.7, P=0.002)
  • Cardiovascular-specific mortality (44% vs. 11%, P<0.001) / (aOR 5.5, 95%CI 3.0–10.3, P<0.001)
  • Frequency of unfavorable neurological outcomes (37% vs. 15%, P<0.001) / (aOR 3.0, 95%CI 1.6–5.7, P=0.001)
• While propensity scoring and match analysis largely confirmed these findings, further regression did not associate epinephrine with all-cause mortality.

Limitations:

• Epinephrine arm: significantly longer time to ROSC, lower blood pH at admission, higher rates of unshockable rhythm, higher levels of arterial lactate at admission, lower LV ejection fraction, and higher levels of myocardial dysfunction.
• Propensity matching always has the potential for confounders.

Summary:

Norepinephrine may be a better choice for persistent post-arrest shock. However, this study is not designed to sufficiently address confounders to recommend abandoning epinephrine altogether, but it does give one pause. 

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A prospective, randomized, open-label, parallel assignment, single-center clinical trial performed by an anesthesiology-based Airway Team under emergent circumstances at UT Southwestern.

801 critically ill patients requiring emergency intubation were randomly assigned 1:1 at the time of intubation using standard RSI  doses of etomidate and ketamine.

Primary endpoint: 7-day survival, was statistically and clinically significantly lower in the etomidate group compared with ketamine 77.3% (90/396) vs 85.1% (59/395); NNH = 13.

Secondary endpoints: 28-day survival rate was not statistically or clinically different for etomidate vs ketamine groups was no longer statistically different: 64.1% (142/396) vs 66.8% (131/395). Duration of mechanical ventilation, ICU LOS, use and duration of vasopressor, daily SOFA for 96 hours, adrenal insufficiency not significant.

Other considerations:

1. Similar to a 2009 study, ketamine group had lower blood pressure after RSI, but was not statistically significant. 2

2. Etomidate inhibits 11-beta hydroxylase in the adrenals. Associated with positive ACTH test and high SOFA scores, but not increased mortality.2

3. Ketamine raises ICP… just kidding.

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