UMEM Educational Pearls - Critical Care

Background: For better or worse, the combination of “vanc-and-zosyn” has long been a go-to empiric regimen for the treatment of septic shock. Piperacillin-tazobactam is known to cause decreased creatinine secretion into the urine leading to an increased serum creatinine without any actual physiologic harm to the kidney, but the results of previous studies have led researchers to posit an increase in actual AKI with the vanc and zosyn combo. This concern has led to some physicians choosing cefepime for anti-pseudomonal gram-negative coverage instead, despite its known potential for neurotoxicity and cefepime-associated encephalopathy.

The ACORN trial: The recently published ACORN trial compared cefepime to piperacillin-tazobactam in adult patients presenting to the ED or medical ICU with sepsis or suspected serious infection. The primary outcome was a composite of highest stage of AKI or death at 14 days.

• Single-center, unblinded, pragmatic, randomized control trial
• 2500 patients, approx. 20% with chronic kidney disease
• Approximately 77% received vancomycin as well
• ~20% antibiotic crossover in each group

Results: 

• No difference between groups in the primary outcome, or in major adverse kidney events, even in subgroup that also received vancomycin
• No difference in hospital length of stay, vasopressor days, ventilator days
• Slightly higher incidence of delirium or coma in the cefepime group 

Bottom Line:  Good antibiotic stewardship would probably decrease the frequency of vanc-and-zosyn administration, but concern for renal dysfunction alone shouldn’t guide the choice between cefepime or piperacillin-tazobactam, even in those with CKD, and even in those patients also receiving vancomycin.

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Hot of the press from the Society of Critical Care Medicine (But most of us would know it already)

Settings: This is a prospective observational population-based study design with non-contemporaneous, nonrandomized clinical trial direct (unadjusted) head- to-head evaluations
Propensity score–matched comparisons of non-shockable cardiac arrest (NS-OHCA) patient survivor using conventional CPR (C-CPR) vs. C-CPR plus Automated Head/thorax up positioning-CPR (AHUP-CPR).

Participants: patients with non-traumatic, non-shockable out of hospital cardiac arrest (NS-OHCA).

Outcome measurement: primary outcome = survival, secondary outcome = survival with good neurologic outcome (Cerebral Performance Category score of 1–2 or modified Rankin Score less than or equal to 3).

Study Results:
•    There was a total of 380 AHUP-CPR vs. 1852 C-CPR patients. After 1:1 matching, there were 353 AHUP-CPR patients and 353 C-CPR patients.
•    In unadjusted analysis
o    AHUP-CPR was associated with higher odds of survival (Odds ratio 2.46, 95% CI 1.55-3.92) and higher odds of survival with good neurologic function (Odds ratio 3.09 (95% CI 1.64-5.81)
•    In matched groups
o    AHUP-CPR was associated with higher odds of survival (Odds ratio 2.84, 95% CI 1.35-5.96) and higher odds of survival with good neurologic function [Odds ratio 3.87 (95% CI 11.27-11.78]

Discussion:
•    There was no difference in rates of ROSC between groups.  The authors argued that there was “neuroprotective effects” for the AHUP-CPR group.
•    Although randomized controlled trials are usually required before clinical interventions are adopted, the aurthors argued that it would be difficult to randomize OHCA patients, and that the risk vs benefits may facilitate early adoption of this strategy.
•    AHUP-CPR should be used first by well-trained clinicians to ensure its benefits.

Conclusion: 
OHCA patients with NS presentations will have a much higher likelihood of surviving with good neurologic function when chest compressions are augmented by expedient application of the noninvasive tools to elevated head and thorax used in this study.

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IVC POCUS is often misapplied in attempts to assess volume status and/or volume “responsiveness.” Here are some important concepts to understand when using IVC POCUS to guide management:

1. IVC measurement is not a reliable predictor of fluid responsiveness
2. Venodilation and obstructive pathology can decrease and increase (respectively) IVC size without any change in actual blood volume or “volume status”
3. IVC size/variation is affected by multiple factors including spontaneous breathing vs. mechanical ventilation (AND actual ventilator settings), and degree of respiratory effort (in both spontaneous and mechanically ventilated patients) so there are no true “cut off” points that determine volume responsiveness
4. Attempting to maximize cardiac output/oxygen delivery (macrocirculation) through IVF can actually cause venous congestion and worsen microcirculation and organ function
5. Some patients with a plethoric IVC (tamponade or tension pneumothorax) may actually benefit from IVF in the acute setting
6. Examine the entire IVC (cephalad and distal portion) and in the short and long axis (the IVC is actually elliptoid, rather than a true cylinder)
7. Interpret IVC size in relation to RA/RV function (pts with chronically elevated RA pressures may have a chronically dilated IVC)

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Many of us in the endovascular resuscitation space were eagerly awaiting some clarity on REBOA from this trial. Unfortunately, this is not the definitive trial that either confirms or denies the utility of REBOA in trauma. 

Unfortunately, even this well-designed trial suffered from major problems, most notably enrollment issues (ITT: of the 46 in the REBOA group, only 19 actually got REBOA!!) and matching issues (Brain AIS was significantly higher in the REBOA group versus standard practice [3 vs 0] & initial systolic pressure was lower in the REBOA group, both of which are known risk factors for poor outcome in REBOA). 

This trial's failure to provide a definitive benefit or the nail-in-the-coffin is frustrating to say the least. Until that day, we will continue to be selective of the "right" patient and to put in femoral arterial lines early and often.

Zaf Qasim has an excellent talk on EMRAP about this study, as does St. Emlyn's.

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As is well known, fluid resuscitation strategy ("liberal" vs “restrictive”) in sepsis is a controversial topic.  An RCT in NEJM called CLOVERS that looked at this and found no difference was recently re-analyzed to answer the following question… should my choice of strategy change if the patient presents with an Acute Kidney Injury (AKI)?  

For the most part, the answer is no.  In the group with AKI, the restrictive group did slightly, but non-statistically-significantly, better.  Interestingly, in the group without AKI, the relationship reversed, and in fact of the 4 groups (AKI vs no AKI, Restrictive vs Liberal), the no AKI but liberal strategy group did best (liberal vs restrictive in the no AKI group almost reached statistical significance in favor of the liberal strategy, but not quite).

Bottom Line: In septic patients presenting with an AKI, we don't know whether liberal or restrictive strategy is better, but either is probably reasonable.  In patients presenting without an AKI, it may be more ok to lean more towards liberal fluid resuscitation than in non-AKI patients*.  

*There are several important caveats here: 1) they didn't closely evaluate for potential side effects of over-resuscitation such as hypoxia or pulmonary edema (the primary outcome was need for renal replacement therapy), 2) as mentioned above, this trended towards but did not reach statistical significance, 3) this is one small study which did a subgroup secondary-analysis of a larger trial.

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Acute-On-Chronic Liver Failure

• Acute-on-chronic liver failure (ACLF) is defined as an acute deterioration of liver function in a patient with cirrhosis that is associated with organ failure and has high short-term mortality.
• Key extrahepatic organ failures in ACLF include the renal, CNS, respiratory, circulatory, and coagulation systems.
• With respect to CNS failure in ACLF:
  • Hepatic encephalopathy (HE) is the most common manifestation
  • A normal ammonia level makes HE unlikely
  • Benzodiazepines should be avoided
  • Primary triggers for HE include infection, GIB, and aggressive diuresis
  • Treatment of HE primarily consists of lactulose and rifaximin

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Bottom line: In the 2023 updated Clinical Practice Guideline, the American Burn Association recommends 2ml/kg/%TBSA (for burns >20% TBSA)as initial starting point for fluid administration in the first 48 hours, guided by clinical factors with consideration of supplemental albumin to limit fluid administration. Fresh frozen plasma should be considered in the context of a clinical trial.  Vitamin C and advanced hemodynamic monitoring are not recommended as they have not demonstrated improved outcomes.

Summary: Burn care has a paucity of high-quality research about some of the fundamental questions for resuscitation. The American Burn Association since 2010 has endorsed fluid volumes for patients with >20% TBSA (i.e. those predicted to develop burn shock) from 2ml/kg/%TBSA to 4ml/kg/%TBSA as a starting point for fluid resuscitation. Further clinical studies since then have demonstrated that lower volumes of fluid targeting urine output and other physiological variables are effective without demonstrating clear improvement in patient centered outcomes.  Further adjuncts such as albumin or fresh frozen plasma have demonstrated reduced fluid administration but no improvement in patient-centered outcomes. While “fluid creep” is increasingly recognized, demonstrating benefits in clinical trials will likely remain elusive as overall practice continues to shift towards less fluids and the adjunctive use of colloid will likely continue to expand. In addition to ABA CPGs and resources, the Joint Trauma System also has several useful resources for burn care.

Sources:

https://doi.org/10.1093/jbcr/irad125

https://jts.health.mil/assets/docs/cpgs/Burn_Care_11_May_2016_ID12.pdf

Settings: systemic review and meta-analysis

Participants: 2 RCTs, 21 observational studies. Fifteen studies were published between 2020-2023.

There was a total of 25721 patients with septic shock

Outcome measurement: Primary outcome was short-term mortality (ICU, hospital, 28-day, 30-day). Secondary outcomes included ICU LOS, Hospital LOS, time to achieve MAP > 65 mm Hg,

Study Results:

Composite outcome of short term mortality: 

• 20 studies and 17470 patients. Early initiation of vasopressors was associated with lower odds of short term mortality (OR 0.775, 95% CI 0.673-0.893, P<0.001, I2 = 68%).
• Early initiation of norepinephrine was associated with lower odds of short term mortality (OR 0.656, 95% CI = 0.544 to 0.790, P <0.001, I2 = 57.2%)
• Early initiation of vasopressin was also associated with lower odds of short term mortality (OR 0.685, 95% CI 0.558-0.840, P < 0.001, I2= 57%)

 Secondary outcome:

• Early vasopressor group was associated with lower odds of RRT use (OR 0.796, 95% CI 0.654-0.968, P = 0.022, I2 = 0%)
• Mean Serum lactate levels at 6 hours was similar in early vasopressor group (Mean Difference 0.218, 95% CI -0.642 to 1.079, P = 0.619).
• However, mean serum lactate levels at 6 hours was lower in early norepinephrine subgroup (mean difference -0.489, 95% CI -0.863 to -0.115, P = 0.01).

Discussion:

• This appears to be a hot topic. When our group did this topic in 2020, there were 8 or 9 studies. Since 2020, there has been a significant increase in the number of publications, although most publications were observation studies.
• Early initiation of norepinephrine may reduce fluid overload, not by reducing fluid input, but by improving host inflammatory response, improving endothelial cell barrier stability.
• Counter-intuitively, early vasopressor was also found to be associated with lower incidence of arrhythmia, which the authors attributed to shorter duration of vasopressors and lower total dosage.

Conclusion: 

More and more studies, although a RCT is still necessary, are showing that early initiation of vasopressor within 1-6 hours of septic shock would be more beneficial to patients with septic shock.

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For the folks who have been in practice for a while, you may be aware of the roller-coaster evidence base looking at steroids for pneumonia.  Once thought to be beneficial and clearly indicated, of late steroids for pneumonia have fallen out of favor.  Hamad et al have published an excellent (and brief) review in Clinical Infectious Diseases which suggests the pendulum might be swinging back in favor of giving steroids to patients with pneumonia.  It's a ~5 minute read, so I recommend glancing through it yourself, but below are my two cents (solely my opinion) on where we are with steroids for pneumonia.

Take Home Points (OPINION ALERT):

1) When you have a condition present that you consider an indication for steroids (e.g. severe COVID-19 for sure; septic shock, s. pneumo infection, and ARDS depending on how you feel about the existing literature) --> strongly consider giving steroids unless there's a contraindication

2) When you have an undifferentiated patient who MAY have one of these conditions (e.g. pneumonia with COVID pending, patient potentially in ARDS or high risk of going into ARDS, etc) who is very sick --> it is reasonable to give steroids (if no contraindication) or not give steroids.  My tendency is to lean towards giving steroids in these cases, but do be aware that society guidelines recommend against steroids here (although debatable if they just haven't caught up to more recent literature)

3) When you have an undifferentiated patient who may have one of these conditions, but is NOT very sick --> I do not think there is significant enough evidence to support empiric steroids

4) Factors that might push you one way or another:

• Severity of disease (more severe favors giving steroids),
• Pathogen (COVID-19 and s. pneumo favor steroids),
• What formulation of steroids you have availabile.  Some of these studies used continuous hydrocortisone infusions, for example, which most hospitals don't routinely do.
• Comorbidities (uncontrolled diabetes, wound healing issues, risk for opportunistic infections might argue against giving steroids)

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IV Fluid Resuscitation

• IVF administration is one of the most common interventions in the resuscitation of critically ill patients.
• The primary goals of IVFs are to augment cardiac output and increase O2 delivery.
• The amount and type of IVF must take into account the patient's pathophysiology and type of shock.
• Sepsis remains one of the most common causes of distributive shock in the ED and ICU.
• Large volumes of IVF in sepsis often do not increase cardiac output and frequently lead to organ congestion.
• Rather than a fixed dose, an individualized approach to IVFs in sepsis based on the patient's history, exam, labs, monitoring, and serial reassessments is likely to lead to better outcomes. 

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Settings: Retrospective study of a national inpatient database (Japan).

Participants:

• All patients who were admitted between April 1, 2018 and March 31, 2021 with a SOFA score > 2 on admission day.
• Propensity score matching using SOFA score at admission was used to group patients according to the first unit of admission. The units of admissions were: ICU, High-dependency unit (HDU, which is also called Intermediate care unit), general ward.

Outcome measurement: Primary outcome was in-hospital mortality, after propensity score matching.

Study Results:

• There were 19770 patients admitted to the IC, 23066 patients in the HDU and 54,234 patients in the ward.
• There were no significant differences in in-hospital mortality among cohorts with SOFA scores of 3–5.
• Patients with SOFA => 6 and admitted to the ICU or HDU were associated with lower mortality than patients with same SOFA score but admitted to the ward (Risk difference -2.3 (95% CI -4.6 to -0.1, P=0.041).
• Patients who had SOFA > 12 and was admitted to the ICU group were associated with significantly lower in-hospital mortality than those with similar SOFA score but was admitted to the HDU (Risk difference -4.3, 95% CI -7.5 to -1.0, P = 0.010)

Discussion:

• Most of the high SOFA scores among ICU patients were due to norepinephrine or mechanical ventilation.
• Patients with SOFA 2-5 and were admitted to the ICU/HDU were associated with higher mortality than those admitted to the ward. This was mostly from patients who needed intensive monitoring, and not support for organ failure.
• ICU admission is also associated with certain adverse events (2).

Conclusion:

Risk-stratifying patients according to SOFA score is a potential strategy for appropriate admission strategies.

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Bottom line: As part of a systematic protocol, peripheral pressors administered through a peripheral line greater 22Ga or larger reduced the number of days of central venous catheter (CVC) use in a MICU population at an academic medical center. 35 (5.5%) patients had an extravasation event all with “minimal” tissue injury complications. None required surgery. 51.6% of patients did not require a CVC as a result of the protocol

Details

• Six hundred thirty-five patients received peripherally administered norepinephrine.
• The median number of CVC days avoided per patient was 1 [IQR 0, 2] days
• 311 patients (51.6%) never required CVC insertion.
• Extravasation of norepinephrine occurred in 35 patients (75.8 events/1,000 d of PIVC infusion [95% CI, 52.8-105.4 events/1,000 d of PIVC infusion]).
• Most extravasations caused no or minimal tissue injury.
• No patient required surgical intervention.

Notes on protocol

PIV were placed and confirmed with US, were between wrist and AC fossa with q2h patency checks. Max allowable dose of NE 15 mcg/min with requirement that patients be able to report pain at site. Initially, max infusion time was set at 48h but was eventually liberalized to indefinite use. 

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The BRASH syndrome (Bradycardia, Renal failure, AV nodal blockade, Shock, Hyperkalemia) has been increasingly described in the literature in the past 3-5 years.  

The inciting factor is generally considered to be something that prompts acute kidney injury, often hypovolemia of some sort.  Rather than AV nodal blocker overdose or severe hyperkalemia causing conduction problems, the combination of AV nodal blocker use (most often beta-blockers, but can be any type) and hyperkalemia (often only moderate) has a synergistic effect on cardiac conduction with ensuing bradycardia that can devolve into a cycle of worsening renal perfusion and shock.

Treatment is supportive, but most effective when the syndrome is recognized and all parts simultaneously managed.  ED physicians should be familiar with its existence for targeted whole-syndrome stabilization and to avoid diagnostic delay.

• Shock – If hypovolemic, IV fluid resuscitation. Concomitantly or if still hypotensive, epinephrine infusion is recommended as it provides both chronotropy and inotropy, and also assists with hyperkalemia.

• Hyperkalemia – usually mild/moderate; IV calcium for any ECG abnormalities, intracellular shifting medications, and kaliuresis (may require high-dose loop diuretics, with IV fluids if needed to maintain volume)

• Bradycardia – will usually respond to IV calcium and chronotropy (epinephrine, isoproterenol); pacing rarely but sometimes needed

• Renal failure – IVF and perfusion support as noted above, but patients may require dialysis if renal failure is severe and hyperkalemia is unable to be medically managed

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When patients fail simple respiratory support therapies like nasal cannula or non-rebreather, it is often a point of debate whether to move next to High Flow Nasal Cannula (HFNC) or Noninvasive Positive Pressure Ventilation (NIPPV).  This study randomized patients in acute respiratory failure (ARF) to CPAP, a form of NIPPV, vs HFNC.  They looked at all comers in ARF, and primary outcome was need for intubation.  Importantly, they excluded asthma/COPD exacerbation, for which BiPAP is typically considered the first line therapy due to improved CO2 clearance.

They found a significantly lower number of patients required intubation in the CPAP (28.9%) group than the HFNC (42.6%) group (p=0.006).  They hypothesized that the enhanced PEEP improved oxygenation (hypoxia being a common trigger for moving to intubation), but as opposed to BiPAP,  the lack of additional driving pressure limited tidal volumes and Patient Self-Inflicted Lung Injury (P-SILI), which is a known mechanism of ARDS and mortality.  They use this argument to explain why trials like FLORALI, pitting HFNC vs BiPAP, tend to not find an advantage for the NIPPV arm.  While this rationale makes sense, it should be noted that the study does not directly investigate if this was the reason for the difference, and for what its worth the inverse argument that using driving pressure to reduce respiratory rate, hypercarbia, and work of breathing (other very common indications for intubation) would also theoretically reduce intubations.  Furthermore, it's not clear why reducing P-SILI, which tends to cause mortality on a much longer duration, would improve the short-term outcome of need for intubation.

Bottom Line: This study demonstrated a benefit to CPAP over HFNC in terms of decreasing need for intubation amongst non-asthma/non-COPD patients with acute respiratory failure, and offered a physiologic rationale but one that requires further verification and discussion.  While it may be reasonable to choose CPAP instead of HFNC in marginal patients at risk of intubation (but stable enough to trial noninvasive support first), in my opinion more studies are likely needed before a wholesale change in practice.  The study also does not take into consideration the enhanced comfort and compliance we tend to see with HFNC over NIPPV, which should be considered as well.  

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Pearls for the Patient in Cardiogenic Shock

• Cardiogenic shock is generally defined as tissue hypoperfusion due to ineffective cardiac output.
• Despite therapeutic advances, 30-day mortality for cardiogenic shock can reach 50%.
• Though there are several different phenotypes and severity of staging, consider the following pearls in the initial resuscitation of patients with cardiogenic shock:
  • Early arterial line placement for accurate blood pressure monitoring.
  • Supplemental oxygen to maintain O2 > 90%.
  • NIPPV to reduce the work of breathing for patients with pulmonary edema.
  • Use of lung-protective ventilation for patients who require intubation and mechanical ventilation.
  • Vasopressor and inotrope therapy for hemodynamic support.
    • Norepinephrine is the preferred first-line vasopressor. 
    • Dobutamine or milrinone for inotrope support.
  • Early revascularization for patients with cardiogenic shock due to acute MI.

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Settings: Single ICU in Poland, randomized trial

Participants: intubated patients who needed arterial catheter placement. Patients who had adequate access to one axillary and one femoral artery were eligible.

Patients were randomized 1:1 for axillary or femoral artery cannulation.

Outcome measurement: Primary outcome was cannulation success rate. Secondary outcomes were first pass success rate, number of attempts.

Study Results:

• A total of 109 patients with data: 55 patients in the Axillary group vs. 54 for femoral group.
• Cannulation success rate for axillary group was 96.4% vs. 96% for femoral group
• First pass success rate for Axillary group was 69% vs. Femoral group of 74% (p=0.56)
• Total number of procedural complications (puncture of opposite wall of artery, puncture of adjacent vein, periarterial extravasation, ischemia of extremity) was non-statistically different between groups.

Discussion:

• There was higher rate of dysfunction of arterial pressure curve among Axillary group (15%) vs. femoral group (2%, P = 0.016).  The reason for this finding is not quite clear.
• Needle visibility was worse with the femoral group. There were 75% patients with excellent and good view for the Axillary group, vs. 24% for the femoral group. This could be due to the difference between out-of-plane cannulation for femoral group vs. in-plane cannulation for axillary group.
• There was overall low rate of complications.

Conclusion:

Ultrasound-guided cannulation of the axillary artery via the infraclavicular route is non-inferior to the cannulation of the common femoral artery. When cannulation of the radial or femoral artery is not available, we can consider axillary artery via the infraclavicular approach.

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Background:
There has been interest in vitamin C as an adjunctive therapy in patients with systemic inflammation and vasoplegia to reduce inflammation. While it was suggested that vitamin C may have some benefit (along with hydrocortisone and thiamine) in septic shock, the LOVIT trial showed possible harm from high-dose vitamin C administration in septic ICU patients. The  VALENCIA trial sought to evaluate whether vitamin C could reduce the duration of vasopressor therapy in patients with moderate vasoplegic shock.

Study:
-double-blinded RCT at two tertiary centers, 71 patients (36 to placebo, 35 to vitamin C)
-adult patients with vasoplegic shock of any cause
-vasopressor requirement >10 μg/min of norepi after hypovolemia was excluded
-notable exclusion criteria: end-stage renal failure and expected survival <12 hrs

Results:
-65 pts with septic shock, 6 pts with non-infectious cause
-no significant difference in the duration of vasopressors between the treatment group (median, 44 h [95% CI, 37-54 hrs]) and the control group (55 hrs [95% CI, 33-66 hrs])
-also no statistically significant difference in the vasopressor dose at 12 hourly time points, ICU or 28-day mortality and ICU or hospital length of stay

Take-home points:
Small study that ultimately may be under-powered but did not show that vitamin C reduces vasopressor duration in moderate vasoplegic shock

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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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