UMEM Educational Pearls - By Lindsay Ritter

RECAP: RECOVERY trial is a large, randomized, open label, adaptive trial studying different treatments on COVID-19. Most well known is the use of dexamethasone which reduced mortality by 1/3 in COVID patients requiring mechanical ventilation and by 1/5 in those requiring oxygen, with no benefit on those patients not requiring oxygen.

They recently published results in the Lancet on the use of tocilizumab. 

Population: 

• Up to 21 days after main randomization, regardless of treatment, RECOVERY trial patients with progressive COVID-19 were eligible for tocilizumab. 

Inclusion: 

• April 23rd 2020 to Jan 24th 2021-- 21,550 patients with hypoxia (<92% on RA or requiring O2), systemic inflammation (CRP > 75 mg/L) eligible for standard care or standard care plus toci 400-800 mg (dosing based on weight), second dose 12-24 hours later if no improvement

Outcomes: 

• Primary outcome 28 day mortality followed by:
• Hospital discharge within 28 days
• Rate of mechanical ventilation 

Results: 

• 621 (31%) tocilizumab patients and 729 (35%) of usual care patients died within 21 days (RR 0.85, p=0.0028). Consistent even in those receiving steroids (83%).
• Tocilizumab group more likely to be discharged from the hospital, less likely to receive invasive mechanical ventilation (35% vs 42%).

Conclusion: 

• Tocilizumab improved survival and other clinical outcomes- by 1/3 for those on simple oxygen, and by ½ for those receiving invasive mechanical ventilation.
• Added to the additional benefit of steroids. 
• Findings support the earlier REMAP-CAP trial on the effectiveness of tocilizumab for ICU COVID patients 

 

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The PARAMEDIC2 trial in NEJM 2018 studied the outcomes of the use of epinephrine in outside hospital cardiac arrest (OHCA) on survival and neurological outcome. 

Methods: Conducted in Britain, randomized 8007 patients to receive either epinepherine 1mg (n=4012) or placebo (n=3995) as part of standard CPR for out-of-hosptial arrest. Their primary outcome was survival at 30 days and their secondary outcomes included length of stay as well as neurological outcomes at 30 days and 3 months.

Results: The epinepherine group had improved survival to hospital admission (23% vs. 8%), at 30 days (3.2% vs. 2.4%) or at 3 months (3% vs. 2.2%). Favourable neurological outcomes, however, had no statistical difference at both hospital discharge and at 3 months.

Bottom line: Epinephrine improves ROSC, though with poor neurological outcomes. 

Important facts: 

• Demographics: Mean age 69 years, 35% female
• Initial cardiac rhythm: shockable 19%, Non-shockable 78%, Undetermined 2%
• Cause of Cardiac Arrest: Medical 91% Traumatic 2%, Drowning 0.2%, substance overdose 2%, Asphyxia 3%, missing data 2%
• Witness of cardiac arrest: none 37%, Paramedic 11%, Bystander 50%, missing data 1%
• CPR Performed by: Paramedic 11%, bystander 59%, missing data 2%
• Time from: emergency call to ambulance arrival 6min, emergency call to administration of drug 22 min, arrival to ambulance departure 50 min

 

Recently, a follow up of the PARAMEDIC2 trial was completed in Resuscitation. 

They reported long-term survival, quality of life, functional and cognitive outcomes at 3, 6 and 12-months.

Results:  At 6 months, 78 (2.0%) of the patients in the adrenaline group and 58 (1.5%) of patients in the placebo group had a favourable neurological outcome (adjusted odds ratio 1.35 [95% confidence interval: 0.93, 1.97]). 117 (2.9%) patients were alive at 6-months in the adrenaline group compared with 86 (2.2%) in the placebo group (1.43 [1.05, 1.96], reducing to 107 (2.7%) and 80 (2.0%) respectively at 12-months (1.38 [1.00, 1.92]). Measures of 3 and 6-month cognitive, functional and quality of life outcomes were reduced, but there was no strong evidence of differences between groups.

Bottom line: Epinephrine improves survival at 12 months, but poor neurological outcomes remain. 

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Ever wonder what to tell the families regarding prognosis of the sickest COVID-19 patients you intubate in the ED or ICU? Introduction: Case fatality rates (CFR) for COVID-19 patients requiring invasive mechanical ventilation have been widely variable. A study in the Blue Journal (AJRCCM) examined patients requiring intubation in a systemic review and meta-analysis.  The case fatality risk of an infection is represented by the proportion of patients who die among all infected cases in a population over a period of time. Methods: 69 studies axross 23 countries for a total of 57,420 patients with COVID-19 who required mechanical ventilation were included in analysis.  Results: Overall case fatality rate was 45%, or about 1 death for every two intubated patients.. Among studies that included age stratification, pooled estimates of CFR were 47.9% in patients <40 (CI 46.4-49.4%) and 84.4% in patients >80 (CI 83.3-85.4%). Overall heterogeneity is high (I 2 .90%), In early COVID epicenters, CFR was 70% among patients aged more than 60 years of age. CFR increased exponentially with increasing age. Specifically in the US across 21 studies (3,811 intubated patients), CFR was 47% (95% CI, 36–57%). Studies from New York reported a CFR of 54% (95% CI, 36–72%) whereas other regions in the United States reported a CFR of 41% (95% CI, 30–53%). Definitive hospital CFR (aka for those with hospital discharge outcomes, 13,120 patients) was 56% (CI 47-65%).  Conclusion: Almost half of patients with COVID-19 receiving IMV died based on the reported CFR. The reported CFR was higher in older patients and in early pandemic epicenters, which may be influenced by limited ICU resources. Limitations: Overall CFR of 45% still included patients in the hospital. Definitive hospital outcomes were only for 13,120 patients (36.6%). Significant variation in CFR exists between studies.

 

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Historically, there has been debate on transporting outside hospital cardiac arrests, as well a trauma, with the question of whether to "scoop and run" or "stay and play". 

Could hasty transportation of cardiac arrest patients put a damper on resuscitation quality? 

A recent propensity-matched study in JAMA analyzed 192 EMS agencies across 10 N American sites.

Methods:

-Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry, which counted 43,969 consecutive cases of nontraumatic adult EMS-treated OHCA (median age 67, 37% of whom were women) in 2011-2015.

-25% of these patients were transported to the hospital

-Matched 1:1 with patients in refractory arrest who were resuscitated on scene 

-Primary outcome was survival to hospital discharge, secondary outcome survival to hospital discharge with a favorable neurological status 

 

Results:

-Duration of out-of-hospital resuscitation was only 6 minutes longer in the intra-arrest transport group (29.1 and 22.9 minutes; not a statistically significant difference)

-Survival to hospital discharge was 3.8% for patients who underwent intra-arrest transport and 12.6% for those who received on-scene resuscitation

-In the propensity-matched cohort, which included 27,705 patients, survival to hospital discharge occurred in 4.0% of patients who underwent intra-arrest transport vs 8.5% who received on-scene resuscitation (risk difference, 4.6% [95% CI, 4.0- 5.1])

-Favorable neurological outcome occurred in 2.9% of patients who underwent intra-arrest transport vs 7.1% who received on-scene resuscitation (risk difference, 4.2% [95% CI, 3.5%-4.9%])

-Intra-arrest transport during resuscitation was associated with worse odds of survival to hospital discharge compared to on-scene resuscitation (4% vs 8.5%, RR 0.48, CI 0.43-0.54)

-Findings persisted across subgroups of initial shockable rhythm vs. non-shockable rhythms (most common initial rhythm was aystole), as well as EMS witness arrests vs. unwitnessed arrests 

 

Conclusion:

-This study does not support the routine transportation of patients in cardiac arrest during rescuscitation.

-The neurologically intact survival benefit associated with on-scene resuscitation is both impressive and intriguing.

-However, what implications could this have on ECPR? 

 

Limitations:

-Potential bias due to observational nature of study 

-Duration of resuscitations very similar, unknown exactly how long transport times were or if this was in urban or rural populations

-External validity not generalizable due to heterogeneity of patient populations and EMS systems

-Further randomized clinical trials are required

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Prior to this study, a Cochrane review and meta-analysis of TXA for upper GI bleeds with 7 trials (1654 patients), showed a large reduction in mortality with TXA (RR 0.61, 95% CI 0.42-0.98, p=0.01)

Design:

-Randomized, international, multicentre, placebo-controlled trial at 164 hospitals in 15 countries Juy 2013-2019

->16/18 years old with upper or lower GI bleeding

-1 g TXA IV over 10 minutes followed by maintenance dose 3 g TXA over 24 hours 

 

Results:

-Main outcome death due to bleeding within 5 days 

-4% (222/5994) died in TXA group vs 4% (226/5981) placebo risk ratio RR 0.99, 95% CI 0.82-1.18 

-Arterial thromboembolic events MI/CVA similar in both groups (0.7% vs 0.8%)

-Venous thromboembolic events PE/DVT higher in TXA group (0.8% vs 0.4%)

 

Pitfalls:

-Initially calculated all cause mortality until realization that over half deaths were due to non-bleeding causes, changed to death related to bleeding, allowing study appropriate power to detect difference 

-Majority of patients had UGIB/variceal bleeding due to liver disease, over 75% deaths in those with liver disease 

-Only 16% patients randomized in <3 hours, most >8 hours (CRASH-2 trial found benefit TXA in trauma patients only <3 hrs to administration) 

 

Takeaway:

-TXA should not be used in the management of GI bleeds

-Increased venous thromboembolic events associated with TXA administration for GI bleeds

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