UMEM Educational Pearls

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A single center (Nebraska, USA), retrospective analysis investigated the prevalence of intubation during hospital stay for 105 patients who had COVID-19 between March 24 to May 5, 2020 (1).   40 patients underwent awake proning vs. 60 patients did not undergo awake proning.

After adjusting for either SOFA or APACHE scores, patients with awake proning were associated with lower Hazard Ratios of intubation for SOFA (HR 0.30, 95% CI 0.09-0.96, p=0.043) and APACHE (HR 0.30, 95%CI 0.1-0.91, p=0.034).

Discussion

While this US study seemed promising, another Brazilian study being published earlier in July 2020 showed no difference in the prevalence of intubation between COVID-19 patients with proning or without proning (2).

These 2 studies highlighted the nature of this disease: high practice variability, uncertainty of therapeutic modalities.  However, the complications from awake proning had been very low.

Conclusion:

Awake proning for hypoxic COVID-19 patients is a promising intervention but we will need more studies.  In the meanwhile, we can try this therapeutic modality as the risk is low.

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Study Question: What is the association of relative hypotension (degree and duration of MPP deficit) in patients with vasopressor-dependent shock with the incidence of new significant AKI and major adverse kidney events (MAKE)? 

• Mean Perfusion Pressure (MPP) = MAP - CVP
• MAKE-14: composite measure of death, new initiation of RRT, or doubling of serum creatinine from the premorbid level at Day 14
• Basal MPP estimated using pre-illness BP readings in the chart, basal CVP estimated using prior echo findings or estimated mean values

Methods:

• Multicenter, prospective observational cohort study with 302 patients
• Notable exclusion criteria:
  • age < 40, trauma as primary reason for ICU admission, active bleeding, unavailability of at least two preillness BP readings, pregnancy, "any condition specifically requiring a higher or a lower blood pressure target in the view of a treating clinician"

Results:

• for every percentage increase in the time-weighted average MPP deficit, the odds of developing new significant AKI and MAKE-14 increased by 5.6% (95% CI, 2.2–9.1; P = 0.001) and 5.9% (95% CI, 2.2–9.8; P = 0.002), respectively.
• Relationships between the risks of developing new significant AKI or MAKE-14 and the percentage of time spent with a MAP < 65 mm Hg were not statistically significant 

Take-aways:

• Critically ill patients in shock who had higher and longer degrees of relative hypotension compared to their baseline BPs had a higher incidence of adverse kidney outcomes
• Sidenote: also consider venous congestion/volume overload when thinking about end-organ damage (e.g. MPP not just MAP)

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PEEP in the Intubated Obese Patient

• Obesity has numerous adverse effects on the respiratory system, most notably a reduction in lung volumes.
• The reduction in lung volumes (i.e., FRC) often result in airway closure and atelectasis.
• The application of PEEP in the mechanically ventilated patient helps maintain alveolar patency by preventing derecruitment.
• Importantly, the typical initial PEEP setting of 5 cm H2O is insufficient for many ventilated obese patients.
• Pearl: In the ventilated obese patient start with an initial PEEP of 10-15 cm H2O.

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Summary

Our group performed a meta-analysis to assess whether it is safe to infuse vasopressor through peripheral venous catheters.  We identified 9 studies with a total of 1835 patients.  The prevalence of complications among the pooled patient population was 9%.  Up to 96% of the complications was extravasation and almost no complications required any treatment.

A few studies reported safe infusion of norepinephrine up to 0.1 mcg/kg/min for up to 24 hours.

In exploratory meta-regression, catheter size 20 or larger was negatively associated with the rate of complications.

We also observed that studies that were published within the past 5 years reported significantly lower rate of complications from older studies.  This suggested that with careful planning and monitoring, it is safe to start vasopressor through peripheral IV.

Limitation

most of the included studies were observational. No studies had enough power to statistically analyze any variables that could predict complications.

Bottom line: we should start vasopressor as soon as indicated, if we have good, reliable IV access.

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As the number of COVID-19 cases rises worldwide, prehospital and emergency department healthcare workers remain at high risk of exposure and infection during CPR for patients with cardiac arrest and potential SARS-CoV-2. 

Existing evidence supports similar cardiac arrest outcomes in airways managed with a supraglottic airway (SGA) compared to endotracheal intubation (ETT).¹  It is generally accepted that the best airway seal is provided with endotracheal intubation + viral filter, but how well do SGAs prevent spread of aerosols? 

In CPR simulation studies:

• Cuffed endotracheal tube + viral filter provides effective seal to prevent aerosolization during CPR.²
• SGA + viral filter decreases AP spread compared to facemask and compared to bag-valve mask ventilation during CPR.³
• Notable aerosolization is seen with SGAs, with no difference between AuraGain, I-gel, LMA Proseal, LMA Supreme, Combitube, or LTS-D.²

• Ventilating through an SGA + viral filter is likely better to limit spread of aerosolized particles than bag-valve mask ventilation.
• SGAs allow egress of aerosolized particles, although the amount and area of distribution in clinical practice is unclear, and endotracheal intubation with a cuffed endotracheal tube remains the best way to avoid ongoing aerosolized particle spread with chest compressions. 
• Appropriate PPE remains crucial to limiting healthcare workers' risk of infection and must be prioritized, even/especially in the management of patients in cardiac arrest. 

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N-acetylcysteine (NAC) is well known as the accepted antidote for acute acetaminophen (tylenol/paracetamol) overdose and is well studied for this indication.  While the literature base is not nearly as strong in other causes of acute liver failure, NAC is increasingly used in these scenarios as well.  In the emergency department in particular, the cause of fulminant hepatic failure is often not known.  NAC may have some protective benefit in non-acetaminophen acute liver failure.  Existing data do not show a mortality benefit to NAC in non-acetaminophen acute liver failure, but do show improvement in transplant-free survival.  The AASLD guidelines (last revised in 2011) do not comment on NAC in non-acetaminophen acute liver failure.  A common practice is to continue NAC until the INR is < 2 and AST/ALT have decreased at least 25% from their peak values.  

Patients in fulminant liver failure should also be strongly considered for transfer to a center that does liver transplant, if presenting to a non-transplant center.  The King's College criteria is the most commonly used prognostic score for determining need of transfer to a transplant center, but in addition to calculating a King's College score providers should generally consider consultation with a transplant hepatologist for any fulminant liver failure patient to discuss the risks/benefits of transfer for transplant evaluation.

Bottom Line: While not as strongly indicated as it is in acute acetaminophen induced liver failure, NAC should be considered in both non-acetaminophen liver failure and liver failure of unknown etiology.  In addition, strongly consider consultation with a transplant hepatologist in any case of fulminant hepatic failure.

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Blood Pressure Management in Acute Ischemic Stroke

• Blood pressure (BP) is elevated in many patients who present to the ED with an acute ischemic stroke (AIS).
• Severe elevations in BP are associated with hemorrhagic transformation, as well as cardiac and renal complications.
• As such, it is important to know the various BP goals for patients with an AIS.
  • Permissive hypertension with a BP less than or equal 220/120 mm Hg is recommended for patients not receiving IV-tPA or endovascular therapy.
  • BP should be lowered to less than or equal to 180/105 mm Hg for patients who have received IV-tPA.
  • BP goals for patients who have received endovascular therapy remain controversial and should be individualized based on the degree of recanalization.

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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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A retrospective study analyzed data from 757 patients with spontaneous intraparenchymal hemorrhage.

Within the first 6 hours of admission, patients who had systolic blood pressure reduction between 40 – 60 mm Hg (OR 1.9, 95% CI 1.1-3.5) or reduction ≥ 60 mm Hg (OR 1.9, 95%CI 1.01-3.8) were associated with almost double likelihood of poor discharge functional outcome (defined as modified Rankin Scale 3-6).

Additionally, large systolic blood pressure reduction ≥ 60 mm Hg in patients with large hematoma (≥ 30.47 ml) was associated with higher likelihood of very poor functional outcome (mRS 5-6).

Take home points: while more studies are still needed to confirm these observations, perhaps we may not want to drop blood pressure in patients with spontaneous intraparenchymal hemorrhage too much and too fast.

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Systematic review and meta-analysis of 5 studies with a total of 929 patients comparing early vs. late initiation of norepinephrine in patients with septic shock

• all were single-center studies
• included RCTs, prospective and retrospective cohort studies

Primary outcome:

• short-term mortality of the early group was lower than that of the late group ([OR] = 0.45; 95% CI, 0.34 to 0.61)

Secondary outcome:

• no difference in ICU LOS
• time to achieved target MAP of the early group was shorter than that of the late group (mean difference = − 1.39; 95% CI, −1.81 to −0.96)
• in the three studies that assessed the volume of intravenous fluids within 6 h, the volume of intravenous fluids within 6 h of the early group was less than that of the late group (mean difference = − 0.50L; 95% CI, −0.68 to −0.3)

Caveat:

• no clear definition of “early” initiation (ranged from within 1 to 6 hrs)

Take home point:

Early norepinephrine usage may improve mortality in septic shock

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While the invasive monitoring of central venous pressure (CVP) in the critically ill septic patient has gone the way of also transfusing them to a hemoglobin of 10 mg/dL, it remains that an elevated CVP is associated with higher mortality^1,2 and renal failure.^2,3

Extrapolating from existing data looking at hepatic vein, portal vein, and renal vein pulsatility as measures of systemic venous hypertension and congestion,^4,5,6 Beaubien-Souligny et al. developed the venous excess ultrasound (VExUS) grading system incorporating assessment of all 3, plus the IVC, using US to stage severity of venous congestion in post-cardiac surgery patients.⁷ They evaluated several variations, determining that the VExUS-C grading system was most predictive of subsequent renal dysfunction.

(Image from www.pocus101.com)
 

High Points

       VExUS Grade 3 (severe) venous congestion:

• Correlated with higher CVP & NTproBNP levels, as well as overall fluid balance
• Had a 96% specificity for development of subsequent AKI

Caveats

• Evaluating all parameters yields the most benefit to avoid false positives
• Can be difficult to obtain all views (>25% of subjects excluded due to poor US image quality)
• Studied in a limited population, notably not primarily RV failure patients

Clinical Uses

• To limit harmful fluid administration in shock
• To help answer the prerenal vs cardiorenal AKI question in CHF
• To indicate when volume removal (diuresis) should be the strategy, even in patients with vasopressor-dependent shock

A great how-to can be found here:

https://www.pocus101.com/vexus-ultrasound-score-fluid-overload-and-venous-congestion-assessment/

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STARRT-AKITrial

The Standard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury

The development of acute kidney injury (AKI) in the critical care setting portends a greater morbidity and mortality for patients. Additionally, it places the patient at high risk of complications and requires a greater use of resources. Several studies in the past have examined if the timing of initiation of renal replacement therapy (RRT) would result in a mortality benefit, but have failed to demonstrate consistent outcomes.

The STARRT-AKI trial was a multinational, randomized controlled trial designed to determine if early initiation of RRT in critically ill adult patients with AKI lowered the risk of 90-day mortality. The Kidney Disease Improving Global Outcomes (KDIGO) classification was used to define AKI and over 2900 patients were randomly assigned to two groups over a 4 year period. Exclusion criteria included: recent RRT, a renal transplant within the preceding year, advanced CKD, an overdose necessitating RRT, or a strong suspicion of obstruction or autoimmune/vascular cause of their AKI.

Groups:

• The accelerated strategy group
  • Initiation of RRT within 12 hours of meeting eligibility criteria (AKI based on KDIGO definition)
• The standard strategy group –
  • General goal of withholding RRT unless the patient met the following specific parameters:
  • K+ >6.0,  pH <7.20,  HCO3 <12mmol/L,  moderate ARDS with clinical picture concerning for volume overload, or persistent AKI >72hr after randomization

Outcomes/Results:

• The study’s primary outcome measure was all cause mortality at 90 days
  •  There was no significant difference between the groups
  •  P=0.92 with RR 1.00
• Secondary outcomes evaluated several things including ventilator and vasoactive free days, hospital length of stay, number of days without RRT at 90 days as well as adverse events directly related to RRT
  • Interestingly, at 90 days, the patients in the accelerated strategy group were more likely to have ongoing RRT needs at 10.4% compared to the standard strategy group at 6.0% (not statistically significant).
  •  Overall, no significant difference between the groups when assessed for death in the ICU, major adverse events, or with regard to hospital length of stay.

Take home points:

• This was a well done, well randomized trial from many countries and ICU settings
• No significant mortality benefit between groups at 90 days
• Interestingly, the patients in the accelerated group were more likely to have suffered adverse events related to RRT and were more likely to be dependent on RRT at 90 days
  • It is unclear why this is, but suggestive that early initiation of RRT may compromise the intrinsic healing of the kidney
  • Emphasizes a greater risk for adverse events without clear benefit
• Ultimately, the decision to initiate RRT should be based on the patient’s clinical picture, acid/base status, electrolyte abnormalities, and volume status and NOT on a general trend of their renal indices.

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Ketamine In the Critically Ill Patient

• Ketamine has become a popular agent in the ED for both RSI and procedural sedation.
• Given the sedative, analgesic, dissociative, antidepressant, and anti-inflammatory properties, ketamine has also been used in a number of other critical illness conditions including:
  • Acute pain management
  • Status asthmaticus
  • Alcohol withdrawal syndrome
  • Status epilepticus
  • Acute agitated delirium
• The authors of a recent review in Critical Care Medicine found that the evidence supporting the use of ketamine in the critically ill is most robust for adjunctive analgesia in the intubated patient.  Surprisingly, the data is very limited to support the use of ketamine in these other conditions.
• Pearl: ketamine does have a myocardial depressant effect, which can be unmasked in states of catecholamine depletion and result in hypotension and bradycadia.

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Another week, another COVID-19 study...

On August 12th, the Metcovid study was e-published ahead of print in Clinical Infectious Diseases.  This was another study looking at steroids in COVID-19 pneumonia, this time performed in Brazil.  Metcovid was a parallel, double-blind, randomized, placebo-controlled phase IIb clinical trial which enrolled 416 patients at a single academic center for the evaluation of methylprednisolone (MP; 0.5 mg/kg BID x 5 days) vs placebo.  As with all COVID studies, Metcovid has some significant limitations, and some equivocal findings.  However, Metcovid was largely in line with RECOVERY and other trials looking at steroids in COVID-19, which lends it some face validity.  Metcovid found no significant difference in the primary outcome (mortality at day 28), but did find a difference in mortality in patients over 60 years old (a post-hoc analysis).  Metcovid was probably underpowered (sample size was based on a 50% reduction in mortality), and did have a very small trend towards reduced mortality in the MP group (37.1% vs 38.2%, p=0.629).

Bottom Line: 

• Steroids (methylprednisolone 0.5 mg/kg BID x 5 days in this case) may have some mild benefit in severe cases of COVID-19 pneumonia, especially in patients who are elderly or have more aggressive inflammatory responses (as measured by CRP here).  
• Steroids in COVID-19 may be associated with some theoretical downsides like reduced viral clearance, but are relatively safe.  Main side effect is the well known hyperglycemia induced by corticosteroids.
• When using steroids in COVID pneumonia, both to stick with the evidence and for theoretical pharmacologic reasons, it may make sense to use dexamethasone or methylprednisolone, as these medications have a higher glucocorticoid:mineralocorticoid activity ratio.  It is hypothesized that using high mineralocorticoid steroids (like cortisone or hydrocortisone) may lead to increased water retention, which could be deterimental in ARDS.  This is purely theoretical.
• There was a signal towards harm in younger and less sick patients in this study, and it probably remains prudent to reserve steroids for older, sicker COVID-19 pneumonia patients, similar to the RECOVERY trial.

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While chest X ray (CXR) is routinely obtained in the setting of traumatic injury, ultrasound (US) is a fast and reliable way to evaluate for life-threatening traumatic injuries requiring emergent intervention, and is supported by the Eastern Association for the Surgery of Trauma (EAST) guidelines. A recent Cochrane Review compared the test characteristics of chest US vs CXR for detection of traumatic pneumothorax when using Chest CT or thoracostomy as the gold standard.

• Primary end point: sensitivity and specificity for pneumothorax
• US performed by nonradiologists.
• 9 studies, 1271 patients, 410 of which had a pneumothorax
• Summary sensitivity: US 0.91 (95% CI 0.85-0.94), ranging from  0.82-0.98 in the included studies, vs. CXR 0.47 (95% CI 0.31- 0.63) ranging from 0.09 to 0.75
• Summary specificity: US 0.99 (95% CI 0.97-1.00, ranging from  0.96-1.00 vs. CXR 1.00 (95% CI 0.97- 1.00), ranging from 0.98 to 1.00

There possible weaknesses of this study, including blinding in the original studies, and several studies may or may not have been at risk for bias as their risk of bias was ‘unclear’.  However, the results were consistent across the studies analyzed and remained similar after sensitivity analysis.

Several anatomical as well as patient care issues may confound US findings for pneumothorax such as the presence of bleb, prior thoracic surgery or pathology, as well as main stem intubation.

Bottom line:  While the presence of pneumothorax is on either CXR or US is highly likely to represent the a true pneumothorax, ultrasound is a far superior screen for the detection of pneumothorax in the trauma patient.

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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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Design
-Two-center prospective observational study with 157 patients admitted to the ICU for pneumonia and being treated with HFNC
-ROX (Respiratory rate-OXygenation) index = ratio of SpO2/FIO2 to RR

Results:
-ROX index ≥4.88 at 12 hours after HFNC onset with a sensitivity of 70.1%, a specificity of 72.4%, PPV of 89.4%, NPV of 42%, LR+ of 2.54, and LR- of 0.41 in predicting treatment failure

Validation study: Roca, 2019
-results similar, but ROX index ≥4.88 at 12 hour with LR+ of only 1.82
-also found that a ROX index of <3.85 at 12 hours had a sensitivity of 23.5%, specificity of 98.4%, PPV of 88.9, NPV 69.9, LR+ of 14.47, and LR- 0.78

Pitfalls:
-decision to intubate was not made based on ROX index
-criteria for intubation was also part of the ROX index
-NIV was not part of their treatment algorithm
-created and validated prior to current COVID-19 pandemic

Takeaways:
- The ROX index can be a tool to help predict whether a patient with pneumonia on HFNC may need mechanical ventilation or higher level of care
- May be most helpful with patients with pneumonia on HFNC boarding in the ED
- At 12 hours of HFNC, ROX index of >4.88 suggests patient likely to succeed with HFNC vs. <3.85 which suggests likely need for mechanical ventilation

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