UMEM Educational Pearls - By Mark Sutherland

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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Central Venous Catheter (CVC; aka central line) placement is a common procedure in both the ED and ICU, and while overall quite safe, does carry some risk.  In particular, many of us regularly are confronted with the challenge of placing a line in a patient with profound thrombocytopenia, which can result in significant bleeding.  In these cases, should we give platelets before we place the line?

Van Baarle et al published a randomized study in NEJM comparing an empiric 1u platelet transfusion vs no transfusion in patients with a platelet count of 10,000-50,000, prior to line placement.  The study included both HD and non-HD (e.g. TLC) lines, from all three major access sites, in patients in their ICU or hematology ward.  They found statistically fewer serious bleeding events in the transfusion group (4.8%) vs no transfusion group (11.9%).  The study wasn't powered to look at more patient oriented outcomes like mortality, but I'm sure we can all agree less bleeding is probably a good thing.  Also importantly, this study did not evaluate the risks/benefits of delaying line placement to obtain platelets when the line is urgently needed, so I would not recommend extending this to conclude platelets must be given before line placement if the line is needed for something highly time-sensitive (e.g. only available access to infuse pressors in a hypotensive patient).  

Bottom Line: It is probably beneficial and appropriate to provide prophylactic platelet transfusion prior to CVC placement in patients with a platelet count less than 50,000, assuming circumstances allow.  

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Ability to move the head and neck freely can be clutch in endotracheal intubation, so in patients such as certain trauma patients who may have c-spine instability and need to be immobilized, it's all the more important to choose the optimal intubation approach to maximize success and minimize head movement.

Choi et al recently published a study in Anesthesia looking at:

-Video laryngoscopy with a standard geometry Mac blade

vs

-Fiberoptic intubation

as the initial method for intubating patients in c-collars about to undergo spinal surgery.  This is an interesting contrast between two extremes, as standard geometry is the most "traditional" approach, whereas fiberoptic is kind of the opposite end of the spectrum, jumping to a more advanced method which might be more flexible (no pun intended) but also introduces new complexities.  

All outcomes actually favored standard geometry VL over fiberoptic, including first pass success (98% vs 91%), time to intubation (50s vs 81s) and need for additional airway maneuvers (18% vs 56%).  There was no difference in complication rates, although a bigger study might be needed to find rare complications (this study had 330 patients).  

In my opinion, it's unfortunate they didn't include hyperangulated VL, as it would be interesting to see how this approach compares.  Personally I think of hyperangulated VL in these patients as a nice blend of the two methods, bringing the familiarity and speed of typical VL intubation, but often requiring less neck movement like fiberoptic.

Bottom Line: This study does not support a fiberoptic first approach to intubating patients with cervical spine instability.  In fact, it may cause harm.

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The classic teaching is that patients with acute pancreatitis should be aggressively hydrated with IV fluids.  But as we increasingly question heavy handed fluid strategies in other areas such as sepsis, should we look at pancreatitis management too?

Li et al did a systematic review of the literature on aggressive fluid resuscitation (the exact protocol/definition varied per study, but we're mostly talking 15-20 mL/kg boluses followed by 3-5 mL/kg/hr infusion) vs less aggressive fluid resuscitation (mostly 10 mL/kg boluses followed by 1.5 mL/kg/hr infusion).  They found that aggressive resuscitation worsened mortality in severe pancreatitis (RR 2.45) and trended towards worse mortality in non-severe pancreatitis (RR 2.26, but CI crossed 1).  Aggressive was associated with more complications in both severe and non-severe pancreatitis pancreatitis.

Multiple society guidelines still call for aggressive IVF resuscitation for acute pancreatitis, but probably need to be updated given mounting evidence that this is harmful.  More recent guidelines suggest "goal-directed therapy", but no one is completely sure what that means.  

Bottom Line:  In acute pancreatitis, a more conservative empiric IVF resuscitation is probably better than the clasically taught aggressive approach.  Whether even less fluids would be better or worse is not known, but for now it's probably best to stick to a 10 mL/kg bolus and 1-2 mL/kg/hr infusion when ordering fluids for these patients unless you have another indication.

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When managing a hypotensive patient who may have some element of cardiogenic shock, it has long been debated whether it is better to start an inodilator like dobutamine, and use a true vasopressor like norepinephrine to offset the vasodilation, or start an inopressor like epinephrine.  Currently, this is largely a practice pattern issue, with different providers and specialties tending to make different choices (in my anecdotal experience, medical intensivists tend to do norepi+dobutamine, whereas cardiac surgeons and intensivists tend to use epi).  

Banothu et al recently studied this question in children with "cold" septic shock (they do not specify how this was defined) and found quicker time to resolution of shock with norepi+dobutamine vs epinephrine.  It should be noted that this was a secondary outcome, was a small study, was in children (who I'm told are not just little adults), and no difference in mortality or patient oriented outcomes was found.  However, this is a good opportunity to review what is known on this topic:

-A small RCT in Lancet 2007 by Annane et al found no difference

-A very small RCT in Acta Pharmacologica Sinica 2002 by Zhou et al suggested norepi-dobutamine has favorable effects on gastric mucosa and tissue oxygenation relative to epi or dopamine

-A small RCT in Intensive Care Medicine 1997 similarly suggested that oxygenation in the splanchnic circulation may be better with norepi+dobut than epi.

Take Home: There is very limited evidence in either direction when choosing between an inodilator + vasopressor (e.g. norepi + dobutamine) vs single inopressor (e.g. epi) strategy for a hypotensive patient in which inotropy is desired.  There is some weak evidence that norepi + dobutamine may be better for maintaing gut oxygenation and may resolve shock faster.  Personally, I would weakly recommend norepi + dobutamine over epinephrine, but continuing to follow provider preference and go with the agent(s) you're most comfortable with is also very reasonable.  If using the inodilator/vasopressor combination, it is recommended to titrate the vasopressor (e.g. norepi) to MAP and inodilator (e.g. dobutamine) to a measure of cardiac function such as CO/CI.  

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Although extubation has historically been the purview of critical care, as ED lengths of stay continue to worsen, and as we see more and more rapidly reversible respiratory failure (e.g. opioid overdose), it is valuable for ED providers to be facile in extubating patients.  In addition, a longstanding debate in critical care has revolved around the proper device to extubate patients to, specifically: regular nasal cannula (NC) vs high flow nasal cannula (HFNC) vs noninvasive positive pressure ventilation (NIPPV).  Although data are mixed, the literature suggests extubation to HFNC or NIPPV may reduce risk of reintubation, esspecially in patients at a high risk of reintubation, but doesn't show a clear difference between HFNC and NIPPV.  

Hernandez et al recently conducted an RCT in two Spanish ICUs looking at HFNC vs NIPPV upon extubation for high risk patients.  NIPPV was associated with a lower reintubation rate (23%) as opposed to HFNC (39%).  Hospital LOS was also shorted in the NIPPV group, but no other differences were observed.  

It should be noted that this study, and pretty much the entirety of this literature base, is in ICU patients.  In fact, in this study, patients were excluded if they were intubated less than 24 hours.  Generally speaking, patients with shorter intubation tend to be lower risk for reintubation and other post-extubation negative outcomes, so I would use caution extrapolating this too much to the ED.  Unfortunately however, there is very limited literature to guide ED extubation practices.  

Bottom Line:

1) Know how to assess readiness for extubation and consider extubation in the ED if they meet  criteria

2) For patients at higher risk of reintubation (older, sicker, CHF, COPD, obesity, airway issues) who you are considering extubating, you may wish to extubate them to Noninvasive Positive Pressure Ventilation, even though there is little solid literature showing best practices in terms of post-extubation respiratory support in the ED.

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Needless to say, therapeutics for COVID-19 pneumonia have been controversial.  From hydroxychloroquine to ivermectin to remedesivir to steroids to bleach (sorry, but it had to be said...),  it depends on who you ask whether medications make a difference in COVID, how much of a difference, when they should be given, and what the correct dose is. 

Dexamethasone, however, ala the RECOVERY trial, is one of the relatively few therapies supported by the majority of the literature and guidelines, and generally is recommended when respiratory support is required for COVID-19 pneumonia.  Further add to this that steroids for ARDS is a long-running point of critical care controversy (e.g. DEXA-ARDS, Meduri, etc), and all you need to say to an intensivist is "how much steroid should I give this patient?" and you can walk away and come back 10 minutes later to find them having not noticed you had ever left.

Wu et all did a fairly small (n=107) single-centered RCT looking at dexamethasone 6 mg daily vs dexamethasone 20 mg daily for COVID-19 requiring O2.  There are several notable limitations to this study, but in short it did NOT add support to the notion that higher dose dexamethasone is a good thing for COVID-19 pneumonia.  In fact, the 20 mg group trended towards worse outcomes.  Small sample size, single-center, limited follow up, variable use of biologics between the groups, and failure to investigate intermediate doses between 6 and 20 are all significant limitations of this trial. Of note, DEXA-ARDS, which was conducted before COVID (2013-2018), looked at 20 mg x 5 days followed 10 mg x 5 days and DID find a significant benefit, as well as pretty darn good NNT and p values (and was a higher quality trial), so in my opinion it is also not unreasonable to use DEXA-ARDS dosing if the patient meets moderate-severe ARDS (P:F < 200) criteria, even though of course DEXA-ARDS was before COVID and Wu et al slightly contradicts it. 

When faced with a very sick COVID-19 pneumonia patients many intensivists will do either RECOVERY or DEXA-ARDS dexamethasone (with relatively limited basis to choose one vs the other), and some will do Meduri protocol methylprednisolone (1-2 mg/kg/day).  Relatively few nowadays will omit steroids unless there's a contraindication.

Bottom Line: It probably remains a good idea to give dexamethasone to your COVID-19 pneumonia patients with hypoxia, but you can probably stick to RECOVERY (see reference below; 6 mg daily x 10 days) dosing as opposed to higher doses.  If they're REALLY sick (P:F < 200), consider DEXA-ARDS (20 mg x 5 days followed by 10 mg x 5 days) dosing.

We previously posted on the COCA trial, which looked at empiric calcium administration in cardiac arrest.  They studied 391 adult Danish cardiac arrest patients.  The immediate and 30 day outcomes showed no benefit, and in fact strongly trended towards calcium being WORSE than placebo.  This article provides the 6 month and 1 year follow up data.  Surprise, surprise... calcium is still not looking good.  

At 6 months survival non-significantly favored the placebo group, and at 1 year it significantly favored the placebo group.  Neurologic outcome for those who survived was also no better, and perhaps slightly worse, in the calcium group. 

Importantly, the trial excluded patients with "traumatic cardiac arrest, known or suspected pregnancy, prior enrollment in the trial, adrenaline prior to possible enrollment, and clinical indication for calcium at the time of randomization."

Bottom Line:  The evidence continues to not support the routine empiric administration of calcium in cardiac arrest.  Patients in whom there is an indication to give calcium (e.g. known ESRD, suspected hyperkalemia, etc) are excluded from these trials, and should likely still receive empiric calcium, but in undifferentiated cardiac arrest you can probably skip the calcium.

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Although it is well-documented that there is no true "maximum" dose of vasopressor medications, further blood pressure support as doses escalate to very high levels tends to be limited.  As such, debate has raged in Critical Care as to when is the "right" time to start a second vasoactive medication.  The VASST trial (Russell et al, NEJM, 2008) is considered to be the landmark trial in this area, and found a trend towards improvement with early addition of vasopressin to norepinephrine, but no statistically significant difference, and may have been underpowered.  

Partly as a result of VASST, the pendulum has tended to swing towards maximizing a single vasoactive before adding a second over the past decade.  The relatively high cost of vasopressin in the US has also driven this for many institutions.  However, more recently a "multi-modal" approach, emphasizing an earlier move to second, or even third, vasoactive medication, is increasingly popular.  Although cost is often prohibitive for angiotensin-2 given controversial benefits, many now advocate for targeting adrenergic receptors (e.g. with norepinephrine or epinephrine), vasopressin receptors (e.g. with vasopressin or terlipressin) and the RAAS system (e.g. with angiotensin 2) simultaneously in patients with refractory shock.  A recent review by Wieruszewski and Khanna in Critical Care (see references) outlines this approach well. 

Bottom Line: When to add a second vasoactive medication (e.g. vasopressin) for patients with refractory shock after a first vasoactive is controversial and not known.  Current practice is trending towards earlier addition of a second (or third) agent, especially if targeting different receptors, but there is limited high-quality evidence to support this approach.  Many practicioners (including this author) still follow VASST and consider vasopressin once doses of around 5-15 micrograms/min (non-weight based) of norepinephrine are reached.

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How to set the correct PEEP remains one of the most controversial topics in critical care.  In fact, just on UMEM Pearls there are 55 hits when one searches for PEEP, including this relatively recent pearl on PEEP Titration.  

A recent Systematic Review and Network Meta-Analysis looked at existing trials on this issue.  They found that:

1) Higher PEEP strategies were associated with a mortality benefit compared to lower PEEP strategies

2) Lung Recruitment Maneuvers were associated with worse mortality in a dose (length of time of the maneuver) dependent fashion.

This fits with recent literature and trends in critical care and bolsters the feeling many intensivists are increasingly having that we may be under-utilizing PEEP in the average patient.  

Bottom Line: As an extremely broad generalization, we would probably benefit the average patient by favoring higher PEEP strategies, and avoiding lung recruitment maneuvers.  Do keep in mind that it is probably best to continue lower PEEP strategies in patient populations at high risk of negative effects of PEEP (e.g. COPD/asthma, right heart failure, volume depleted with hemodynamic instability, bronchopleural fistula) until these groups are specifically studied.

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   There are several well known medications that we tend to give by default during cardiac arrests.  It seems like for each of them, every few years someone does an RCT to see if they really help anybody, and we're all disappointed by what they find.  Well... prepare to be disappointed again, I'm afraid.

   These Danish authors randomized 391 patients in cardiac arrest to either calcium or saline (given IV or IO).  They gave 2 doses of either calcium chloride or saline, with the first dose being along with the first epi dose.  Primary outcome was ROSC.  They also looked at modified Rankin at 30 and 90 days.

  The trial was stopped early for harm.  Now, we all know the dangers of interpreting studies that were stopped early, but this doesn't look great for calcium.  19% of the calcium group had ROSC compared to 27% of the saline group (p = 0.09).  Percentage of patients alive, and with favorable mRS at 30 days also both favored the saline group (although also not statistically significantly).  By the way, of the patients who had calcium levels sent, 74% in the calcium group, vs 2% in the saline group, were hypercalcemic.  Whether that had anything to do with the outcome, we may never know.

Bottom Line:  Is this saying that calcium hurts patients in cardiac arrest?  Maybe... but I don't think this is high quality enough data to draw that conclusion.  At the very least, however, just giving everyone in arrest calcium is probably not terribly helpful.  If you have a reason to give it (known severe hypocalcemia, recent parathyroid surgery, suspected hyperkalemia, etc) then go for it, otherwise you can probably focus your resus on more important things.

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The debate around post-arrest management recently has revolved around whether therapeutic hypothermia should go cold, or LESS cold.  But what if we went MORE cold?  While recent TTM trials have compared temps such as 33 to 36 and 33 to 37.5 or less, a recent trial called CAPITAL CHILL looked at 34C vs 31C.  There is a solid physiologic basis for cooling post-arrest patients, so do they do better if we lower their temp even further?  Maybe we're not going cold enough with 33?

Bottom Line: No, 31C is not better than 34C for post-arrest patients.  This study compared death and poor neurologic outcome at 180 days with 31 and 34C targets for post-arrest patients, and found no difference (in fact the 31C group did slightly, but not significantly, worse on the primary outcome, and worse on a few secondary outcomes).  

While debate remains for 33 vs 36 vs afebrile, the literature does not currently support consideration of temps below 33.  

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The much anticipated REMAP-CAP trial was epublished ahead of print July 12th in Intensive Care Medicine.  It was an RCT investigating four antiviral strategies in critically ill adults with COVID-19: lopinavir-ritonavir, hydroxychloroquine, a combination of the two, and no antiviral therapy (control group).  

Despite the hype around protease inhibitors, hydroxychloroquine, and other unproven therapies in COVID (lookin at you next, Ivermectin...), all three strategies had WORSE outcomes than placebo.  They all decreased organ-support-free days (all reaching statistical significance), which was the primary outcome.  They also all led to longer ICU time, longer time to hospital discharge, and reduced 90 day survival.  Not only does this study show no benefit, it shows fairly convincing signs of harm to these therapies.

Bottom Line: Protease inhibitors (e.g. lopinavir-ritonavir) and hydroxychloroquine are unproven therapies for critical COVID-19 infection, and are not recommended.  Providers should focus on interventions with demonstrated benefit, most notably steroids and good supportive/critical care.  

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Norepinephrine is widely considered the first-line vasopressor for patients in septic shock.  Vasopressin is often added to norepinephrine in patients requiring escalating doses, but when to add vasopressin, and what exactly the benefit is (as opposed to just further titrating up the norepinephrine) remain unclear.  Given the limited evidence for a patient-oriented benefit and the increasing cost of vasopressin, some centers are becoming more judicious in the use of vasopressin.  A systematic review in AJEM October 2021 examined the literature on early (< 6 hours of diagnosis) addition of vasopressin to the management of septic shock patients, compared to either no vasopressin or starting it after 6 hours.

Improved with early vasopressin: Need for renal replacement therapy (RRT; secondary outcome)

No difference: mortality, ICU length of stay, hospital length of stay, new onset arrhythmias

Bottom Line: When, and if, to start vasopressin in patients requiring escalating doses of norepinephrine remains controversial.  Based on the prior VASST trial, many providers will start vasopressin when norepi doses reach ~ 5-15 mcg/min (approx 0.1-0.2 mcg/kg/min), but there remains limited data to support this practice, and either starting vasopressin or continuing to titrate the norepinephrine as needed are both reasonable approaches in most patients.

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Two items from the recent INSPIRATION trial UMEM pearl were very well pointed out by our own Dr. Michael Scott and require clarification.  Thank you to all our readers for their close attention, and please know that we always appreciate you reaching out with questions/comments.  

• Dosing Correction - The "standard-dose" prophylactic dosing of enoxaparin in this trial was 40 milligrams/day.  Please excuse the error in the prior post stating 40 mg/kg/day (we will revise the post).  Standard dosing of enoxaparin for DVT/VTE prophylaxis was a flat 40 mg/day, and was not weight based.

• Major Bleeding - While the difference in major bleeding (2.5% vs 1.4%) was relatively small, this endpoint DID NOT meet non-inferiority.  In other words, the study appeared to detect a statistically significant difference in major bleeding between the dosing regimens.  Given that this is a single study and there are concerns with this finding (the authors themselves describe this as "exploratory"), I would interpret this with caution, but this supports the very intuitive notion that the intermediate (higher) dose regimen of enoxaparin would be associated with more bleeding than the standard dose regimen.  

COVID-19 is generally regarded as a hypercoagulable state, and the role of pulmonary emboli and other VTE in COVID remains unclear.  As a result, how to optimally provide prophylactic anticoagulation in COVID-19 patients who are not known to have VTE has been a point of debate.  

The INSPIRATION trial looked at 600 patients admitted to academic ICUs in Iran, and compared what is often-referred to as "intermediate-dose" prophylaxis (in this case 1 mg/kg daily of enoxaparin) to standard dose prophylaxis (40 mg/day of enoxaparin).  The study utilized a combined endpoint of venous thromboembolism, arterial thromboembolism, need for ECMO, or mortality.  As a reminder, composite endpoints can skew results.  However, the dose and type of anticoagulant chosen is similar to many academic centers around the world, and pharmacy guidelines often recommend providing this type of "intermediate-dose" prophylaxis in COVID-19 patients, sometimes based on clinical status, d-dimer or other coagulation-related patient-data.  As with many things with COVID-19, this practice is based on limited data.

There was no significant difference between groups in the primary outcome (45.7% in intermediate ppx group vs 44.1% in standard group), and while safety outcomes were similar (major bleeding in 2.5% in the intermediate ppx group vs 1.4% in standard group), the intermediate regimen failed to demonstrate non-inferiority to the standard regimen for major bleeding.

Intermediate vs standard-dose ppx was similar in this study with a small, but statistically significant increase in major bleeding in the intermediate-dose group.

Bottom Line: Although this study had methodologic flaws and there are external validity concerns, the INSPIRATION trial supports the notion that standard dose (e.g. 40 mg/g/kg/day enoxaparin) and intermediate-dose (e.g. 1 mg/kg/day enoxaparin) VTE prophylaxis are equivalent in critically ill COVID-19 patients who do not already have a known VTE in terms of preventing negative VTE outcomes.  Intermediate-dose may be associated with increased bleeding.  As more critically ill patients require ED boarding, the dose of VTE prophylaxis may remain controversial, but the need to start it remains an important consideration.

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Optimal oxygenation targets and the possible, theoretical, benefits of hyperoxygenating critically ill patients have long been points of controversy.  Multiple studies have suggested harm in pursuing aggressive hyperoxygenation amongst critical patients with various conditions ranging from myocardial infarction to sepsis to neurologic conditions.  In addition, oxygen toxicity is a known mechanism causing ARDS.

The HOT-ICU trial adds to the list of arguments against hyperoxygenation, by looking at 2928 ICU patients on high levels of supplemental oxygen and targeting a paO2 of 60 mm Hg (low oxygen group) vs paO2 of 90 mm Hg (high oxygen group).  There was no difference in mortality, or other significant difference in outcomes.

Bottom Line: A lower paO2 goal of 60 (correlates to an O2 sat of 90%) is noninferior to a higher paO2 goal of 90 (O2 sat of approximately 96%).  When titrating oxygen, targeting a pulse ox of 90-96% is reasonable in critically ill patients.  Be sure to include an upper limit on the sat goal, beware an O2 sat of 100%, and titrate down supplemental oxygen when the spO2 is above goal, as the paO2 may be dangerously high.

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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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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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As has been previously noted, the white blood cell count is "the last refuge of the intellectually destitute."  However, within a CBC (especially if a differential is obtained), there is information that can sometimes be of value.  One measure, which was noted before COVID but has come under increasing attention in the current pandemic, is the Neutrophil-To-Lypmhocyte Ratio (NLR).  Because physiologic stress typically causes the Absolute Neutrophil Count (ANC) to increase and the Absolute Lymphocyte Count (ALC) to decrease, the ratio of the two values (NLR = ANC/ALC) should increase when the body is under stress.  Similar to the WBC however, it should be noted that ANY source of physiologic stress can cause abnormalities of the NLR, and thus this is not limited strictly to infectious etiologies.  

With that caveat in mind, the NLR can sometimes be a clue to the degree of physiologic stress the patient is under.  As lymphopenia is a frequent finding in COVID, the NLR has come under particular interest in the setting of COVID and appears to have prognostic value in COVID+ patients.

It should be kept in mind that inflammatory stressors (e.g. sepsis) are likely to disproportionately raise the NLR relative to noninflammatory stressors (e.g. pulmonary embolism), so a septic patient with an NLR of 10 might not be all that ill, whereas a PE patient with an NLR of 10 may be sicker.  As with any single lab, and particularly one so nonspecific, there are no hard and fast cutoffs, and the NLR has to be interpreted in the context of other clinical data (it is very much possible to have a high NLR and not be that sick, or to have a low NLR and be sick... this is only one datapoint and does have pitfalls associated with it).  As a rough guide however, a Pulmcrit post by Josh Farkas from 2019 suggested the following interpretation of the NLR:

1-3: Normal

6-9: Mild stress (e.g. uncomplicated appendicitis)

9-18: Moderate stress, may be associated with critical illness

>18: Severe stress, commonly associated with critical illness

The post (see references below) provides an excellent overview of NLR, further information on the uses and pitfalls of NLR, and several additional sources on the subject.  It's a very worthwhile read.  

Bottom Line: The Neutrophil-To-Lymphocyte Ratio (NLR = ANC/ALC) is one indicator of the degree of physiologic stress, and may be used in conjuction with other clues to determine how sick your patient is.  

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