UMEM Educational Pearls - By Mark Sutherland

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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As the debate regarding the pathophysiology and ventilator mechanics of COVID pneumonia rages on, it is important to have a method to evaluate the distensibility of patients' lungs so that we can minimize lung injury.  It has been well shown that both under- and over-distention lead to acute lung injury and inducing or worsening ARDS.

One method to find the "best" level of PEEP is through the PEEP titration test (also called a Driving Pressure titration test).  High Driving Pressure (DP), which is equal to Plateau Pressure - PEEP, has been shown to be associated with lung injury, and the minimal DP obtainable for a given patient while still meeting ventilatory goals is often an objective in the ICU (common DP goal is < 15 cm H2O).  A PEEP titration is optimally done on paralyzed patients, although it can be used on sedated or very calm patients as a "best guess" approximation.  It will not work well on agitated patients or those participating heavily in their ventilation.  Be sure not to do this if you are not authorized to make vent changes, and always make sure to coordinate appropriately with your RT.

To perform a PEEP titration:

*Consider placing the patient on square waveform VC, as this will also allow evaluation of stress index (if patient is not participating).  This can be skipped if not evaluating stress index

1) Make a table for yourself on a piece of paper where you can record PEEP, Plateau Pressure, Driving Pressure, Blood Pressure, and SpO2.

2) Write down the initial PEEP, BP, and SpO2.  Clearly document for yourself that this is the initial PEEP, so you do not inadvertantly leave the vent on different settings at the end.  Perform an inspiratory hold to measure a plateau pressure.  Fill in DP by using the equation DP = Pplat - PEEP

3) Change the PEEP.  You can either increase or decrease.  If you have a suspicion that the patient is over or under distended, go towards optimal distention, but if unsure it is ok to guess.  Usually we go by increments of 2 cm H2O.  Wait about 20-30 seconds on the new PEEP.

4) Measure a new plateau pressure and calculate a new DP.  At each step, write down the BP and SpO2 as well to ensure you are not generating decreased cardiac preload or derecruitment/hypoxia (keep in mind that due to pulse ox lag, you may not see hypoxia for up to a few minutes).  

5) Repeat at a few different PEEP levels.  Typically in more unstable patients who may not tolerate aggressive vent changes you may only want to check 2-3 levels of PEEP.  In more stable patients or if concern for ongoing lung injury is high, you might check up to 5-6 different levels of PEEP.  Please note that some COVID ARDS patients are so unstable that they will not tolerate any derecruitment, and this manuever should not be used in those patients as they could desaturate during the titration.

Once you have all of your data, consider changing to whichever PEEP level gives the lowest driving pressure.  Keep in mind that while data from a PEEP titration can be very useful, it is only one data point and should be considered in combination with blood pressure, volume status, CXR findings, habitus, FiO2 weaning, and other factors.  PEEP titrations should be reperformed periodically (usually daily in most semi-stable ICU patients, more often in unstable patients).  it is also recommended to write a note in the chart with your initial vent settings, data from the titration, and settings upon termination of the titration -- and call your RT if you changed the vent settings.

Bottom Line: PEEP titration (aka Driving Pressure titration) aims to identify the PEEP level where (PPlat - PEEP) is minimal and may help reduce risk of ongoing lung injury in ventilated patients.

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Within the past few days we completed a review of complications of COVID-19, to describe what sequelae and clinical patterns, besides the obvious (URI, respiratory failure, ARDS, sepsis, etc), are noted in the literature.  This review, along with a plethora of other information focusing on critical care of the COVID-19 patient, will be posted in the next few days to http://covid19.ccproject.com/.  Below are the key points from that review:

• Acute cardiovascular complications appear to be the most common and concerning sequelae:  

                 -Acute myocardial injury (7-17% of hospitalized patients in one study),   

                 -Myocarditis (primary cause of death in 7% of COVID deaths in one study),  

                 -Arrhythmias (16.7% of hospitalized and 44.4% of ICU patients in one study), 

                  -Venous thromboembolism (incidence unknown).   

• Concerns for sudden cardiac death, even after recovery, have been raised but are not well documented in the literature.  Proposed mechanisms include respiratory compromise, myocarditis, malignant tachydysrhythmias, heart failure, and coronary plaque instability (i.e. Type 1 MI) secondary to inflammation 

• Co-infection and secondary infection rates are unknown but estimates range from 4.8% to 21%, with higher rates in sicker patients. Viral co-infection is more common than bacterial co-infection, but both may be seen. The ability to rule out COVID-19 by a positive multiplex respiratory viral panel is questionable. 

• Cytokine release syndrome and secondary HLH are both described complications, but their incidence is unknown.  The relation of this finding to purported benefits of tocilizumab (which is also a therapy for HLH) is unknown. 

• Other extrapulmonary complications are relatively typical of sepsis, such as kidney injury, abnormal LFTs, and delirium 

If anyone would like a copy of the full document, which details known complications by organ system, please feel free to email me at msutherland@som.umaryland.edu.  Thanks to David Gordon for organizing the project.

Everyone stay safe, and be sure to take care of each other, as well as our patients.

Don't forget cerebral fat embolism syndrome (FES) on the differential for altered trauma patients.  FES is typically associated with long bone fractures, but has been reported with other fractures, orthopedic reaming (i.e. aggressive orthopedic procedures), and in rare cases even with non-fracture (soft-tissue) trauma.  Typically symptoms occur between 24 and 72 hours after injury, but there have been cases both earlier and later.  Diagnosis is clinical, but MRI may be helpful, and will often show multiple cerebral white matter lesions.  It is debated whether FES is truly an embolic phenomena (i.e fat molecules traveling to and blocking blood supply of organs), or rather an inflammatory response to free fatty acids in the blood stream (i.e. more of a vasculitis type pathology).  Management is supportive care, but give these patients time as there can be favorable outcomes, even after prolonged coma.

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There are few conditions that can be as dramatic or difficult to control as variceal GI bleeding in a cirrhotic patient.  It is important to be familiar with all options in these cases, from Blakemore/Minnesota tube placement to massive transfusion to when and which consultants to get involved.  In cases that are refractory or not amenable to endoscopic intervention, emergent interventional radiology consultation for Transjugular Intrahepatic Portosystemic Shunt (TIPS) may be a consideration.  In high risk cases, think about getting IR on the phone at the same time as you engage GI, in case endoscopic management fails.  Variceal bleed patients can decompensate rapidly, get your consultants involved early!

Generally accepted indications for emergent TIPS (both of the following should be true):

-GI bleeding not amenable or not controllable by endoscopy

-Cause is felt to be variceal. May also consider in portal hypertensive gastropathy

Contraindications:

-Right heart failure or pulmonary hypertension

-Severe liver failure (MELD > 22, T Bili > 3 or Child-Pugh C. In these cases TIPS may not confer a significant survival benefit)

-Hepatic encephalopathy (relative contradindication.  HE may be worsened by TIPS).

-Polycystic liver disease (makes TIPS technically challenging)

-Chronic portal vein thrombus (makes TIPS technically challenging. Acute PV thrombus is NOT considered a contraindication)

Bottom Line: In cases of variceal GI bleeding from portal hypertension, consider getting IR on the phone early to discuss emergent TIPS.

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Ever been in an acute rescucitation and found yourself unable to remember all of those famous ACLS Hs and Ts?  I know I have.  A few years ago Littman et al published an alternative approach to critically ill, hypotensive medical patients with non shockable rhythms.  Unfortunately, it seems like some of the enthusiasm for this approach has died down, but I still think it's something you're more likely to recall in a pinch than the Hs and Ts and is a better way of getting started with a hypotensive non-trauma patient.  And it's so simple you may actually remember it!

1) Look at the monitor.  Is the rhythm narrow or wide?  

2a) Narrow - more likely a mechanical problem (tamponade, tension PTX, autoPEEP, or PE). Give IVF and search for one of these causes (and correct it!).  Keep in mind that ultrasound can help you differentiate a lot of these.

2b) Wide - more likely a metabolic problem (hyperK, sodium channel blockade, etc*). Give empiric calcium, bicarb, and other therapies targeted for these problems (if desired) and get stat labs.

Take a minute and either go to this REBEL EM post:

https://rebelem.com/a-new-pulseless-electrical-activity-algorithm/

To review this, or look at the attached diagrams.  

*Dr. Mattu would want me to remind you that hyperkalemia IS a sodium channel poisoned state, so there's no need to think of these two separately

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It's important to remember the differential for the patient with Ventricular Assist Device (VAD) difficulties, as these patients are likely to show up in your ED. 

1) Assess the patient as you usually would (signs of life, mental status, breathing, arrhythmias on monitor, etc). Listen for a hum over the chest.  Don't expect to feel a pulse.

2) Look at the VAD including controller, driveline, and power source for alarms, disconnections, signs of infection, and other obvious issues.

3) Look at the power (displayed flow), pulsatility index, and pump speed on the controller to help determine the cause of the issue (see attached chart).  Once you have a suspected etiology, typical management of these issues is usually similar to non-VAD patients (i.e. gentle IVF for hypovolemia, vasodilators if low flow is due to afterload/hypertension, defibrillation/CPR for arresting pts, etc).

Don't forget to call your VAD coordinator when able.  Consider a-line placement for precise evaluation of blood pressure (focus on MAP).

Bottom Line: Consider obstruction/thrombosis, bleeding, infection, hypovolemia, afterload/hypertension, arrhythmia, worsening LV function, and suction events when troubleshooting VADs.  The power, pulsatility index, and pump speed help differentiate these conditions.

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With increasing critical care boarding and the opioid crisis leading to more intubations for overdose, extubation - which was once a very rare event in the ED - is taking place downstairs more often.  Prolonged mechanical ventilation is associated with a ton of complications, so it's important for the ED physician to be comfortable assessing extubation readiness.  There is no single accepted set of criteria, but most commonly used are some variant of the following:

• Reason for intubation (e.g. overdose, pneumonia, pulmonary edema, AMS, etc) has resolved
• Minimal vent settings - Typically FiO2 < 40%, PEEP <= 5
• Spontaneous breathing present (i.e. pt breathes with reasonable rate on PS, SIMV, VS, PPS, etc) and able to maintain reasonable pH and pCO2 on these settings
• Neuromuscular function adequate - Ask patient to lift head off bed
• Mental status adequate - Ask patient to give thumbs up or squeeze hands
• Secretions tolerable - Ask RN or RT for frequency of suctioning and sputum character.  Think twice about extubation if getting purulent, thick secretions every 15 minutes.
• Clinical course does not require further intubation (i.e. no immediate trips planned to OR, MRI; pt not hemodynamically unstable, etc.)

If the above criteria are met, two additional tests are frequently considered:

• Spontaneous Breathing Trial (SBT) - Typically done by placing pt on PS with low settings (0/0 to 5/5).  Let pt equilibrate (time of SBT is variable) on these settings, then calculate RSBI (RR/Vt). RSBI < 105 is traditionally considered acceptable for extubation.  Remember - lower is better.  Ask RT for this. 
• Cuff Leak Test - becoming less popular, but may consider in patients at risk for laryngeal edema (e.g. prolonged intubation, angioedema, etc). Historically thought to predict airway swelling, but data is mixed.  Ask RT for this.

And don't forget to consider extubating high risk patients directly to BiPAP or HFNC!

Bottom Line: For conditions requiring intubation where significant clinical improvement may be expected while in the ED (e.g. overdose, flash pulmonary edema, etc), be vigilant about, and have a system for, assessing readiness for extubation.

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With a shortage of push dose epi, this may be an opportune time to review alternative options (see also Ashley's email on the subject).

The dose of vasopressor required to reverse hypotension has been most studied in pregnant women undergoing c-section who get epidurals and experience spinal-induced vasoplegia and hypotension (not necessarily our patient population, but we can extrapolate...)  

Phenylephrine was found to reverse hypotension 95% of the time at a dose of 159 micrograms (a neo stick has 100 ug/mL, so around 1-2 mL out of the stick)

Norepinephrine reversed hypotension in 95% of patients at a dose of 5.8 ug.  The starting dose for our norepi order in Epic is 0.01 ug/kg/min, so if you have a levophed drip hanging and have an acutely hypotensive patient, you may want to briefly infuse at a higher rate such as 0.1 ug/kg/min (for a typical weight patient), or bolus approximately 3-7 ug for a typical patient.  Of course the degree of hypotension, particular characteristics of your patient and clinical context should be taken into consideration.  When your a lucky enough to have this resource, always consult your pharmacist.

Bottom Line: To reverse acute transient hypotension you may consider:

-A bolus of phenylephrine 50-200 ug (0.5-2 mL from neo-stick)

-A bolus of norepinephrine 3-7 ug

-Briefly increasing your norepinephrine drip (if you have one) to something around 0.1 ug/kg/min in a typical weight patient

-Always search for other causes of hypotension and consider clinical context.

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Some patients with severe pulmonary hypertension receive continuous infusions at home of prostacyclins, such as epoprostanol (flolan).  These are generally delivered via a pump that the patient wears, which is attached to an indwelling catheter.  As with any indwelling device, they are at risk for infection and other complications, including malfunction.

Interruption of delivery of the medication can result in rapid cardiovascular collapse, sometimes within minutes.  In this instance, the medication should be resumed as quickly as possible (by a traditional IV if the catheter is not functional), and the patients should be treated as one would approach a patient with decompensated right heart failure.

I once saw a patient in the ED whose listed chief complaint was "medication refill", but was actually there for dislodgement of her prostacyclin catheter (thankfully she was ok).  With more patients receiving devices they are dependent upon (insulin pumps, AICDs, prostacyclin catheters), be wary of chief complaints such as "medication refill" or "device malfunction."

Bottom Line: Interruption of continuous prostacyclin therapy for pulmonary hypertension can be rapidly fatal and should be addressed immediately.

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• ANDROMEDA-SHOCK compared using capillary refill time versus lactate clearance as a guide for resuscitation in septic shock patients
• The cap refill group showed better SOFA scores at 72 hours, and a trend to lower mortality
• In the study, cap refill was performed by pressing a glass microscope slide to the ventral surface of the second finger distal phalanx, holding until blanched for 10 seconds, and releasing.  Cap refill > 3 seconds was considered abnormal.

Bottom Line: Consider using capillary refill as an alternate (or complimentary) endpoint to lactate clearance when resuscitating your septic shock patients.

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Many, if not nearly all, of our intubated patients in the ED have altered mental status, a potential to clinically worsen, or a requirement for medications that would alter their respiratory status (e.g. propofol, opioids, paralytics).  It is imperative to place these patients on appropriate ventilator modes to avoid apnea when their respiratory status changes.

• Spontaneous modes (see partial list below) REQUIRE patients to initiate breaths on their own.  No ventilation occurs in a true spontaneous mode without patient effort.  
• Patients who have alterations in respiratory drive, neuromuscular function, or are receiving paralytics should NOT be placed on:
  • Pressure Support (PSV),
  • Volume Support (VSV),
  • CPAP/BiPAP/APAP,
  • Pressure-Assisted Ventilation (PAV) / Proportional Pressure Support (PPS),
  • or other spontaneous modes
• Our hypothermia order set includes a prn paralytic (cisatracurium infusion, vecuronium bolus) to combat shivering.  Discontinue these medications for patients on spontaneous modes.
• Our Servo-I ventilators automatically backup to a control mode (VS-->VC, PS-->PC) after a period of apnea (default is anywhere from 15-45 seconds, but it depends on how the RT has set the ventilator) as a safety mechanism, but this could still cause dangerous hypoxia or hypercapnea in severely ill patients.
• If the mechanics of pressure support are desired in patients at risk of apnea, there are other methods to achieve this (PC, descending flow VC, SIMV VC+PS with a low rate, and others).
• Always consult your RT when changing ventilator settings, and be sure to take vent alarms seriously.

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