Linezolid, an antimicrobial agent in the oxazolidinone class, often used to cover MRSA and/or VRE, is a reversible MAOI that increases the risk of serotonin syndrome, particularly when administered with other serotonergic agents.

In 2011, the US FDA issued a warning against concomitant use of Linezolid and other serotonergic agents, particularly SSRIs and SNRIs.  When use of linezolid is absolutely indicated, an appropriate washout period prior to initiation was recommended.

Based on published reports and retrospective reviews, the incidence of linezolid-associated serotonin toxicity is between 0.54% and 18.2%.

A study published in the Journal of Clinical Psychopharmacology in Oct 2017 examined the incidence of serotonin syndrome with combined use of linezolid and SSRIs/SNRIs compared with linezolid alone and though there was a trend toward increased incidence in patients on SSRI/SNRIs, the authors were unable to find a statistically significant difference.

Several flaws:

-Study was retrospective

-Incidence of serotonin syndrome in both groups was very low: 1/87 (1.1%) in Linezolid + SSRI/SNRI group compared to 1/261 (0.4%) in Linezolid alone group.

-Patients in “Linezolid alone” group  were not on SSRIs or SNRIs, but were allowed to be on other serotonergic medications.

Despite this study, there are many (>30) case reports of Linezolid-associated serotonin syndrome in patients taking other serotonergic agents.

Cyproheptadine (the “antidote”) is an H1 antagonist and nonspecific serotonin antagonist.  A single case study published in 2016, reported successful use of cyproheptadine for prophylaxis against serotonin toxicity in a patient with schizophrenia, depression, and severe osteomyelitis requiring treatment with linezolid while on fluoxetine.

Bottom Line:

Risk of linezolid-associated serotonin syndrome may be lower than previously thought, however, it is still not recommended for use in patients taking concomitant serotonergic agents without an appropriate washout period.  

In case of resistant infection with no other antibiotic treatment options, the risks and benefits of concomitant administration must be weighed seriously and providers must familiarize themselves with and be vigilant in watching for signs/symptoms of serotonin toxicity.

In situations where use of linezolid is unavoidable in patients on concomitant serotonergic agents, prophylactic cyproheptadine may be considered.

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Acute on Chronic Liver Failure

• Patients with cirrhosis can comprise up to 5% of an ICU population.
• Many of these patients will present to the ED, and be admitted to the ICU, for acute on chronic liver failure.
• A few management pearls for these patients include:
  • Consider albumin in patients with hepatorenal syndrome, large-volume paracentesis (> 5 L), and SBP
  • Norepinephrine is the initial vasopressor of choice; target a MAP ≥ 60 mm Hg
  • The INR does not accurately reflect bleeding in these patients.  Use platelet count and fibrinogen.
  • There is no need to correct coagulation abnormalities prior to routine procedures (e.g., central venous catheterization)

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• The current Surviving Sepsis Campaign Guidelines recommend treating septic patients with bundled care to improve outcomes. 
• The first bundle should be completed within 3 hours of suspicion of sepsis and includes:
  • Obtain blood cultures before antibiotics
  • Obtain lactate level
  • Administer broad-spectrum antibiotics
  • Administer 30mL/kg crystalloid fluid for hypotension  (MAP <65, lactate >4)

• A recent study in Critical Care Medicine examined the time frame when the delay of specific 3-hour bundle guideline recommendations applied to severe sepsis or septic shock becomes harmful and impacts mortality.
• Retrospective cohort study of all adult patients hospitalized with severe sepsis or septic shock from January 2011 to July 31, 2015. Of the 5,072 patients enrolled, 95.8% received the 3-hour bundle.
• Results:
  • Overall in-hospital mortality = 27.8%
  • If patient did not receive any of the 3-hr bundle items, in-house mortality = 41.1%
  • Statistically significant delays were linked to increased mortality for all bundle items
  • Delays beyond 3 hours were associated with minimal additional harm already caused by the 3-hour delay

Bottom Line: Implement sepsis protocols as soon as sepsis is suspected prior to the end of the 3 hour treatment window.

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Background:

Animal studies in post-ROSC management after cardiac arrest have repeatedly demonstrated poorer neurological outcomes with higher amounts of oxygen administration.¹ Studies in humans have also demonstrated dose-dependent associations between hyperoxia and poorer neurologic outcomes, as well as in-hospital mortality.^2,3

Recent Data

A retrospective analysis of prospectively-collected data in 187 OHCA patients undergoing postarrest care with targeted temperature management found worse neurologic outcomes in patients experiencing hyperoxia in the first 6 hours following ROSC.⁴

This association was dose-dependent, with worsening outcomes as with higher PaO2 levels >200.

• Adjusted OR 1.659 [95% CI, 1.194–2.305] at 200 mmHg
• Adjusted OR 3.969 [95% CI, 1.450–10.862] for 300 mmHg
• Trend towards worsening at 150 mmHg that did not reach statistical significance

Bottom Line:

• Our initial management of these patients in the ED is crucial
• In post-cardiac arrest patients, titrate immediate FiO2 to SpO2 ≥ 94% and PaO2 75 to 150/200 mmHg to avoid hyperoxia and worsening neurologic and survival outcomes. 

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Worsening hypoxemia is not uncommon upon initiation of VV ECMO for severe ARDS as tidal volumes drop to double digits  (often <20cc) after transition to “lung rest” ventilator settings. The following are strategies to improve peripheral oxygenation:

1. Increase the blood’s oxygen content

-       Ensure FIO2 of ECMO sweep gas is 1

-       Increase ECMO blood flow

o   Limited by cannula size and configuration – may require placement of additional venous drainage cannula

o   Also limited by greater risk of recirculation and hemolysis

-       Increase blood oxygen-carrying capacity

o   Transfuse PRBCs – some advocate for goal hemoglobin 12-14, though institutional practices vary significantly

2. Minimize recirculation

-       Maximize distance between drainage and return cannulae

3. Reduce oxygen consumption

-       Optimize sedation and neuromuscular blockade. (This is not the appropriate scenario for awake ECMO.)

-       Consider therapeutic hypothermia

4. Decrease cardiac output and intrapulmonary shunt

-       Consider beta blocker (esmolol) infusion

-       Prone positioning (only if staff are experienced with proning on ECMO as this poses significant risk of cannula displacement)

5. Consider switching to hybrid configuration (VVA – continued venous drainage cannula and venous return cannula with addition of arterial return cannula)  

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Peri-Intubation Cardiac Arrest

• Endotracheal intubation is a high-risk procedure, especially in the critically ill patient.
• The incidence of peri-intubation cardiac arrest ranges from 2% to 5%, and is associated with significant increases in morbidity and mortality.
• Authors of a recent retrospective analysis across 64 French ICUs sought to determine risk factors for cardiac arrest during ICU intubation.
• Among 1,847 intubations, the main predictors of cardiac arrest during intubation were:
  • Pre-intubation arterial hypotension (SBP < 90 mm Hg) (OR 3.4)
  • Pre-intubation hypoxemia (OR 3.99)
  • Absence of preoxygenation (OR 3.58)
  • Obesity (OR 2)
  • Age > 75 years of age (OR 2.25)
• Take Home Point
  • Pay close attention to these risk factors and "resuscitate before you intubate".

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Which septic patients should receive empiric antifungal therapy?

Patients with fungemia only make up about 5% of patients presenting with septic shock, but invasive fungal infections are associated with increased hospital mortality (40-50%), prolonged ICU and hospital length of stay, and increased costs of care.¹

The EMPIRICUS trial showed no mortality benefit to empiric antifungals for all, even patients with candidal colonization and recent exposure to antibiotics.²

Bottom Line

Therapy should always be tailored to the specific patient, but providers should strongly consider admininistering empiric echinocandin (micafungin, caspofungin) over fluconazole in patients with severe sepsis/septic shock and:

• Immunosuppression (chronic steroids, neutropenia, organ transplant)
• Prolonged central venous catheters
• TPN
• Yeast colonization
• Severe pancreatitis
• Recent abdominal surgeries or procedures (perforation repairs, resections, etc.) or concern for impaired gut integrity

*Especially consider addition of antifungal in patients who do not show improvements after initial management with IVF and broad spectrum antibiotics in the ED.*

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-Nonischemic cardiomyopathy, classically seen in post-menopausal women preceded by an emotional or physical stressor

-Named for characteristic appearance on echocardiography and ventriculography with apical ballooning and contraction of the basilar segments of the LV – looks like a Japanese octopus trap or “takotsubo" (pot with  narrow neck and round bottom)

-Clinical presentation usually similar to ACS with chest pain, dyspnea, syncope, and EKG changes not easily distinguished from ischemia (ST elevations – 43.7%, ST depressions, TW inversions, repol abnormalities) and elevation in cardiac biomarkers (though peak is typically much lower than in true ACS)

** Diagnosis of exclusion – only after normal (or near-normal) coronary angiography **

-Care is supportive and prognosis is excellent with full and early recovery in almost all patients (majority have normalization of LVEF within 1 week)

-Supportive care may include inotropes, vasopressors, IABP, and/or VA ECMO in profound cardiogenic shock

** LVOT Obstruction **

-occurs in 10-25% of patients with Takotsubo’s cardiomyopathy

-LV mid and apical hypokinesis with associated hypercontractility of basal segments of the LV predisposes to LV outflow tract obstruction

-Important to recognize as it is managed differently:

            -may be worsened by hypovolemia, inotropes, and/or systemic vasodilatation

            -mainstay of treatment is avoidance of the above triggers/exacerbating factors while increasing afterload

                    *phenylephrine is agent of choice +/- beta blockade 

Take Home Points:

***Diagnosis of exclusion!!! Presentation very similar to ACS and ACS MUST be ruled out

* Treatment is supportive and similar to usual care for cardiogenic shock. Can be severe and require mechanical circulatory support!

*10-25% have LVOT obstruction. Manage with phenylephrine +/- beta blockade

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Hyperoxia and the Post-Arrest Patient

• Current post-arrest guideilnes recommend titrating supplemental O2 to avoid hypoxia and limit exposure to hyperoxia.
• Importantly, these recommendations are based primarily on retrospective studies that have used ABG values within the first 24 hours following ROSC.
• The latest study to evaluate the impact of hyperoxia following cardiac arrest was just published in Circulation. 
• This study is a prospective, cohort study that evaluated the association between early hyperoxia and poor neurologic outcome in adults following cardiac arrest. (ABGs were obtained at 1 hour and 6 hours following ROSC)
• Of 280 patients, 38% were exposed to early hyperoxia (defined as a PaO2 > 300 mm Hg)
• Take Home Points
  • Early hyperoxia was found to be an independent predictor of poor neurologic outcome at hospital discharge.
  • One hour longer duration of hyperoxia was associated with a 3% increase in the risk of poor neurologic outcome
  • SaO2 could not reliably exclude the presence of hyperoxia.

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As hospital volumes increase and ED patient boarding becomes more commonplace, emergency physicians may find themselves managing critically ill patients beyond the initial resuscitation.

The benefit of glucocorticoids in critically ill patients with septic shock has remained a topic of controversy for decades due to conflicting studies, including the 2002 Annane trial and the 2008 CORTICUS trial, which had opposing results when it came to the mortality benefit of steroids.

The results of the eagerly-awaited ADRENAL trial, a multicenter randomized controlled trial investigating the benefit of steroids in septic shock, were released earlier this month:

• 3658 patients from 69 different medical and surgical ICUs
• Adults with septic shock requiring mechanical ventilation (including noninvasive) and vasopressors/inotropes for at least 4 hours
• Continuous infusion hydrocortisone 200mg/day vs placebo for 7 days or until ICU discharge, if shorter
• No mortality benefit at 90 days (primary outcome) or at 28 days (secondary outcome)
• Other secondary outcomes:
  • Hydrocortisone group = Shorter ICU LOS, shorter duration of shock, shorter duration of initial mechanical ventilation, fewer # of patients receiving a blood transfusion
  • No difference in: mortality at 28 days, hospital LOS, recurrence of shock, total vent-free days, mean volume of blood transfused in patients receiving blood products, use of renal replacement therapy, development of new bacteremia/fungemia

Take Home Points:

1. Administration of standard daily dose hydrocortisone by infusion does not seem to affect mortality in septic shock.

2. Emergency providers should continue to consider stress-dose steroids in patients with shock and a high risk of adrenal insufficiency (e.g., chronic steroid therapy, genetic disorders, infectious adrenalitis, etc).  

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Septic Cardiomyopathy

• Cardiac dysfunction is common in patients with sepsis.
• Though mulitiple definitions exist, sepsis cardiomyopathy (SCM) is generally defined as an "acute syndrome of cardiac dysfunction that is unrelated to ischemia in patients with sepsis".
• Depending on the study, the incidence of SCM ranges anwywhere from 7% to 70%.
• Risk factors for SCM include:
  • Male
  • Younger age
  • High lactate at admission
  • History of heart failure
• The best approach to treating patients with SCM is to maximize your treatment of sepsis.
• Dobutamine is no longer routinely recommended for SCM based solely on measurements of ScvO2.

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Although the data is limited, current published rates of in-hospital, non-operating room peri-intubation cardiac arrest (PICA) range from 2 to 6%.^1,2,3

Several risk factors associated with PICA have been identified and include:

• Preintubation hemodynamic instability (shock index ≥ 1 or systolic blood pressure < 90mmHg)^1,2,3
• Elevated Body Mass Index (and increased risk with every 10kg body weight)¹
• Use of succinylcholine as paralytic³
• Intubation occurring within one hour of nursing shift change³

Other common findings:

• Most PICA occurs within 10 minutes of rapid sequence induction (RSI)^1,2
• PEA is the initial recorded rhythm 80-100% of the time.^1,2,3
• Even if ROSC obtained, PICA is associated with higher rates of in-hospital mortality compared to patients requiring emergent intubation who do not experience cardiac arrest.^1,2,3

Bottom Line:  Endotracheal intubation is one of the riskiest procedures we regularly perform as emergency physicians.

• Resuscitate hypotensive patients prior to or concomitantly with RSI and/or have a vasopressor at the ready in patients with higher risk of cardiovascular collapse.
• Consider use of vecuronium or rocuronium, rather than succinylcholine, in patients who require a paralytic for intubation but are at higher risk of hyperkalemia or have an unknown history. 

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Sedating The Critically Ill Patient

• Sedating critically ill ED patients can be challenging.
• Excessive sedation is associated with a prolonged duration of mechanical ventilation, ICU LOS, and may increase mortality.
• Important pearls to consider when managing these patients include:
  • Prioritize pain management first - may reduce the need for sedative medications
  • When possible, target a calm and interactive patient shortly after intubation - consider adding a atypical antipyschotic with propofol or dexmedetomodine
  • Use a validated tool (i.e., RASS) to dose opioids and sedative medications
  • Avoid continuous infusions of benzodiazepines

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Severe acute respiratory failure among patients with PCP pneumonia, especially among those newly diagnosed with AIDS, remains a disease of high morbidity and mortality. Among those requiring mechanical ventilator support, the mortality rate has been reported between 50-70%.

According to ELSO guidelines, pharmacologic immunosuppression (specifically neurtrophil <400/mL) is a relative contraindication. Furthermore, a status predicting poor outcome despite ECMO should also be considered a relative contraindication.

That said, there are several case reports now of successful use of ECMO in AIDS patients, particularly those suffering with PCP pneumonia.

In a case report and literature review published in BMJ in Aug 2017, 11 cases of ECMO (including 1 VA) in AIDS patients were described.

• 7 survived to hospital discharge (including 1 VA)
• 2 survived to decannulation, but ultimately died in hospital
• 2 died on ECMO
• Length of ECMO runs in survivors varied between 4 days (VA) to 31 days

Bottom Line: HIV/AIDS is not an absolute contraindication to VV ECMO therapy in ARDS and may be particularly useful in the treatment of severe PCP pneumonia. Initiation of ECMO in this patient population should be considered on an individual case by case basis. 

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Background:

We are all familiar with the Surviving Sepsis Campaign recommendation (& CMS core measure) for an initial 30ml/kg bolus of IV crystalloid within the first 3 hours for our patients with septic shock. There is minimal data, however, on how much IVF we should be giving our patients with BMIs ≥30.

A recent study in obese patients with septic shock retrospectively stratified the total fluids administered at 3 hours into 3 different weight categories, to categorize patients as having received 30mL per kg of ___ body weight, whether actual (ABW), adjusted (AjdBW), or ideal (IBW**).

AdjBW = (ABW – IBW) *40% + IBW

They found:

• Most patients received fluids based on actual body weight, BUT
• Patients at highest BMIs received ABW fluids less often
• 30ml/kg dosing according to adjusted body weight was associated with improved mortality compared to IVF per actual or ideal body weight.

Bottom Line:

• If the 30ml/kg IVF bolus seems clinically appropriate for your obese patient, consider administering according to Adjusted Body Weight first.
• As always, reevaluate your septic shock patients frequently to determine if additional fluids are necessary, and go to vasopressors early if they are not fluid responsive.

**IBW calculated using Devine’s formula for men and women:

• Males:  IBW = 50 + 2.3*(# inches over 5 feet)
• Females: IBW = 45.5 + 2.3*(# inches over 5 feet)

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Mechanical Ventilation in Shock

• Emergency physicians and intensivists routinely resuscitate patients in shock.
• For patients who manifest signs of persistent shock (i.e., rising lactate), consider intubation and mechanical ventilation, even in the absence of acute respiratory failure.
• The respiratory muscles are avid consumers of oxygen.  In fact, up to 50% of available O2 can be used by the respiratory muscles to perform the work of breathing.
• Initiation of mechanical ventilation can reduce oxygen consumption and allow oxygen to be shunted to other vital organs.

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Should that patient be admitted to the floor? 

Several studies have evaluated factors associated with upgrade in admitted patients from the floor to an ICU within 24 or 48 hours. Elevated lactate, tachypnea, and "after-hours" admissions have been repeatedly identified as some of the risk factors for decompensation. 

Two recent studies tried again to identify predictors of eventual ICU requirement...

Best predictors of subsequent upgrade:

• Hypercapnia*
• Tachypnea (in sepsis patients)*
• Hypoxemia (in pneumonia patients)
• Nighttime admission
• Initial lactate ≥ 4

The most common reasons for upgrade:

1. Respiratory failure
2. Hemodynamic instability

Effect on mortality? 

Despite a more stable initial presentation, mortality of patients who decompensated on the floor (25%) matched that of patients initially admitted to the ICU.

*One of the studies noted that although respiratory rate was demonstrated to be the most important vital sign, it was missing in 42% of the study population, while PCO2 was only obtained in 39% of patients.

Bottom Line: 

• Make sure to physically reassess patients you've stabilized/improved in the ED with current vital signs (including an accurate respiratory rate!) before okaying their admission/transfer to the floor. 
• If you get a blood gas, make sure to pay attention to the PCO2 and address any abnormalities appropriately.

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Core Temp <32 degrees leads to impaired shivering and confers increased risk for malignant ventricular dysrhythmias. Core Temp <28 degrees substantially increases risk of cardiac arrest. 

If in cardiac arrest:

• VA ECMO. Rewarming rate ~6 degrees per hour.
• Cardio Pulmonary Bypass. Rewarming Rate ~9 degrees per hour.
• Consider transfer to center with ECMO or CPB capabilities
• Consider up to 3 defibrillation attempts for shockable rhythm
• Consider with holding epi until core temp >30 degrees and doubling interval between doses (q6-10 minutes) until core temp >35 (European Resuscitation Council recs – note this differs from AHA guidelines/recommendations)

If perfusing rhythm:

• Institute active external rewarming (warm environment, forced-air heating blankets, arctic sun, warm parenteral fluids). Rewarming Rate ~ 0.1-3.4 degrees per hour.
• Consider minimally invasive rewarming with TTM cooling/rewarming catheter (Alsius/Zoll) via femoral vessel. Rewarming Rate ~3.5 degrees per hour.
• Hemodialysis or CRRT can be considered if intravascular rewarming device unavailable. Rewarming rate 2-4 degrees per hour.
• Avoid IJ or SC central lines, rewarming catheters, and HD catheters -- myocardial irritation with wire/catheter may precipitate ventricular dysrhythmia.

Consider addition of more invasive rewarming techniques in those with hemodynamic/cadiac instability or without access to VA ECMO/CPB:

• Thoracic lavage. Rewarming rate ~ 3 degrees per hour
• Peritoneal lavage. Rewarming rate ~ 1-3 degrees per hour  
•  

Consider stopping resuscitation efforts if/when:

• K >12- suggests hypoxia before cooling, no reported survivors. Some recommend K of 10 as cutoff in adults.
• Rewarmed to 32 degrees and no signs of life.

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Improving CPR Performance

• High-quality CPR is the cornerstone of successfull resuscitation from cardiac arrest.
• In fact, high-quality CPR is considered the most important intervention for achieving ROSC and good neurologic recovery.
• Pearls for optimizing CPR performance include:
  • Use a team-focused approach
  • Avoid leaning and ensure complete recoil of the chest
  • Target a chest compression fraction of at least 60%
  • Use POCUS, but pay attention to the duration of hands-off time
  • Target ETCO2 of > 20 mm Hg

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Molecular Adsorbent Recirculating System (MARS) is an artificial liver support system colloquially known in the medical field as "dialysis for the liver."  

• Limited data, small studies
• Consistently shown to improve hemodynamics, toxin clearance, and hepatic homeostasis
• No consistent proven mortality benefit
• Only performed by limited number of US hospitals (including the University of Maryland)
• May depend on the acute liver failure subpopulation, but best use currently seems to be for severe acute liver failure due to a potentially reversible/recoverable cause (toxin ingestion, trauma, acute alcoholic hepatitis, etc) or as a bridge to transplant

Take-Home:

1. Consider MARS in your patient with severe acute liver failure due to potentially reversible/recoverable etiology

2. Know if and where MARS is offered near you

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