The highly-awaited PARAMEDIC2 trial results are in:

• Multicenter, double-blinded, randomized controlled trial of prehospital OHCA care
• 1mg IV epinephrine vs saline placebo, every 3-5 minutes
• 8014 OHCA patients over the age of 16 (excluded pregnant patients, anaphylactic and asthmatic cardiac arrests)
• Primary outcome: 30 day survival
• Secondary outcomes: 
  • Survival to hospital admission
  • ICU and hospital LOS
  • Survival to hospital discharge and at 3 months
  • Neurologic outcomes at hospital discharge and at 3 months, "favorable" if mRS≤3
• Results: 
  • Higher 30 day survival in Epi group (3.2 vs 2.4%, unadj OR 1.39; 95% CI 1.06 to 1.82; P=0.02)
  • No difference in ICU or hospital LOS
  • No difference in favorable neurologic outcomes at discharge or 3 month
  • Worse neurologic outcomes in the epinephrine survivors (mRS 4 or 5 in 31% of epi group vs. 17.8% of placebo)

Interestingly, the authors also queried the public as to what mattered to them most: 

Bottom Line:

• As has been demonstrated in previous studies, use of bolus-dose epinephrine results in increased rates of ROSC. 
• This survival comes with the trade-off of worsened neurologic function, a condition not in a majority of patients' personal wishes.
• Epinephrine "1mg every 3-5 minutes'" should no longer be the dogma of OHCA resuscitation.

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Respiratory alkalosis is the most common acid-base disturbance in acute severe asthma.

Lactic acidosis is also extremely common, developing in up to 40%. This may be related to:

- tissue hypoxia

- increased respiratory muscle usage related to work of breathing

- beta agonist therapy

The first report of beta agonist administration associated with hyperlactatemia was in 1981 in patients treated for preterm labor with terbutaline. Since then, numerous case reports and studies have linked IV and inhaled beta agonist administration with the development/worsening of lactic acidosis in severe asthmatics in the ICU and in the ED.

The exact mechanism is unclear, but is thought to be related to adrenergic stimulation leading to increased conversion of pyruvate to lactate.

In a study published in Chest in 2014, investigators evaluated plasma albuterol levels and serum lactate levels, as well as FEV1.

They found plasma albuterol levels correlated with lactate concentration and maintained significant association after adjusting for asthma severity (suggesting the association was independent of work of breathing/respiratory muscle usage).

Furthermore, several reports have suggested that dyspnea may improve in patients with elevated lactate and acidosis after beta agonists are withheld.

Take Home Points:

- Beta agonist therapy may contribute to lactic acidosis.

- Lactic acidosis may contribute to respiratory distress.

- In patients on prolonged, high-dose beta agonist therapy, consider checking a serum lactate periodically. If elevated, consider whether worsening lactic acidosis is contributing to respiratory distress and contemplate transitioning to less frequent treatments.

-Patients with severe asthma exacerbation and elevated serum lactate must have thorough evaluation for true tissue hypoxia/hypoperfusion. **Beta agonist associated hyperlactatemia should be a diagnosis of exclusion.**

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Improving Analgesia in Mechanically Ventilated ED Patients

• An analgosedation approach for mechanically ventilated patients has been shown to decrease the duration of mechanical ventilation and ICU LOS.
• The latest guidelines from the Society of Critical Care Medicine recommend an opioid as the initial agent, followed by a non-benzodiazepine sedative.
• Benzodiazepines have been shown to increase ICU delirium, increase the duration of mechanical ventilation, and increase ICU LOS.
• In a recent cohort study, ED physicians increased the use of opioid analgesics and markedly decreased the use of benzodiazepines in mechanically ventilated ED patients through an educational campaign and implementation of an electronic orderset.
• Take Home Point: An electronic health record orderset for mechanically ventilated ED patients can be helpful to guide clinicians and utilize an analgosedation approach.

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When a do-not-intubate (DNI) hospice patient arrives in the ED with respiratory distress, consideration of non-invasive positive pressure ventilation (NIPPV) could invoke either a “What other option do I have?” or “Why torture the patient and prolong the dying process?” sentiment.

But what’s the data?

A recently-published meta-analysis¹ found that in DNI patients receiving NIPPV, there was a 56% survival rate to hospital discharge and 32% survival to 1-year.

• Higher survival was seen in patients with COPD and pulmonary edema as the cause of their respiratory failure, as opposed to pneumonia or malignancy.
• In surviving patients, there was no decrease in quality of life at 3 months; quality of life was not assessed in the time before death in nonsurvivors.
• In comfort-measures only (CMO) patients, patients receiving NIPPV had a mildly lower dyspnea score with less opiates required/administered.

Independent studies have demonstrated:

• Better survival with NIPPV for DNI COPD and CHF patients^2,3,4 who are awake and have a good cough.⁴
• No decrease in health-related quality of life or post-ICU psychological burden (symptoms of PTSD, anxiety, or depression) in DNI survivors receiving NIPPV.³
• 63% survival to hospital discharge & 49% survival to 90 days in DNI patients receiving NIVV, with no decrease in health-related quality of life in survivors. Survival was lower for CMO patients (14% and 0% at discharge and 90 days, respectively).⁵

Bottom Line:

1. NIPPV can benefit DNI patients -- most identifiably those with COPD or cardiogenic pulmonary edema as the etiology for their respiratory distress.
2. Mild benefits to dyspnea have been seen in CMO patients, without survival benefit. A trial of NIPPV therapy may be reasonable (especially in COPD or CHF) after frank discussion with the patient and his/her loved ones, with quick cessation if comfort is not achieved and/or more discomfort is caused.

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Legionella is an important cause of community-acquired pneumonia. It ranks among the three most common causes of severe CAP leading to ICU admission and carries a high mortality rate – up to 33%. Resulting from inhalation of aerosols containing Legionella species and subsequent lung infection, it is often associated with contaminated air conditioning systems, and other hot and cold water systems.

Recommended antibiotic regimens include a fluoroquinolone, either in monotherapy or combined with a macrolide (typically Levaquin +/- or Azithromycin).

A retrospective, observational study published in the Journal of Antimicrobial Chemotherapy in 2017 looked at 211 patients admitted to the ICU with confirmed severe legionella pneumonia treated with a fluoroquinolone vs a macrolide and monotherapy vs combination therapy. Combination therapy included fluoroquinolone + macrolide, fluoroquinolone + rifampicin, or macrolide + rifampicin.

Of these 211 cases, 146 (69%) developed ARDS and 54 (26%) died in the ICU. Mortality was lower in the fluoroquinolone-based group (21%) than in the non-fluoroquinolone based group (39%), and in the combination therapy group (20%) than in the monotherapy group (34%). In a multivariable analysis, fluoroquinolone-based therapy, but not combination therapy was associated with a reduced risk of mortality (HR 0.41).

Take Home Points:

-Remember, our usual blanket coverage with vanc + zosyn in the ED does not cover atypicals!

-Consider Levaquin instead of Azithro if there is clinical concern for Legionella PNA

           -hyponatremia, abnormal LFTs may be clues in the appropriate context

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Volume Responsiveness, Carotid Ultrasound, and the PLR

• Passive Leg Raise (PLR) is accomplished by starting with the patient at a 45’ semi recumbent position, lowering the body to horizontal, passively raising the patients legs to 45’ for 30-90 seconds, then returning the patient to the semi-recumbent position.
• To assess volume responsiveness using PLR, you must assess cardiac output (CO) and not simply look at the changes in blood pressure or heart rate.
• Previous papers have shown EtCO2 to be a reasonable surrogate of CO with PLR when ventilation is unchanged.
• Another option for measuring CO is carotid ultrasound. One study demonstrated good correlation between carotid ultrasound and invasive measurements on ICU patients.  It is calculated using the equation Diameter * VTi, where VTI is the velocity time integral.
• Take Home Point - Be sure to measure CO with a PLR to help determine volume responsiveness- EtCO2 or carotid ultrasound can be considered as surrogates of CO.

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Although not specifically a part of current recommendations due to lack of data, the AHA has previously recommended shifting upward on the sternum during CPR in the pulseless pregnant patient in order to account for upward displacement of the heart by a gravid uterus. Should the same be done for our obese patients?

Lee et al. performed a retrospective study that reviewed chest CTs to determine the location on the sternum that corresponded to the optimal point of maximal left ventricular diameter (OPLV), in both obese and non-obese patients. 

They found that the OPLV was higher (more cranial) on the sternum for obese patients than for patients with normal weight, although 96% of obese patients' OPLV fell within 2cm of where the guidelines recommend standard hand placement should be, compared to a notable 52% in non-obese patients.

*as measured from the distal end of the sternum

Bottom Line: Radiographically, the location on the sternum that corresponds to optimal compression of the LV is more cranial in obese patients than in non-obese patients. It remains to be seen whether the recommendations for hand placement in CPR should be adjusted, but we may want to consider staying within 4cm of the bottom of the sternum in patients of normal weight. 

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• The Surviving Sepsis Campaign recently republished the 2018 update to their guidelines, namely, the recommendation that physicians initiate treatment measures using a "1-Hour Bundle" rather than the 3 and 6-hour bundles previously recommended:

• Also included was the level of evidence for each bundle component. There was no additional evidence provided to support the within-one-hour recommendation. 

• There has been no well-designed, randomized trial to demonstrate benefits to administration of the various bundle components at specific time points. There are observational studies that show benefits to early protocolized therapy, including a restrospective study by Seymour et al. that showed benefits to earlier administration of antibiotics (but notably, not IV fluid administration), primarily in patients with septic shock requiring pressors.²

• There have been a variety of studies demonstrating harm with unecessary IV fluid administration,^3-5 and inappropriate antibiotic use puts patients at risk for C.difficile colitis, drug reactions, and promotes drug-resistant organisms. Studies to date do not examine adverse events in patients initially treated for sepsis who do not end up being septic.

Take Home Points: 

1. Early recognition of sepsis is crucial to initiating necessary therapies and improving outcomes.
2. Patients with sepsis and septic shock benefit from early appropriate antibiotics, source control, and appropriate resuscitation.
3. Empiric treatment of all-comers with possible sepsis with broad spectrum antibiotics and 30ml/kg of IV fluids, in order to meet a 1-hour deadline, has definite potential for harm. 

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Precedex (dexmedetomidine) is a selective alpha-2 adrenergic receptor agonist used as a sedative.

It is unique among sedatives typically used in the ICU in that it lacks GABA activity and lacks anticholinergic activity.

Previous studies have shown significant positive changes in sleep patterns in critically ill patients sedated with dexmedetomidine:

-improved sleep efficiency – decreased sleep fragmentation, decreased stage 1 sleep, increased stage 2 sleep

-improved distribution of sleep (with more than ¾ sleep occurring at night)

Given importance of sleep and preservation of day-night cycles/ circadian rhythms in prevention of delirium, a recent randomized controlled trial evaluated dexmedetomidine's effect on delirium.

100 delirium-free critically ill adults receiving sedatives were randomized to receive nocturnal (21:30-06:15) IV dexmedetomidine (titrated to RASS -1 or max 0.7 mcg/kg/hr) OR placebo until ICU discharge.

80% of patients in the dexmedetomidine group remained delirium-free vs 54% in the placebo group.

There was no difference in the incidence of hypotension, bradycardia, or both between groups.

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DOACs and the Critically Ill

• The use of DOACs for the prevention of stroke and venous thromboembolism is increasing.
• Though DOACs may be non-inferior to warfarin for these indications, it is important to consider the following pearls on DOACs in the critically ill patient:
  • Acute kidney injury can double the half-life of dabigatran to more than 30 hours
  • Hepatic failure can markedly increase the half-life of the factor Xa inhibitors
  • PT, aPTT, and INR may not accurately assess the risk of bleeding. Use dilute thrombin time (TT), ecarin clotting time (ECT), or TEG/ROTEM to assess coagulopathy
  • Can consider PCC (25 to 50 IU/kg) for life-threatening hemorrhage. The evidence supporting this recommendation is not robust.

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ED physicians frequently utilize modailities such as noninvasive positive pressure ventilation (NIV) and high flow nasal cannula (HFNC) to support and potentially avoid intubation in patients presenting with acute hypoxic respiratory failure. Unfortunately, failure of these measures, resulting in "delayed" intubation, has been associated with increased mortality.^1,2

A recent post-hoc analysis of data from a multicenter randomized controlled trial evaluated 310 patients with acute hypoxic respiratory failure managed with supplemental O2 by regular nasal cannula, HFNC, or NIV.³

The following factors were predictive of eventual intubation in the different groups: 

• For nasal cannula patients, RR > 30 at 1 hour
• For HFNC patients, tachycardia at 1 hour (No respiratory variables were found to predict intubation).
• For NIV patients, tidal volume > 9ml/kg predicted body weight or PaO2:FiO2 ratio < 200 at 1 hour

Of note, 45% of the 310 patients eventually required intubation, and these patients in general had a higher initial respiratory rate and lower PaO2 at presentation, and were more likely to have bilateral infiltrates on CXR. 

Bottom Line: Reevaluate your patients frequently. If RR remains high, P:F ratio remains low, or patient respiratory effort/work of breathing is not alleviated by noninvasive measures, consider pulling the trigger on intubation earlier.

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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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