UMEM Educational Pearls - By Ashley Menne

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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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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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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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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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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-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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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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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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Risk of Pneumocystis pneumonia  (PCP) increases with degree of immunosuppression. If clinical suspicion exists (CD4 <200 with cough, pulmonary infiltrates, hypoxic respiratory failure), it is reasonable to initiate empiric therapy. 

First line treatment is trimethoprim-sulfamethoxazole (TMP-SMX) orally or IV for 21 days.  IV pentamidine has equivalent efficacy to IV TMP-SMX but greater toxicity and is generally reserved for patients with severe PCP who cannot tolerate or are unresponsive to TMP-SMX.

Importantly, adjunctive corticosteroids have been shown to significantly improve outcomes (mortality, need for ICU admission, need for mechanical ventilation) in HIV-infected patients with moderate to severe PCP (defined by pO2 <70 mmHg on Room Air).

·      Ideally steroids should be started BEFORE (or at the same time as) Pneumocystis-specific treatment to prevent/mitigate the sharp deterioration in lung function that occurs in most patients after initiation of PCP treatment. This is thought to be secondary to the intense inflammatory response to lysis of Pneumocystis organisms, which can cause an ARDS-like picture.

·      Recommended dosing schedule: 40mg prednisone twice daily for 5 days,  then 40mg once daily for 5 days, followed by 20mg once daily for the remaining 11 days of treatment.

Bottom Line: In patients with moderate to severe PCP (pO2 <70 mmHg on RA), don’t forget to initiate adjunctive corticosteroids early (at the same time you initiate empiric therapy for PCP). 

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