UMEM Educational Pearls

While taking metronidazole it is advised that patients avoid ethanol use for at least 3 days after therapy due to the possibility of a disulfiram-like reaction.  The disulfiram-like reaction presents as abdominal cramps, nausea, vomiting, headaches, and/or flushing and can cause extreme discomfort for patients.  A recent case report describes a case of a disulfiram-like reaction in a patient receiving metronidazole and an oral prednisone solution that contained 30% alcohol.  This case highlights an important point.  Not only should we counsel patients about avoiding alcoholic beverages for at least 3 days after metronidazole therapy, but they should also avoid all alcohol-containing products, such as oral solutions and mouthwash.

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Question

Clinical Question: Will resuscitation guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes?

Methodology:

Design: Randomized, unblinded clinical trial among adults with sepsis-associated hypotension comparing PLR-guided SV responsiveness as a guide for fluid management (intervention) versus “usual care” at 13 hospitals in the United States and the United Kingdom (randomization was in a 2:1 allocation of SV-guided to usual care).

Inclusion criteria:

-patients presenting to the ED with sepsis or septic shock and anticipated ICU admission.

-refractory hypotension (MAP ≤ 65mmHg after receiving ≥ 1L and < 3L of fluid)

Exclusion criteria:

-infusion of > 3L of IV fluid prior to randomization

-hemodynamic instability due to active hemorrhage

-pregnancy or being incarcerated

-indication for immediate surgery

-acute CVA, acute coronary syndrome, acute pulmonary edema, status asthmaticus, major cardiac arrhythmia, drug overdose, injury from burn or trauma, status epilepticus

-inability or contraindication to passive leg raising

Intervention (in ICU):

-PLRs were performed prior to any treatment of hypoperfusion with either fluid bolus or vasopressors for the first 72 hours after ICU admission or until ICU discharge (whichever occurred first)

-If patient was FR (increase in SV ≥10%) a 500 ml crystalloid fluid bolus was given with repeat PLRs after every fluid bolus

-If the patient was non-FR, initiation or up-titration of vasopressors was prompted with repeat PLRs after significant escalation (an increase of 1 mcg/kg/min norepinephrine)

Results:

-83 patients in Intervention arm, 41 in Usual Care arm

-Both arms received a similar volume of resuscitation fluid prior to enrollment (2.4 ± 0.6 L Intervention vs. 2.2 ± 0.7L Usual Care)

-Positive fluid balance at 72 hours or ICU discharge, was significantly less in the Intervention arm (-1.37L favoring Intervention, 0.65 ± 2.85L Median: 0.53L Intervention vs. 2.02 ± 3.44L Median: 1.22L Usual Care, p=0.02).

-Fewer patients required RRT (5.1% vs 17.5%, p=0.04) or MV in Intervention arm compared to Usual Care (17.7% vs 34.1%, p=0.04)

-ICU length of stay was similar in the two arms  

-There was no difference in overall 30-day mortality (6.3% difference, Intervention: 15.7% vs. Usual Care: 22.0%, 95% CI -21.2%, 8.6%)

Implications:

Although this is a smaller, unblinded (also funded by maker of SV monitoring device) study, Douglas et al. demonstrate that limiting fluid administration using dynamic assessments of fluid responsiveness to guide resuscitation in patients in septic shock is likely safe. In fact, this may actually decrease the need for renal replacement therapy and mechanical ventilation amongst this patient population. At the very least, this study adds to the body of literature showing the harms of excessive fluid administration and positive fluid balance.

Bottom line:

If possible, use dynamic assessments of fluid responsiveness in patients with septic shock to guide interventions, particularly for further resuscitation beyond initial fluid resuscitation (~2 liters in this study).

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Over the past several days, riot control agents have been used against the protest participants (related to Mr. George Floyd’s death). There are 3 widely used riot control “lacrimating” agents: 

1. Mace (2-chloroacetophenone)
2. Pepper spray (capsaicins)
3. Tear gas (O-chlorobenzylidene malonitrile)

These agents (irritants) primarily affect the eye, skin, and respiratory tract.

Mangement:

• Initial management involves copious irritation of the affected area with water. 
• There is limited evidence that decontamination with milk, milk of magnesia, or baby shampoo is better than water. 
• Always consider projectile or blunt trauma that may be associated with the riot-control-related ED visits/complaint. 
• Protect yourself by wearing PPE when evaluating/treating these patients.

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• Although significant data has been accumulated regarding Covid-19 infection in adults, the epidemiologic characters and clinical course descriptions in the pediatric population lags.
• Studies to date report that children have mild self-limiting disease with low mortality, even in Immunocompromised children.
• Less than half have fever.
• However, recent reports of a severe illness similar to Kawasaki Disease and/or toxic shock syndrome have led to the newly dubbed Multisystem Inflammatory Syndrome in Children (MIS-C)
• MIS-C CDC Criteria: <21 years of age, laboratory evidence of inflammation, clinically severe illness requiring hospitalization with multisystem involvement, no alternative diagnosis, and positive Covid-19 test or exposure within 4 weeks of presentation.
• MIS-C seems to spare infants and toddlers, and is mostly described in school aged and adolescent groups.
• MIS-C often begins with fever and GI symptoms (mild vague abdominal pain,diarrhea and/or vomiting). 
• Telltale presentation of an erythematous rash that spares the limbs and is associated with conjunctival injection.  Hence the initial misdiagnosis of Kawasaki and Toxic Shock in the first reported cases.
• MIS-C patients quickly decompensate to severe shock that is often refractory to typical treatments.
• Providers should have a higher index of suspicion for MIS-C in any child who presents with concern for Covid-19 infection with these symptoms, and especially with abnormal vital signs. Closer monitoring of heart rate and blood pressure, which is often neglected is vital.

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ILE is considered as one of the “last resort” therapy in cases of life-threatening drug-induced cardiogenic shock or cardiac arrest. Although there are numerous case reports and case series that showed “successful” or “positive” outcome with ILE, here is no clear evidence that lipid emulsion therapy is effective. 

A group of researcher reviewed the National Poison Data System (NPDS) to investigate the failure of ILE therapy by reviewing the overdose fatalities reported to NPDS between 2010 and 2015.

Result:

• Out of 6026 fatalities, 459 fatal overdose cases received ILE.
• Majority involved either CCB or BB overdose (n=285; 62.1%)

Response to therapy (study cohort)

• No response: 45%
• Unknown response: 38%
• Transient/minimal response: 7%
• ROSC: 7.4%
• Immediate worsening: 3%

Adverse effect (n=49)

• ARDS with hypoxemia: 39
• Lipemia causing delay in laboratory evaluation: 3
• Lipemia causing failure of CRRT filter: 2
• Worsening/new seizure: 2
• Asystole: 2
• Fat embolism: 1

Conclusion

• The number of published cases of failed ILE outnumbers the published cases of ILE success.
• Less than 5% of the patients with CCB or BB overdose had ROSC after ILE therapy.

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Background:

· Empiric broad spectrum antibiotic therapy is a mainstay of the management of critically ill patients with septic shock.

· Vancomycin is widely used for the coverage of potential MRSA infection

• PROS: cheap, widely available, relatively widespread tissue penetration when given IV, and is generally well-tolerated

• CONS: has a complicated dosing regimen requiring specifically-timed serum concentration sampling and subsequent dose changes, frequently subtherapeutic, carries a risk of AKI especially when used concomitantly with piperacillin/tazobactam,¹ as it commonly is during empiric therapy for septic shock.         

· Continuous infusion of vancomycin has been repeatedly demonstrated to reach target serum concentrations faster, maintain consistent serum vancomycin levels better, with fewer serum concentration sampling required, and less overall vancomycin required to do so, in both adult and pediatric populations.^2-5

Current Article: 

Flannery AH, Bissell BD, Bastin MT, et al. Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: a Systematic Review and Meta-Analysis. Crit Care Med. 2020;48(6):912-8.

· Systematic review and meta-analysis of 11 studies for a total of 2123 patients

· Comparing continuous versus intermittent vancomycin infusion.

· Primary outcome of AKI, secondary outcome of mortality

· Found a reduction in the incidence of AKI in the continuous infusion cohort:

• OR 0.47 (95% CI 0.34-0.65) even when taking into account trough levels /area under the curve concentrations and the severity of AKI examined by the individual studies.

· No association between infusion strategy and mortality

Considerations:

· Initial loading dose used in most of the studies (15 mk/kg) probably underdosed, current recommendation for 25mg/kg initial loading dose⁷ (which is not even always effective by itself)⁸ (Reardon)

· Continuous infusion may be difficult with limited IV access

· AKI associated with increased hospital stay, costs, mortality (although didn’t pan out in study) – worth preventing if possible.

Take Home:

· Give a 25-30mk/kg loading dose of vancomycin in critically ill patients with suspicion of MRSA to achieve target serum concentrations sooner.

· Continuous vancomycin is a viable option and could be considered in ED boarders, especially if there is concern for impending renal injury.

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Post concussion musculoskeletal injuries

Sport related concussion (SRC) impairs numerous functions of the CNS.

Traditional research has focused on risk of repeat concussion following clearance and return to sport

Several studies have shown a consistent elevated risk of lower extremity injuries from 90 days up to one year following SRC.

These include lateral ankle sprains and ACL injuries. Risk ranges, 1.3-3.4x.

This risk may be greater in those with multiple concussions.

This elevated rate has been seen in populations ranging from high school, college to professional athletes and has also been seen in the general population.

Persistent neurological deficits in cognitive and postural control, stability and gait deviations have been postulated as potential mechanisms.

These may be potential modifiable risk factors before return to play/activity. This may be a role best served by sport physical therapists to assist with sport specific rehabilitation post concussion.

NHTSA recommends that car seats be replaced following a moderate or severe crash. Car seats do not automatically need to be replaced following a minor crash.

A minor crash is one in which ALL of the following apply:

-The vehicle was able to be driven away from the crash site.
-The vehicle door nearest the car seat was not damaged.
-None of the passengers in the vehicle sustained any injuries in the crash.
-If the vehicle has air bags, the air bags did not deploy during the crash
-There is no visible damage to the car seat.

NEVER use a car seat that has been involved in a moderate to severe crash. Always follow manufacturer's instructions.

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Question

A 19 year old man presents with a scalp lesions/burns after an exposure to incendiary agent. His wounds were smoking and they flouresce under UV light. 

What is the causative agent?

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• Previous studies suggest more than 1/3 of head CTs are avoidable by evidence-based guidelines.
• It is controversial whether patients respond to financial incentives for healthy behavior.
• A study by Iyengar et al. surveyed 913 ED patients using a hypothetical mild TBI scenario that does not need a head CT by the Canadian CT Head Rule.
• Patients were randomly assigned the consideration of benefit (0.1% of 1%), risk (0.1% or 1%), or financial incentive ($0 or $100) associated with obtaining a head CT.
• Overall, 54.2% (495/913) patients elected to obtain a head CT.
  • An increase in test benefit was associated with a 9.3% increase in CT use (49.6% to 58.9%).
  • An increase in test risk was associated with a 10.2% decrease in CT use (59.3% to 49.1%).
  • An increase in financial incentive was associated with a 11.7% decrease in CT use (60.6% to 48.3%).

Bottom Line: Discussion of benefit/risk and financial incentive associated with head CT in mild TBI affects patient decision. Interestingly in this population studied, more than half of patients will elect to obtain a head CT even in a low-risk scenario.

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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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MRI for Concussion Testing in the ED

The increased sensitivity of MRI may have a role in detecting more subtle intracranial injuries.

135 patients with mild TBI were prospectively evaluated for acute head injury in emergency departments of 3 LEVEL I trauma. 

27% of these patients with a normal initial head CT had an abnormal brain MRI including contusions and microhemorrhages. A greater number of these subtle findings was associated with neuropsychological defects on both short-term memory function and with poorer 3 month cognitive outcomes. Inherent difficulties of access, actionable results and reimbursement issues prevent application of MRI for concussion evaluation in the ED.

Note: Mild TBI defined as GCS 13-15 is not the same as sport or activity related concussion which I consider to be GCS 14-15.

Take home: There is currently no role for MRI in the acute evaluation of concussion in the ED.

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Question

If you have an intuition your patients older than 65 are at increased risk of infection, especially pneumonia (4-11 times the risk of the under 65 cohorts), you are correct.

If you are concerned your patients co-morbidities, such as COPD, heart disease, and malnutrition will contribute to prolonged mechanical ventilation (the rate of VAP increases 1-3% every extra day on the vent), you are correct.

After age 70, the ICU length of stay and duration of mechanical ventilation increase by 5 days and 9 days respectively. 

In the age of COVID-19, itself associated with prolonged mechanical ventilation, it's fair to prepare patients and families for this. We are fortunate we do not need to ration ventilators, so our discussions remain centered on the wishes of our patients, informed by a realistic understanding of what treatment and recovery entail.

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Short periods of AKI have been linked to prolonged hospitalizations, development of CKD/ESRD and in-hospital mortality.  Historically, AKI in the ED has been studied with respect to the receipt of contrast media with little data available on nephrotoxic medications.

A recent 5-year retrospective cohort study sought to determine the impact of prescribing nephrotoxic medications in the ED and the development of AKI within 7 days defined as an increase in SCr of ≥ 0.3 mg/dL or 1.5 x baseline.  The categories of potentially nephrotoxic medications included ACE-i/ARB, antibiotics, diuretics, NSAIDs, and other (antifungal, antineoplastic, and antivirals).

Inclusion: Adult patients ≥ 18 years, with an initial and repeat SCr measured 24-168h after the initial test, under admitted or observation status (discharged patients were included if they had a repeat SCr in the time window).

Exclusion: previous hospital or ED visit within 7 days, initial SCr < 0.4 mg/dL, initial SCr > 4.0 mg/dL, missing data, dialysis, or transplant history.

The authors assessed 46,965 hospitalized encounters and found that 13.8% of patients developed AKI.  Risk factors included older age, African American patients, history of CHF or CKD, higher initial SCr, and higher complexity and mortality.  AKI developed within 48 hours in half of the patients and the reminder did so by 120 hours.  Approximately 22% had ≥ 1 potentially nephrotoxic medication administered and 6% had ≥ 2 classes.

Diuretics were associated with the highest risk of AKI (64% increased risk), followed by ACE-i/ARBs (39%), and antibiotics (13%).  NSAIDs were not associated with an increased risk. The antibiotics associated with the highest risk of AKI were piperacillin-tazobactam, sulfamethoxazole-trimethoprim, and quinolones.

Bottom Line: Medications prescribed in the ED have an impact on the development of AKI during hospitalization.  While these cannot always be avoided, use caution when combining multiple nephrotoxic medications and discontinue therapy early when feasible.

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Recently, “disinfectants,” or germicides, has gain public attention during COVID-19 pandemic. So, what types of agents are considered as “disinfectants?”

Germicides as classified into three broad categories

1.    Antiseptics – chemicals applied to living tissue to kill or inhibit microorganisms

a.    Iodine & iodophors (e.g. Povidone-iodine; aka Betadine)

b.    Chlorine, bleach (sodium hypochlorite)

c.     Chlorhexidine

d.    Hydrogen peroxide

e.    Alcohols (ethanol and isopropanol)

2.    Disinfectants – chemicals applied to inanimate objects to kill or inhibit microorganisms

a.    Formaldehyde

b.    Phenol (aka carbolic acid)

c.     Substituted phenols (e.g. hexachlorophene; aka pHisoHex)

d.    Quaternary ammonium compounds (benzalkonium chloride; aka Zephiran)

3.    Sterilants – chemicals applied to inanimate objects to kill all microorganisms including spores

a.    Ethylene oxide

b.    Glutaraldehyde

Although ethanol is frequently found in alcoholic beverage and consumable, no other chemicals should be ingested or injected.

Vitamin C for Septic Shock?

• In 2017, a single center before-and-after study demonstrated benefit for patients with sepsis who received vitamin C, hydrocortisone, and high-dose thiamine.
• At present, there are more than 30 trials evaluating the use of vitamin C in sepsis.
• The VITAMINS Trial was recently published and evaluated shock resolution in patients with septic shock who received vitamin C, hydrocortisone, and high-dose thiamine compared to those that received only hydrocortisone.
• In this randomized controlled trial of 211 ICU patients, the authors found no difference in the primary outcome of time alive and free of vasopressors at 7 days between the two groups.
• There was also no difference in the secondary outcomes of hospital, 28-day, and 90-day all-cause mortality.
• Though we still await the results of ongoing trials, the VITAMINS Trial and the recent CITRIS-ALI Trial have not demonstrated benefit of vitamin C for select patient populations with sepsis.

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Comparison of Oral Ibuprofen at Three Single-dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial

Ibuprofen is one of the most commonly used medications in the ED for the acute treatment of pain. Analgesic ceiling doses are not well supported. Some adverse effects of NSAIDs are dose dependent (GI and cardiovascular).

A recent study looked to compare the analgesic effect of oral ibuprofen at 3 different doses 

Population:  Adult ED patients (aged 18 and older) with acute pain.

Methods: Randomized double-blind trial.

Goal: To examine the efficacy of ibuprofen at 400, 600 and 800mg.

Only 225 patients enrolled (75 per group). Outcome was difference in pain scores at 60 minutes.

Results:  Difference in mean pain scores at 60 minutes between 400 and 600mg (0.14), 400 and 800mg (0.14) and 600 and 800mg (0.00).

Conclusion:  Reduction in pain scores was similar between all 3 dosing groups. Consider lower dosing of ibuprofen in ED patients presenting with acute pain. 

This analgesic ceiling dose is lower than recommended by the FDA and most EM textbooks.

Consider using the 400mg ibuprofen dose for ED patients with acute pain

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• A number of small studies in the past suggested that cervical collars can increase intracranial pressure (ICP) in patients with traumatic brain injury (TBI).
• In patients with severe head injury with poor intracranial compliance and impaired cerebral autoregulation, compression on the jugular veins may result in an increase in jugular venous pressure, increase in ICP, and decrease cerebral perfusion.
• A recent meta-analysis included 5 studies comprising 86 adult patients with moderate-severe TBI.
• 3 studies used rigid collars (Stifneck), while 1 used semi-rigid, and 1 used a mix of cervical collars.
• All 5 studies monitored ICP before and after collar application, 2 also monitored ICP after collar removal.
• Cervical collar application was associated with an overall ICP increase of approximately 4.4 mmHg (95%CI 1.70, 7.17; p<0.01), while removal was associated with an overall decrease of approximately 3 mmHg (95%CI -5.45, -0.52; p=0.02).
• The use of rigid cervical collars was strongly associated with raised ICP compared to semi-rigid collars (WMD=4.86; 95%CI 2.13, 7.60; p<0.01).

Bottom Line: Cervical collars can increased ICP in moderate-severe TBI.  In patients with poor cerebral compliance and impaired cerebral autoregulation, even a small increase in ICP can affect cerebral perfusion.

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Buprenorphine (BUP) is increasingly prescribed/used to treat opioid use disorder (OUD) in the United State. BUP is mainly metabolized by CYP3A4 where its enzymatic activity can be either induced or inhibited by many agents. 

For example, a study showed that Rifampin administration for 15 days, a potent 3A4 inducer, resulted in (1): 

• Reduction of plasma BUP concentration (70% reduction in area under the curve [AUC]) 
• 50% of the study subjects (12 out of 24) experienced opioid withdrawal symptoms (OWS)
• 4 out of 12 who experience OWS received transient increase in their BUP dose (25-100%)

On the contrary, exposure to voriconazole – strong 3A4 inhibitor - resulted in (n=12 health volunteers) (2):

• Increased the plasma BUP AUC by 4.3 fold
• Increased peak BUP concentration by 3.9 fold
• Documented adverse effects were dizziness and nausea only

Cannabis use – (CBD is a CYP 3A4 inhibitor) also increased the BUP concentration by 2.7 fold. (3)

Bottom line:

1. Be mindful of drug-drug interaction when initiating a new medication in patients with OUD on BUP
2. Inquire about any recent medication change in patients who may be experiencing OWS while on steady dose of BUP for their OUD. 

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