On May 3, the FDA approved adexanet alfa, the reversal agent for factor Xa inhibitors - apixaban and rivaroxaban. It received both U.S. Orphan Drug and FDA Breakthrough Therapy designations. 

Unlike indarucizumab (a monoclonal antibody fragment) to reverse dabigatran (direct thrombin inhibitor) associated bleeding, adexanet alfa is a recombinant modified human factor Xa decoy protein. 

A phase 3 study showed that adexanet alfa decreased the anti-factor Xa activity of rivaroxaban by 92% from baseline and by 94% in apixaban treated participants.

ANNEXA-4 study involving participants with acute major bleeding (GI and intracranial) showed a significant decrease in the anti-factor Xa activity after the bolus dose of adexanet alfa and "effective" hemostasis was noted in 79% of the participants at 12 hours post infusion.

Andexanet alfa is expected to become available in June 2018.

• CT angiography (CTA) spot sign is a strong predictor of intracerebral hemorrhage (ICH) expansion.
• However, since CTA is not part of the routine diagnostic workup of acute ICH, other predictors using noncontrast head CT have been reported in the past.
• A 5-point BAT score can be used to identify patients at high risk of hematoma expansion:

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• Patients with a score ≥ 3 have a higher risk of hematoma expansion. 

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- Half of elderly patients presenting with pneumonia will manifest signs of delirium

- Tachypnea is the most reliable and earliest vital sign abnormality

- Classic symptoms are not often helpful at predicting severity of illness

- Symptoms are unreliable

- Cough (63-84%)

- Dyspnea (58-74%)

- Fever by history (53-60%)

- Fever at arrival (12-32%)

- Pleuritic chest pain (8-32%)

- Sputum (30-65%)

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Nursemaid’s elbow is a common pediatric injury with peak incidence occurring between two and three years of age.  It is a condition that typically arises from a sudden upward pull of the arm as an axial traction is placed on the forearm, and the radius is pulled through the annular ligament, resulting in subluxation of the radial head. Over the years, various maneuvers have been attempted, but the two most common are supination with flexion and hyperpronation. A 2017 Cochrane meta-analysis analyzed 8 trials specifically comparing supination with flexion versus hyperpronation.  Data from those trials suggested that hyperpronation resulted in less failures at ?rst attempt than the supination-?exion, and although there was limited data, there was no obvious difference in adverse events or pain between the two techniques.

Bottom Line: There is likely a lower risk of failure with first attempt reduction with hyperpronation than with supination-flexion for nursemaid’s elbow.

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Despite initial excitement for the use of intravenous lipid emulsion (ILE) therapy as an antidote for serious poisonings due to lipohphilic drugs there remains an absence of evidence combined with an incomplete understanding of its efficacy, mechanisms of action, safety, and analytical interferences to recommend its use except in a few clinical scenarios.

The lipid emulsion workgroup performed a comprehensive analysis of four systematic reviews and based recommendations from consensus of expert panelists from the American Academy of Clinical Toxicology, the European Association of Poison Centres and Clinical Toxicologists, the American College of Medical Toxicology, the Asia Pacific Association of Medical Toxicology, the American Association of Poison Control Centers, and the Canadian Association of Poison Control Centers. Toxins evaluated had to have a minimum of three human cases reported in the literature.They concluded that ILE could be indicated for the following clinical situations:

•  In Bupivacaine poisoning resulting in cardiac arrest or life threatening toxicity (dysrhythmias, VTach  with compromised organ perfusion, VFib, status epilepticus, and/or hypotension with organ compromise defined as  increased lactate concentration, acute kidney injury, increased troponin, altered mental status, or decreased capillary refill) ILE is recommended after standard ACLS is started  and if other therapies fail or as last resort.

• In life-threatening toxicity due to other local anesthetics,  ILE recommended if other therapies fail/in last resort

• In cardiac arrest due to toxicity from Amitriptyline (or other tricyclic antidepressants), lipid soluble and non-lipid soluble Beta-receptor antagonists,  Bupropion, Calcium channel blockers (diltiazem, verapamil and dfihydropyridines), Cocaine, Diphenhydramine, Lamotrigine,  Baclofen, Ivermectin and other Insecticides, Malathion and other Pesticides, Olanzapine and other Antipsychotics, and SSRIs.

• Most common regimen of ILE was a bolus of 1.5 mL/kg of ILE 20% followed by infusion of 0.25 mL/kg/min

• The use of ILE with extracorpeal membrane oxygenation may cause fat deposition in the circuit and increase blood clot formation causing malfunction and limitation of use of this potentially life saving modality. This should be considered if VA-ECMO is a treatment option.

The Bottom Line:

The use of Intravenous Lipid Emulsion in severe poisoning is recommended only for a few poisoning scenarios and was based on very low quality of evidence, and consideration of risks and benefits, adverse effects, laboratory interferences as well as related costs and resources.

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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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Exercise talking points for the pregnant patient

(from ACSM 2017 Consesnsus statement)

Exercise throughout pregnancy is generally safe but should be monitored

No evidence of higher rates of preterm or prolonged labor, or deliveries that require induction or episiotomy

No evidence of negative effect on APGAR scores

Other benefits:

Avoidance of excessive weight gain, improved balance, and decreased back pain

Improved well-being, energy levels, and sleep patterns

Improved labor symptoms and facilitation of post-partum recovery

Lower risk of C-section

Reduced risk of having a large for gestational age (LGA) or small for gestational age (SGA) infant

Risks include environmental exposure, dehydration, hypoxia, and uterine trauma:

High impact or high-strain physical activity during the fetal implantation phase may lead to slightly higher risk of miscarriage

Sports with high risk of trauma last in pregnancy could result in placental abruption

Scuba diving is contraindicated because the fetus is not protected from decompression problems

Limit use of sauna or hot tub to fewer than ten minutes or omit altogether

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Non-pharmaceutical fentanyl (NPF) is a major contributor to opioid overdoses and overdose fatality. In certain urban areas such as Vancouver, over 80% of heroin samples contain NPF.  For isolated heroin overdose ED patients, they can be safely discharged after brief observation period (~2 hours). However,  “safe” observation time for fentanyl is unknown.

Recently, a retrospective study evaluating the safe observation period in 1009 suspected (uncomplicated) fentanyl overdose ED visits (827 unique patients).

Results:

 In the field:

• 476 (47.1%) received bystander naloxone
  • 422 (44.1%) had field GCS of 15
  • 547 (57.2%) had pulse oximetry of >= 95%.
•  EMS administered naloxone to 546 (57.1%) patients (mean dose 0.4 mg IV)

In the ED:

• 16 patients received additional naloxone in the ED
• Mean length of stay: 173 minutes (IQR: 101 to 267 minutes)
• 90% of the patients were discharged within 380 minute.
• One patient was admitted and one patient died after discharge within 24 hours.

Conclusion:

• Majority of the patients were safely discharged after 3 - 4 hours after receiving naloxone and if able to maintain GCS 15 with oxygen level 95% while able to ambulate normally.
• However, some patient may require up to 6 hours of observation.  

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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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Unsuccessful lumbar punctures (LP) may lead to epidural hematoma (EH) formation at the site of needle insertion which may affect subsequent attempts and lead to no success or a grossly bloody sample.  There is no standard definition of a traumatic LP based on CSF red blood cell counts.  Gross blood may also be obtained by interrupting the vascular structures outside the spinal canal which would not result in EH formation.

This was a prospective study of children younger than 6 months who had an LP at a single children’s hospital.  Post LP ultrasounds were completed by the investigating team and interpreted by a pediatric radiologist. 74  patients were included in the study.  31% of the patients had evidence of a post LP EH.  17% fully effaced the thecal sac which would likely preclude future success at that anatomic site.  25% of patients where the clinician did not feel there was a traumatic attempt had evidence of an EH.The study was not powered to determine the risk factors for EH formation.  The study also did not look at any other consequences to EH.

Key points: Point of care ultrasound to evaluate EH and bleeding at the failed LP site my provide useful information for a location of subsequent attempts.  Also US to evaluate for bleeding in the spinal canal may help with interpretation of the CSF when a large number of red blood cells are present.  

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Bradycardias caused by poisoning are due to the toxin's effects on cardiovascular receptors and cellular channels and transport mechanisms and are often refractory to standard ACLS drugs. The most common drug classes responsible for bradycardias are calcium channel and beta blockers and digoxin (cardiac glycosides). Sodium channel blockers, clonidine, and opiates also can cause bradycardias. Antidotes are as follows:

• Glucagon 5-10mg IV bolus followed by 1-5 mg/hr (Always pretreat with antiemetic) - Beta Blockers
• Calcium infusion 1-3 grams IV Bolus - Calcium Channel Blockers
• High Dose Insulin Euglycemic therapy of reg insulin 0.5-2 unit/kg Bolus (ie. 100 Units) with D50 IV bolus followed by reg insulin 0.5-1 units/kg/hr and dextrose 0.5 grams/kg/hr - Calcium channel and Beta Blockers
• **Intravenous Lipid Emulsion therapy bolus 1.5 mL/kg of ILE 20% followed by an infusion of 0.25 mL/kg/min-  Very small subset of toxins. See below.
• Atropine 2mg IV - Acetylcholinestrase inhibitors (Organophosphates)
• Sodium Bicarbonate 1-3 amps IV - Sodium Channel Blockers
• Digibind  for acute toxicity10 vials IV (20 Vials in cardiac arrest) and for chronic toxicity 2 vials and repeat as needed - Cardiac gylcosides
• Narcan 2 mg IV repeat boluses up to 10 mg- Opiates and Clonidine

** ILE is recommended only in life threatening poisonings where other accepted therapies have been use first or in cardiac arrest clinical scenarios. 

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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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Female Athlete Triad

1. Low energy availability
   1. With or without eating disorders
2. Menstrual dysfunction
3. Low bone mineral density (BMD)

Energy availability considers the amount of remaining energy for metabolic processes based on calories takin in with eating and calories burned through exercise or both.

Menstrual dysfunction occurs as a result of low energy availability causing decreased GnRH inhibition and ovarian suppression and decreased estrogen.

Low bone mineral density occurs due to amenorrhea and decreased energy availability. Estrogen limits bone resorption (stimulates calcitonin and renal calcium retention).

This is very important for young girls as by age 12 they have 83% of their total BMD & 95% two years after menarche.

If you see an athlete in the ED with one component of the triad, inquire about the other two. A 15yo athlete with a stress fracture may not realize that her disordered eating, excessive exercise or amenorrhea may by contributing factors and may benefit from follow up with PCP, dietitian, Gyn, etc.

Clonidine, (central alpha-2 receptor agonist) can produce opioid-like toxidrome in addition to its cardiac effects (bradycardia and hypotension). Previous studies have shown that naloxone has variable (~40%) success in reversing CNS/respiratory depression and cardiac effect.

A recent retrospective study (n=51) of pediatric poisoning showed that administration of 5 to 10 mg had improved reversal of clonidine toxicity.

Total of 51 somnolent patients: 5- 10 mg of naloxone reversed 40 patients

• 22 patients awoke with 6 mg or less
• Bradycardia reversed in 17 of 44 patients
• Hypotension reversed in 7 of 11 patients

There was no adverse effect from naloxone administration.

Repeat administration of naloxone was required in some patients.

Bottom line

• For pediatric clonidine toxicity, consider initial naloxone dose of 5 mg IV. 

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In the past couple of weeks, there have been reports from Illinois about patients using adulterated synthetic cannabinoids, resulting in elevated INR and bleeding. To date, there are approximately 70 cases including 3 fatalities. Brodifacoum, a long-acting vitamin K mediated anticoagulant (similar to warfarin) has been identified in 10 cases. Brodifacoum is frequently used as rodenticide.

This week, Maryland Poison Center received our first notification of a patient with bleeding and elevated INR due to suspected adulterated synthetic cannabinoid use.

When evaluating our patient population:

• Ask about synthetic cannabinoid use in patients with unexplained bleeding and elevated INR
• Carefully examine patients with synthetic cannabinoid intoxication for any signs of bleeding, bruising or petechiae.  
   

Patient management of suspected cases:

• ACTIVELY bleeding:
  • Fresh frozen plasma
  • Activated prothrombin complex concentrate (KCentra®) in life threatening bleeding.
  • Vitamin K 10 mg IV
  • *** Start oral vitamin K at 50 mg TID and titrate to goal INR < 2 ***
• NOT bleeding and INR < 10: vitamin K 50 mg PO BID with titration if needed.
• NOT bleeding and INR > 10: vitamin K 50 mg PO TID with titration if needed.

Patient can be discharged when INR < 2 is achieved with oral vitamine K regimen only (without recent FFP infusion).

Review of published cases highlights that most patients are started on a median doses of 100 mg/day (range: 15 - 600 mg) and stabilize on a PO regimen of 50-100 mg/day. Prolonged PO vitamin K course of 2 – 3 months or longer should be anticipated.

Pease call the Maryland Poison Center at 1-800-222-1222 as we are working with the Maryland Department of Health and CDC to track these cases. 

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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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25% of U.S. health care spending goes to the 6% of people who die every year. ICUs account for 20% of all health care costs. A new study has shown that patients with POLST (Physician Orders for Life-Sustaining Treatments) forms are less likely to receive unwanted life sustaining treatments when compared to patients with traditional Do-Not-Resuscitate orders (http://www.ohsu.edu/polst/). Using the POLST did not impact the degree of comfort care received for symptom management and helped individuals make more informed choices about the type and level of end-of-life care they wish to receive.

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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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• Stevens-Johnsons like rash and mucositis
• Most common in children and adolescents, with a mean age of 12 years old
• More common in males than females, 2:1
• Prodromal symptoms of cough, fever, and malaise precede
• Mucositis far out of proportion to body rash, 90% vs 10%
• Mucositis is primarily oral > ocular > genital in distribution, and can be severe
• Body rash may involve palms and soles
• Complications: dehydration, GIB, epiglottitis, blindness, pericardial effusion
• Testing: PCR nasal wash/BAL; agglutination assays IgM/IgG
• Treatment: azithromycin and supportive care; occasionally steroids; rarely IVIG
• Unlike Stevens-Johnsons, prognosis is good.