Background: It is estimated that nearly 6% of U.S. adults and children report having a food allergy.1,2 Epinephrine autoinjectors are used to provide life-saving pre-hospital treatment for patients experiencing anaphylaxis in the community, but can have serious consequences if administered incorrectly. Accidental finger-stick injuries with epinephrine auto-injector can result in significant pain and ischemia due to vasoconstriction and decreased blood flow to the digit. Treatments for digital epinephrine injection include supportive care, topical vasodilators, and injectable vasodilators.3
Supportive care3,4:
DOACs (dabigatran*, apixaban, rivaroxaban) each have different dosing strategies based on indication and patient characteristics. While there is no official term for the doses, the higher initial doses for apixaban (10 mg BID for 7 days) and rivaroxaban (15 mg BID for 21 days) for the treatment of venous thromboembolism (VTE) are commonly referred to as “loading doses.” However, the term “loading dose” is actually a misnomer.
Loading doses are used to reach therapeutic drug levels quicker with medications such as vancomycin and phenytoin/fosphenytoin. However, this is not the purpose of the higher initial doses of apixaban and rivaroxaban. The purpose of the higher doses is to provide increased levels of anticoagulation during the acute phase of VTE when patients are hypercoagulable. For this reason, VTE and heparin-induced thrombocytopenia are the only indications where a higher dose is used initially, all other indications start with the standard dose. The difference in duration of these higher doses between apixaban (7 days) and rivaroxaban (21 days) are due to the durations used in trials by the drug company, versus any pharmacokinetic reasons.
To apply this concept:
Apixaban/Rivaroxaban: For the treatment of VTE, a higher dose is only required for the initial 7- (apixaban) or 21-day period (rivaroxaban). After this period, if there is any interruption in therapy, the standard dose can be restarted because therapeutic levels are rapidly achieved and higher doses are not needed outside of the acute phase.
One caveat to this would be if the patient developed a new VTE while therapy is interrupted, in which case another period of the higher dosing could be considered.
*Remember: Dabigatran cannot be used for initial treatment of VTE and must be started only after at least 5 days of a parenteral anticoagulant. (Dabigatran and the parenteral anticoagulant should not be overlapped).
ACLS guidelines state that thrombolytics may be considered for suspected pulmonary embolism during cardiac arrest. There is limited data supporting the recommendation; however, it is noted that the benefits likely outweigh the risks. There is also no consensus on the appropriate thrombolytic timing, drug, or dose.
Our institution recently implemented the use of tenecteplase for acute ischemic stroke, ST-elevation myocardial infarction (STEMI), and pulmonary embolism (PE). When using tenecteplase for suspected PE during cardiac arrest, we use the same weight-based dose used for STEMIs. We include a label on the outside of the tenecteplase box that lists all the doses for the various indications.
Tenecteplase Dose
<60 kg: 30 mg
≥60 to <70 kg: 35 mg
≥70 to <80 kg: 40 mg
≥80 to <90 kg: 45 mg
≥90 kg: 50 mg
The tenecteplase dose is administered as an IV bolus over 5 seconds.
There is also limited data for the duration of CPR after thrombolytic administration, with no recommendations being made in most literature. Our current institutional guidelines recommend to consider continuing CPR for 60-90 minutes before resuscitation efforts are terminated. The only guideline that makes any mention of duration of CPR is the European Resuscitation Council Guidelines 2021, which makes the same recommendation.
Citrate is an anticoagulant added to blood products to maintain stability for storage. With the administration of large volumes of blood products, citrate binds to ionized calcium, which can cause hypocalcemia. Evidence for specific calcium administration during massive transfusion protocols is limited; however, a proposed strategy has been to administer calcium gluconate 2 grams for every 2-4 units of red blood cells.
Robinson, et al. performed a retrospective analysis attempting to determine the optimal Citrate:Ca ratio (a novel ratio created for this study) to reduce 30-day mortality. They did not find any differences in mortality; however, they found a Citrate:Ca ratio of 2-3 produced a normalized ionized calcium level with 24 hours of a massive transfusion protocol.
Based on their calculations, this would equate to supplementing 1 g of calcium gluconate for every 3 units of red blood cells given.
***Reminder: Based on the amount of elemental calcium in each gram of calcium gluconate (4.7 mEq) and calcium chloride (13.6 mEq); 3 g calcium gluconate=1 g calcium chloride.***
Bottom Line: Supplementing with calcium gluconate 1 g for every 3 units of red blood cells should be sufficient to maintain normal ionized calcium levels after a massive transfusion protocol.
Nitroglycerin easily migrates into polyvinyl chloride (PVC), a plastic commonly used in intravenous tubing due to its flexibility and low cost. A slow rate of flow and long tubing length increase the loss of nitroglycerin. While using less absorptive tubing (i.e. polyethylene or polypropylene) when administering nitroglycerin is recommended, most published clinical studies looking at nitroglycerin have used PVC tubing.
A 1989 study compared nitroglycerin delivery through PVC tubing and low sorbing tubing at various concentrations and flow rates.1 Samples were obtained from the nitroglycerin bottle and the distal end of the tubing at several time points.
A 2018 study enrolled 8 volunteers to receive nitroglycerin infusions through PVC tubing and low sorbing polyolefin tubing.2
Bottom Line: Most studies evaluating nitroglycerin use in various clinical scenarios have used PVC tubing. Doses based on use with PVC tubing may be too high when using less absorptive tubing. Employing more conservative dosing strategies when using low sorbing tubing can help mitigate the risk of adverse effects (i.e. hypotension, headache).
Emergency contraception is highly effective at preventing unwanted pregnancies and has been on the market for 20+ years.
Levonogestrel (LNG) 1.5 mg PO x 1 dose (OTC Available)
Ulipristal acetate (UPA) 30 mg PO x 1 dose (Requires RX)
Original studies with LNG was estimated to prevent up to 80% of expected pregnancies. In the subsequent trials that brought UPA to the market and compared the two medications, LNG prevented 69% (95% CI, 46-82%) and 52.2% (95% CI, 25.1-69.5%).
While pregnancy rates are low with both options there is concern with patients of higher weight/BMI that the effectiveness of levonorgestrel decreases as weight rises. One large study of over 1700 patients specifically noted that a weight > 75 kg was associated with up to 6.5% pregnancy rate (95% CI 3.1-11.5) compared to 1.4% (95% CI 0.5-3.0) in patients weighing 65-75 kg. Patients weighing > 85 kg had similarly high rates at 5.7% (95% CI 2.9-10.0).
The cost difference is minimal between products, especially when considering costs associated with treatment failures and subsequent need for care- the largest difference is with respect to access as LNG is OTC and UPA requires an RX. Either can be administered in an ED setting as long as they are on formulary.
ACOG also recommends that ulipristal be utilized for it higher overall efficacy compared to levonorgestrel.
Consider:
For patients above 75 kg, ulipristal can be used as first line emergency contraception for up to 5 days following unprotected intercourse.
Patients < 75 kg and < 72 hours following unprotected intercourse can use levonorgestrel or ulipristal as an appropriate emergency contraception method.
Patients < 75 kg and 72-120 hours following unprotected intercourse should use ulipristal due to its efficacy beyond 72 hours.
Myasthenia gravis is an autoimmune disease of the neuromuscular junction, most commonly due to antibodies attacking acetylcholine receptors in the postsynaptic membrane. Up to 30% of patients with myasthenia gravis will experience a myasthenic crisis during their disease course. If rapid sequence intubation is indicated, the unique characteristics of this patient population must be considered in the event use of a paralytic is necessary. All paralytic agents can be expected to last significantly longer, and an unpredictable response may be seen with depolarizing agents - therefore non-depolarizing agents are preferred in this population.
Non-Depolarizing Agents (Rocuronium, Vecuronium)
Depolarizing Agents (Succinylcholine)
Non-dihydropyridine calcium channel blockers, verapamil and diltiazem, can induce hypotension when administered intravenously (IV) in approximately 4% of patients. It has previously been taught that administering IV calcium before administering these medications may prevent the hypotension. Previously, this theory was tested for verapamil and found success with reducing hypotension. Only one study has been done exclusively with diltiazem and it found no benefit.
In a new multicenter retrospective cohort study of adults in the ED, patients were randomized into two groups: those who received diltiazem alone and those who received calcium with diltiazem for atrial fibrillation/atrial flutter (AF/AFL) with a HR ≥ 120 bpm. Patients were excluded if they required electrocardioversion, had other agents prior to diltiazem, incomplete information, were pregnant or incarcerated. The primary outcome was change in SBP 60 minutes (+/-30 minutes) after diltiazem administration.
Baseline characteristics: 73 year old, equal male:female, predominantly white patients. 40% had new onset AF/AFL and the initial HR was 140 in both groups. There were 198 patients in the diltiazem group and 56 patients in the combination group. Notably, patients in the combination group had a lower presenting SBP 109 (101-121) vs 123 (114-132) P<0.0001 which matches classical teaching for when to consider calcium use. Additionally, patients in the combination group received a lower diltiazem dose of 10mg vs 15mg in the monotherapy group p=0.004 with both group receiving doses lower than the standard 0.25 mg/kg dosing recommendation.
Outcomes:
Take Home Point:
Administration of IV calcium may not be as beneficial as previously thought to prevent hypotension induced by diltiazem administration. This particular study is confounded by the relatively low doses of diltiazem overall, but utilizing a lower dosing strategy in patients with low SBP is a reasonable safety strategy.
ACE-inhibitor (ACEi) induced angioedema is mediated by bradykinin and there are no proven medications for the treatment of this disease. Theoretically, a C1-esterase inhibitor (C1INH) could be beneficial; however, data has not demonstrated any efficacy for these agents.
Strassen et al. recently published a double-blind, randomized, controlled, multicenter trial of 30 patients comparing C1NH (Brand Name: Berinert) to placebo. In addition to standard treatment, a dose of C1INH (Berinert) 20 IU/kg or placebo (0.95% NaCl) was administered intravenously.
The primary endpoint was the time to complete resolution of signs and symptoms of edema (TCER). When compared to placebo, the original primary analysis demonstrated that the placebo arm (15 hours) resolved faster than the C1INH arm (24 hours, p=0.046).
This study is further evidence against the use of C1INH for ACE-inhibitor induced angioedema. The primary focus in the treatment of ACEi induced angioedema should continue to be airway management.
For reference, at our institution we have both C1INH (Berinert) and icatibant on formulary and they are restricted to only being used for acute hereditary angioedema attacks and cannot be used for ACEi induced angioedema.
Magnesium has been associated with function of serotonin and vascular tone regulation, both of which are mechanisms that implicate there may be a role in treatment of migraine. As this is a well-tolerated medication with a good safety profile, there is interest in utilizing this medication in the treatment of migraines. However, studies comparing magnesium to standard migraine treatments are lacking.
A recent single-center, double-blinded, randomized controlled trial compared magnesium, metoclopramide and prochlorperazine for treatment of migraine in the ED. Patients received either magnesium sulfate 2 grams, metoclopramide 10 mg or prochlorperazine 10 mg intravenously over 20 minutes. Adjunctive and rescue medications could be used at the providers discretion.
Pain was assessed with the 11-point Numeric Rating Scale at baseline and at several timepoints after completion of the infusion. Median change in pain score was found to be -3 in all groups at 30 minutes. Post-hoc analysis found magnesium to be non-inferior to prochlorperazine and metoclopramide at this time point. No difference in ED length of stay was found between groups. Adverse events were reported in 5% of patients receiving magnesium, 4.5% in patients receiving metoclopramide and 11.5% in prochlorperazine patients (p = 0.51). The most common adverse events were dizziness, akathisias, and anxiety.
Bottom Line: Magnesium can be used as an adjunctive agent in the treatment of migraines, and may also be considered as an alternative agent when other options such as prochlorperazine and metoclopramide are not appropriate. A reasonable dose would be 2 grams IV infused over 20 minutes. The team should follow-up 30-60 minutes after infusion to assess response to therapy.
Over half of U.S. adults in the United States consume dietary supplements.
Study design: A quality improvement study using data from the FDA’s Center for Drug Evaluation and Research, Tainted Products Marketed as Dietary Supplements
Dates: 2007 through 2016.
Results: Unapproved pharmaceutical ingredients were identified in 776 dietary supplements.
146 different dietary supplement companies were involved.
Most of these products were marketed for sexual enhancement (353 [45.5%]), weight loss (317 [40.9%]), or muscle building (92 [11.9%].
157 adulterated products (20.2%) contained more than 1 unapproved ingredient.
A 2015 NEJM study estimated that 23,000 ED visits per year are attributed to adverse effects associated with dietary supplements.
Estimated 2154 hospitalizations annually.
Frequently involve young adults between 20 and 34 years of age in addition to unsupervised children.
Excluding children, almost 66% of ED visits involve herbal or complementary nutritional products and 31.8% involved micronutrients.
Products for weight loss or increased energy were commonly implicated.
Finally, herbal and dietary supplements now account for 20% of cases of hepatotoxicity in the US.
The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements.
Anabolic steroids (marketed as bodybuilding supplements) typically induce a prolonged cholestatic, self-limiting liver injury.
Green tea extract and many other products, in contrast, tend to cause an acute hepatitis like injury.
Sugammadex works by chelating non-depolarizing neuromuscular blocking agents (NMBA) such as rocuronium and vecuronium to reverse the effects of paralysis. Dosing per package insert varies based on time from administration of the NMBA, and side effects, although rare, include severe bradycardia, hypotension, and asystole. While sugammadex is routinely used by our anesthesia colleagues, it is rarely utilized in the emergency department (ED) or intensive care unit (ICU) setting.
A recent single-center study assessed 11 patients with either a traumatic brain injury (TBI) or intracranial hemorrhage (ICH) who received sugammadex for neurologic assessment in the ED or ICU. The median dose was 240mg and the median time since last NMBA administration was 101 minutes.
In 6/11 patients, the neurosurgical plan changed and it affirmed a poor prognosis in 3/11 patients. In the ICU patients, sugammadex was associated with reduction in unnecessary tests.
All patients had a GCS of 3T prior to administration and 67% responded to sugammadex with a median increase to 8T (P=0.0156). MAP reductions were common with a median of -8 mmHg.
Bottom Line: Sugammadex can assist in determining a neurosurgical or clinical prognosis plan in patients with TBI and ICH. Larger studies are needed in this patient population and caution should be used inpatients who are already hypotensive or bradycardic. A reasonable dose, especially when given >1h from intubation would be 200mg. The team should be available at administration to note changes in GCS.
Piperacillin-tazobactam is one of the most commonly used antipseudomonal antibiotics in the empiric management of patients with septic shock. The package insert recommends dose reductions for renal impairment in other infectious etiologies, but the impact of dose reduction has not been previously studied in patients with septic shock.
A recent retrospective, observational cohort study compared outcomes of patients with septic shock who received ≥ 27 grams (at least 3.375 gm q6 hours x 48 h-“NORM”) versus those who received < 27 grams (“LOW”) over the initial 48 h of septic shock (defined as concomitant norepinephrine infusion).
Patients were excluded if they had death or hospice disposition within the 48h study period. The primary outcome was the number of norepinephrine free days (NFD) at day 28. Propensity matching was utilized to account for confounders.
Results: 351 in the LOW group, 928 in the NORM group with 608 pairs in the propensity matched assessment.
Bottom Line: Dose reductions of piperacillin-tazobactam appears to be harmful early in the management of patients with septic shock.
Intraosseous (IO) administration uses bone marrow to deliver fluids and medications during cardiac resuscitation or other emergent situations where IV access cannot be established.
IV versus IO
Considerations When Using IO Access
Prior studies have found that patients are at an increased risk for hypoglycemia when administered insulin for the acute management of hyperkalemia when they have renal dysfunction. A new single-center, retrospective study investigated the risk of hypoglycemia and the overall effect of potassium lowering in patients with renal dysfunction and stratified outcomes based on the CKD level.
Patients were included if they were ordered insulin for hyperkalemia using a hospital driven order set and had CKD stages 3a, 3b, and 4. They were excluded if they had dialysis within 6h of insulin administration, had DKA, or no repeat labs. The hospital order set encourages 5 units of insulin instead of 10 when “renal failure” is present without clear guidance.
377 patients were included: 186 received 5 units and 191 received 10 units. The average age was 65 years old, predominantly male, weighing 90 kg. In the 5 unit group, significantly more patients had CKD stage 4 (60% v 30%) and in the 10 unit group, significantly more patients were CKD stage 3a (p<0.001). The baseline serum potassium was 6 in each group.
The hypoglycemia incidence was not different between groups, with severe hypoglycemia occurring twice per group. All patients received dextrose according to the protocol.
There was a significant difference in the reduction of serum potassium between the 5 and 10 unit groups: -0.63 mmol/L vs -0.9 mmol/L (p 0.001).
Bottom line: Hypoglycemia occurred even with insulin dose reduction. Potassium lowering was higher in patients who received the 10 unit dose.
A recent prospective cohort study investigated the effect of low-dose droperidol on QTc in an emergency department:
Low-dose droperidol has a small effect on QTc and most patients remained below 500 ms.
Diphenhydramine (B) has historically been utilized in combination with haloperidol 5mg (5) and lorazepam 2mg (2) in the treatment of acute agitation. The most common rationale for adding diphenhydramine is prevention of EPS, however literature to support this is lacking. A recently published paper examined diphenhydramine/haloperidol/lorazepam combination (B52) vs haloperidol/lorazepam combination therapy (52) to compare the need for additional agitation treatments as a surrogate for clinical efficacy.
This retrospective, multicentered noninferiority study included 400 emergency medicine patients, 200 per treatment arm. On average, the patients were 40 years old, 64% male, and predominantly Caucasian. More patients in the B52 group had psychiatric illness listed as their primary cause for agitation compared to the 52 group. The two most frequently reported substances on urine drug screens, if collected, were amphetamines (35%) and cannabinoid (35.5%).
Results:
-No difference in the use of additional agitation medications within 2 hours
-More patients in the 52 group were noted to receive anticholinergic medications within 2 days, but indications varied and were not associated with EPS treatment
The B52 combination was associated with:
---Increased length of stay 17 h (10-26) vs 13.8 h (9-12), p = 0.03
---Increased use of restraints 43% vs 26.5%, p = 0.001
---Hypotension 16% vs 3.5%, p <0.001
---Use of nasal canula oxygen 3% vs 0%, p < 0.01
The addition of diphenhydramine may not be necessary to prevent EPS in patients receiving haloperidol for agitation and is associated with increased length of stay and adverse events, likely due to its additive sedative properties.
Background:
Multisystem inflammatory syndrome in children (MIS-C) as defined by CDC Health Advisory in May 2020 is:
1) An individual aged <21 years presenting with fever*, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
2) No alternative plausible diagnoses; AND
3) Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.
*Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
**Including, but not limited to, one or more of the following: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
As of January 31st, 2022 the CDC reports the following statistics related to MIS-C in the United States:
· Total MIS-C patients meeting case definition= 6,851
· Total MIS-C deaths meeting case definition = 59
· The median age of patients with MIS-C was 9 years. Half of children with MIS-C were between the ages of 5 and 13 years.
· 59% of the reported patients with race/ethnicity information available occurred in children who are Hispanic/Latino (1,746 patients) or Black, Non-Hispanic (2,050 patients).
· 98% of patients had a positive test result for SARS CoV-2, the virus that causes COVID-19. The remaining 2% of patients had contact with someone with COVID-19.
· 60% of reported patients were male.
Management:
First-Line Treatment:
· IVIG 2 g/kg dosed based on ideal body weight with a maximum of 100 grams (1000 mL)
o For patients with significant myocardial dysfunction and concern for fluid overload, the infusion can be given in divided doses over 2 days (1g/kg q12 x 2 doses)
PLUS
· Methylprednisolone 1 mg/kg (max of 30 mg/dose) IV twice daily and switch to PO and taper when clinically appropriate
Upon Consultation with Pediatric Hematology/Cardiology will consider adding the following therapies to IVIG and steroids:
· Enoxaparin treatment versus prophylactic dosing depending on D-dimer elevation and whether or not being admitted to PICU
· Aspirin 3-5 mg/kg (max 81 mg/dose) daily unless platelet count < 80 K/mcl
Second-Line Treatment (refractory to IVIG defined by symptoms and fever persisting >36 hours)*:
· Methylprednisolone pulse dosing- 30 mg/kg (max of 1000 mg/dose) x 3-5 days
OR
· High dose anakinra
OR
· Infliximab 5-10 mg/kg IV x1
*All second-line treatment options require peds infectious diseases and PICU attending approval
UMMS COVID/MIS-C Pathway: https://intra.umms.org/-/media/intranets/umms/pdfs/dept/pharmacy-and-therapeutics/guidelines/umms-pediatric-covid-pathway.pdf?upd=20220125144550
Calcium is commonly administered during cardiac arrest, but there is little data to support or refute its use. The Calcium for Out-of-Hospital Cardiac Arrest trial was a randomized, double-blind, placebo-controlled parallel group study conducted in Denmark. Their EMS system responds to all cardiac arrests with an ambulance and a physician-manned mobile emergency care unit.
Adult patients were included if they had out of-of-hospital (OOH) cardiac arrest and received at least 1 dose of epinephrine. Exclusion criteria were traumatic arrest, known or suspected pregnancy, prior enrollment in the trial, receipt of epinephrine from an EMS unit not in the trial, or a clinical indication for calcium during the arrest (i.e. hyperkalemia or hypocalcemia).
Patients received 735mg calcium chloride dihydrate (5 mmol CaCl –US standard product is 1000mg) or saline control immediately after the first dose of epinephrine. A second dose was administered after the second dose of epinephrine if cardiac arrest ongoing. Teams were blinded to the treatments. The primary outcome was ROSC for at least 20 minutes.
397 patients were randomized (197 calcium, 200 saline). The average age was 68 years old, 70% were male, and over 80% of the cardiac arrests occurred at home, 60% witnessed arrests, and 82% received bystander CPR. Only 25% were in a shockable rhythm. The time to first epinephrine and study drug was approximately 17 minutes and over 70% received two doses.
ROSC rates were low and not statistically different between groups, 19% in the calcium group vs 27% in the saline group. There was no difference in survival to 30d or neurologic function. In the patients who did achieve ROSC in the calcium arm, 74% had hypercalcemia.
Bottom Line: The routine use of calcium in out-of-hospital cardiac arrest is not recommended.
Kcentra (four-factor prothrombin complex concentrate, 4f-PCC) is approved for the reversal of warfarin using a weight-based dosing strategy based on INR. However, since the approval of Kcentra, data has shown a fixed-dose strategy and use for direct-acting oral anticoagulants (DOAC) is appropriate. There are even recommendations to use a fixed-dose for DOACs in some situations. Utilizing a fixed-dose strategy can help with decreasing drug preparation/delivery times and costs.
Our institution now only uses a weight-based Kcentra dose of 50 units/kg for patients on DOACs with ICH or trauma-induced coagulopathy. All other patients receive a fixed-dose of Kcentra 1,500 units or 2,000 units based on anticoagulant and other criteria.
Below is a diagram summarizing our current dosing strategy for Kcentra at our institution.
ICH=intracerebral hemorrhage
DOAC=direct-acting oral anticoagulant (rivaroxaban, apixaban, and edoxaban)
Other points of interest at our institution:
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