The liver performs an essential role in the metabolism and clearance of many drugs. Liver damage due to cirrhosis can decrease first-pass metabolism of oral medications and increase free-drug concentrations of protein-bound medications due to decreased albumin production. In the absence of cirrhosis, patients with chronic hepatitis or hepatic cancer may only have a small decrease in drug clearance. Hepatic dose adjustments are not as prevalent or readily available as renal dose adjustments, which can create difficulty in finding the balance between pain relief and adverse effects.
The most common medications used for pain control in the emergency department are acetaminophen, NSAIDs, and opioids.
Acetaminophen
It is sometimes misconceived that acetaminophen should never be used in patients with cirrhosis due to the common knowledge that acetaminophen overdoses can cause hepatotoxicity. Alcoholics may have an increased risk of hepatotoxicity due to induction of CYP2E1 and decreased glutathione stores. However, acetaminophen is safe in patients with cirrhosis when used at appropriate doses. Limit the total daily dose of acetaminophen to 2 g daily in patients with cirrhosis and avoid acetaminophen in patients that are actively drinking. Also, educate patients that over-the-counter (OTC) and prescription medications may contain acetaminophen.
NSAIDs
In patients with cirrhosis, NSAIDs have increased bioavailability due to decreased CYP metabolism and decreased protein binding. In addition, prostaglandin inhibition can precipitate renal failure and sodium retention, worsening ascites and increasing the risk of hepatorenal syndrome, and increase the risk of gastrointestinal bleeding. Thrombocytopenia from NSAID use can further increase the risk of bleeding. Thus, avoid NSAID use in patients with cirrhosis. Topical NSAIDs can be considered.
Opioids
Opioid metabolism is altered in patients with cirrhosis and can contribute to complications with cirrhosis, such as precipitating encephalopathy. Generally, the bioavailability is increased and half-life is extended; thus, lower doses of immediate-release (IR) formulations at extended dosing intervals should be utilized. Common opioids for acute pain control in the emergency department are fentanyl, hydrocodone/oxycodone, hydromorphone, and morphine.
Take Home Points
| Drug/Class | Preferred Agent | Considerations |
| Acetaminophen | Max daily dose 2 g/day | Avoid if actively drinking. Be cautious if patient also taking OTC or combination products. |
| NSAIDs | None; Avoid | Topical NSAIDs may be considered. |
| Opioids | Hydromorphone, Fentanyl | Start with IR products at lower doses and extended intervals. |
Pain management can be challenging in patients with acute or chronic renal failure. Opioid medications should always be used with caution, but some are safer than others. Morphine and codeine specifically should be avoided in these patients due to accumulation of active metabolites that can prolong the duration of effect and adverse events.
| Opioid | Renal Failure Impacts | Renal Failure Recommendation | Dialysis Recommendation |
| Morphine | Active metabolites accumulate | | |
| Codeine | Active metabolites accumulate | | |
| Hydromorphone | Minimal active metabolites | | |
| Oxycodone | Minimal active metabolites | | |
| Fentanyl | No active metabolites | | |
| Methadone | Active metabolites are inactive | | |
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.
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.
Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality
A recent article published in JAMA Internal Medicine questioned the utility of empiric anti-MRSA pneumonia therapy. It was a retrospective multicenter cohort study conducted in the Veteran’s Health Administration healthcare system that looked at 88,605 patients with community-onset pneumonia. They compared 30-day mortality of patients hospitalized for pneumonia receiving empirical anti-MRSA therapy plus standard therapy against standard therapy alone. Secondary outcomes analyzed development of kidney injury and secondary infections with C. difficile, VRE, or gram-negative rods. They also analyzed subgroups: ICU admission, MRSA risk factors, positive MRSA surveillance test, and positive MRSA culture on admission.
Anti-MRSA Therapy: Vancomycin (98%), Linezolid (2%)
Standard Therapy: Beta-lactam + macrolide/tetracycline, or respiratory fluoroquinolone
Outcomes
Mortality: aRR=1.4 [95% CI, 1.3-1.5]
Kidney Injury: aRR=1.4 [95% CI, 1.3-1.5]
Secondary C. difficile: aRR=1.6 [95% CI, 1.3-1.9]
Secondary VRE: aRR=1.6 [95% CI, 1.0-2.3]
Secondary gram-negative rods: aRR=1.5 [95% CI, 1.2-1.8]
Mortality in Subgroups
ICU: aRR=1.3 [95% CI, 1.2-1.5]
MRSA Risk Factors*: aRR=1.2 [95% CI, 1.1-1.4]
Positive MRSA Surveillance: aRR=1.6 [95% CI, 1.3-1.9]
MRSA Detected on Culture: aRR=1.1 [95% CI, 0.8-1.4]
*MRSA Risk Factors
-History of MRSA infection/colonization within the past year
-Or 2 of the following: previous hospitalization, nursing home residence, and previous intravenous antibiotic therapy
Take-Home Point
Empirical anti-MRSA therapy did not decrease mortality for any groups of patients hospitalized for pneumonia. Given that healthcare-associated pneumonia is no longer a definition supported by the IDSA/ATS, be judicious in your use of anti-MRSA therapy in community-onset pneumonia and reserve for those patients at higher risk for MRSA, such as those with post-influenza pneumonia.
Influenza is a common cause of community-acquired pneumonia and invasive bacterial coinfection may occur. In addition, secondary bacterial pneumonia due to MRSA is becoming more prevalent. Due to the higher incidence of MRSA, it is recommended that antibiotics with activity against MRSA (vancomycin or linezolid) be included in the empiric treatment regimen, especially if the patient is critically ill.
Take Home Point: Don’t forget to add MRSA coverage to your empiric treatment regimen in those influenza patients with severe disease or secondary bacterial pneumonia.
Adenosine is an atrioventricular nodal blocking agent that is commonly used in the treatment of supraventricular tachycardia. It is dosed as 6 mg IV Push x 1, followed by dose escalation to 12 mg IV Push if the initial dose was unsuccessful. In patients with central access or prior orthotopic heart transplantation, the initial recommended dose is 3 mg.
Due to its short half-life (< 10 seconds) it is imperative to administer in the most proximal access and follow with a 20 mL bolus of saline. Traditionally this is done using a two-way stopcock.
A new study compared single syringe (adenosine 6mg + 18 mL saline) vs two syringes (adenosine 6mg in one, 20 mL saline in the other) in 53 patients with SVT. The single syringe arm converted to NSR 73.1% after one dose compared to 40.7% in the two-syringe arm (p=0.0176). After up to three doses, the single syringe arm had 100% conversion compared to 70.4% in the two-syringe arm (p=0.0043).
Single syringe adenosine has been recommended in FOAM for several years. Although small, this study is the first to compare the two methods. This method simplifies administration and may improve cardioversion rates.
Phenytoin can be a complex medication. There are different levels than can be ordered, adjustments based on albumin, various pharmacokinetic equations, and multiple formulations. Below are the simplified answers to some of the most common questions (see in-depth section for explanations):
Which phenytoin level (free or total) do I order?
Total Phenytoin Level.
What do I do after the level results?
Undetectable Level: Load patient with 20 mg/kg of total body weight (max dose 1,500 mg).
Subtherapeutic Level (<10 mcg/mL): Calculate an approximate loading dose using this equation….Phenytoin Dose (mg)=(15-measured total level)*(0.7*patient weight).
Therapeutic Level (10-20 mcg/mL): Add an additional agent.
Supratherapetutic/Toxic Level (>20 mcg/mL): Contact Poison Center (1-800-222-1222).
What formulation do I order for loading?
IV: Use fosphenytoin.
PO: Any formulation will work. Give as a single loading dose or, if concerned for GI upset, give in 2-3 divided doses separated by 2 hours.
***Disclaimer: These answers are simplified for the initial management of most patients in the ED. More complex answers may be required in some situations.***
Droperidol is a butyrophenone with primary action as a dopamine D2 receptor antagonist. Historically, it has been used to treat a variety of conditions from nausea and headaches to acute agitation. In 2001, the FDA issued a black box warning for risk of cardiac arrhythmias. Following this warning, droperidol was on national shortage for several years, further limiting its use.
Several months ago, droperidol returned to the US market and is available at some institutions. Below is a refresher on dosing and monitoring. Similar to haloperidol, droperidol can cause extrapyramidal symptoms. Consider pre-treatment with diphenhydramine.
Dosing Recommendations:
Nausea and vomitting: 1.25 mg IV
Headache: 2.5 mg IV, 5 mg IM
Acute agitation: 5mg IM/IV
QTc prolongation is still a concern, especially at higher doses. If using doses > 2.5mg, or using repeated doses, obtain an ECG to ensure safe use of this medication. If the QTc is greater than 440 msec for males or 450 msec for females, droperidol is not recommended. There is little data regarding the risk with lower doses. Utilize clinical judgement and assess patient risk factors.
The American Diabetes Association requires a plasma glucose concentration greater than 250 mg/dL to diagnose diabetic ketoacidosis (DKA). However, with the new diabetic agents this is not always the case. With the introduction of SGLT2 inhibitors (canagliflozin [Invokana], dapagliflozin [Farxiga], empagliflozin [Jardiance]) there have been reported cases of DKA and patients being euglycemic.
Take Home Point
Patients with a low/normal blood glucose can still have DKA. Especially if they are taking newer medications, such as the SGLT2 inhibitors.
Alteplase may be considered in some patients with a presumed or confirmed pulmonary embolism. Below is a list of the different patient populations and the associated alteplase dosing.
-Hemodynamically Stable/Submassive: Alteplase usually not indicated.
-Hemodynamically Unstable/Massive: Alteplase IV 100 mg as an infusion over 2 hours.
-Cardiac Arrest: Alteplase IV/IO 50 mg bolus over 2 minutes. Can repeat a second 50 mg bolus 15 minutes later if unable to achieve return of spontaneous circulation.
Continuous home infusion therapies of medications such as insulin, milrinone, dobutamine, and pulmonary hypertension medication such as treprostinil are becoming more common. As a result, you may see these patients present to the emergency room and need to know the basics for checking the pump.
These questions are very important to determine if you will need to order a replacement infusion bag and run it on a hospital infusion pump, or if the patient can safely remain on their pump during the initial medical evaluation.
Identifying serotonin syndrome in the emergency department can be difficult without an accurate patient history. Furthermore, the physical symptoms may look similar to many other disorders such as neuroleptic malignant syndrome and anticholinergic toxicity. If you remember the acronym SHIVERS, you can easily recognize the signs and symptoms of serotonin syndrome.
Shivering: Neuromuscular symptom that is unique to serotonin syndrome
Hyperreflexia and Myoclonus: Seen in mild to moderate cases. Most prominent in the lower extremities. This can help differentiate from neuroleptic malignant syndrome which would present with lead-pipe rigidity.
Increased Temperature: Not always present, but usually observed in more severe cases
Vital Sign Abnormalities: Tachycardia, tachypnea, and labile blood pressure
Encephalopathy: Mental status changes such as agitation, delirium, and confusion
Restlessness: Common due to excess serotonin activity
Sweating: Autonomic response to excess serotonin. This symptom can help differentiate from anticholinergic toxicity in which the patients would present with increased temperature but dry to the touch
Once serotonin syndrome is identified, it is important to discontinue all serotonergic agents, provide supportive care with fluids, and sedate with benzodiazepines. Sedation with benzodiazepines helps to decrease myoclonic jerks which also helps with temperature control. If patients are hyperthermic, they will require intensive cooling. Cyproheptadine, a potent antihistamine and serotonin antagonist, should also be administered. The initial dose of cyproheptadine in serotonin syndrome is 12mg which can be followed by 2 mg every 2 hours as needed for symptom control.
| Mechanism of Action | Tranexamic Acid (TXA) is an antifibrinolytic agent that is a competitive inhibitor of plasminogen activation, and a non-competitive inhibitor of plasmin Inhibits the breakdown of fibrin mesh allowing clot formation
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| When is it Indicated? | Epistaxis/Oral Bleeds/Fistula Bleeds
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| Trauma
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| Adverse Reactions |
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---Early antiviral treatment can shorten the duration of fever and illness symptoms, and may reduce the risk of some complications from influenza.
---Early treatment of hospitalized adult influenza patients with oseltamivir has been reported to reduce death in some observational studies.
---Clinical benefit is greatest when antiviral treatment is administered within 48 hours of influenza illness onset.
Antiviral treatment is recommended for patients with confirmed or suspected influenza who:
---are hospitalized;
---have severe, complicated, or progressive illness; or
---are at higher risk for influenza complications. (See below for in-depth information)
Oral oseltamivir is the recommended antiviral for patients with severe, complicated, or progressive illness who are not hospitalized, and for hospitalized influenza patients.
Treatment:
Doses: Oseltamivir 75 mg twice daily
Renal Impairment Dosing
CrCl >60 mL/minute: No dosage adjustment necessary
CrCl >30 to 60 mL/minute: 30 mg twice daily
CrCl >10 to 30 mL/minute: 30 mg once daily
ESRD undergoing dialysis: 30 mg immediately and then 30 mg after every hemodialysis session
Duration of Treatment:
Recommended duration for antiviral treatment is 5 days for oral oseltamivir. Longer daily dosing can be considered for patients who remain severely ill after 5 days of treatment.
Providing naloxone to patients at risk for opioid overdose is now standard of care. A retrospective study evaluated the rate of naloxone obtainment after standardizing the process for prescribing naloxone in the emergency department and dispensing from the hospital outpatient pharmacy.
55 patients were prescribed naloxone. Demographics: mean age 48 years old, 75% male, 40% primary diagnosis of heroin diagnosis, 45.5% were prescribed other prescriptions.
Outcomes:
Barriers identified included lack of ED dispensing program, cost of medication, even though cost is minimal and can be waived, and likely multifactorial reasons why patients did not present to pharmacy as instructed.
Take Home Points:
The most common methods of medication administration in the emergency department are oral, intravenous (IV), and intramuscular (IM). If the oral route is not available, if IV/IM are not necessary, or if obtaining IV access is challenging, intranasal (IN) medication delivery is a reasonable alternative. More concentrated products are preferred and a volume of 1 mL or less per nostril should be utilized. Below is a table of the commonly used medications used via the IN route.
| Drug | Concentration | Indication | IN Dose | Time to Peak Effect | Adverse Events |
| Fentanyl | 50 mcg/mL | Analgesia | 0.5-2 mcg/kg | 5 min | Nasal irritation, rhinitis, headache |
| Ketamine | 100 mg/mL | Analgesia, Agitation, Sedation | 3-6 mg/kg | 5-10 min | Poor taste, HTN, hypersalivation, agitation, emergence reaction |
| Lorazepam | 2 mg/mL | Agitation, Seizures | 0.1 mg/kg Max: 4 mg | 30 min | Poor taste, lacrimation, nasal/throat irritation |
| Midazolam | 5 mg/mL | Agitation, Sedation, Seizures | 0.1-0.4 mg/kg Max: 10 mg | 5-10 min | Same as lorazepam |
| Naloxone | 1 mg/mL | Opioid Reversal | 0.1 mg/kg Usual dose: 0.4-2 mg | 1-5 min | N/V, headache, withdrawal symptoms |
Clonidine is an alpha-2 agonist commonly used to treat hypertension. Clonidine can also be used to mitigate symptoms of opioid withdrawal as it easily crosses the blood brain barrier and reduces sympathetic effects.
When using clonidine for acute withdrawal or blood pressure control, oral tablets are the preferred route. Clonidine transdermal patches have slow absorption and take 2-3 days for the effect to be seen. Once removed, clonidine patches can provide therapeutic levels for up to 20 hours.
Bottom Line: If clonidine is needed acutely for your patient, select oral tablets and titrate to effect.
The Centers for Medicare and Medicaid Services (CMS) require broad spectrum antibiotics to be administered within 3 hours of presentation of sepsis to be in compliance with the sepsis measure.
Not only do the antibiotics that are chosen determine compliance with this measure, but the order in which antibiotics are given can also significantly affect compliance.
According to CMS, for combination antibiotic therapy, both antibiotics must be started within the three hours following presentation; however, they do not need to be completely infused within this time frame.
Combination therapy typically includes a monotherapy antibiotic (see list in detailed information below) plus vancomycin (daptomycin or linezolid could also be used).
So which antibiotic should be given first?
If a monotherapy antibiotic is given first within the 3 hours of presentation, then compliance for the sepsis measure is met. These antibiotics cover a broader range of bacteria and are typically infused over ~30 minutes, which allows plenty of time for your second antibiotic to be initiated.
If vancomycin is given first, compliance with this measure can become difficult. First, vancomycin has a narrower spectrum of activity and is not a monotherapy antibiotic. Second, vancomycin infusion rates range from 1 to 2 hours. Given that antibiotics are usually given after sepsis is flagged, this infusion rate only gives a short period of time for the second antibiotic to be initiated. Thus, vancomycin should almost always be the second antibiotic infused.
In addition, patients may also have limited intravenous access or antibiotics may not be compatible with resuscitation fluids. All of these factors together must be considered when trying to gain compliance with this measure.
Take-Home Point:
Administer monotherapy antibiotics (e.g. piperacillin/tazobactam and cefepime) prior to administering vancomycin in your septic patients to improve compliance with the sepsis measure.
