Local anesthetic systemic toxicity: A narrative review for emergency clinicians

a b s t r a c t

Introduction: Emergency clinicians utilize local anesthetics for a variety of procedures in the emergency depart- ment (ED) setting. Local anesthetic systemic toxicity (LAST) is a potentially deadly complication.

Objective: This narrative review provides emergency clinicians with the most current evidence regarding the pathophysiology, evaluation, and management of patients with LAST.

Discussion: LAST is an uncommon but potentially Life-threatening complication of local anesthetic use that may be encountered in the ED. Patients at extremes of age or with organ dysfunction are at higher risk. Inadvertent intra-arterial or intravenous injection, as well as repeated doses and higher doses of local anesthetics are associ- ated with greater risk of developing LAST. Neurologic and cardiovascular manifestations can occur. Early recog- nition and intervention, including supportive care and Intravenous lipid emulsion 20%, are the Mainstays of treatment. Using ultrasound guidance, aspirating prior to injection, and utilizing the minimal local anesthetic dose needed are techniques that can reduce the risk of LAST.

Conclusions: This focused review provides an update for the emergency clinician to manage patients with LAST.

Published by Elsevier Inc.

  1. Introduction

Local anesthetic systemic toxicity (LAST) is a severe complication of local anesthetic use, primarily affecting the cardiovascular and central nervous system (CNS) [1-6]. Beginning shortly after injection of the local anesthetic, LAST may present with a multitude of symptoms, including seizure, altered mental status, hypotension, dysrhythmias, acute respiratory failure, and cardiac arrest. The re- ported incidence of LAST is low, with events reported in 2 to 2.8 per 10,000 peripheral nerve blocks in recent literature [4-13]. Accu- rate data on morbidity and mortality related to LAST are limited. The 2019 American Association of Poison control centers National Poison Data System Annual Report documented 686 local anesthetic exposures in which LAST was considered, noting that almost half of such cases had no symptoms [12]. Of those patients with some

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, USA.

E-mail addresses: [email protected] (B. Long), [email protected] (W.J. Brady).

form of LAST, 36% developed minor symptoms, 14% had moderate symptoms, and 3.5% had severe symptoms. 0.4% of patients died as a result of LAST [12]. Similar data were documented in the 2020 re- port [13]. Therefore, it is important for emergency clinicians to be aware of this important complication.

  1. Methods

This narrative review provides a focused overview of LAST for emer- gency clinicians. The authors searched PubMed for English language ar- ticles from January 1, 1970 to February 28, 2022 using the keyword and Medical Subject Heading “local anesthetic systemic toxicity” OR “LAST” for production of this narrative review. Authors included retrospective and prospective studies, systematic reviews, meta-analyses, narrative reviews, clinical guidelines, case reports, and case series. non-English language articles were excluded. Article inclusion was determined by author review and consensus based on clinical relevance to ED evalua- tion and management. A total of 98 articles were determined to be of relevance to emergency clinicians by author consensus and included in this narrative review. 0735-6757/Published by Elsevier Inc.

  1. Discussion
    1. Pharmacokinetics and pathophysiology

Local anesthetics differ in several regards, including their acid disso- ciation constant (pKa), lipophilicity, and protein binding [14-20]. These factors, along with the vascular supply of the injection site, affect peak plasma concentration and the time required to achieve peak levels, all of which impacts the likelihood of developing LAST [3,15-17]. The lipo- philicity of the local anesthetic is associated with potency, and the pro- tein binding ability of an agent correlates to effective circulating levels of the agent [3,15-17]. Agents with higher protein binding have reduced free circulating levels.

Local anesthetics block cell membrane-based voltage-gated sodium channels, preventing sodium influx, subsequent depolarization, and generation of action potentials, primarily in the cardiac and central ner- vous system (CNS) [1,2,14,16-20]. Local anesthetics can also block cal- cium and potassium channels, affect cholinergic and N-methyl-D- aspartate receptors, and may interfere with intracellular metabolic pro- cesses [20-29]. Thus, local anesthetics can present with a range of toxi- cologic manifestations.

The pathophysiology of LAST relates to the local anesthetic binding to cardiac sodium channels and/or cerebral neurons [1,2,5,6,30,31]. All local anesthetics can cause LAST, but the cardiac and CNS toxicity varies among the anesthetics. Within the CNS, the Sodium channel blockade disrupts inhibitory neuron depolarization, which leads to neural excita- tion with findings including muscle activation, sensory and vision changes, and seizures [1,2,30,31]. As plasma levels of the local anes- thetic increase, CNS depression can occur, resulting in altered mental status, coma, and even respiratory arrest. Within the cardiovascular system, local anesthetics can produce myocardial dysfunction, distur- bances in conduction, and vascular tone lability [1-3,15,30,31]. Conduc- tion system abnormalities are due to sodium channel blockade primarily at the bundle of His, impairing action propagation and leading to prolonged intervals (PR and QRS intervals) [3,15,30,31]. The QT inter- val may also be prolonged through potassium channel (efflux) blockade [3,15,30,31]. Myocardial dysfunction occurs through blockade of the calcium channel and sodium-channel exchange pump [3,15,30]. Of note, LAST may occur at lower serum concentrations than expected due to the fact that local anesthetics accumulate in mitochondria and cardiac tissue at a ratio of at least 6:1 relative to the plasma [32]. Bupiv- acaine and ropivacaine are more likely to cause cardiac dysrhythmias, whereas lidocaine and mepivacaine are more likely to decrease contrac- tility, manifesting as systemic hypotension [30,33,34].

The cardiovascular and CNS toxicities are numerically represented by the cardiovascular-collapse-to-CNS ratio (CC:CNS) [1,2]. The CC: CNS ratio is the drug dose required to cause catastrophic Cardiovascular collapse compared to the drug dose required to produce seizures [1,2,25]. Those with higher CC:CNS ratios tend to have greater margins of safety, as there is an earlier presentation of CNS symptoms before the onset of cardiac toxicity; conversely, a low CC:CNS ratio is seen in local anesthetics with greater cardiac toxicity at lower tissue concentra- tions [1,2,25]. Local anesthetics with a lower CC:CNS ratio demonstrate more Rapid progression from CNS signs and symptoms to cardiovascular collapse. While the toxic impact on the two target organ systems (CNS and cardiovascular) can both be significant medically, cardiac toxicity is considered to be the most important in terms of LAST severity and ul- timate outcome. Thus, the CC:CNS ratio is not only helpful in determin- ing the risk of cardiac toxicity of the various local anesthetics but also

Bupivacaine demonstrates a more rapid progression from CNS symptoms to cardiovascular collapse compared to levobupivacaine and ropivacaine, and thus, it has a low CC:CNS ratio, followed in order by levobupivacaine, ropivacaine, and lidocaine [25,30,35-37]. Ester local anesthetics include benzocaine, chloroprocaine, procaine, proparacaine, and tetracaine. These are metabolized by plasma cholin- esterase, producing water-soluble metabolites that are excreted in the urine. Esters tend to have short plasma half-lives, which reduces the in- cidence of LAST [1-3,14,15].

    1. Risk factors

Several categories of risk factors are associated with likelihood of de- veloping LAST, including pharmacologic (i.e., medication), patient, and drug administration issues (Table 2). Medication factors include the specific local Anesthetic agent and the total dose administered. An important pharmacologic factor is the CC:CNS ratio, as previously described. Agents with lower CC:CNS ratios are associated with earlier cardiotoxicity, while those with higher ratios have greater safety mar- gins – in other words, minimal and/or delayed development of cardiotoxicity [1,2,25]. Other important pharmacologic risk factors as- sociated with LAST are the amount of local anesthetic administered and subsequently absorbed. The dose of local anesthetic is important to consider, as doses greater than the recommended maximum dose place the patient at higher risk of LAST (Table 1). Using the lowest effec- tive dose of the local anesthetic is recommended [1-3,15,25].

The second risk category includes patient factors. Populations most susceptible include those at extremes of age such as infants and the el- derly, as well as those with Mitochondrial dysfunction (e.g., patients with carnitine deficiency) [1,2,30,31]. Infants have reduced concentra- tions of binding protein alpha1-acid glycoprotein (AAG) and immature hepatic clearance, which increase free levels of the local anesthetic in the plasma [38-40]. While the overall reported incidence of LAST is lower in children compared to adults, 8 per 100,000 injections versus 27 per 100,000 injections, more than half of recorded cases of LAST in children occur in patients younger than 3 years of age [7-13,41]. Elderly patients have decreased organ perfusion and Hepatic function, which reduces clearance of local anesthetic [42-45]. End-organ dysfunction is also associated with LAST. Patients with severe renal disease have a hyperdynamic circulation and decreased clearance of local anesthetic, but they also tend to have higher levels of AAG [46]. Thus, these patients typically are not at higher risk unless the patient presents with uremia and metabolic acidosis which further decrease local anesthetic clear- ance [46]. end-stage liver disease may also increase the risk of LAST with continuous infusions or repeat blocks due to decreased clearance of local anesthetics [45,47,48]. Severe cardiac disease increases the risk of LAST, including those with active ischemia, decreased ejection frac- tion, and pre-existing conduction disorders [31,45,49,50]. These pa- tients are also at increased risk of LAST due to reduced hepatic and renal perfusion, as well as reduced cardiac tolerance to physiologic dis- turbances [31,45,46]. Other metabolic factors include acidosis, hypoxia, and hypercarbia [51]. Pregnancy increases the risk of developing LAST due to increased cardiac output and reduced AAG concentration, which increase uptake from Injection sites and lead to both faster anes- thetic absorption and higher peak serum concentrations [52-55]. Finally, patients with substantially decreased muscle mass are at higher

Table 1

Suggested local anesthetic dosing.

the time of presentation of the cardiac toxicity.

Amide local anesthetics include bupivacaine, levobupivacaine, lido-

Local Anesthetic Plain maximum dose

With epinephrine maximum dose

caine, mepivacaine, and ropivacaine [35-37]. These are metabolized in the liver via the Cytochrome P450 system [3]. Bupivacaine is associated with significant cardiac toxicity and increased risk of dysrhythmias due to a higher affinity for inactive sodium channels and slower dissociation from these channels, which delays recovery from action potentials.

Bupivacaine/Levobupivacaine 2 mg/kg 3 mg/kg

Lidocaine 5 mg/kg 7 mg/kg

Mepivacaine 5 mg/kg 7 mg/kg

Prilocaine 6 mg/kg 8 mg/kg

Ropivacaine 3 mg/kg 3 mg/kg

risk for LAST, as skeletal muscle acts as a depot for systemically absorbed local anesthetics [56].

Table 3

Signs and symptoms of LAST

Medication administration factors play a role in LAST. The site of ad- ministration impacts the risk of LAST development. Highly vascular tis- sues, local anesthetic agent use without co-application of epinephrine, and direct injection into the vasculature increase the likelihood of LAST development [1,2,15,25]. Intravascular injection is associated with the greatest risk of LAST [1,2,15,25]. However, even topical admin- istration can result in LAST, particularly with application to mucosal membranes in high doses (e.g., prior to airway instrumentation for awake intubation). Multiple cases of LAST following administration of oral viscous lidocaine have been reported [57-59]. EMLA cream and top- ical tetracaine can also result in LAST [60,61]. Local anesthetic adminis- tration in a highly vascular site increases the risk of LAST due to greater and more rapid plasma uptake and systemic absorption. These sites include tumescent anesthesia (a form of local anesthesia used in dermatosurgical procedures where dilute anesthetic solution is injected into subcutaneous tissues), intercostal blocks, caudal/epidural anesthe- sia, interfascial abdominal wall plane blocks, psoas compartment blocks,

General Signs & Symptoms

Nausea / vomiting tinnitus

Metallic taste Perioral numbness Shivering

Weakness / dizziness

Central Nervous System Signs & Symptoms

Blurred vision Slurred speech Seizures


Altered mental status (ranging from agitation to unresponsiveness)

Cardiovascular & Respiratory Signs & Symptoms

Extremes of blood pressure (hypotension & hypertension)

Bradycardia & tachycardia

AV block & bundle branch block

Malignant dysrhythmias Acute respiratory failure

(due to altered mental status)

Cardiac arrest

sciatic blocks, and brachial plexus and cervical blocks [62,63]. A large registry study of >25,000 peripheral nerve blocks revealed that ultra- sound guidance was associated with a reduced risk of LAST (odds ratio, 0.23, CI: 0.088-0.59, p = 0.002) [9]. Ultrasound guidance may re- duce the volume of local anesthetic needed to achieve a successful block and decrease the number of unidentified intravascular injections [1,2]. Refer to Table 2 for a list of risk factors for LAST development.

    1. Presentation

Patients may present with a variety of symptoms (Table 3), but the time course depends upon the injection location (i.e., intra-arterial, in- travenous, subcutaneous, etc.), amount injected, and the CC:CNS ratio of the agent used [1-4,6,64]. Approximately 25% experience symptoms within 1 min of injection, 22% within 1-5 min, 10% within 6-10 min, and 20% within 11-30 min [64]. In patients with inadvertent intravascu- lar injection, symptoms typically occur within 5 min [31]. For those with LAST from systemic injection, symptoms typically occur within 20-30 min [5,65,66]. Variation of onset time has been reported, however, with one study noting 22% development after 30 min while another in- vestigation reported that 23% of patients manifested the initial signs and symptoms after 60 min [5,31,67]. CNS toxicity is the most common ini- tial presentation, noted in approximately 80% of patients; of the various CNS toxic manifestations, seizures are encountered in up to 68% of pa- tients [1,2,31,67-69]. Almost half of symptomatic patients will present

Table 2

Risk factors for LAST Development, including pharmacologic, patient, and administration technique issues.


Specific medication used

Amount of Medication administered Cardiovascular-collapse-to-CNS ratio (CC:CNS)

Patient-based Extremes of age Small patient size Female gender Pregnancy

Chronic malnourished state

Severe end-organ disease / dysfunction? (cardiac, renal, hepatic, CNS)

Acidosis (metabolic +/- respiratory) Hypoxia


Administration technique (topical < injection) Application site

Vascularity of tissue site injection Intravascular injection

* (acute +/- chronic).

with both CNS and cardiovascular symptoms, while approximately 10% will present with cardiovascular symptoms alone [31].

Early symptoms can include metallic taste, perioral paresthesias, changes in vision/hearing, dizziness, dysarthria, dysgeusia, muscle twitching, agitation, hallucinations, and altered mental status [1,2,31,67-69] (Table 3, Fig. 1). Up to one-third of cases will progress to significant cardiovascular manifestations with dysrhythmia and/ or hypotension, while 20% of patients with LAST have isolated, less severe cardiovascular signs [1,2,31,67-69]. There is a wide spectrum of cardiovascular features, including conduction deficits (AV block and bundle branch block), dysrhythmias, hypotension or hyperten- sion, and cardiac arrest (typically asystole) [1,2,31,67-69]. Dysrhyth- mias include both bradycardia, with or without AV block, and supraventricular tachycardias; malignant ventricular dysrhythmias can occur as well with ventricular tachycardia (with and without a pulse) and ventricular fibrillation. Severe forms of LAST can progress rapidly over minutes to bradycardia and hypotension, followed by further progression to malignant dysrhythmia and cardiac arrest [1,2,31,67-69].

    1. Management

ED management of LAST includes early recognition, ensuring ade- quate oxygenation and ventilation, treating seizures, and supporting the cardiovascular system (Tables 4 and 5, Fig. 2). The American Society of regional anesthesia and Pain Management (ASRA) provides a

Image of Fig. 1

Fig. 1. Signs and symptoms of lidocaine toxicity and serum concentration.

Table 4

General Management considerations in the LAST patient.


Recognition of Reaction

Lipid Emulsion 20% Bolus / Infusion



Airway & Breathing

Support Oxygenation & Ventilation Early Endotracheal Intubation


IV fluids (isotonic) Vasopressor (norepinephrine)



Cardioversion & Defibrillation as Appropriate

Cardiac Arrest

Standard Approach

Epinephrine – Lower Doses Recommended (Bolus Dosing <=1 ug/kg)

Avoid These Interventions Standard Bolus Dose Epinephrine Standard-dose Propofol

Calcium Channel & Beta blockers Procainamide & Lidocaine

dedicated set of management recommendations using the 2020 LAST checklist as a means of ensuring appropriate care [1,2,4,50,69]. Refer to Table 4 for a list of potential interventions in the patient with known or suspected LAST.

General issues in the approach to the patient with a moderate to se- vere LAST include standard resuscitation in most instances with the noted exceptions of the use of lipid emulsion 20% and the use of low- dose epinephrine [1,2,4,50,69-71]. The first step in the management is recognition of its occurrence. Of course, subtle signs and symptoms can make early diagnosis challenging. If LAST is suspected, the injection should be discontinued. General resuscitative equipment and supplies should be obtained and positioned in close proximity [1-4,50,69-71]. Supplemental oxygen should be administered as needed. Both hypoxia and acidosis (metabolic and respiratory) can potentiate toxicity, in- crease the likelihood and effects of toxicity, and prolong LAST; if possi- ble, such issues must be addressed to the best of the clinician’s ability [1-4]. If the airway is compromised, oxygenation is impaired, and/or ventilation is inadequate, then early endotracheal intubation and me- chanical ventilation are recommended [1-4,6]. If the patient is actively seizing, benzodiazepines should be administered [70]; if Seizure activity persists after the initial treatment, subsequent doses of benzodiazepine should be administered over short time intervals until the maximum total amount has been administered. If the patient continues to seize, low-dose propofol or ketamine can be utilized, with endotracheal intu- bation if necessary.

Table 5

Lipid emulsion 20% therapy indications, dosage, and administration.

Lipid Emulsion 20% intravenous therapy Indications


Malignant Dysrhythmias Hypotension

Cardiac Arrest

Dosing & Administration

> 70 kg: bolus dose 100 mL IV over 2-3 min with infusion of 200-250 mL IV over 15-20 min

<= 70 kg: bolus dose 1.5 mL/kg IV over 2-3 min with infusion of 0.25 mL/kg/min IV infusion


Lipid emulsion 20% can be administered during active cardiac arrest

For persistent significant toxicity, bolus may be repeated twice & the infusion rate doubled

If the patient is hypotensive, begin intravenous fluid resuscitation with appropriate crystalloid infusions with the addition of norepineph- rine if the blood pressure remains low [1-4]. Among those with ventric- ular tachycardia or ventricular fibrillation, the First-line treatment is amiodarone, while lidocaine and other sodium channel blocking agents should be avoided [1-4]. Cardioversion and/or defibrillation should occur as clinically indicated using the standard indications and ap- proaches for these electrical therapies. In patients with cardiac arrest as- sociated with LAST, epinephrine dosing should be reduced to <1 ug/kg, as full-bolus doses (i.e., epinephrine [1:10,000] 1 mg IV) can increase the risk of worsened arrhythmic conditions, such as further degenera- tion to other, more malignant rhythms, persistence of the dysrhythmia, and refractory dysrhythmia [4,72,73]. Of note, this recommendation for epinephrine dosing is based on animal studies, and optimal epinephrine dosing remains unknown [74,75]. In addition, vasopressin, calcium channel blockers, and beta blockers should be avoided, as they can worsen hypotension [1-3,72]. For patients with refractory cardiac ar- rest, cardiopulmonary bypass with extracorporeal membrane oxygena- tion (ECMO) and/or airway intervention may also be required [1-4,72]. A key medication component of therapy is intravenous (IV) lipid emulsion 20% (intralipid 20%) (Table 5) [1-4,71,76-78]. The mechanism of action for treatment of LAST is unclear. Historically, lipid emulsion 20% was thought to act as a lipid sink, removing local anesthetic from target tissues and transporting it to other body areas for detoxification [1-4,71,77,78]. Lipid emulsion 20% may improve sodium channel func- tion and potentiate inotropy through increased myocyte intracellular calcium. Lipid emulsion 20% also improves mitochondrial metabolism and fatty acid processing [1,2,79-86]. Unfortunately, much of the litera- ture evaluating lipid emulsion 20% for LAST treatment primarily consists of case reports in which patients have failed to respond to other cardiac life support therapies; the other primary literature support includes an-

imal studies [76-78].

Lipid emulsion 20% should be administered in patients with seizures or severe cardiotoxicity (e.g., hemodynamically compromising dys- rhythmias, hypotension, cardiac arrest) associated with LAST [87-89], and it can be administered during active cardiac arrest. Patients with mild CNS toxicity (e.g., perioral paresthesias, changes in vision/hearing, dizziness, dysarthria, dysgeusia, muscle twitching) do not typically re- quire treatment with lipid emulsion 20%, but they should receive sup- portive care and be closely monitored for symptom progression. Per ASRA recommendations, an Intravenous bolus should be provided over 2-3 min, with subsequent infusion over 15-20 min based on ideal body weight [4]. For those patients >70 kg, ASRA recommends an initial bolus of 100 mL IV over 2-3 min, followed by an infusion of 200-250 mL IV over 15-20 min [4]. For those <70 kg, the bolus dose is 1.5 mL/kg IV over 2-3 min, followed by 0.25 mL/kg/min IV infusion. If patients have persistent cardiovascular instability 2-3 min after re- ceiving the bolus, the bolus can be repeated every 5 min [1,2,4]. The American College of Medical Toxicology (ACMT) and Association of Anaesthetists of Great Britain and Ireland (AAGBI) recommend a bolus of 1.5 mL/kg of lipid emulsion for all patients [90,91]. If patients signifi- cantly improve with lipid emulsion 20% bolus and infusion, the infusion can be reduced to 0.025 mL/kg/min. However, if instability reemerges, according to ACMT guidelines another bolus may be administered, or the infusion should be increased to 0.25 mL/kg/min [90]. Of note, propofol is not a suitable replacement for lipid emulsion 20%, as propofol is prepared in lipid emulsion 10% and can result in cardiovas- cular depression. Lipid emulsion 20% also contains egg yolk phospho- lipids and soybean oil, and thus it should not be used in patients with allergies to either of these substances [4].

    1. Prevention

Several strategies are available to reduce the risk of LAST. Aspirating prior to injection is key to ensuring drug delivery does not occur directly in a vessel. Prior to injecting, the maximum dose should be calculated

Image of Fig. 2

Fig. 2. LAST management.

based upon the specific local anesthetic used [1-4,45]. The goal is to provide the lowest dose of local anesthetic that will achieve the desired duration and extent of anesthesia for the procedure or condition [1-4,45]. The maximum dose should be reduced in those who are frail, have decreased muscle mass, are pregnant, elderly, infants, uremic, and those with severe heart failure (approximately 10-20% reduction) [1,2,67]. Of note, in overweight patients, ideal body weight should be utilized to calculate the maximal permissible dose. The use of local anes- thetics with higher CC:CNS ratios (ropivacaine and levobupivacaine) is preferable if possible [1,2,67]. Using epinephrine in combination with local anesthetic may be beneficial, as direct intravascular injection will result in increased heart rate (> 10 beat per minute increase) and systolic blood pressure (> 15 mmHg increase) [92]. If a significant increase in heart rate and blood pressure is observed, intravascular injection is likely, and LAST may develop. Ultrasound can reduce the

risk of LAST in Regional blocks by improving the accuracy of drug delivery, reducing the total required dose, visualizing vessels at risk of puncture in the anatomic area, and assessing for potential intravascular injection if visual spread in the target structures does not occur [9,92- 98]. When performing a regional block, local anesthetics should be administered in 3-5 mL aliquots, followed by 30-45 s (one circulation time) prior to repeat injection [1,2,67]. This may allow the detection of excessive dosage prior to further administration. Similarly, intermittent aspiration before injection can help identify inadvertent intravascular puncture.

  1. Conclusions

This focused review provides an update for the emergency clinician to manage patients with LAST. LAST is a potentially life-threatening

complication of local anesthetic use that may be encountered in the ED. Patients most commonly present with CNS and cardiac signs and symp- toms. Those at extremes of age or with organ dysfunction are at higher risk. Inadvertent intra-arterial or intravenous injection, as well as re- peated doses and higher doses of local anesthetics are associated with greater risk of developing LAST. Early recognition and intervention, in- cluding supportive care and intravenous lipid emulsion 20%, are the mainstays of treatment. Using ultrasound guidance, aspirating prior to injection, and utilizing the minimal local anesthetic dose needed are techniques that can reduce the risk of LAST.

Conflicts of interest


CRediT authorship contribution statement

Brit Long: Writing – review & editing, Writing – original draft, Visu- alization, Validation, Conceptualization. Summer Chavez: Writing – review & editing, Writing – original draft, Visualization, Validation. Michael Gottlieb: Writing – review & editing, Validation, Supervision. Tim Montrief: Writing – review & editing, Writing – original draft, Visu- alization, Validation, Resources. William J. Brady: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Conceptualization.


All authors conceived the idea for this manuscript and contributed substantially to the writing and editing of the review. This manuscript did not utilize any grants, and it has not been presented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electroni- cally without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. government, Depart- ment of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.


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