Opioid Overdose in Adults

Quick Reference

Critical Alerts

Critical Alert: IMMEDIATE ACTIONS

• Airway and ventilation FIRST: Bag-valve-mask (BVM) ventilation before and during naloxone administration
• Naloxone reverses opioid overdose: Titrate to adequate respiratory drive, NOT to full consciousness
• Fentanyl overdoses may require higher/repeated doses: Maintain ventilation while titrating naloxone
• Observe for renarcotization: Opioid duration of action may exceed naloxone duration (30-90 minutes)
• Consider polysubstance use: Benzodiazepines, alcohol, stimulants commonly coinvolved
• Harm reduction saves lives: Prescribe take-home naloxone to every overdose survivor at discharge

Classic Opioid Toxidrome (Triad)

Emergency Naloxone Dosing Summary

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Overview

Opioid overdose is a life-threatening medical emergency characterized by the triad of central nervous system (CNS) depression, respiratory depression, and miosis, resulting from excessive opioid effect at mu-opioid receptors. [1] It represents one of the leading causes of preventable death worldwide, with the global opioid epidemic causing over 100,000 drug overdose deaths annually in the United States alone, the majority involving opioids. [2]

The clinical landscape has shifted dramatically over the past decade with the emergence of illicitly manufactured fentanyl and its analogues, which now account for the majority of opioid overdose fatalities. [3] Fentanyl's extreme potency (50-100 times that of morphine) and its unpredictable presence in the illicit drug supply have made overdose prevention and reversal increasingly challenging. [4]

Prompt recognition and treatment with the opioid antagonist naloxone, combined with adequate ventilatory support, can reverse the life-threatening effects within minutes. [1] Emergency clinicians play a critical role not only in acute resuscitation but also in preventing future overdoses through harm reduction interventions, including take-home naloxone prescribing and linkage to medication-assisted treatment for opioid use disorder. [5]

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Epidemiology

Global Burden

The opioid crisis represents a major global public health emergency with escalating mortality rates over the past two decades. [2,3]

Temporal Trends

The opioid epidemic has evolved through distinct phases: [3]

Risk Factors for Opioid Overdose

Exam Detail: High-Yield Epidemiology Points for Exams:

• Post-incarceration overdose risk is highest in first 2 weeks after release (RR 129 in first week) [7]
• Concurrent benzodiazepine-opioid prescriptions account for 30% of opioid overdose deaths [6]
• Fentanyl has surpassed heroin as the leading cause of opioid overdose death since 2016 [3]
• The risk of overdose increases linearly with morphine milligram equivalents (MME) above 50 mg/day [8]

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Pharmacology and Pathophysiology

Opioid Receptor Pharmacology

Opioids exert their effects through binding to G-protein coupled opioid receptors, with mu-receptors being the primary mediators of both analgesic and toxic effects. [1,9]

Classification of Opioids

Comparative Potency and Duration

Exam Detail: Pharmacokinetic Pearls:

• Fentanyl patches: Transdermal absorption continues after patch removal; depot in subcutaneous fat
• Methadone: Highly variable half-life (15-60 hours); accumulates with repeated dosing; QTc prolongation (Torsades risk)
• Extended-release formulations: May contain 2-3 days' worth of opioid; crushing/chewing defeats extended-release mechanism → immediate release of entire dose
• Heroin (diacetylmorphine): Rapidly deacetylated to 6-monoacetylmorphine (6-MAM) then morphine; 6-MAM is specific marker for heroin use on toxicology
• Buprenorphine: Partial agonist with ceiling effect on respiratory depression; high receptor affinity makes displacement by naloxone difficult

Mechanism of Respiratory Depression

The sine qua non of opioid toxicity is respiratory depression, which occurs through multiple mechanisms: [1,9]

1. Medullary respiratory centre depression

   • Reduced sensitivity to hypercapnia (CO2)
   • Decreased respiratory rate (bradypnea)
   • Decreased tidal volume (hypopnea)
   • Irregular breathing patterns (Cheyne-Stokes, ataxic breathing)

2. Chemoreceptor blunting

   • Reduced peripheral chemoreceptor response to hypoxia
   • Reduced central chemoreceptor response to hypercarbia
   • Loss of hypoxic ventilatory drive

3. Upper airway effects

   • Decreased pharyngeal muscle tone → airway obstruction
   • Suppressed cough reflex → aspiration risk
   • Increased airway resistance

4. Chest wall rigidity (especially with fentanyl/sufentanil)

   • "Wooden chest syndrome"
   • Severe truncal rigidity impairing ventilation
   • May require neuromuscular blockade for adequate ventilation

Other Pathophysiological Effects

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Clinical Presentation

Classic Opioid Toxidrome

The diagnostic triad of opioid overdose consists of: [1,10]

1. Altered mental status (depressed level of consciousness)
2. Miosis (pinpoint pupils)
3. Respiratory depression

Clinical Pearl: Important Caveats to the Classic Triad:

• Miosis may be absent with:
  • Meperidine (normeperidine metabolite)
  • Dextromethorphan
  • Coingestants (anticholinergics, sympathomimetics)
  • Severe hypoxia (pupils may become dilated)
  • Pontine lesions (stroke, hemorrhage)
• Respiratory depression is the critical finding - miosis is supportive but not essential for diagnosis
• Response to naloxone confirms the diagnosis retrospectively

Detailed Clinical Features

Severity Assessment

Complications of Opioid Overdose

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Differential Diagnosis

Differential Diagnosis of Depressed Consciousness with Respiratory Depression

Clinical Pearl: The Coma Cocktail Approach: Traditional teaching advocated empiric administration of:

• Dextrose (for hypoglycemia)
• Naloxone (for opioid overdose)
• Thiamine (before dextrose in suspected alcoholism)
• (Previously flumazenil - now rarely used due to seizure risk)

Modern approach: Point-of-care glucose testing is rapid and should be performed immediately. Naloxone should be given when opioid overdose is suspected based on clinical presentation (toxidrome).

Approach to the Unknown Overdose

When the substance is unknown, systematic toxidrome assessment guides management: [10]

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Diagnostic Approach

Clinical Diagnosis

Opioid overdose is fundamentally a clinical diagnosis based on the characteristic toxidrome and response to naloxone. [1,10] Laboratory testing is confirmatory and guides management of complications but should never delay treatment.

Immediate Bedside Assessment

Laboratory Investigations

Exam Detail: Critical Points About Urine Drug Screens (UDS):

1. Fentanyl is NOT detected on standard immunoassay UDS (requires specific fentanyl immunoassay or GC-MS)
2. Synthetic opioids often missed: Methadone, tramadol, meperidine, buprenorphine may not cross-react
3. False positives: Poppy seeds, dextromethorphan, quinolones, rifampin
4. False negatives: Synthetic opioids, dilute urine, timing
5. Clinical decision: Do NOT withhold naloxone based on negative UDS if clinical picture suggests opioid overdose
6. Qualitative only: UDS indicates presence, not quantity or timing

ECG Considerations

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Management

Principles of Management

1. Resuscitation: Airway, breathing, circulation (ABC) takes priority
2. Oxygenation: Bag-valve-mask ventilation before and during naloxone
3. Antidote: Naloxone administration titrated to respiratory drive
4. Supportive care: IV access, monitoring, treating complications
5. Observation: Duration based on opioid half-life and formulation
6. Harm reduction: Naloxone prescription, OUD treatment referral

Immediate Resuscitation (First 0-5 Minutes)

Step 1: Scene Safety and Universal Precautions

• Personal protective equipment
• Fentanyl exposure risk is minimal with skin contact; mask/gloves adequate
• Remove transdermal patches if present

Step 2: Assess Responsiveness

• Verbal and painful stimuli
• Sternal rub, trapezius squeeze

Step 3: Call for Help

• Activate emergency response
• Request naloxone

Step 4: Airway Management

• Head tilt-chin lift or jaw thrust
• Suction secretions
• Oropharyngeal or nasopharyngeal airway if needed
• Position in recovery position if breathing adequately

Step 5: Breathing Support

• If apneic or hypoventilating: Begin BVM ventilation with 100% O2
• Target SpO2 > 94%
• Rate: 10-12 breaths/minute
• Avoid hyperventilation

Critical Alert: VENTILATION BEFORE NALOXONE Bag-valve-mask ventilation is the most critical intervention in opioid overdose. Oxygenation reverses hypoxia immediately, while naloxone takes 1-5 minutes to work depending on route. Never delay ventilation to give naloxone.

Naloxone Administration

Mechanism of Action: Naloxone is a competitive mu-opioid receptor antagonist with higher affinity than most opioids. It displaces opioids from receptors, rapidly reversing respiratory depression, sedation, and miosis. [1,11]

Pharmacokinetics:

Dosing Strategies

Opioid-Naive or Unknown Dependence Status:

Opioid-Dependent Patients (To Avoid Precipitated Withdrawal): [1,12]

Exam Detail: Titration Strategy for Opioid-Dependent Patients:

1. Start with 0.04 mg (40 mcg) IV = 0.1 mL of 0.4 mg/mL solution
2. Wait 2-3 minutes
3. If no response: Give 0.08 mg
4. If no response: Give 0.16 mg
5. Continue doubling until respiratory rate > 12 and SpO2 > 94%
6. Goal: Restore respiratory drive, NOT full alertness

Rationale: Precipitating severe withdrawal in opioid-dependent patients causes:

• Projectile vomiting → aspiration risk in patient with impaired airway protection
• Severe agitation → combativeness, absconding, falls
• Intense craving → immediate drug seeking
• Loss of therapeutic relationship

Repeat Dosing and Non-Response

If No Response After 10 mg Total Naloxone: [1,13]

• Strongly reconsider the diagnosis
• Consider:
  • Non-opioid cause (other sedatives, medical condition)
  • Massive ingestion
  • Buprenorphine overdose (difficult to reverse)
  • Carfentanil (may require > 10 mg)
  • Hypoxic brain injury already established

Fentanyl Overdose:

• May require higher and more frequent doses
• Continue BVM ventilation throughout titration
• Some cases require 10+ mg total [14]

Naloxone Infusion

Indication: Recurrent respiratory depression after initial response (renarcotization)

Preparation and Administration:

• Calculate effective bolus dose that reversed overdose
• Infusion rate = 2/3 of effective bolus dose per hour
• Example: 0.4 mg reversed patient → Infuse 0.25-0.3 mg/hour

Preparation:

• Dilute 2 mg naloxone in 500 mL NS or D5W = 4 mcg/mL
• Or 4 mg in 1000 mL = 4 mcg/mL
• Titrate to maintain adequate respiratory drive

Managing Precipitated Withdrawal

Precipitated withdrawal is uncomfortable but not life-threatening. Management is supportive: [12]

Advanced Airway Management

Indications for Endotracheal Intubation:

• Persistent apnea despite naloxone
• Inadequate response to naloxone (coma persists)
• Unable to protect airway (GCS ≤8 with poor gag)
• Aspiration pneumonitis
• Severe pulmonary edema
• Anticipated prolonged unconsciousness

Considerations:

• RSI may be required
• Chest wall rigidity (fentanyl): May require high-dose rocuronium or succinylcholine
• Caution with ketamine in polysubstance use
• Prepare for difficult airway (secretions, vomiting)

Management of Specific Complications

Non-Cardiogenic Pulmonary Edema (NCPE):

• Occurs in 2-10% of heroin overdoses [15]
• Mechanism: Neurogenic; increased pulmonary capillary permeability
• Management:
  • Supplemental oxygen, CPAP/BiPAP, or mechanical ventilation
  • Diuretics generally not helpful (not cardiogenic)
  • Usually resolves within 24-48 hours

Rhabdomyolysis:

• IV crystalloid resuscitation (target UOP 200-300 mL/hour)
• Monitor CK, renal function, electrolytes
• Avoid NSAIDs
• Consider bicarbonate if severe (pH less than 7.1)

Compartment Syndrome:

• Urgent surgical consultation
• Fasciotomy if confirmed

Methadone-Associated QTc Prolongation:

• Continuous cardiac monitoring
• Correct electrolytes (K> 4.0, Mg> 2.0)
• Avoid QTc-prolonging medications
• If Torsades: Magnesium sulfate 2g IV, defibrillation if pulseless

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Observation and Disposition

Duration of Observation

The critical concept is that naloxone's duration of action (30-90 minutes) is shorter than many opioids. Patients may experience renarcotization as naloxone wears off. [1,13]

Safe Discharge Criteria

All of the following must be met before ED discharge: [13]

1. Adequate observation period completed (based on opioid type)
2. No recurrent respiratory depression after naloxone has worn off
3. Stable mental status (GCS 15, able to ambulate safely)
4. Stable vital signs (RR ≥12, SpO2 ≥95% on room air)
5. No evidence of complications (aspiration, NCPE, rhabdomyolysis)
6. Ambulatory and coordinated
7. Eating and drinking without difficulty
8. Safe disposition plan (responsible adult supervision)
9. Harm reduction completed:
   • Naloxone kit prescribed and education provided
   • Resources for addiction treatment offered
   • Overdose prevention counseling

Admission Criteria

Leaving Against Medical Advice (AMA)

If patient wishes to leave before adequate observation:

1. Assess capacity to make informed decision
2. Document discussion of risks (renarcotization, death)
3. Provide naloxone kit regardless of AMA status
4. Provide harm reduction counseling
5. Offer addiction treatment resources
6. Arrange safe transport if possible
7. Document thoroughly

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Harm Reduction and Prevention

Take-Home Naloxone (THN)

Take-home naloxone programs have been demonstrated to reduce opioid overdose mortality at the community level. [16,17]

Evidence:

• Massachusetts THN program: 27-46% reduction in opioid overdose death rates in communities implementing THN [16]
• OEND (Opioid Education and Naloxone Distribution) programs reduce overdose mortality
• Cost-effective intervention

Who Should Receive THN:

• Every patient presenting with opioid overdose
• Patients with opioid use disorder
• Patients on high-dose opioid prescriptions (> 50 MME/day)
• Family members/friends of high-risk individuals
• People recently released from incarceration
• People exiting detoxification programs

Available Formulations:

Overdose Prevention Education

Teach patients and their contacts: [17]

1. Recognize overdose: Unresponsive, not breathing, blue lips, snoring/gurgling
2. Call 911: Do not delay
3. Administer naloxone: Intranasal or intramuscular
4. Rescue breathing: Until breathing resumes
5. Recovery position: If breathing but unresponsive
6. Stay with person: Naloxone wears off; repeat if needed
7. Good Samaritan laws: Many jurisdictions protect callers from prosecution

Safer Use Counseling

Supervised Injection Sites

Also known as overdose prevention sites (OPS) or drug consumption rooms: [18]

Evidence:

• InSite (Vancouver): No deaths at facility since opening in 2003
• Associated with reduced public injection, needle sharing
• Increased uptake of addiction treatment services
• Not associated with increased drug use or crime

Status:

• Legal in several countries (Canada, Australia, parts of Europe)
• Emerging in some US jurisdictions (NYC, Rhode Island)
• Politically contentious; evidence supports harm reduction

ED-Initiated Treatment for Opioid Use Disorder

Emergency departments are a critical opportunity to initiate treatment for opioid use disorder (OUD): [5,19]

X-waiver no longer required (US): As of 2023, any clinician with DEA registration can prescribe buprenorphine without additional training requirements.

ED-Initiated Buprenorphine:

• D'Onofrio et al. (JAMA 2015): ED-initiated buprenorphine doubled engagement in addiction treatment at 30 days compared to referral alone (78% vs 37%) [5]
• NIDA CTN-0079: Confirmed feasibility and effectiveness

Protocol:

1. Confirm moderate-severe OUD (DSM-5 criteria)
2. Patient in mild-moderate withdrawal (COWS score ≥8)
3. No contraindications (severe liver disease, concurrent opioid agonist in system)
4. Initial dose: Buprenorphine/naloxone 4/1 mg SL
5. Additional 4/1 mg after 1 hour if withdrawal not controlled
6. Prescribe 3-day supply with next-day follow-up
7. Arrange follow-up with addiction medicine/clinic

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Special Populations

Opioid-Dependent Patients

• Start with low-dose naloxone (0.04-0.1 mg IV)
• Titrate to respiratory drive, NOT full consciousness
• Goal: Avoid precipitated withdrawal
• Accept mild sedation if breathing adequate
• Explain to patient what happened and why withdrawal may occur

Pregnancy

Management:

• Naloxone is safe and indicated in pregnancy for maternal overdose
• Fetal survival depends on maternal resuscitation
• Precipitated withdrawal may cause fetal distress
• Use lowest effective naloxone dose
• Continuous fetal monitoring after stabilization
• OB/neonatology consultation

Considerations:

• Opioid withdrawal in pregnancy historically thought dangerous; evidence suggests short-term withdrawal does not cause miscarriage
• Long-term: Buprenorphine or methadone maintenance recommended for pregnant patients with OUD

Pediatric Patients

Common scenarios:

• Accidental ingestion of opioid medications
• Exploratory ingestion in toddlers
• Transdermal patch contact

Naloxone dosing:

• 0.1 mg/kg IV/IM/IN (max 2 mg per dose)
• May require repeat dosing
• Lower threshold for admission given exploratory nature

Extended-release ingestions:

• Prolonged observation (> 24 hours) for extended-release formulations
• Whole bowel irrigation may be considered for recent ingestions

Cardiac Arrest (Opioid-Associated)

AHA Guidelines (2020 update): [20]

• Standard ACLS algorithms apply
• Early ventilation with BVM is critical
• Empiric naloxone 2 mg IV/IO/IM/IN recommended
• If IV access: Give 2 mg IV
• If no IV: 2 mg IM or 4 mg IN
• Continue CPR; do not delay for naloxone effect
• If ROSC: Standard post-arrest care + opioid overdose management

Patients on Buprenorphine Maintenance

Overdose on buprenorphine:

• Rare due to ceiling effect
• Usually occurs with polysubstance use (benzodiazepines)
• Difficult to reverse with naloxone due to high receptor affinity
• May require very high naloxone doses or prolonged infusion
• Respiratory support is primary management

Overdose on other opioids in patient on buprenorphine:

• Buprenorphine has high affinity and may be protective
• If overdose occurs, likely due to massive ingestion or other substances

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Exam Focus: Viva Questions and Model Answers

Common Viva Questions

Q1: A 25-year-old male is brought by ambulance, found unresponsive near a syringe. GCS 3, RR 4, SpO2 70%, pupils pinpoint. How do you manage this patient?

Viva Point: Model Answer: "This patient has a clinical syndrome consistent with severe opioid overdose presenting with the classic triad of depressed consciousness, respiratory depression, and miosis. My immediate priorities are:

Resuscitation (simultaneous):

1. Airway: Head tilt-chin lift, suction secretions, insert OPA if tolerated
2. Breathing: Immediate bag-valve-mask ventilation with 100% oxygen
3. Circulation: Assess pulse, establish IV access

Specific antidote: 4. Administer naloxone - I would give 0.4-2 mg IV. If I suspected opioid dependence, I would start with 0.04-0.1 mg and titrate to respiratory drive. 5. Repeat every 2-3 minutes until respiratory rate > 12

Supportive: 6. Continuous monitoring: ECG, SpO2, BP 7. Check fingerstick glucose 8. Full exposure to look for patches, injuries, track marks

If inadequate response to 10 mg naloxone:

• Reconsider diagnosis
• Consider coingestants, buprenorphine, massive fentanyl
• Proceed to intubation if cannot protect airway

After stabilization:

• Observation period based on opioid type
• Screen for complications: aspiration, rhabdomyolysis
• Prescribe take-home naloxone
• Offer treatment for opioid use disorder"

Q2: What are the important differential diagnoses for a patient with depressed consciousness and respiratory depression?

Viva Point: Model Answer: "The differential includes:

Toxicological causes:

• Opioid overdose (miosis characteristic)
• Benzodiazepine/sedative-hypnotic overdose
• Alcohol intoxication
• GHB
• Barbiturate overdose (rare now)
• Carbon monoxide poisoning

Metabolic causes:

• Hypoglycemia (critical to exclude with fingerstick glucose)
• Hepatic encephalopathy
• Severe hypothyroidism (myxedema coma)
• Uremia

Neurological causes:

• Pontine stroke or hemorrhage (may have miosis)
• Head injury with raised ICP
• Postictal state
• CNS infection (meningitis, encephalitis)

Other:

• Hypothermia
• Septic shock with encephalopathy

The key distinguishing features for opioid overdose are the combination of miosis, respiratory depression, and response to naloxone. However, I would perform a fingerstick glucose immediately and give dextrose if hypoglycemic."

Q3: How would you counsel a patient being discharged after opioid overdose?

Viva Point: Model Answer: "I would address several key areas:

Explain what happened: 'You had an overdose - the opioid slowed your breathing and you could have died. Naloxone reversed the overdose and saved your life.'

Prescribe take-home naloxone: Provide naloxone kit (nasal spray preferred) and teach patient and any accompanying person:

• How to recognize overdose: unresponsive, not breathing, blue lips
• How to administer: spray in nostril, rescue breathing, call 911
• Naloxone wears off in 30-90 minutes - second dose may be needed

Risk reduction counseling:

• Never use alone
• Tolerance decreases quickly after any break - start with smaller amounts
• Don't mix opioids with benzodiazepines or alcohol
• Fentanyl contaminates the drug supply - test strips available
• Always carry naloxone

Offer treatment: 'Treatment is available and works. We can start medication today that reduces cravings and prevents withdrawal. Can I connect you with our addiction medicine team?'

If patient declines treatment, provide resources and leave the door open for future engagement."

Q4: Why do we titrate naloxone to respiratory drive rather than full consciousness?

Viva Point: Model Answer: "There are several important reasons:

1. Precipitated withdrawal: Giving a large dose of naloxone to an opioid-dependent patient causes immediate and severe opioid withdrawal. This causes:

   • Projectile vomiting - aspiration risk in patient with impaired airway
   • Severe agitation - patient may become combative, abscond, or injure themselves or staff
   • Intense craving - patient immediately seeks opioids to relieve withdrawal

2. Clinical goal: The goal is to reverse the life-threatening feature, which is respiratory depression. Once respiratory drive is adequate (RR > 12, SpO2 > 94%), the therapeutic endpoint is achieved.

3. Patient experience: Precipitated withdrawal is extremely unpleasant and damages the therapeutic relationship, reducing likelihood of engagement with harm reduction and treatment.

4. Lower doses are effective: Starting with 0.04-0.1 mg IV and titrating allows reversal of respiratory depression while minimizing withdrawal.

5. Safety: A mildly sedated patient who is breathing adequately is safer than an agitated patient in severe withdrawal attempting to leave."

What Fails Candidates

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Key Clinical Pearls

Diagnostic Pearls

• The classic triad (miosis + respiratory depression + decreased consciousness) is highly specific for opioid overdose
• Miosis may be absent with meperidine, severe hypoxia, or coingestants
• Response to naloxone is diagnostic - improvement confirms opioid involvement
• Fentanyl is NOT detected on standard urine drug screens
• Polysubstance use is the rule, not the exception - expect coingestants

Treatment Pearls

• Ventilate first, then give naloxone - oxygenation is the priority
• Start low in dependent patients (0.04 mg IV) to avoid precipitated withdrawal
• Titrate to respiratory drive, not full consciousness
• Fentanyl may need higher and repeated doses - keep ventilating
• Duration of naloxone (30-90 min) is shorter than most opioids - renarcotization risk

Disposition Pearls

• Minimum 4-6 hours observation for short-acting opioids
• 12-24+ hours for methadone, extended-release formulations, and patches
• Prescribe naloxone to EVERY overdose survivor
• Offer treatment for OUD - ED-initiated buprenorphine works
• Document observation period and harm reduction comprehensively

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Quality Metrics and Documentation

Performance Indicators

Documentation Requirements

• Substance: Known or suspected opioid(s)
• Route: IV, intranasal, oral, transdermal
• Time course: Estimated time of exposure, last known well
• Prehospital care: EMS naloxone doses and response
• Hospital management: Naloxone doses, routes, response times
• Observation period: Start and end times, clinical status throughout
• Complications: Aspiration, NCPE, rhabdomyolysis, other
• Disposition plan: Discharge criteria met, follow-up arranged
• Harm reduction: Naloxone prescribed, education provided, treatment offered

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References

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7. Binswanger IA, Stern MF, Deyo RA, et al. Release from prison—a high risk of death for former inmates. N Engl J Med. 2007;356(2):157-165. doi:10.1056/NEJMsa064115

8. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152(2):85-92. doi:10.7326/0003-4819-152-2-201001190-00006

9. Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747-758. doi:10.1093/bja/aen094

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11. Chou R, Korthuis PT, McCarty D, et al. Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Ann Intern Med. 2017;167(12):867-875. doi:10.7326/M17-2224

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