01Approach to the Critical Patient/attcp75

Immediate priorities

›Airway and breathing

›Airway compromise indications

›GCS < 8 or inability to protect airway

›Refractory seizures with apnea

›Aspiration from vomiting during agitation

›Rapid sequence intubation if needed

›Ketamine 1–2 mg/kg IV preferred induction agent

›Succinylcholine 1.5 mg/kg IV or rocuronium 1.2 mg/kg IV

›Oxygenation target SpO2 > 94%

›Supplemental oxygen via nasal cannula or facemask

›Circulation threats

›Hemodynamic monitoring

›Continuous cardiac monitoring for dysrhythmias

›IV access x2 large bore

›Core temperature monitoring via rectal probe

›Cardiac arrest management

›Standard ACLS protocol

›Consider extracorporeal life support (ECLS) for refractory arrest

›AHA 2025 guidelines support ECLS consideration in toxicological cardiac arrest

›Agitation — primary treatment priority

›Benzodiazepines first-line

›Midazolam 5–10 mg IM or IV, repeat every 5 minutes as needed

›Lorazepam 2–4 mg IV as alternative

›Large cumulative doses may be required

›Minimize physical restraints

›Sustained physical restraint without sedation associated with death

›Use chemical sedation in parallel if restraints applied

02History/hx65

Substance use history

›α-PVP (flakka) exposure

›Route of administration

›Smoked or vaporized (most common)

›Insufflated (snorted)

›Intravenous injection

›Oral or rectal administration

›Dose and quantity used

›Potent at doses as low as 5–10 mg

›Dose estimation often unreliable

›Time of last use

›Intranasal peak effects approximately 40 minutes post-use

›Duration of effects 3–5 hours; faster onset with smoking or IV

Symptom timeline

›Neuropsychiatric symptoms

›Agitation and combativeness

›Often presenting or prodromal complaint

›May have resolved before ED arrival

›Hallucinations

›Visual and auditory

›Paranoia and persecutory ideation

›Aggression and self-injurious behavior

›Suicidal ideation

›Risk of injury to self or others

›Cardiovascular symptoms

›Chest pain

›Coronary vasospasm pattern

›Pleuritic vs. non-pleuritic distinction

03Physical Exam/exam50

Vital signs

›Cardiovascular parameters

›Tachycardia

›Present in 80% of cases

›Rate often > 120 bpm

›Hypertension

›Present in 33% of cases

›Severe hypertension risk of aortic dissection

›Core temperature

›Rectal probe essential — peripheral measurement underestimates

›Temperature > 40°C = life-threatening emergency

›Respiratory parameters

›Tachypnea from agitation and acidosis

›Respiratory rate trend

›Oxygen saturation

›Baseline SpO2 before supplemental oxygen

Neurological exam

›Mental status assessment

›Level of consciousness

›Agitation, delirium spectrum

›GCS if obtunded

›Pupillary exam

›Mydriasis (dilated pupils) expected in sympathomimetic toxidrome

›Reactive to light

›Neuromuscular findings

›Hyperreflexia

›Tremor

›Clonus (raises concern for serotonin syndrome overlap)

04Differential Diagnosis/ddx50

Sympathomimetic toxidromes

›Other stimulant substances

›Methamphetamine toxicity (ICD-10: T43.621)

›Clinically indistinguishable from α-PVP

›Treatment approach identical

›Cocaine toxicity (ICD-10: T40.5X1)

›Shorter duration of action

›Sodium channel blockade adds QRS widening risk

›MDMA (ecstasy) toxicity (ICD-10: T43.641)

›Additional serotonergic component

›Hyponatremia risk

›PCP (phencyclidine) toxicity (ICD-10: T40.991)

›Dissociative features more prominent

›Nystagmus characteristic finding

›Other synthetic cathinones (bath salts) (ICD-10: T43.691)

›MDPV, mephedrone, alpha-PiHP variants

›Cannot distinguish clinically

Toxidromes requiring differentiation

›Anticholinergic toxidrome (ICD-10: T44.3)

›Distinguishing features

›Dry skin vs. diaphoresis in sympathomimetics

›Urinary retention

›Absent bowel sounds

›Flushed appearance

›Serotonin syndrome (ICD-10: T43.9)

›Distinguishing features

›Clonus more prominent

›Diarrhea common

05Laboratory Tests/lt49

Essential metabolic labs

›Renal and metabolic panel

›Comprehensive metabolic panel

›Creatinine for acute kidney injury assessment

›Electrolytes including sodium, potassium

›Glucose for hypoglycemia exclusion

›Acid-base status

›Acid-base disorder present in 63% of cases

›Severe metabolic acidosis (pH < 7.0) in fatal cases

›Lactate

›Elevated in > 70% of flakka intoxication cases

›Marker of tissue hypoperfusion and metabolic stress

Muscle injury markers

›Creatine kinase (CK)

›Rhabdomyolysis screening

›Elevated in 75% of flakka toxicity cases

›CK > 5,000 U/L threshold for aggressive fluid resuscitation

›Serial measurements every 6–8 hours to trend

›Urinalysis for myoglobinuria

›Dipstick positive for blood without RBCs on microscopy

›Dark tea-colored urine characteristic

Cardiac markers

›Troponin

›Myocardial injury assessment

›Cocaine and stimulant-associated MI risk

›Takotsubo cardiomyopathy marker

›Serial troponins if initial elevation

›ECG correlation required

06Diagnostic Tests/dt70

Scoring Systems

›Severity classification for α-PVP toxicity

›Mild toxicity

›Tachycardia with agitation

›Mild hypertension

›Resolves with observation and low-dose benzodiazepines

›Moderate toxicity (60% of cases)

›Persistent sympathomimetic findings

›Elevated CK

›Metabolic acidosis

›Coagulopathy

›Severe toxicity (17% of cases)

›Hyperthermia > 40°C

›Seizures

›Refractory agitation

›Rhabdomyolysis

›Cardiac dysrhythmias

›Fatal toxicity (5% of cases)

›Refractory VT or VF

›Multiorgan failure

›Cerebral edema

›Hunter Serotonin Toxicity Criteria

›Used when serotonin syndrome is differential concern

›Spontaneous clonus — most specific feature

›Inducible clonus plus agitation or diaphoresis

›Ocular clonus plus agitation or diaphoresis

›Tremor plus hyperreflexia

›Hypertonia plus temperature > 38°C plus clonus

07Disposition/dispo43

ICU admission criteria

›Indications for intensive care

›Hyperthermia > 40°C

›Active cooling therapy requirement

›Seizures

›Refractory or recurrent seizures

›Cardiac dysrhythmias or ischemia

›Sustained VT or VF

›Myocardial infarction

›Takotsubo cardiomyopathy

›Rhabdomyolysis with AKI

›CK > 5,000 U/L or rising

›Creatinine elevation

›Severe metabolic acidosis

›pH < 7.2

›Refractory agitation requiring continuous sedation

›Intubated patients requiring ventilator management

Observation unit criteria

›Parameters for observation (6–8 hours minimum)

›Moderate sympathomimetic findings responding to benzodiazepines

›Trending vital sign normalization

›Serial lab monitoring

›CK trend every 6 hours

›Renal function and electrolytes

›Lactate clearance

›Mental status monitoring

›Expected improvement as drug clears

08Treatment/t133

Airway and resuscitation

›Initial stabilization

›Airway assessment and management

›RSI if GCS < 8 or apnea

›Ketamine preferred induction (1–2 mg/kg IV) — maintains hemodynamics

›Succinylcholine 1.5 mg/kg IV or rocuronium 1.2 mg/kg IV

›IV access and monitoring

›Two large-bore peripheral IVs

›Continuous cardiac monitoring

›Core temperature probe placement

Agitation management

›Benzodiazepines (first-line)

›Midazolam

›5–10 mg IM or IV

›Repeat every 5 minutes as needed

›No established maximum dose in excited delirium — titrate to effect

›Lorazepam

›2–4 mg IV

›Repeat every 5–10 minutes as needed

›Diazepam

›5–10 mg IV

›Alternative in IV access-available patients

›Antipsychotics (adjunctive)

›Haloperidol

›5–10 mg IM

›Use with caution — QTc prolongation risk

›Droperidol

›2.5–5 mg IM or IV

›Faster onset than haloperidol

›Olanzapine

›10 mg IM

›Avoid combination with benzodiazepines IV (respiratory depression risk)

›Refractory agitation

›Dexmedetomidine infusion

›0.2–1.5 mcg/kg/hr IV

›Dual benefit: sedation and sympatholysis

›Titrate to Richmond Agitation-Sedation Scale target

›Propofol infusion

›5–50 mcg/kg/min IV

›Requires intubation for higher doses

›Propofol infusion syndrome risk with prolonged high-dose use

›Phenobarbital

›10–20 mg/kg IV loading dose

›Rate of administration: maximum 60 mg/min

›For refractory seizures or agitation

Hyperthermia treatment

›External cooling

›Ice water immersion (preferred)

›Fastest cooling method available

›Target rate > 0.15°C/min

›Associated with improved survival at this rate

›Evaporative cooling (alternative)

›Tepid water spray with high-flow fan

›Effective but slower than immersion

›Ice packs to high-perfusion areas

›Axillae, groin, neck

›Adjunct only

›Cold IV fluids

›1–2 L chilled normal saline IV

›Helps with rhabdomyolysis fluid resuscitation simultaneously

›Pharmacological cooling adjuncts

›Dantrolene

›Conflicting evidence in stimulant-associated hyperthermia

›Not routinely recommended

›May be considered when hyperthermia persists despite cooling

›Paralysis and intubation

›Eliminates muscle heat production

›Non-depolarizing neuromuscular blockade (vecuronium, rocuronium)

›Reserved for hyperthermia refractory to sedation and cooling

Cardiovascular management

›Hypertension and tachycardia

›Adequate sedation is primary intervention

›Benzodiazepines often resolve hypertension and tachycardia

›Persistent hypertension after sedation

›Nicardipine IV

›5 mg/hr infusion, titrate by 2.5 mg/hr every 5–15 minutes

›Maximum 15 mg/hr

›Clevidipine IV

›1–2 mg/hr infusion, titrate by doubling every 90 seconds

›Maximum 32 mg/hr

›Phentolamine IV

›5 mg IV bolus, repeat as needed

›Alpha-adrenergic antagonist — addresses mechanism

›Avoid long-acting antihypertensives

›Risk of hemodynamic collapse as drug wears off

›Beta-blocker caution

›Pure beta-blockers generally contraindicated

›Risk of unopposed alpha-adrenergic stimulation

›May worsen hypertension paradoxically

›If beta-blockade required, use agents with alpha-1 antagonism

›Labetalol or carvedilol preferred

›Coronary vasospasm management

›Nitroglycerin sublingual or IV

›For suspected vasospasm-induced ischemia

›Calcium channel blockers

›Diltiazem or verapamil for vasospasm

›Takotsubo cardiomyopathy with cardiogenic shock

›Intra-aortic balloon pump consideration

›Cardiogenic shock unresponsive to vasopressors

›Veno-arterial ECMO

›Refractory cardiogenic shock

›Often resolves in days to weeks with supportive care

›Cardiac arrest management

›Standard ACLS protocol

›CPR and defibrillation per AHA guidelines

›Extracorporeal CPR (ECPR) consideration

›AHA 2025 guidelines support ECLS in toxicological arrest

›Transfer to ECMO-capable center if indicated

Rhabdomyolysis treatment

›IV fluid resuscitation

›Aggressive crystalloid hydration

›Normal saline or lactated Ringer solution

›Initial bolus 1–2 L IV for volume depletion

›Maintenance targeting UOP 1–3 mL/kg/hr

›Urine output monitoring

›Foley catheter placement mandatory

›Adjust rate based on UOP response

›Urinary alkalinization

›Sodium bicarbonate infusion (controversial)

›Some guidelines suggest targeting urine pH > 6.5

›Reduces myoglobin precipitation in tubules

›Avoid if pH > 7.45 or hypocalcemia present

›Renal replacement therapy

›If AKI progresses to oliguria unresponsive to fluids

›Nephrology consultation

›Continuous RRT preferred in hemodynamically unstable patients

Seizure management

›First-line antiepileptic

›Benzodiazepines

›Lorazepam 0.1 mg/kg IV (up to 4 mg per dose)

›Diazepam 0.15 mg/kg IV (up to 10 mg per dose)

›Midazolam 10 mg IM if no IV access

›Second-line antiepileptic

›Phenobarbital

›20 mg/kg IV loading dose

›Maximum infusion rate 60 mg/min

›Propofol

›1–2 mg/kg IV induction dose then infusion

›Requires intubation

09Special Populations/sp68

Pregnancy

›Maternal considerations

›Sympathomimetic effects in pregnancy

›Uterine vasoconstriction risk

›Placental abruption risk from hypertension

›Preterm labor from catecholamine surge

›Fetal monitoring

›Continuous fetal heart rate monitoring if viable gestation

›Obstetrics consultation for all pregnant patients

›Treatment modifications in pregnancy

›Benzodiazepines

›Generally acceptable in acute life-threatening agitation

›Neonatal respiratory depression risk if near delivery

›Risk-benefit strongly favors treatment in excited delirium

›Antipsychotics

›Haloperidol limited data in pregnancy

›Use lowest effective dose for shortest duration

›Cooling measures

›External cooling safe in pregnancy

›Hyperthermia itself is teratogenic in first trimester

›Avoid

›Dantrolene in pregnancy (Category C, limited data)

›Phentolamine with caution — uterine vasodilation possible

Geriatric

›Physiologic considerations

›Cardiovascular vulnerability

›Higher risk of dysrhythmias from catecholamine surge

›Pre-existing coronary artery disease increases MI risk

10Background/b93

Epidemiology

›Substance classification and prevalence

›α-PVP (alpha-pyrrolidinovalerophenone)

›Second-generation synthetic cathinone

›Street name: Flakka, gravel

›Schedule I controlled substance in the United States

›Prevalence data

›Significant epidemic documented in South Florida 2014–2015

›Re-emergent use documented in Europe and Asia 2020s

›Low cost (approximately $5 per dose) drives availability

›User demographics

›Young males predominate (median age 27–32 years)

›Approximately 79% male in case series

›Chemsex context increasingly documented

›Mortality and morbidity

›Mortality rate approximately 5% in severe cases

›Leading cause of death: refractory hyperthermia

›Cardiac dysrhythmia as second cause

›Polydrug use rate high

›85.6% co-use with synthetic cannabinoids

›Polydrug use complicates management and increases mortality

Pathophysiology

›Mechanism of action

›Monoamine transporter reuptake inhibition

›Potent dopamine transporter (DAT) inhibitor

›Potent norepinephrine transporter (NET) inhibitor

›Negligible serotonin transporter (SERT) activity

›Distinguishes from MDMA and mephedrone which have SERT activity

›Comparative potency

›More effective reinforcer than cocaine in animal models

›More effective reinforcer than methamphetamine

›Higher abuse liability score than classical stimulants

›Clinical toxicological consequences

›Dopamine excess

›Psychosis, hallucinations, paranoia

›Hyperthermia via hypothalamic dysregulation

›Reward pathway dysregulation and high addiction potential

›Norepinephrine excess

›Tachycardia and hypertension

›Peripheral vasoconstriction

›Coronary vasospasm

›Sympathomimetic toxidrome

›Hyperthermia mechanism

›Psychomotor agitation generates heat

›Impaired heat dissipation from vasoconstriction

›Central hypothalamic temperature setpoint dysregulation

›Rhabdomyolysis mechanism

›Sustained muscle hyperactivity from agitation

›Direct catecholamine-mediated muscle damage

›Hyperthermia-induced enzyme denaturation

›Pharmacokinetics

›Onset of action

›Intranasal: peak at approximately 40 minutes

›Smoked or IV: faster onset, minutes

›Duration of effect

›3–5 hours for intranasal route

›Variable depending on dose and route

›Metabolism

›Hepatic metabolism via CYP enzymes

›Urinary excretion of metabolites

›Not detected on standard immunoassay drug screens

›Confirmation by LC-MS/MS required

Therapeutic Considerations

›Evidence base for treatment

›Benzodiazepines

›ACEP and AHA guidelines support benzodiazepines as first-line

›No specific antidote available for α-PVP

›Treatment is supportive and symptomatic

›Cooling interventions

›Ice water immersion shown superior to other methods

›Target cooling rate > 0.15°C/min associated with survival benefit

›Class I recommendation level from emergency medicine literature

›Physical restraints

›Associated with sudden death — positional asphyxia

›Should not be maintained without concurrent chemical sedation

›Minimize duration of restraint

›ASAM/AAAP stimulant use disorder guidelines

›No FDA-approved pharmacotherapy for stimulant use disorder

›Behavioral interventions remain cornerstone of treatment

›Contingency management has strongest evidence base

›Referral to addiction medicine services

›Connect all patients to treatment resources at discharge

›Harm reduction counseling regarding drug screen limitations

›Substance use disorder screening tools

›AUDIT-C for alcohol

›DAST-10 for drug abuse

›Cardiotoxicity considerations

›QTc prolongation

›Direct drug effect and indirect via antipsychotic co-administration

›Continuous ECG monitoring during acute phase

›Vasospasm and acute MI

›Catecholamine-mediated coronary vasospasm

›No role for thrombolytics if vasospasm mechanism suspected

›Takotsubo cardiomyopathy

›Catecholamine-mediated stress cardiomyopathy

›Typically reversible with supportive care

11Patient Discharge Instructions/pdi28

copy discharge instructions

›Discharge instructions for Flakka (alpha-PVP) toxicity

›What happened

›You were treated in the emergency department for toxic effects from a synthetic stimulant drug called Flakka (alpha-PVP)

›This drug is extremely dangerous and can cause life-threatening heart problems, seizures, dangerously high body temperature, and kidney damage

›Medications prescribed

›Take all prescribed medications exactly as directed

›Do not take other stimulants, cocaine, or amphetamines with any medications

›Activity restrictions

›Rest at home for 24–48 hours

›Avoid all stimulant substances including Flakka, cocaine, methamphetamine, and similar drugs

›Do not drive or operate machinery for at least 24 hours

›Return to emergency department immediately for

›Chest pain or pressure

›Difficulty breathing

›Seizures or convulsions

›Confusion or agitation that is worsening

›Dark brown or tea-colored urine

›Decreased urine output

›Fever over 38.5°C (101.3°F)

›Thoughts of hurting yourself or others

›Follow-up appointments

›Primary care physician within 48–72 hours

›Addiction medicine consultation recommended

›Psychiatry if mood or thought symptoms persist

›Resources

›Poison Control Center: 1-800-222-1222 (available 24 hours)

›Substance abuse helpline: SAMHSA 1-800-662-4357

12References/r31

Guidelines and key sources

›Primary references

›Kolesnikova TO et al. DARK Classics in Chemical Neuroscience: Alpha-Pyrrolidinovalerophenone (Flakka). ACS Chemical Neuroscience. 2019. PMID: 30384587

›Mechanism of action, abuse liability, and comparative potency data

›Nobrega L, Dinis-Oliveira RJ. The Synthetic Cathinone Alpha-Pyrrolidinovalerophenone (alpha-PVP): Pharmacokinetic and Pharmacodynamic Clinical and Forensic Aspects. Drug Metabolism Reviews. 2018. PMID: 29540067

›Pharmacokinetics, clinical presentation, and management

›Umebachi R et al. Clinical Characteristics of Alpha-Pyrrolidinovalerophenone (alpha-PVP) Poisoning. Clinical Toxicology. 2016. PMID: 27227375

›Severity classification, laboratory findings prevalence data

›Beck O et al. Toxicity Evaluation of Alpha-PVP: Results From Intoxication Cases Within the STRIDA Project. Clinical Toxicology. 2016. PMID: 27412885

›European epidemiology and clinical outcomes

›De la Rosa G et al. Acute Pharmacological Effects of Alpha-PVP in Humans: A Naturalistic Observational Study. Frontiers in Pharmacology. 2025. PMID: 40672373

›Recent human pharmacological data

›Society guidelines

›Lavonas EJ et al. 2023 AHA Focused Update on Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning. Circulation. 2023

›ACLS in toxicological emergencies

›Cao D et al. Part 10: Adult and Pediatric Special Circumstances of Resuscitation: 2025 AHA Guidelines for CPR and Emergency Cardiovascular Care. Circulation. 2025

›Updated toxicological cardiac arrest management

›The ASAM/AAAP Clinical Practice Guideline on the Management of Stimulant Use Disorder. Journal of Addiction Medicine. 2024. PMC: 11105801

›Stimulant use disorder treatment and referral standards

›Sandau KE et al. Update to Practice Standards for Electrocardiographic Monitoring in Hospital Settings. AHA Scientific Statement. Circulation. 2017

›Cardiac monitoring recommendations

›Additional references

›Palamar JJ et al. Flakka Use Among High School Seniors in the United States. Drug and Alcohol Dependence. 2019. PMID: 30709657

›US adolescent prevalence data

›Richards JR et al. Treatment of Toxicity From Amphetamines, Related Derivatives, and Analogues: A Systematic Clinical Review. Drug and Alcohol Dependence. 2015. PMID: 25724076

›Systematic review of sympathomimetic toxidrome treatment

›Banks ML et al. Synthetic Cathinones (Bath Salts). Journal of Emergency Medicine. 2014. PMID: 24565885

›Foundational synthetic cathinone toxicology review

Evidence & Review