01Approach to the Critical Patient/attcp64

Immediate stabilization

›Airway and respiratory threats

›Inspiratory spasms risk airway compromise

›Early intubation for progressive spasms or apnea

›Rapid sequence intubation preferred

›Apneic episodes from brainstem dysfunction

›Bag-mask ventilation bridge

›Avoid stimulation during laryngoscopy preparation

›SpO2 target >= 94%

›Supplemental oxygen titration

›Mechanical ventilation if spasms prevent adequate oxygenation

›Hemodynamic and autonomic threats

›Dysautonomia physiology

›Alternating hypertension and hypotension

›Tachycardia and bradycardia episodes

›Myocarditis pattern

›ECG for arrhythmia and ST changes

›Continuous telemetry mandatory

›Vasopressor support for refractory hypotension

›Norepinephrine first-line

›MAP target >= 65 mmHg

›CNS agitation and seizure control

›Extreme agitation and hydrophobic spasms

›Midazolam IV for immediate sedation

›Ketamine IV adjunct for spasm control

›Seizure management

›Lorazepam IV first-line

›Levetiracetam for recurrent seizures

02History/hx64

Exposure history

›Animal contact

›Dog bite or scratch in Asia or Africa

›Accounts for 98% of global human rabies deaths

›Incubation 1 to 3 months typical; range 5 days to years

›Bat exposure in the Americas

›Most common source in the US (70% of indigenously acquired cases)

›May be unrecognized — bat found in room of sleeping person

›Other animals

›Raccoon, skunk, fox in North America

›Any warm-blooded mammal in endemic regions

›Exposure characteristics

›Bite location

›Head and neck bites shorten incubation period

›Highly innervated areas increase transmission efficiency

›Wound depth

›Deep muscle bites higher risk

›Scratch or mucous membrane exposure counts

›Geographic region at time of exposure

›Asia and Africa highest endemic burden

›Travel to endemic region without pre-exposure prophylaxis

Prodromal and neurological symptoms

›Early prodromal phase (2-10 days)

›Fever, malaise, headache, nausea

›Nonspecific; easily attributed to other causes

›Missed at first clinical encounter in nearly all US cases

›Pain, paresthesia, or pruritus at bite site

›Earliest and highly suggestive neurological symptom

03Physical Exam/exam65

Vital signs and general appearance

›Hemodynamic and autonomic profile

›Tachycardia

›Autonomic denervation and dysautonomia

›Loss of heart rate variability is characteristic

›Hyperpyrexia

›Temperature > 39 C common

›Hypothalamic dysfunction contributor

›Blood pressure lability

›Alternating hypertension and hypotension

›Vasomotor instability reflects brainstem involvement

›Respiratory pattern

›Ataxic or periodic breathing

›Inspiratory spasms visible on observation

›General appearance

›Extreme agitation and combativeness

›May require immediate sedation for safety

›Alternating with periods of calm and lucidity

›Hypersalivation

›Foaming at the mouth

›Inability to swallow secretions

Neurological examination

›Provocative tests

›Hydrophobia test

›Offer water; visible pharyngeal spasms and terror response

›Do not force — observation of reaction to offered cup is sufficient

›Aerophobia test

›Blow air toward face; triggers spasms

04Differential Diagnosis/ddx66

Infectious encephalitides

›Herpes simplex encephalitis (HSV-1)

›ICD-10 B00.4

›Temporal lobe predilection on MRI

›Hemorrhagic changes; fever and focal deficits

›No hydrophobia; acyclovir responsive

›Treat empirically until excluded

›CSF PCR diagnostic

›Arboviral encephalitides

›West Nile, Eastern equine, La Crosse

›Seasonal and geographic epidemiology

›Serology and PCR panel for differentiation

›No hydrophobia or aerophobia

›Mosquito exposure history

›Acute flaccid paralysis in West Nile

›Enteroviral encephalitis

›ICD-10 A85.0

›Summer-fall seasonality

›Rash and hand-foot-mouth disease associations

›CSF pleocytosis typically more pronounced

›RT-PCR of CSF or throat swab

›No specific antiviral treatment

Non-infectious and autoimmune

›Autoimmune encephalitis

›Anti-NMDAR encephalitis ICD-10 G04.81

›Subacute psychiatric features and seizures

›Orofacial dyskinesias

›LGI1 and other antibody-mediated encephalitis

05Laboratory Tests/lt69

Antemortem rabies diagnostic panel

›Saliva RT-PCR

›Sensitivity approximately 86% for RABV RNA

›Highest yield specimen type

›Collect early in disease course

›Coordinate with CDC or state public health laboratory

›Specialized testing not available at routine hospital labs

›Sequential sampling if initially negative

›Nuchal skin biopsy

›Full-thickness punch biopsy at nape of neck

›Must include hair follicle-containing dermis

›Immunohistochemistry for rabies antigen in cutaneous nerves

›High specificity when positive

›Sensitivity improved with multiple biopsy sites

›Repeat biopsy if initial negative and suspicion persists

›CSF analysis for rabies

›RT-PCR for RABV RNA

›Sensitivity approximately 45% antemortem

›Higher sensitivity postmortem

›Rabies virus neutralizing antibody (RFFIT)

›CSF antibody in unvaccinated patient confirms diagnosis

›Serum antibody appears later in disease

›No single test sufficient; multiple specimen types required

›IDSA/ASM 2024 guideline recommendation

›Contact CDC for coordinated antemortem panel

Routine laboratory studies

›Complete blood count

›Neutrophil leukocytosis common

06Diagnostic Tests/dt74

Scoring Systems

›Encephalitis severity and etiology tools

›GCS

›Serial monitoring for deterioration

›GCS < 8 indicates need for airway protection

›FOUR Score (Full Outline of UnResponsiveness)

›More sensitive than GCS for brainstem function

›Brainstem reflexes and respiratory pattern components

›No rabies-specific validated scoring system exists

›Clinical presentation with hydrophobia/aerophobia is diagnostic trigger

›Exposure history plus neurological syndrome guides management

›Prognosis indicators

›Favorable factors for aggressive ICU treatment

›Prior partial vaccination before symptom onset

›Young age and immunocompetent status

›Bat RABV variant (slightly better prognosis)

›Unfavorable prognosis markers

›Canine RABV variant

›No prior vaccination

›Rapid progression to coma

MRI

›MRI brain indications and findings

›Preferred imaging modality over CT for rabies encephalitis

›Better brainstem and limbic system visualization

›Laothamatas AJNR 2003; Bhat et al. Journal of Neuroimaging 2021

›Non-comatose phase findings

›Subtle ill-defined T2/FLAIR hyperintensities

›Brainstem, hippocampi, hypothalami, deep subcortical white matter

07Disposition/dispo45

ICU admission

›All symptomatic cases require ICU admission

›Neurological instability

›Seizures and altered consciousness

›Fluctuating GCS requiring close monitoring

›Respiratory instability

›Inspiratory spasms with apnea risk

›Mechanical ventilation often required

›Autonomic instability

›Hemodynamic lability requiring vasoactive support

›Cardiac arrhythmia monitoring

›No role for observation unit or outpatient management

›Disease is almost 100% fatal once symptomatic

›Average survival 5.7 days from symptom onset (furious form) without ICU

›Only approximately 34 well-documented survivors in medical literature

›Goals-of-care discussion with family on admission

›Palliative approach appropriate for most cases

›Aggressive approach reserved for select favorable-prognosis cases

Infection control and transfer

›Infection control precautions

›Contact and droplet precautions

›Gown and gloves for all patient contact

›Mask for potential saliva exposure

›Healthcare worker exposure protocol

›PEP for any mucous membrane or open wound contact with patient saliva

›Occupational health evaluation within 24 hours

›Transfer considerations

›Tertiary center with neurology and infectious disease

08Treatment/t115

Airway and ventilatory management

›Early intubation strategy

›Indications for intubation

›Progressive inspiratory spasms

›Apneic episodes

›GCS < 8 or inability to protect airway

›RSI medication selection

›Ketamine 1-2 mg/kg IV induction

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

›Avoid stimulation during laryngoscopy preparation

›Lights dimmed

›Minimize auditory stimuli

›Ventilator management

›Lung-protective strategy

›Tidal volume 6-8 mL/kg ideal body weight

›PEEP 5-8 cmH2O starting point

›Sedation on ventilator

›Deep sedation required to prevent self-extubation

›Midazolam or propofol infusion

›ARDS management if develops

›Prone positioning when P/F ratio < 150 mmHg

›Neuromuscular blockade consideration

Sedation and symptom control

›Agitation and spasm management

›Midazolam IV infusion

›Loading dose 0.1-0.2 mg/kg IV

›Infusion 0.05-0.2 mg/kg/hour titrated to effect

›Richmond Agitation Sedation Scale (RASS) target -2 to -3

›Ketamine IV adjunct

›1-2 mg/kg IV bolus for acute severe agitation

›Infusion 0.5-2 mg/kg/hour for sustained spasm control

›Analgesic and bronchodilatory properties beneficial

›Opioid analgesia for comfort

›Morphine 0.1 mg/kg IV PRN

›Fentanyl infusion in hemodynamically unstable patients

›Seizure management

›First-line acute seizure

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

›Repeat after 5 minutes if no response

›Second-line and maintenance

›Levetiracetam 60 mg/kg IV loading dose (max 4500 mg)

›Maintenance 1000-3000 mg IV per day in divided doses

›Avoid phenytoin as sole agent

›Less effective for limbic seizures

›Valproate alternative

Autonomic and cardiac management

›Dysautonomia treatment

›Sympathetic surges

›Short-acting beta-blocker for tachycardia-hypertension episodes

›Esmolol infusion 50-300 mcg/kg/minute

›Labetalol IV 5-20 mg boluses alternative

›Minimize triggering stimuli

›Dim lighting, quiet environment

›Cluster nursing care activities

›Hemodynamic support

›Vasopressors for refractory hypotension

›Norepinephrine 0.01-0.5 mcg/kg/minute titrated to MAP >= 65 mmHg

›Vasopressin 0.03 units/minute adjunct

›Arrhythmia management

›Antiarrhythmics per ACLS protocol

›Transcutaneous pacing for complete heart block

›Nimodipine consideration for vasospasm

›60 mg PO/NG every 4 hours if vasospasm suspected

›Severe hypotension risk; use with extreme caution

Post-exposure prophylaxis (PEP) — pre-symptomatic only

›PEP is the only effective intervention

›Must be initiated before symptom onset

›No benefit once clinical symptoms develop

›Life-saving when given promptly after exposure

›Wound care as first step

›Wash wound with soap and water for >= 15 minutes

›Apply povidone-iodine antiseptic

›Unvaccinated PEP schedule (ACIP 2022)

›Human rabies immune globulin (HRIG)

›20 IU/kg infiltrated into and around wound on day 0

›Remaining volume IM at anatomically distant site

›Do not exceed 20 IU/kg; excess blunts vaccine response

›Rabies vaccine IM (4-dose schedule)

›Days 0, 3, 7, and 14

›Deltoid injection in adults

›Anterolateral thigh in infants

›Previously vaccinated PEP schedule

›Rabies vaccine IM on days 0 and 3 only

›No HRIG required

›2-dose schedule per ACIP 2022

›Immunocompromised patients

›5-dose vaccine schedule regardless of prior vaccination

›Serology to confirm seroconversion after series

Treatment not recommended

›Milwaukee Protocol — abandoned

›Therapeutic coma plus ketamine plus ribavirin plus amantadine

›At least 64 documented failures (Jackson, Clin Infect Dis 2025)

›No longer recommended by any major authority

›Ribavirin and interferon-alpha

›Disappointing results in clinical use

›No survival benefit demonstrated

›Agents contraindicated

›Corticosteroids

›May aggravate rabies disease

›Associated with worse outcomes

›Minocycline

›Experimental use without clinical benefit

›Avoid outside research protocols

Supportive care and complication management

›Fluid and nutritional support

›IV hydration

›Oral intake impossible once hydrophobia develops

›Maintain euvolemia; monitor for DI and SIADH

›Enteral nutrition via NGT

›Early enteral feeding when intubated

›Aspiration precautions

›Complication management

›Diabetes insipidus

›Desmopressin 1-4 mcg IV/SC every 8-12 hours

›Urine output and serum sodium monitoring

›SIADH

›Fluid restriction 800-1000 mL/day

›Hypertonic saline for symptomatic hyponatremia

›GI bleeding prophylaxis

›Pantoprazole 40 mg IV daily

›Enteral feeding when feasible reduces mucosal stress

09Special Populations/sp69

Pregnancy

›Rabies in pregnancy

›PEP is NOT contraindicated in pregnancy

›Rabies is almost universally fatal without PEP

›Risk-benefit strongly favors PEP administration

›HRIG and rabies vaccine are safe in all trimesters

›Maternal rabies encephalitis

›ICU admission for maternal stabilization

›Fetal monitoring when gestation is viable

›Delivery considerations

›Emergency caesarean section for fetal indications in viable pregnancy

›Neonatal team standby

›Medication safety in pregnancy

›Midazolam and lorazepam

›Use is justified given severity of disease

›Neonatal benzodiazepine effects if near delivery

›Levetiracetam for seizures

›Preferred over valproate in pregnancy

›Supplemental folate ongoing

›Ketamine

›Generally acceptable for symptom control

›Uterine blood flow effect monitoring

Geriatric

›Modified clinical presentation in older adults

›Atypical and subdued agitation

›Confusion and delirium may dominate over classic hydrophobia

›Hydrophobia and aerophobia may be less dramatically expressed

›Increased comorbidity burden

10Background/b76

Epidemiology

›Global burden

›Approximately 59,000 human rabies deaths annually worldwide

›98% linked to dog bites in Asia and Africa

›Jackson AC, Rev Sci Tech 2018

›Asia and Africa bear 95% of rabies mortality

›India contributes approximately 36% of global burden

›Rural populations disproportionately affected

›United States and Americas epidemiology

›Fewer than 5 human cases per year in the US

›Bat exposures account for 70% of indigenously acquired US cases

›Pieracci et al., MMWR 2019

›Domestic animal transmission essentially eliminated in US

›Canine rabies variant eliminated through vaccination programs

›Wildlife reservoir (bats, raccoons, skunks, foxes) persists

›Case fatality and survivors

›Almost 100% fatal once clinical symptoms develop

›Approximately 34 well-documented survivors in world literature

›Most survivors had partial vaccination before symptom onset

›Average survival 5.7 days from symptom onset (furious form)

›ICU support extends survival but rarely prevents death

›Significant neurological sequelae in rare survivors

Pathophysiology

›Viral entry and transport

›RABV inoculated into muscle or subcutaneous tissue at bite site

›Initial replication in muscle cells at inoculation site

›Enters peripheral nervous system via neuromuscular junction

›Retrograde axonal transport to CNS

›Travels along peripheral motor and sensory nerves

›Transport rate approximately 12-24 mm/day explains incubation variability

›Incubation period 1-3 months typical; 5 days to years reported

›Shortened by bites to head and neck

›Prolonged with bites to extremities

›CNS invasion and spread

›RABV infects limbic system, hypothalamus, brainstem

›Explains hydrophobia, aerophobia, autonomic dysfunction

›Hippocampal involvement drives behavioral changes

›Centrifugal spread from CNS to peripheral organs

›Salivary glands — enables transmission to next host

›Cornea, skin — enables antemortem diagnosis

›Minimal neuronal death despite severe encephalopathy

›Neuronal dysfunction rather than destruction

›Explains why brain appears relatively intact at autopsy

›Cardiac pathophysiology

›Vagus nerve neuritis

›Autonomic denervation of heart

›Loss of heart rate variability

›Myocarditis

›Direct viral invasion of cardiomyocytes

›Mimics STEMI on ECG (Park et al., Open Forum Infect Dis 2019)

›Catecholamine surge from dysautonomia

›Stunned myocardium physiology

›Supraventricular and ventricular arrhythmias

Therapeutic Considerations

›No curative antiviral therapy exists

›Milwaukee Protocol abandoned

›Therapeutic coma rationale was to protect CNS while immune response develops

›At least 64 failures; single survivor attributed to pre-existing partial immunity

›Jackson, Clin Infect Dis 2025

›Ribavirin, interferon-alpha, amantadine all failed in clinical use

›Appolinario and Jackson, Antiviral Therapy 2014

›Research into monoclonal antibodies ongoing

›Treatment goal dichotomy

›Aggressive ICU care — select cases only

›Favorable factors: prior partial vaccination, bat RABV, young age, immunocompetent

›Neutralizing antibody in CSF early suggests immune response

›Palliative/comfort-focused care — most cases

›Canine RABV variant has no documented survivors

›Comfort sedation relieves suffering in near-universally fatal disease

›Prevention is the only reliable intervention

›Pre-exposure prophylaxis (PrEP) for at-risk groups

›Single-visit 2-dose intradermal schedule now validated (Overduin et al., Lancet Infect Dis 2024)

›Traditional IM schedule days 0 and 7 still used

›PEP within 24 hours of exposure is goal

›Wound cleansing alone reduces transmission by 50%

›HRIG neutralizes virus at wound site before neural uptake

›Global elimination goal: zero human rabies deaths from dogs by 2030

›WHO/OIE/FAO/GARC joint initiative

›Mass dog vaccination as primary strategy

11Patient Discharge Instructions/pdi52

copy discharge instructions

›You have been evaluated for possible rabies exposure

›Rabies is a serious viral infection affecting the brain

›It is almost always fatal once symptoms appear

›Prevention (post-exposure prophylaxis shots) is the only reliable treatment

›If you are receiving rabies shots (post-exposure prophylaxis)

›Complete all scheduled doses exactly as directed

›Days 0, 3, 7, and 14 for unvaccinated persons

›Missing doses reduces protection — contact your doctor immediately if you miss one

›Warning signs — return to the emergency department immediately if you develop

›Numbness, tingling, or itching at the animal bite site

›May be the earliest neurological sign of rabies

›Do not wait to see if it resolves

›Difficulty swallowing or fear of water or swallowing

›Pathognomonic sign requiring emergency evaluation

›Call 911 if unable to safely travel

›Extreme anxiety, confusion, agitation, or unusual behavior

›Unexplained aggression or mood change

›New hallucinations

›Fever with any neurological symptom

›Headache, stiff neck, or seizure with fever

›Muscle spasms or jerking movements

›Difficulty breathing or repeated choking spells

›Respiratory muscle spasms are an emergency

›Call 911

›Wound care instructions

›Keep the bite wound clean and dry

›Wash gently with soap and water twice daily

12References/r46

Guidelines and key sources

›ACIP rabies prevention guidelines

›Rao AK et al. MMWR 2022 — modified PrEP vaccination schedule

›Single-visit 2-dose schedule validation

›Updated PEP recommendations

›Rupprecht CE et al. MMWR 2010 — 4-dose PEP schedule

›Reduced from 5 doses; non-inferior immunogenicity

›Standard unvaccinated PEP schedule

›CDC resources

›CDC Yellow Book 2025 — Wallace and Shlim

›Travel-associated rabies prevention

›PrEP and PEP protocols for travelers

›CDC antemortem diagnostic guidance

›Specimen types and collection protocols

›Public health laboratory coordination

Key clinical studies

›Pathogenesis and clinical features

›Jackson AC. Rev Sci Tech 2018 — rabies medical perspective

›Comprehensive review of pathogenesis, clinical features, management

›Hemachudha T et al. Lancet Neurol 2013 — neuropathogenesis and management

›Seminal review; diagnosis and management framework

›Warrell DA. Trans R Soc Trop Med Hyg 1976 — clinical picture in humans

›Classic clinical description of hydrophobia and furious form

›Treatment evidence

›Willoughby RE et al. NEJM 2005 — Milwaukee Protocol original case

›Single survivor; protocol subsequently abandoned after 64+ failures

›Jackson AC. Clin Infect Dis 2025 — demise of Milwaukee Protocol

›Definitive statement abandoning the protocol

Evidence & Review