Critical Care Combined

What is a seizure?

momentary disruption of brain function resulting from hypersynchronous, atypical firing of cortical neurons

What is epilepsy?

recurrent, unprovoked seizures; patients with epilepsy generally have a chronic pathological state or genetic susceptibility which predisposes them to seizures

What is status epilepticus?

a seizure lasting greater than 5 mins

What is refractory status epilepticus?

persistent seizures despite appropriate use of two IV medications one of which is a BZD

What is super-refractory status epilepticus?

seizures that persist or re-emerge in the setting of an IV anesthetic infusion for more than 24 hours

What are the two hallmark features of seizures?

hyperexcitability and neuronal hypersynchrony

What is hyperexcitability?

a neuron’s response to stimulation is intensified; rather than firing a single action potential in response to synaptic input the cell may fire multiple action potentials

What is neuronal hypersynchrony?

increases neuron firing within region of the brain; cells near one another repeatedly fire

What is an inhibitory neurotransmitter?

GABA

What are excitatory neurotransmitters?

glutamate, aspartate, acetylcholine

What can provoke a seizure?

intoxication, withdrawal, trauma, meningitis, psychiatric, metabolic derangements, non-comliance

What are true about unprovoked seizures?

more difficult to determine causes, may or may not need treatment with antiepileptic medications (true unprovoked first time seizure does not require medication therapy

What are the steps in acute seizure management?

1. achieve rapid and safe termination of the seizure

2. prevent seizure recurrence

3. avoid adverse drug effects on the CV and respiratory systems

What class if first line in an acute seizure?

benzodiazepine

What is the MOA of benzodiazepines in seizures?

bind to the GABA receptor complex and increase GABA-ergic transmission

What are the ADRs of BZDs?

impaired consciousness, hypotension, respiratory depression

What two benzodiazepines are first line in acute seizures?

lorazepam (IV) and diazepam (IV)

What benzodiazepines are second line?

midazolam (IM) and diazepam (PR)

What IV antiepileptics should be used second line in acute seizures?

phenytoin, valproic acid, and levetiracetam

What dose of phenytoin should be used?

20mg/kg (max 2000mg)

What dose of valproic acid should be used?

40mg/kg (max 3000mg)

What dose of levetiracetam should be used?

60mg/kg (max 4500mg)

What is the MOA of phenytoin?

stabilizes neuronal membranes and decreases seizure activity by increasing efflux OR decreasing influx of Na ions across the cell membranes

What are the pharmacokinetics of phenytoin?

peak brain levels ~6 mins after infusion is complete; metabolized by hydroxylation in the liver; 90% protein bound

What are the ADRs of phenytoin?

P-450 interactions, hirsutism, enlarged gums, nystagmus, yellow browning of skin, teratogenicity, osteomalacia, interference with folate metabolism, neuropathies, rashes/fever (SJS, neutropenia, thrombocytopenia)

True or False: phenytoin is primarily eliminated by hepatic metabolism; follows Michaelis Menten or saturable PK

true

What is the goal phenytoin level?

10-20 mcg/dL (total phenytoin)

What levels of therapeutic drug monitoring are associated with provoking seizures?

>30

When should you check phenytoin levels?

4-6h after loading dose (ensure level >10); once on maintenance therapy can check levels in 2-4 days

What must you correct phenytoin level for?

albumin less than 3.5 and poor renal function (CrCl <30mL/min)

What is the formula to calculate the true phenytoin level if albumin <3.5?

True Phenytoin level = Measured phenytoin level/ [(0.275 x albumin) + 0.1]

What is the formula to calculate the true phenytoin level if CrCl <10 mL/min?

True Phenytoin level = Measured phenytoin level / [(0.1 x albumin) + 0.1]

What is the MOA of levetiracetam?

precise mechanism is unknown; binds to synaptic vesicle protein SV2A which is involved in neurotransmitter release

What are the pharmacokinetics of levetiracetam?

renally cleared; needs dose adjustment for CrCl <30 mL/min and ESRD

What are the ADRs of levetiracetam?

agitation (aggression, anger, emotional liability) and drowsiness

What is the MOA of valproic acid?

increases GABA synthesis & release; reduces neuronal excitation mediated by NMDA receptors; blocks voltage dependent Na channels

What are the ADRs of valproic acid?

drowsiness, headache, thrombocytopenia, hyperammonemia, hepatotoxicity

What is the MOA of lacosamide?

stabilizes hyper-excitable neuronal membranes and inhibits repetitive neuronal firing by enhancing slow inactivation of Na channels

What are the ADRs of locasamide?

dizziness, abnormal vision, ataxia

True or False: after several doses of IV BZDs and ASM with continued seizures a patient can no longer protect their airway and they are intubated

true

True or False: after paralytics are given the patient will continue to exhibit the seizure symtpoms

false

What does a patient require if they become intubated and administered paralytics?

continuous IV infusion of ASM and long-term monitoring EEG

What is the MOA of propofol?

general anesthetic causing global CNS depression, likely through GABA-A receptor agonism and inhibition of NMDA receptor

What is the preparation of propofol?

lipid emulsion, caution with egg and soy allergy

What are the PK parameters of propofol?

short acting, highly lipphilic

What are the ADRs of propofol?

hypotension, decrease awareness, increased triglycerides, propofol-related infusion syndrome (PRIS)

What is the dosing of propofol?

IV infusion beginning at 10 mcg/kg/min and increasing to a maximum of 60m cg/kg/min

What is the MOA of midazolam?

bind to stereospecific BZD postsynaptic GABA neuron enhancing the inhibitory effect of GABA on neuronal excitability

What is the dosing of midazolam?

0.2 mg/kg OV push + IV infusion starting at 0.05 mg/kg/hr up to 2mg/kg/hr

What are the pharmacokinetics of midazolam?

short acting, lipophilic and can accumulate after extended use and in renal failure

What are the adverse effects of midazolam?

respiratory depression, hypotension

What is the MOA of phenobarbital?

long-acting barbiturate with sedative, hypnotic and anti-seizure properties

What is the dosing for pehnobarbital?

loading dose: 20mg/kg IV

maintenance dose: 2mg/kg IV divided into 2-3 doses

What are the pharmacokinetics of phenobarbital?

very long half life— up to almost 80 hours

Whare are the ADRs of phenobarbital?

hypotension, respiratory depression, decreased gut motility, hepatotoxicity

What is the MOA of ketamine?

produces a cataleptic-like state where patient is dissociated from the surrounding environment; non-competitive NMDA receptor antagonist

What is the dosing of ketamine?

loading dose: 1.5mg/kg IV

maintenance dose: 0.1-4 mg/kg/hr IV infusion

What are the pharmacokinetics of ketamine?

short acting, lipophilic and can accumulate after extended use and in renal failure

What are the ADRs of ketamine?

prolonged emergence from anesthesia w/ agitation, confusion, delirium; arrythmia

What non-pharmacologic can be used for super refractory status epilepticus?

ketogenic diet

What is a ketogenic diet?

regime focused on a reduction in carbohydrates alongside a relative increase in protein and fat to promote fat metabolism

What are the proposed mechanisms of the ketogenic diet?

slow energy production and potentiate GABA inhibition, alter neurotransmitter localization and release, alter mitochondrial dynamics in the face of oxidative stress, or modulate proinflammatory cytokine expression & release

What is the goal of therapy for status epilepticus?

burst suppression for 24-48hrs

What are modifiable risk factors for ischemic stroke?

hypertension, smoking, postmenopausal hormonal therapy, oral contraceptives, physical activity, obesity, asymptomatic carotid stenosis, diabetes, dyslipidemia, atrial arrythmias, non-atrial arrhythmia cardiac conditions

How can you determine if a patient is at risk for a a stroke?

CHA2 DS2 VASc

What is ischemic brain injury due to?

blood loss to an area of the brain

What are the two things that can cause an ischemic stroke?

• local thrombus formation from rupture of cerebral artery atherosclerosis plaque

• embolism from intra or extracranial origins

What does FAST stand for?

face, arms, speech, and time

What quick assessment can be done to determine if someone can be having a stroke?

FAST

What patient evaluation tool should be used once the patient arrives to the hospital?

NIH Stroke Scale

What is the primary goal at first evaluation?

confirm the patient’s symptoms are due to ischemia rather than other neurological process; consider stroke mimics

What are required neuro imaging once stroke has been confirmed through patient evaluation?

non-contrast head CT scan— rule out hemorrhage

What other nuero imaging (NOT required) can be done to determine if the patient had a stroke?

CT stroke study or MRI

What is the role of the pharmacist in assessing lytic eligibilty?

consider contraindications to fibrinolytics, blood pressure goals, current weight

What is the treatment option for someone that is within 4.5 hours of symptom onset?

fibrinolytics ± thrombectomy

What is the treatment option for a large vessel occlusion that is 4.5 - 24 hours since symptom onset?

thrombectomy

What is the treatment option for a small vessel occlusion that is 4.5 - 24 hours since symptom onset?

permissive hypertension; heparin infusion

When are fibrolytics approved for?

within 4.5h of symptom onset

What are the absolute contraindications for IV fibrinolytics?

<18, ischemic stroke within 3 months, intracranial/intraspinal surgery within 3 months, gastrointestinal malignancy or GI bleed within 21 days, LMWH within 24hrs, infective endocarditis, intra-axial intracranial neoplasm, unclear time of onset or >4.5h since symptoms onset, current intracranial hemorrhage, severe head trauma within 3 months, subarachnoid hemorrhage, platelets < 100,000, INR > 1.7, aPTT >40s, DOAC within 48h, aortic arch dissection

What is the maximum time that it should take for a lytic to be administered from the time of arrival?

60 mins

What is the MOA of IV fibrinolytics?

activate plasminogen → plasminogen activates plasmin → plasmin dissolves fibrin

What is the dose of alteplase?

0.9 mg/kg max 90mg

What is the dose of tenecteplase?

0.25 mg/kg max 25mg

How does alteplase get administered?

bolus 10% of dose over 1 min then infusion 90% of dose over 60 mins

What is the half-life of alteplase?

5 mins

How does Tenecteplase get administered?

IV push over 5-10 seconds

What is the half-life of tenecteplase?

20-24 mins

Which IV fibrinolytic is more specific for fibrin?

tenecteplase

When compared with alteplase, what is true about tenecteplase?

improved perfusion when given prior to thrombectomy, better functional outcomes at 90 days, similar rates of bleeding

What BP is detrimental and increases the risk of hemorrhagic conversion?

>220/120

What BP is required for a thrombolytic bolus?

<185/110 mmHg

What BP is required for a thrombolytic infusion?

<180/105 mmHg

When is permissive hypertension allowed?

if patient meets exclusion criteria and fibrinolytic is NOT given (unless >220/110)

What are the first line medications for BP management in stroke management?

labetalol, nicardipine

What are the second line medications for BP management in stroke management?

hydralazine, enalaprilat, clevidipine

What are possible complications of fibrinolytics?

angioedema, symptomatic ICH

When should you consider symptomatic ICH?

worsening of symptoms, change in mental status, nausea, vomiting

What does ICH stand for?

intracranial hemorrhage

How do you diagnose an ICH?

immediate head CT scan (no dye)

How do you treat an ICH?

stop alteplase infusion, order fibrinogen level, if fibrinogen < 150: cryoprecipitate, tranexamic acid 1,000mg IV x1 OR aminocaproic acid