Problem: prolonged status epilepticus leads to upregulation of NMDA receptors, glutamate-mediated excitotoxicity and resistance to conventional antiepileptics.
1. Refractory status epilepticus – either generalized or complex partial status epilepticus that fails to respond to first and second line therapies
2. Superrefractory status epilepticus – status epilepticus that remains unresponsive despite 24 hours of therapy with general anesthesia
Mechanisms of conventional AEDs:
- GABA agonist – cortical inhibition / reduction of epileptogenicity and lateral spread; e.g. benzodiazeipne, valproate, propofol, barbiturates, clonazepam, clobazam, vigabatrin, and topiramate
- Na blockers – phenytoin, carbamazepine, lamotrigine, oxcarbazepine, zonisamide, and rufinamide
- Ca blockers – gabapentin and pregabalin,
Molecular Changes in Prolonged Status Epilepticus:
- GABA A downregulation – depletes receptors for benzodiazepines, etc, also subunit alterations in GABAA receptor lead to impaired binding –> resistance to GABA-mediated AEDs
- p-glycoprotein molecular transporter upregulation – occurs at the level of BBB ~20 to 30 minutes into status epilepticus; these transporters export phenytoin and phenobarbital molecules and efficacy of phenytoin and phenobarbital is greatly diminished
- upregulation of NMDA receptors – leads to glutamate-mediated activation of these receptors, leads to intracellular calcium influx and excitotoxicity
- proinflammatory mediators can also alter BBB permeability and induce neuronal damage which can lead to AED resistance and excitotoxicity
Advantages of Ketamine in RSE / SRSE:
- NMDA receptor antagonists target a receptor known to be upregulated during SE/RSE/SRSE
- NMDA receptor antagonists provide neuroprotection (studied in TBI population)
- drug is readily available and cheap
- sympathomimetic properties = vasopressor sparing effects
- side effect profile low
- mild hypertension
- ICP elevation? – old literature, should not be factored in
- Effectivity: 110 patients = 56.5% responded (cessation of SE)
- Duration of Treatment: 16 hours to 140 days
- Usual dosing: bolus 0.5 to 5 mg/Kg then continuous infusion 0.12 to 10mg/kg/hr, duration of 2h to 27d
- most common duration: 7 days, most responding within 48-72h
- Start ketamine within 24-48 hours of SE onset, after failure of first trial with anesthetics of choice (midazolam, propofol, pentobarbital)
- Suggested dosing: bolus 3mg/kg, followed by continuous infusion up to 10mg/kg/hr, duration up to 7 days
Zeiler, F. A. “Early Use Of The NMDA Receptor Antagonist Ketamine In Refractory And Superrefractory Status Epilepticus”. Critical Care Research and Practice 2015 (2015): 1-5.
What to do when patients say they are PCN allergic?
- determine whether an IgE-mediated response (i.e. anaphylaxis) occurred
- If so
- third- and fourth-generation cephalosporins can be used generously
- first- and second-generation cephalosporins with R1 side chains similar to PCN should be avoided (see table below)
- first- and second-generation cephalosporins with different R1 side chains can be given (see table below)
- Skin testing not recommended for determining safety of administering cephalosporins to PCN-allergic patients (because it is unreliable)
- Skin testing does predict true PCN allergy
Penicillin and cephalosporins known to have a risk of allergic cross reaction:
Patients who are allergic to amoxicillin or ampicillin should avoid the cephalosporins listed, because they have similar R1-group side chains.
Myth: ~10% of patients with history of PCN allergy will have an allergic reaction if given cephalosporin.
True: Overall cross-reactivity rate is ~1% when using first gen cephalosporins or cephalosporins with similar R1 chains. PCN-allergic patients, use of 3rd or 4th generation cephalosporins carries a negligible risk of cross allergy.
Campagna, James D. et al. “The Use Of Cephalosporins In Penicillin-Allergic Patients: A Literature Review”. The Journal of Emergency Medicine 42.5 (2012): 612-620.
Summarizing an old article on the CSF Cell Index published in 2004, study has not been validated, but information is “nice to know.”
The CSF cell index is a ratio between the blood cells in the ventricles (in intracranial hemorrhage) and the peripheral blood. At the time of bleeding, blood in the ventricles is diluted within the CSF, and the relationship between WBC:RBC should equal that in the peripheral blood. This ratio, called the CSF cell index, should approximate 1 in the absence of infection.
The CSF cell index is calculated using to the following formula:
This study reported that the cell index rises 3 days before diagnosis of a catheter-related ventriculitis, and proper antimicrobial treatment led to a rapid decrease of the cell index. The study concluded that a significant increase in the cell index is highly indicative of nosocomial EVD-related ventriculitis in patients with IVH, and that the increase of the cell index usually precedes diagnosis by conventional means by 3 days.
Pfausler, B. et al. “Cell Index ? A New Parameter For The Early Diagnosis Of Ventriculostomy (External Ventricular Drainage)-Related Ventriculitis In Patients With Intraventricular Hemorrhage?”. Acta Neurochirurgica 146.5 (2004): 477-481.
Clinical signs of ventriculitis are difficult to recognize in SAH patients who are sedated, who have recently undergone neurosurgery, or have a sterile inflammatory response in the CSF due to the SAH. Clinical symptoms of SAH (headache, nuchal rigidity, AMS) closely resemble bacterial ventriculitis.
- new fever
- Fever occurs in 40 % after SAH +/- infection
- new nuchal rigidity
What to do?
Exclude other causes of infection
- physical examination
- blood / sputum / urinary cultures
Exclude other causes of AMS (HCP and ischemia)
- Neuroimaging with plain CT scan
- Clincally suspected bacterial ventriculitis – empirical antibiotic treatment for bacterial ventriculitis, but negative CSF cultures
- Confirmed Bacterial ventriculitis – (+) CSF culture for bacteria; if staph epidermidis – needs 2 consecutive positive cultures to rule out contamination
- No good discriminative tests, treatment initiated on first suspicion
- Antibiotic regimen for bacterial ventriculitis
- ceftriaxone 2 g BID + vancomycin 2 g BID
- ceftazidime 2 g TID + vancomycin 2 g BID if external CSF catheter in place
- culture negative – discontinue ABx (after 72h)
- culture positive – 2 weeks
- Physical Examination
- clinically suspected bacterial ventriculitis
- confirmed bacterial ventriculitis
- Blood work:
- CBC (WBC)
- BMP (glucose)
- Blood cultures x 2
- sputum cultures
- urinalysis with reflex to urine culture if (+)
- Plain CT scan
- CSF studies
- cell count
- Gram stain and culture
- CSF glucose
- CSF protein
- calculate cell index
- CSF lactate
- *CSF cytokine levels
- *CSF PCR for bacterial pathogens
- Treatment x 2 weeks
- ceftriaxone 2 g BID + vancomycin 2 g BID
- ceftazidime 2 g TID + vancomycin 2 g BID if (+) EVD
- discontinue within 72 hours if cultures are negative
Hoogmoed, J. et al. “Clinical And Laboratory Characteristics For The Diagnosis Of Bacterial Ventriculitis After Aneurysmal Subarachnoid Hemorrhage”. Neurocritical Care (2016): 1-9.
- Hypothermia for Brain Enhancement Recovery by Neuroprotective and Anticonvulsivant Action after Convulsive Status Epilepticus Trial
- multicenter, open-label, parallel-group, RCT
- 11 French ICUs
- 03/2011 to 01/2015
- convulsive status epilepticus – >=5mins continuous clinical seizure activity or >2 sz without return to baseline in interval
- admitted <8hours after onset
- return to baseline state of consciousness
- need for ‘E’ surgery that would preclude therapeutic hypothermia
- post-anoxic status epilepticus
- imminent death
- DNR order
- bacterial meningitis
- lower T to 32-34C x 24h
- IV fluids at 4C, ice packs at groin and neck, cold-air tunnel around body
- repeated propofol boluses if seizures continue followed by maintenance IV infusion to maintain burst-suppression EEG pattern x 24 hours
- Outcomes assessed:
- Primary: absence of functional impairment at 90d (GOS score of 5)
- death rates: ICU, hospital, day 90
- progression to EEG-confirmed status epilepticus (coma +/- subtle convulsive movements but with generalized or lateralized ictal discharges on EEG between 6 and 12 hours after randomization
- refractory status epilepticus on day 1 (continuous or intermittent clinical seizures, EEG-confirmed seizures, or both despite two AEDs within 24 hours after onset)
- super-refractory status epilepticus (ongoing or recurrent status epilepticus between 24 and 48 hours after initiation of anesthetic treatment)
- total seizure duration
- ICU LOS
- Hospital LOS
- 268 patients included in analysis, 138 in hypothermia group, 130 in control group
- PRIMARY OUTCOME = GOS5 — 49% vs 43% (OR 1.22 95% CI 0.75-1.99 p=0.43)
- 15 (hypothermia group) vs 29 patients had progression to EEG-confirmed status epilepticus (OR 0.40 95% CI 0.2-0.79, p=0.009)
- no other secondary outcomes differed significantly
- no beneficial effect of therapeutic hypothermia vs standard care alone in patients with status epilepticus who are receiving mechanical ventilation.
Current Evidence for Therapeutic Hypothermia in Neurocritical Care:
- TBI- controversial
- refractory intracranial hypertension, ischemic stroke and ICH – incorporated into treatment
- Bacterial meningitis with coma – may be harmful
Legriel, Stephane et al. “Hypothermia For Neuroprotection In Convulsive Status Epilepticus”. New England Journal of Medicine 375.25 (2016): 2457-2467.
<click here for MS Powerpoint file>
“Introduction To Imaging: What Am I Looking At?”. YouTube. N.p., 2016. Web. 19 Dec. 2016.
||INR ≥ 1.4: Vitamin K 10 mg IV + KCentra OR FFP 10-15 ml/Kg IV if not available
||50 g activated charcoal if within 2 + KCentra 50 units/kg IV
50 g activated charcoal within 2 h + idarucizumab 5 g IV
HD or repeat idarucizumab for refractory bleeding
Other DTIs: KCentra 50 units/kg IV
||Protamine 1 mg IV q 100 U heparin for the past 2–3 h
(up to 50 mg in a single dose)
Within 8h: Protamine 1 mg IV per 1 mg enoxaparin (up to 50 mg in single dose)
Within 8–12 h: Protamine 0.5 mg IV per 1 mg enoxaparin (up to 50 mg in single dose)
>12 h: minimial utility
Dalteparin, Nadroparin and Tinzaparin:
Within 3–5 half-lives: Protamine 1 mg IV per 100 anti-Xa units (up to 50 mg in single dose)
OR rFVIIa 90 mcg/kg IV if protamine contraindicated
||rFVIIa 90 mcg/kg IV
||Activated PCC (FEIBA) 20 units/kg IV or rFVIIa 90 mcg/kg IV
||Cryoprecipitate 10 units IV OR
Antifibrinolytics (TXA 10–15 mg/kg IV over 20 min or aminocaproic acid 4–5 g IV) if cryoprecipitate contraindicated
||DDAVP 0.4 mcg/kg IV × 1
If neurosurgical intervention: Platelet transfusion (one apheresis unit)
Frontera, Jennifer A. et al. “Guideline For Reversal Of Antithrombotics In Intracranial Hemorrhage”. Neurocritical Care 24.1 (2015): 6-46.
ENLS 2017 Pharmacotherapy. Neurocritical Care Journal.