Acute Neurology

Prognosis of brain damage after cardiac arrest

By Kai Knudsen, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital and
Christian Rylander, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
Updated 2018-12-21


Prognostic factors at least 72 hours after cardiac arrest

InvestigationPositive Predictive ValueNegative Predictive Value
Reaction levelRLS ≤ 4RLS ≥ 6
Pupil reflexNo valueBilateral abscence
Corneal reflexNo valueBilateral abscence
NSE in serum Lower than 33 μg/LHigher than 60 μg/L
EEG background activityContinousDiscontinous (Burst Suppression)
EEG reactivityPreservedDisappearance
EEG patternBenignHighly malignant
Flat background < 10 uV with periodic discharges
suppression- Burst suppression > 50%"
CT of the brain within 24 hoursNo valueSigns of anoxic brain damage
MR of the brain day 2-5Limited injuriesDiffuse widespread injuries

The neurological prognosis is very poor in the following combinations:

1. RLS 7-8 after 3 days calculated from cardiac arrest AND bilateral absence of pupil and corneal reflexes.
RLS 7-8 after 3 days calculated from cardiac arrest AND bilateral absence of SEP N20 potential.

2. RLS 7-8 after 4 days calculated from cardiac arrest AND at least two of the following
a. Status of myoclonus <48 h after cardiac arrest
b. NSE values above 60 μg/L at 48h and increasing 24-48 h
c. Burst-suppression or status EP of EEG
d. Diffuse anoxic brain damage at MR

Status Epilepticus – Treatment

Written by a working group led by Johan Bjellvi, Specialist Physician in Neurology at Sahlgrenska University Hospital in Gothenburg, Sweden.

This document reflects current procedures at Sahlgrenska University Hospital in Gothenburg, and contains recommendations on off label use of drugs. Last updated 2017-05-31.


Background and definition

Status epilepticus (SE) is a condition of abnormally prolonged or frequent epileptic seizures, which in some cases poses a risk of long-term effects.1 The overall mortality rate at SE is up to 20% and depends, inter alia, on the patient’s age, sexual orientation, seizure type, consciousness and in some cases time spent on treatment. The cause of SE is, however, the most crucial prognostic factor.2 The majority of patients with SE have no prior known epilepsy, which further underlines the importance of acute etiological investigation.2 The treatment of SE is done according to accepted practice in defined steps, where the next drug is added if SE is not terminated.

Treatment of convulsive status epilepticus

Convulsive SE (or generalized tonic-clonic SE) is the most serious form of SE and involves a generalized tonic-clonic seizure lasting more than 5 minutes or repeated generalized tonic-clonic seizures during the same period without the patient regaining consciousness between seizures. The time limit has been determined based on the fact that the majority of generalized tonic-clonic seizures expire spontaneously before this time. Already after 30-60 min attack activity, there is a risk of nerve cell injury, so the aim should be to control the symptoms within 60 min.

The clinical diagnosis is usually simple, but with long-term convulsions SE, the motor symptoms often become less prominent. An important differential diagnosis of convulsive SE is psychogenic non-epileptic seizures, which, if confused with SE, can lead to risky over treatment.3 Seizures (brain stem-triggered tone increase) can also be confused with SE.

The following treatment schedule can be used for convulsive SE in the vast majority of clinical situations. In some specific cases, for example in intensive care and early postoperative post neurosurgery, it is often motivated to prematurely insert or re-enter anesthetic agents.4

STABILIZATION PHASE (0-5 minutes from seizure start)

Initial measures:

  • Note the start time of the attack.
  • Assess and secure vital parameters.
  • Initiate continuous monitoring of ECG and blood pressure.
  • Observe symptoms, consider differential diagnoses.
  • Take capillary P-glucose: give in hypoglycaemia 50 ml 30% glucose iv and 100 mg thiamine iv.
  • Give oxygen through nasal cannula or by mask.
  • Establish two peripheral venous catheters (at least pink needles in size).
  • Take blood samples: P-glucose, Hgb, LPC, TPC, CRP, P-electrolytes including Ca, albumin, liver parameters, lactate, serum concentrations of current drugs for patients on anti-epileptic medicines, intoxication screening samples as needed.
  • In case of suspected meningitis/encephalitis, prepare for cultures and empirical treatment (at GCS < 6 and/or focal neurological failure, lumbar puncture is performed only after CT brain).

STEP 1: EARLY STATUS EPILEPTICUS (about 5-30 minutes from seizure start)

As soon as SE > 5 min, please do one of the following:

  • Diazepam (Stesolid® novum 5 mg/ml) 10 mg iv (5-7.5 mg if the patient weighs <40 kg), injection time about 2 min.
  • Lorazepam (Ativan® 4 mg/ml, off-label license) 4 mg iv (2 mg if the patient weighs <40 kg), injection time about 2 min.

If the patient lacks venous access, give in the first place:

  • Midazolam (Dormicum®, Midazolam®) 10 mg intranasally or 10 mg intramuscularly (5 mg if the patient weighs <40 kg). Intranasal midazolam is divided into two equal doses in each nostril by syringe with luer and an atomizer (“Olive Olive”/MAD) syringe.

If the patient lacks venous access, give in second hand:

  • Midazolam (Buccolam®) 10 mg buckalt
  • Diazepam (Stesolid®, Diazepam®) 10 mg rectally via cleanser or rectal solution

If SE has not stopped 5 minutes after a given dose of diazepam or lorazepam and the patient has not received prehospital treatment, the dose may be repeated once. In this case, parallel processing is prepared in step 2 below.

Comment: According to randomized controlled studies, diazepam and lorazepam are safe and effective for early SE early prehospital and hospital.10 The same applies to midazolam in prehospital use. 11 Also for intranasal midazolam, there is support in randomized studies, but evidence is weaker for adults than for children.12 Given doses differ between studies, which complicates direct comparisons between the preparations.8.10 The effect of lorazepam may, for pharmacokinetic reasons, be expected to be slightly longer than for other preparations, and in some reviews it has been concluded that it is more effective than diazepam.10 However, the difference is small and others have assessed the preparation as equivalent.8 It is important to give benzodiazepines at a sufficiently high dose. All benzodiazepines may cause respiratory failure but the risk of respiratory failure is higher for untreated convulsive SE than for SE treated with benzodiazepines.13 Some guidelines have weight-based doses for benzodiazepines, 14 but most indicate fixed standard doses for adults.4-6.8.9

STEP 2: ESTABLISHED STATUS EPILEPTICUS (approximately 20-60 minutes from seizure)

If SE continues, give phosphenytoin or sodium valproate, in other hand, levetiracetam. Note contraindications. For all preparations, doses may be need to be reduced with regard to age and other diseases, but primarily a full-dose preparation is chosen. Give half dose if the patient is already on the preparation in question. Continuous monitoring of pulse and blood pressure is necessary for the infusion of phosphenytoin, desirable for sodium valproate and levetiracetam. Note any contraindications.

Pro-Epanutin treatment

Phosphenytoin (Pro-Epanutin® 50 mg FE/ml) 20 mg FE/kg, max 1500 mg FE, diluted with NaCl 0.9% or glucose 5% and given as an infusion at a rate of 150 mg FE/min. Note that phosphenytoin is prescribed as phenytoin equivalents (FE). Hypotension or bradycardia that may occur during ongoing infusion can often be treated with reduced infusion rate and/or simultaneous infusion of fluid via another infusion.

Contraindications: AV block II-III, SA block, heart rate < 50/min, systolic blood pressure < 100 mmHg, porphyria, progressive myoclonal epilepsy.

Treatment with Pro-Epanutin

Body weight (kg)Prescribed dose (mg FE) Number of ml Dilute with the number of mlTotal Volume ml Injection Speed (ml/min) Injection Time (min)
≥ 80 1500303060610
701400282856610
60120024244868
50100020204067
4080016163266

Sodium Valproate treatment

Sodium Valproate (Ergenyl®, an ampull = 400 mg) 40 mg/kg, max 3000 mg, given in 10 min. Note: Avoid combination with meropenem due to drug interaction.

Contraindications: Pregnancy, known mitochondrial disease, known disorder in the urea cycle, porphyria. Caution in liver disease.

Treatment with Sodium Valproat

Body Weight (kg) Prescribed dose Ergenyl (mg) Number of Injection BottlesInjection Time (min)
≥ 80 30007.510
702800710
602400610
502000510
401600410

Levetiracetam treatment

In case of contraindication or complicated interactions, Levetiracetam (Keppra®, Kevesy®, Levetiracetam) provides 60 mg/kg, max 4500 mg, infusion time 10 min. Keppra and generic Levetiracetam are available as a concentrate for solution for infusion 100 mg/ml, which is mixed with NaCl 0.9% as below. Kevesy is available as a reconstituted solution in 100 ml and 500, 1000 or 1500 mg levetiracetam per package. Dose reduction in severe renal insufficiency.

Levetiracetam Treatment

Body Weight(kg) Prescribed Dose levetiracetam (mg) Volume (ml) Number of injection bottlesVolume of dilution liquid (ml) Infusion time (min)
≥ 80 450045930010
70420040830010
60360035730010
50300030630010
40250025530010

Serum concentrations of S-phenytoin and S-valproate are taken 1-2 hours after the completion of the infusion and, if necessary, a refill dose is given. Maintenance treatment is given twice daily with daily serum concentrations, trough value before morning dosage, but clinical progress is crucial. For levetiracetam, 1500 mg x 2 is usually an appropriate maintenance dose. For maintenance treatment, the drugs may be given as slow injection/infusion, for phosphenytoin 25-50 mg FE/min with pulse and blood pressure every 5 minutes. For patients who have previously been on epilepsy medications these are prescribed in parallel.

Parallel with the treatment, aetiological investigation continues.

Prepare CT brain scan if the cause of SE is not obvious (eg, medication deposition in known epilepsy).

Prepare lumbar puncture in suspected meningitis/encephalitis.

Comment:

The evidence of anti-epileptics as treatment of status epilepticus after benzodiazepines comes mainly from open studies. There is support for the use of the above recommended preparations, but it is uncertain if any preparation is more effective or safe than others.10.15 We recommend phosphenytoin and sodium valproate in levetiracetam due to the long experience of the former preparations in convulsive SE. Recommended doses are consistent with a current evidence-based guideline.8 There is no evidence of effective serum concentrations at SE. It is reasonable to seek high concentrations after loading dose, about 100 μmol/l for S-phenytoin and 800 μmol/L for S-valproate. For maintenance treatment of SE, reference should be made to valley values ​​in the upper reference range of the respective preparations, S-phenytoin 70-90 μmol/l (usually 40-80 μmol/l), S-valproate 500-800 μmol/L (normally 300-700 μmol/L). This often corresponds to a maintenance dose of 4-5 mg FE/kg and day and 20-25 mg valproate/kg and day respectively. For levetiracetam, dose-response relationship is unavailable. S-levetiracetam can be analyzed acute in suspicion of toxicity values, for example in connection with renal impairment. Both phenytoin and valproate have a high degree of protein binding, which means that total serum concentrations are difficult to age at high age, low albumin value, renal failure, liver failure and combination therapy.

STEP 3: REFRACTORY STATUS EPILEPTICUS (> 60 MIN)

If convulsive SE does not cease within 10-20 minutes after treatment in step 2, the patient is intubated, if not earlier, anesthesia treatment is commenced and the patient is placed in the ventilator. The treatment is done together with the anesthetist on call. The initial goal is to achieve and maintain clinical seizure freedom. If possible, start continuous EEG monitoring as soon as possible.

If the patient lacks clinical seizure symptoms and EEG does not show any remaining electrographic seizure activity or electrographic SE, wake up and extubation or continued anesthesia treatment is discussed after consultation with a neurologist.

If the patient still has clinical seizure symptoms and/or EEG shows continued electrographic seizure or electrographic SE, anesthesia is deepened with the goal of maintaining clinical and electrographic seizure freedom for at least 24 hours. Often this means that a so-called “Burst Suppression” pattern on EEG is aimed.

Simultaneous treatment with antiepileptic drugs is given with anesthetic treatment. For patients who have not previously received epilepsy medications, it is usually motivated to administer two or at most three antiepileptics in relatively high doses. Refractory SE requires careful monitoring of the development of secondary organ effects and side effects of the treatment itself. In addition to basic intensive care, active normothermia or moderate hypothermia may be considered. Etiological investigation continues in parallel with treatment and usually begins with a CT brain scan and lumbar puncture, if this has not already been done.

The anesthetic treatment begins in the vast majority of cases with an infusion of propofol. This is ideally combined early with midazolam, as it is difficult to achieve the desired depth of sleep only with propofol without exceeding recommended doses. In longer periods of treatment, this anesthesia is supplemented with thiopental in some cases, but at the same time the propofol dose should be reduced or the preparation is discontinued. Ketamine may in some cases be considered.

Below are the dosage suggestions for these preparations. Intervals for treatment doses are wide and individual adjustments are necessary as well as close dialogue between responsible neurologist, intensive care physician and clinical neurophysiologist. Continuous EEG reading and positioning for adjustment of treatment regimen should be done at least twice a day, more often with treatment with tiopental and in the few cases the treatment target is isoelectric EEG. When the patient is awakened from deep anesthesia, this should be done gradually and with careful monitoring of the return of clinical or electrographic seizure activity or abundant epileptiform activity.

  • Propofol (Diprivan®, Propolipid®, Recofol®, Propofol) bolus dose 2-3 mg/kg followed by infusion 1 to 3 mg/kg/h. Additional bolus doses 1-2 mg/kg can be administered to descend into sleep depth. Maximal dose of 4 mg/kg/h should be avoided and should not be used for more than 48 hours due to the risk of propofol infusion syndrome.
  • Midazolam (Dormicum®, Midazolam®) may be inserted at an early stage to supplement propofol. Treatment may be initiated with bolus dose 0.2 mg/kg followed by infusion 0.05-0.4 (-2) mg/kg/h. Tachyfylaxis (need for increasing doses) develops over time.
  • Tiopental (Pentocur®, Pentothal®) may be used alone or as a supplement for patients already propofolised. Induction dose of 2-3 mg/kg is used for patients who are not already anesthetized. For other patients, the dose should be adjusted and possibly fractionated. Additional bolus doses of 50 mg every 2-3 minutes may be repeated to clinical and electrographic seizure control. Continued infusion is added with 2 (-5) mg/kg. Note that after reaching sleep depth, the rate of infusion must be reduced to avoid risk of overdose. In this situation, close contact is required between the responsible neurologist, the intensive care physician and the clinical neurophysiologist.
  • Ketamine (Ketalar®, Ketamine) is usually not the first choice but can be considered as a supplement. Initial bolus dose of 0.5-3 mg/kg with continued infusion of 0.5-5 mg/kg can be used.

Comment:

Because long-term convulsive SE represents a high risk of nerve cell damage and system complications, international consensus prescribes early intubation and general anesthesia.2.5-8 Complications are common both as a result of given treatment and of SE itself and need to be monitored actively. Metabolic acidosis is a natural consequence of SE and needs to be rarely corrected.16 There are no controlled studies in the management of the choice of preparation and duration and intensity of treatment. The above is based on practical experience and international expert recommendations.2.17 Thiopentone should be considered a second-hand option due to higher complication risk.2.17 Anesthetic treatment with the aim of isoelectric EEG poses a high risk of serious complications and is reserved for selected cases after special consideration.

If SE continues or returns 24 hours after initiation of anesthesia treatment, you are talking about superrefractory SE. This occurs in patients with obvious, severe acute brain injury (trauma, infection, stroke), and in patients with no known epilepsy who get SE without obvious cause. In the latter case, extensive ethiological investigation is important, since etiology is crucial to the prognosis. Particular consideration should be given to autoimmune encephalitis and to assess immunological treatment as soon as bacterial and viral meningoencephalitis has been ruled out, although positive antibody responses are not yet available.17 A large number of treatment methods are used in super refractory SE and may be considered on an individual basis. There is no evidence of treatment with antiepileptics associated with refractory and super refractory SE. International expertise recommends that you limit yourself to two high dose antiepileptic drugs, avoiding frequent drug changes and taking into account the interaction and side effects profile.

Other types of Status Epilepticus

For other forms of SE, the treatment is more individualized, and choice of treatment depends on the type of SE as well as on the patient’s general condition. The scientific support for treatment is more limited than for convulsive SE, and specific recommendations are often lacking in published guidelines. Compared with convulsive SE, it is more unclear for these types of SE to what extent SE continues to contribute to long-term effects.2,18 Convulsive SE can pass into non-convulsive SE. This is a condition with high mortality and is treated according to practice of convulsive SE as described above.2.5

Focal Non-Convulsive SE

It is a condition with varying degrees of consciousness in combination with electrographic seizure activity. By definition, there are no major motor manifestations, but minor movements, e.g. myoclonia around the eyes may occur. EEG is crucial for the diagnosis of focal non-convulsive SE. However, the EEG image is often unclear, which means that the EEG image, clinical symptoms and treatment responses must be compared to the assessment. Non-convulsive SE does not in itself involve any risk of system complications, and it is uncertain to what extent the epileptic activity affects long-term prognosis and the patient’s condition in addition to underlying etiology.2,5,18

According to international recommendations, non-convulsive SE should be treated with benzodiazepines and antiepileptics as soon as possible. Levetiracetam 2000-3000 mg iv may be considered as an alternative to phosphenytoin and sodium valproate given the favorable side-effect and interaction profile of this preparation. An alternative with the same benefits but less supportive experience is lacosamide (Vimpat®) 200-400 mg iv. Oral treatment is sometimes possible. Anesthesia treatment should only be applied in exceptional cases to focal non-convulsive SE which has not begun as convulsive SE with regard to complication risk and uncertain treatment gains.2,5,6,14,18

Focal Motor SE

Focal clonic long-term dysfunction is often a part of epilepsy in adults following stroke or traumatic brain injury. The patient is generally awake or mildly unconscious. Considering the level of consciousness and other co-diseases, if one or two doses of diazepam or lorazepam should not break SE consider to give non-sedative antiepileptics with a favorable side-effect and interaction profile. Sodium valproate, levetiracetam or lacosamide may be used. Intravenous anesthesia treatment is not relevant.

Absence Status Epilepticus

Seems like mild unconsciousness or confusion, and the EEG image shows generalized spike wave activity with frequency around 3 Hz. The condition has very good prognosis and is most often treated successfully with benzodiazepines according to the schedule for convulsive SE, alternatively with a half dose repeated as needed. If abscence status is due to discontinuation of antiepileptics, these are reinserted, otherwise sodium valproate is given. 18 Intravenous anesthesia treatment is not applicable.

Status Epilepticus (SE) after cardiac arrest

Among patients returning circulation after cardiac arrest, it is common for electrographic SE with or without clinical symptoms. For this situation, refer to the routine cardiac arrest – intensive care protocols.

References

  1. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification or Status Epileptic. Epilepsy 2015; 56: 1515-23.
  2. Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol 2015; 14: 615-24.
  3. Hocker SE. Status Epilepticus. Continuum (Minneap Memory) 2015; 21: 1362-83.
  4. Shorvon S, Baulac M, Cross H, Trinka E, Walker M, TaskForce on Status Epilepticus of the ICfEA. The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus. Epilepsy 2008; 49: 1277-85.
  5. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010; 17: 348-55.
  6. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17: 3-23.
  7. Claassen J, Silbergleit R, Weingart SD, Smith WS. Emergency neurological life support: status epilepticus. Neurocrit Care 2012; 17 Suppl 1: S73-8.
  8. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epileptic in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016; 16: 48-61.
  9. Healthcare Improvement Scotland. SIGN 143: Diagnosis and management of epilepsy in adults. , 2015.
  10. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant Therapy for Status Epilepticus. Cochrane Database Syst Rev 2014: CD003723.
  11. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J With 2012; 366: 591-600.
  12. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous medications for acute convulsive seizures: A network meta-analysis. Neurology 2015; 85: 1859-68.
  13. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J With 2001; 345: 631-7.
  14. Pharmaceutical treatment of epilepsy – new recommendation. Information from the Swedish Medicines Agency 2011: 1-17.
  15. Yasiry Z, Shorvon SD. De relatieve effectiviteit van vijf antiepileptische geneesmiddelen in de behandeling van benzodiazepine-resistente convulsieve status epilepticus: een meta-analyse of gepubliceerde studies. Season 2014; 23: 167-74.
  16. Hocker S. Systemic complications of status epilepticus-An update. Epilepsy Behav 2015; 49: 83-7.

Steroid Substitution for Adults

By Kai Knudsen, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
Updated 2018-12-21


Dosage of Betametason is individual, weight-based and is determined and prescribed by the surgeon. Children’s steroid schedule is recommended for children < 30 kg. For children weighing 30-60 kg, the half-adult schedule is recommended. Children over 60 kg are counted as adults and recommended adult schedule.

Injection Betametason 4 mg/mlDose (ml)Dose (mg)
Preoperatively2 ml x 18 mg x 1
Day 12 ml x 28 mg x 2
Day 22 ml + 1.5 ml8 mg + 6 mg
Day 31 ml x 24 mg x 2
Day 41 ml x 24 mg x 2
Day 50 5 ml x 22 mg x 2
Day 60 5 ml x 22 mg x 2
Day 70 5 ml x 12 mg x 1
Day 80 5 ml x 12 mg x 1
OrallyTablet 0.5 mgDose (mg)
Preoperatively (night before)16 x 18 mg x 1
Day 116 x 28 mg x 2
Day 216 + 128 mg x 6 mg
Day 38 x 24 mg x 2
Day 48 x 24 mg x 2
Day 54 x 22 mg x 2
Day 64 x 22 mg x 2
Day 74 x 12 mg x 1
Day 84 x 12 mg x 1