Chapter 8. Procedural Sedation and Analgesia

Procedural sedation and analgesia (PSA) has been proven safe and efficacious within the ED environment, and should be utilized when patients undergo painful procedures. The most important step beyond monitoring the patient involves extensive preparation, and at conclusion of the procedure, patients should return to their mental and physiologic baseline. In scenarios where the patient's severity of illness questions the applicability of ED sedation, one must judiciously review the risks and consider consultation with the anesthesiologist. Although the degrees of sedation can at times be ambiguous, observing the patient's progression and remaining vigilant for respiratory depression can diminish untoward effects and facilitate successful recovery and disposition.

Sedation is often utilized to facilitate care in the ED. PSA has replaced the previous nomenclature of “conscious sedation.” The American College of Emergency Physicians (ACEP) defines PSA as the “administration of sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. Procedural sedation and analgesia is intended to result in a depressed level of consciousness that allows the patient to maintain oxygenation and airway control independently.”

The controversy over nonanesthesiologists providing PSA primarily involves this last statement. Patients can easily progress to each successive stage of sedation to the point of apnea and respiratory arrest. The practitioner's goal should be to avoid progressive unconsciousness and remain capable in managing their cardiopulmonary function when necessary. Despite concerns, the efficacy and safety of ED procedural sedations have been demonstrated in numerous studies, and PSA has become a core skill in emergency medicine training and practice.

Levels of Sedation

PSA is a spectrum involving light, moderate, deep, and general anesthesia levels necessitating the practitioner to be capable of recognizing the levels of sedation, and be prepared to rescue the next level of sedation if necessary. Some experts have proposed adding a separate category for dissociative anesthetics such as ketamine since its performance and side-effect profile differ a great deal from other forms of sedation. Each degree of sedation increases risk of cardiopulmonary instability with a likely need for aggressive intervention.

• Minimal sedation (anxiolysis)

A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and physical coordination may be impaired, airway reflexes, and ventilatory and cardiovascular functions are unaffected.

• Moderate sedation/analgesia (“conscious sedation”)

A drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

• Deep sedation/analgesia

A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. Reflex withdrawal from a painful stimulus is not considered a purposeful response. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

• General anesthesia

A drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Patients often require assistance in maintaining a patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

Assessment

PSA is indicated for the anticipated need of pain relief, amnesia, and anxiolysis required for the patient's comfort. The sedative rugs, the dosage, depth, and duration of sedation must be considered prior to the initiation of the procedure. PSA requires a presedation assessment, sedation monitoring, and postsedation assessment prior to disposition. In the presedation assessment, history of prior anesthesia/sedation complications should be evaluated along with comorbid conditions and allergies. The American Society of Anesthesiologists (ASA) developed a physical status classification system. It describes patients' illness severity as categories I–VI (Table 8–1). Each category involves escalating degrees of progressive systemic disease, and is meant to be used for assessing the illness of the patient prior to surgery.

Patients scored as an ASA I–II can be reasonably sedated within the ED without elevating the risk of sequelae from underlying systemic pathology. Once the patient is deemed to be more ill (ie, ASA III–IV), it is often more appropriate to involve anesthesia within the parameters of elective or non-life-threatening scenarios. ASA III classifications have been shown to be an independent risk factor for adverse outcomes in general anesthesia and pediatric sedation cases. Categories V and VI are usually not applicable within the ED setting. The downside to ASA classification is the inherent ambiguity of the definitions and the variable scoring between practitioners.

Patients should be screened for recent illnesses, hospitalizations, smoking, illicit drug use, GERD, CAD, HTN, cirrhosis, and other metabolic disorders as well. Pulmonary diseases such as asthma, cystic fibrosis, pulmonary fibrosis, tracheomalacia, and COPD could all potentially result in profound hypoxemia. Patient using supplemental oxygen at home would indicate an ASA class of III or IV requiring a critical review for the need of ED PSA. A history of GERD may predispose the patient to passive aspiration while sedated, and could result in laryngospasm or aspiration pneumonitis. A history of significant CAD or severe CHF would suggest a higher risk for myocardial events should hypoxemia or hypotension ensue. ED PSA would not be a satisfactory option for these patients.

Food and medication allergies should also be documented since egg and soy allergies would preclude the option to utilize propofol. Liver disease may indicate a decreased ability to metabolize barbiturates and benzodiazepenes, potentially prolonging sedation. Methohexital may induce seizure activity in patients with a history of a seizure disorder.

Airway assessment is integral in establishing an adequate sedation plan should aggressive maneuvers be necessary. Will the planned procedure involve occluding the airway (ie, oral laceration repairs, GI endoscopy)? Does the patient wear dentures, or have a large tongue, an overbite, or micrognathia? Patients with a Mallampati classification greater than III, inability to open the mouth more than 4 cm, a thyromental distance less than 6 cm, history of cervical spinal inflexibility, or history of previous difficult intubation all indicate a high risk for intubation failure. Should the patient be deemed at a high risk for airway failure, appropriate precautions should be implemented and the decision to abort the PSA should be entertained.

Airway adjuncts beyond direct laryngoscopy such as an intubating LMA, GlideScope, light wand, or fiberoptic scope should remain at the bedside. Supplemental oxygen may need to be delivered via non-rebreather (NRB) or nasal trumpet if the patient becomes unexpectedly obtunded. Above all else, protection of the patient's airway, and avoidance of respiratory depression, is tantamount to a successful sedation.

Hemodynamic stability must also be maintained. Many sedative agents and regimens result in vasodilatation, and once the patient develops a depressed level of consciousness, his or her sympathetic output may also decrease further potentiating bradycardia and decreased mean arterial pressure. Patients taking antihypertensive medications and those with dehydration or acute blood loss anemia should be volume resuscitated prior to PSA. Cardiac patients taking calcium channel blockers or beta-blockers have been shown to have a higher incidence of bradycardia and hypotension with PSA. Pressor agents such as norepinephrine, epinephrine, phenylephrine, dopamine, or ephedrine should be available in the event that fluid refractory shock takes place.

Patients should also be assessed for recent oral intake. Patients are at risk for aspiration of gastric contents when they reach deeper levels of sedation and lose their protective airway reflexes. Although small ED studies have shown no significant adverse outcomes with known oral intake prior to procedures, ASA guidelines recommend safety parameters of liquids requiring 2 hours and solids requiring 6 hours prior to a procedure.

Aspiration under general anesthesia has been estimated to have an incidence of 1:3420 with mortality in 1:125,109 cases with little data to suggest long-term sequelae. General anesthesia is at the extreme end of the sedation spectrum, and often mandates advanced airway manipulation; therefore, aspiration is much more likely. Although no study has demonstrated an elevated risk of aspiration for moderate to deep PSA in the ED, it is imperative to consider gastric contents and depth of sedation. Most authors have concluded that their sample sizes were often not large enough to detect statistically significant differences in study subjects. Patients presenting with a full stomach would benefit from observation and procedural delay for gastric emptying. Care should be taken to minimize the likelihood of aspiration, and precautions made to manage aspiration should it occur with wall suction, suction catheter, and additional personnel should the patient need to be log rolled into the lateral decubitus position.

Monitoring

Once the need for procedural sedation has been assessed, informed consent should be obtained from the patient. Patients should have mental status and function documented prior to and following the procedural initiation. Pediatric and adult patients alike should be placed on a cardiac monitor, pulse oximetry, blood pressure cuff, and, if available, end-tidal CO2 (ETCO2). Studies have shown ETCO2 to be more sensitive in detecting patients with respiratory depression than pulse oximetry, although there was no significant difference in outcome. Patients with deep sedation resulting in respiratory depression will show an increase in ETCO2 greater than 10 mm Hg from baseline or a level above 50 mm Hg total before they demonstrate a decrease in oxygen saturation. Although the ETCO2 does not differentiate the level of sedation, it can accurately detect respiratory depression.

While monitoring the patient's sedation course, heart rate, blood pressure, and oxygen saturations should be documented in serial timed intervals. Adverse events should be documented with additional descriptions of executed interventions. Standard reporting of adverse events includes apnea, oxygen saturation less than 90%, ETCO2 > 50 mm Hg, bradycardia, hypotension, and emesis. Continuous cardiac monitoring is important to detect adverse rhythms, and can be helpful to determine pain response when the patient develops a sinus tachycardia. Additional tools that can often prove to be vital during sedations include ACLS medication access, advanced airway equipment, and supplemental oxygen via nasal cannula, NRB, or bag valve mask (BVM) (Table 8–2).

Sedation Scales

Multiple scales have been created and described for measuring patients' levels of comfort, agitation, and sedation in the ICU, OR, and ED environments. The scales provide practitioners a guide to determine depth of sedation, and need for smaller titrations, reversal, or additional medications. Most of the sedation scales include monitoring agitation that does not directly relate to elective procedural sedation in the ED.

The Ramsay Sedation Scale (RSS) has been utilized in studies on ED PSA to describe levels of sedation. It is a simple 6-score system with 1 being anxious or restless and 6 being no response to stimulus (Table 8–3). It has been validated for inter-rater reliability, and simplifies the PSA assessment.

The Richmond Agitation–Sedation Scale (RASS) is a 10-score system with 4+ (combative) to 1+ (restless) range for grading decreasing agitation, 0 for calmness, and −1 (drowsy) to −5 (unarousable) to quantify degree of responsiveness (Table 8–4). The RASS scale differentiates the varying degrees of agitation, whereas the RSS scale has only one category (1) for anxious, agitated, or restlessness. The RSS scale utilizes a physical stimulus (glabellar tap) to grade responsiveness, but the RASS scale implements both verbal and physical stimuli to grade consciousness.

Sedation Conclusion and Patient Disposition

Care should be taken toward the conclusion of the PSA to limit additional medication administration. Should the noxious stimuli cease (ie, distal radius fracture is reduced and splinted) shortly after the last dose, respiratory depression, hypotension, and bradycardia could likely ensue. Depending on the sedative regimen utilized, rapid degradation would mitigate these effects (ie, propofol, dexmedetomidine, etomidate). Longer-acting agents such as fentanyl and versed could create overt sedation 20–30 minutes beyond the last dose and completion of the ED procedure.

Patients should be capable of responding verbally once sedation has worn off, and once assessed they should return to the baseline mental status documented prior to the PSA. Postprocedural emesis can be common following agents such as ketamine, so complete return to baseline is recommended prior to administering oral intake. Studies suggest that a minimum post-PSA observation period of 30 minutes be exercised. Most adverse events such as hemodynamic instability and emesis should have been resolved by that time. Once the patient has successfully completed the post-PSA observation period, he or she may be safely discharged from the ED.

The ideal procedural agent for the ED acts quickly, creates excellent comfort for the patient, and resolves soon thereafter with little to no side effects. No sedative agent is perfect, but multiple agents exist to tailor to each patient encounter (Table 8–5). Analgesia can often be controlled with narcotics, but procedural sedation requires the addition of an amnestic to reach a steady state of comfort. Benzodiazepines are often included with narcotics to facilitate adequate sedation. Some agents such as ketamine can often serve as the sole agent in short procedures, whereas versed and fentanyl regimens remain the mainstay in numerous emergency departments. Propofol, although a strong agent for moderate to deep sedation, does not truly satisfy analgesic requirements; however, in multiple studies, it is often used solely for the entire PSA.

Fentanyl

Fentanyl is a strong synthetic opiate with potency nearly 100 times that of morphine. It lacks amnestic properties, so it is often used in combination with versed or propofol. The likelihood of respiratory depression increases greatly when fentanyl is administered with the aforementioned sedatives. It is renally excreted with a half-life of 3.5 hours. Dosing for analgesia is 1–2 μg/kg IV, but is more optimal if administered as 0.5–1 μg/kg IV aliquots every 2–3 minutes. Time of onset is 1–2 minutes, with a duration of 30–45 minutes. Fentanyl does not induce histamine release, and is less likely to induce hypotension. It is also unlikely to cause a cross-reaction allergic response in patients with a known morphine allergy. Adverse effects include bradycardia, hypotension, increased intracranial pressure, and the potential for chest wall rigidity with large doses.

Ketamine

Ketamine is a dissociative anesthetic that produces analgesic, amnestic, and sedative effects. It increases endogenous catecholamines by blocking the reuptake pathway facilitating sympathomimetic effects. It maintains protective airway reflexes, and can increase the heart rate and blood pressure as well as intracranial and intraocular pressures. Ketamine can also cause laryngospasm that may present as persistent coughing to complete occlusion with resultant hypoxemia. A recent history of viral upper respiratory infection, age < 3 months, parainfluenza infection with resultant subglottic narrowing (croup), and stimulation of the posterior pharynx (aggressive suctioning, endoscopy, bronchoscopy) has been demonstrated to increase the likelihood of laryngospasm.

The patient often demonstrates a persistent nystagmus with nonpurposeful movements, but he or she is unable to communicate. Prior to PSA initiation, it may be helpful to describe this phenomenon to friends or family in the room. Ketamine should be avoided in patients currently intoxicated with sympathomimetics such as cocaine or methamphetamine, patients with head or ocular trauma, and patients with significant cardiovascular disease.

Drawbacks with ketamine use include the well-known emergence phenomena and postprocedural emesis. Benzodiazepenes have been shown to marginally decrease both effects. Ketamine dosing is 1–2 mg/kg IV with onset within 1–2 minutes, peak levels reached within 5 minutes, and total duration at 20–60 minutes. Ketamine is administered IM at 3–5 mg/kg with onset in 5–10 minutes, peak at 10–15 minutes, and duration 1–2 hours.

Ketamine is a sialagogue, and can produce an increase in tracheobronchial and salivary secretions. An anticholinergic such as atropine or glycopyrolate should be given to mitigate these effects. Glycopyrolate can be given IM/IV at 0.004 mg/kg (usual injection solution is 0.2 mg/mL). Atropine dosing should be 0.01 mg/kg IM/IV with a minimum dose of 0.1 mg, and maximum dose of 0.5 mg. Ketamine, versed, and atropine can be given within the same syringe.

Dexmedetomidine (Precedex)

Precedex is a centrally acting β2-adrenergic agonist with sedating and analgesic effects. Although few studies have evaluated the use of dexmedetomidine for PSA in the ED setting, multiple studies have demonstrated the safety and efficacy of dexmedetomidine for PSA, surgical interventions, and ICU management. Dexmedetomidine has been utilized in pediatric and adult patients. Primary concerns with dexmedetomidine involve its ability to mitigate central sympathetic output. Patients can develop profound bradycardia, sinus arrest, heart block, and hypotension. Patients with a history of cardiovascular disease, heart block, or cardiomyopathy should not be administered dexmedetomidine for PSA. Anticholinergics are required to preempt adverse cardiac events. The standard regimen involves utilizing glycopyrolate at 0.2 mg IV prior to initiation of the PSA. Studies have shown this simple preventative measure significantly reduced episodes of bradycardia. The loading does for PSA is 1 mcg/kg bolus over 10 minutes followed by 0.5–0.75 mcg/kg/h. The loading does should not be shorter than 10 minutes in order to avoid bradycardia. Patients are capable of participating in painful procedures without developing respiratory depression, and once the PSA is completed, the agent is rapidly metabolized with a short recovery time. Patients should be continuously monitored while on dexmedetomidine, and a preprocedural ECG should be considered.

Midazolam (Versed)

Midazolam is a benzodiazepine with sedating, anxiolytic, and amnestic effects, but no analgesic effects. It functions through GABA receptors resulting in an influx of chloride, and CNS depression occurs. It is often used in combination with a narcotic such as fentanyl, or a dissociative anesthetic such as ketamine. It is more rapid in onset than diazepam or lorazepam. Midazolam can be given PO, PR, IV, and IM, and atomized intranasally. It has been shown to diminish episodes of postprocedural emesis and emergence reactions with ketamine. Midazolam can cause hypotension and respiratory depression. PSA doses for adults should be titrated slowly with 1–2.5 mg IV doses at a time waiting 2–5 minutes between doses to assess response. Typical dosing regimen is 0.03–0.1 mg/kg IV. Pediatric patients should be dosed 0.05–0.1 mg/kg IV if age 6 months to 5 years, 0.025 mg to 0.05 mg/kg IV if 6–12 years of age, and 1–2.5 mg IV if aged 12–16 years. Patients who are administered narcotics simultaneously should have the midazolam dose decreased by 30% if under 60 years of age and 50% if over the age of 60. Alternate routes of midazolam and doses include:

• IM: 0.1–0.15 mg/kg
• Oral: 0.25–1 mg/kg
• Intranasal: 0.2–0.6 mg/kg
• Rectal: 0.25–0.5 mg/kg

Midazolam given IM will peak at 30 minutes with greater than 90% bioavailability. However, oral administration varies with peak onset depending on age (0.17–2.6 hours) with only 36% bioavailability. Elimination half-life IV is 3 hours in adults, and 2.9–4.5 hours in pediatric patients aged 6 months to 16 years. Median time of PSA with midazolam has been demonstrated to be 23 minutes versus 10 minutes for etomidate. Primary metabolism is hepatic with renal excretion highlighting the need to decrease dosages in patients with hepatic or renal disease. Pediatric patients requiring gentle anxiolysis for radiologic imaging can receive atomized intranasal midazolam to facilitate the study without the need for parenteral administration. Midazolam is dosed at 1 mg/mL IV, and it is compatible with fentanyl.

Propofol

Propofol is a nonopioid, nonbarbiturate, sedative hypnotic that is delivered via a lipid emulsion vehicle. Since the emulsion is composed of soy and egg products, patients with these food allergies should not receive this agent. Concentration is 10 mg/mL, and is given IV. Propofol for PSA is administered as a 1 mg/kg IV loading dose followed by 0.5 mg/kg IV maintenance dose, and is best given as 10–20 mg IV doses in adults over 1–2 minutes until desired level of sedation is attained. Propofol drips are initiated at 5–50 μg/kg/min and titrated to appropriate level of awareness for mechanical ventilation.

Propofol has no analgesic effects, and should be administered with a narcotic such as fentanyl if administered for mechanical ventilation. Risk for respiratory depression and apnea is increased if propofol is given in large, rapid boluses, and significantly more likely if given along with narcotics. It is often very difficult to correctly titrate the level of sedation with propofol, so it is imperative that continuous assessment of the patient's awareness be attained. Should a deeper level of sedation be achieved than warranted, discontinue the agent, observe, and execute rescue maneuvers as needed.

Propofol has the benefit of being rapidly metabolized following discontinuation of the PSA or drip, and this enables the practitioner to carefully observe the patient for a short period of time until resolution of sedation. Propofol is beneficial in emergent neurologic cases where serial examinations may be necessary to document progression, and it has been shown to decrease intracranial pressures. It also has been shown to have antiemetic and anticonvulsant properties. Long-term sequelae with propofol are not seen with short-term PSA doses, but include hyperlipidemia, pancreatitis, zinc deficiency, hepatomegaly, rhabdomyolysis, and propofol infusion syndrome. Short-term adverse effects include hypotension, hypoxemia, decreased cardiac output, respiratory depression, and apnea.

Ketamine and propofol combined or “ketofol” is a PSA regimen that has been utilized in the OR, and described in the anesthesia literature. The theory behind its benefits resides within the adverse event profiles of both drugs. Since ketamine can induce vomiting and emergence reactions following sedation, propofol can mitigate the events with its amnestic and antiemetic properties. Propofol can cause respiratory depression, apnea, hypotension, and depressed cardiac output, but when given with ketamine, there is a statistically significant decrease in respiratory depression, hypotension, and apnea. However, a study comparing propofol with fentanyl to propofol with ketamine demonstrated that nausea, vomiting, vertigo, and visual disturbances were much higher in the “ketofol” group suggesting that “ketofol” was a less than optimal regimen. The literature demonstrates that “ketofol” is fairly safe, and future comparative studies should consider evaluating the regimen against other common PSA strategies.

Etomidate

Etomidate is a short-acting nonbarbiturate hypnotic with GABA-like effects. It has been studied exhaustively in induction of general anesthesia, rapid sequence intubation (RSI), and PSA. Typical dosing for RSI is 0.3 mg/kg, and dosing regimens for PSA are 0.1–0.2 mg/kg IV. The benefits include rapid onset of action, stable hemodynamic effects, and rapid metabolism.

Adverse events can include laryngospasm, hiccoughs, and myoclonus. Myoclonus can occur in upwards of 20–30% of cases that may make the procedure more difficult to complete (ie, shoulder reduction). No long-term sequelae are evidenced from the myoclonus, but the appearance may mimic seizure activity and may prompt an unnecessary workup. Etomidate has been shown to blunt response to the ACTH stimulation test suggesting an etiology for adrenal suppression. However, emergency department studies have not been able to demonstrate a statistically significant difference in outcome with hospitalized patients who received a single dose of etomidate for RSI. Although the adrenal suppressive effects typically last no longer than 6–8 hours, studies continue to debate this effect. Greater concern for adrenal suppression is found in patients receiving multiple doses or continuous infusions of etomidate.

Methohexital

Methohexital is an ultra-short-acting barbiturate used for anesthesia induction and PSA, and can be given IV, IM, and rectally. The dosing for PSA is 0.75–1.0 mg/kg IV, and can be redosed at 0.5 mg/kg IV every 2–5 minutes as needed. Pediatric patient dosing is 0.5–1.0 mg/kg IV. Its onset of action is 30 seconds with lasting clinical effect of 5–7 minutes. Although rapid progression of sedation can take place, airway protective mechanisms are functional. Similar to propofol, it is an amnestic with no analgesic effects. Methohexital can cause laryngospasm, hiccoughs, and if extravasated may result in tissue necrosis. It has also been shown to be a cardiac depressant that may result in hypotension.

Rarely, one may need to administer reversal agents in the event that the patient has been deeply sedated to the state of general anesthesia. Although most agents are rapidly metabolized, and no additional medication is necessary, the midazolam and fentanyl regimen could last for 20–30 minutes. Narcan is more commonly given for opioid overdose, and flumazenil is indicated for benzodiazepine overdose. Although naloxone (Narcan) is relatively benign (symptoms of withdrawal excluded), flumazenil can potentially be dangerous in patients dependent on benzodiazepenes, and precipitate a refractory seizure.

Naloxone (Narcan)

Naloxone is an opioid antagonist that competes directly with systemic narcotics. It binds all the opiate receptors, but appears to have a higher affinity for the mu receptor. Naloxone may be given through the endotracheal tube, IM, IV, IO, or subcutaneously. It is not recommended to administer Narcan via ET tube in newborn infants. Narcan is dosed at 0.4–2 mg IV for adults, and it is recommended to give smaller amounts for patients chronically on opioids in order to avoid overt withdrawal. Abrupt reversal in patients chronically administered narcotics may result in seizures, cardiac arrythmias, pulmonary edema, or profound agitation. Age-appropriate dosing is as follows:

• Newborns: 0.1 mg/kg IV/IM
• Pediatric < 5 years of age or < 20 kg: 0.1 mg/kg IV/IM/IO/SQ
• Pediatric > 5 years of age or > 20 kg: 2 mg IV/IM/IO/SQ

Flumazenil

Flumazenil directly competes for the benzodiazepine binding site on the GABA receptor effectively reversing some aspects of the CNS depression (ie, respiratory depression). It does not facilitate the metabolism of benzodiazepenes, and resedation can occur once the flumazenil wears off. It is given IV, undergoes hepatic metabolism, and is excreted renally. The systemic half-life for adults is 40–70 minutes, and in pediatric patients it may range from 20 to 75 minutes. The initial dosing in adults is 0.2 mg IV over 30 seconds with additional doses of 0.3–0.5 mg given IV for a total maximum dose of 3 mg. Pediatric patients are dosed at 0.01 mg/kg up to 0.2 mg IV over 15 seconds. Repeat doses may be given in increments of 0.01 mg/kg up to a maximum dose of 0.05 mg/kg total or 1 mg total. Flumazenil can cause refractory seizures in patients on chronic benzodiazepenes, or patients with cyclic antidepressant overdoses. Should a patient develop seizure activity following flumazenil administration, benzodiazepenes are unlikely to work despite large doses for competitive binding. Alternative adjuncts to mitigate the seizures include propofol or barbiturates.