Status Epilepticus: A Ketamine-Deficient State?

Status epilepticus (SE) is a life threatening emergency associated with high morbidity and mortality rates. The International League Against Epilepsy (ILAE) defined SE more than twenty years ago as a single seizure that that lasts more than 30 minutes. The alternative definition is a series of epileptic seizures during which the patient’s baseline function is not regained between ictal events, within a 30 minute period. Recently, status epilepticus has been re-defined as: ≥5 minutes of continuous seizures OR ≥2 discrete seizures during which there’s an incomplete recovery of consciousness. Refractory status epilepticus (RSE) is defined as generalized or complex partial seizure activity that is refractory to conventional therapies for seizure disorder, such as benzodiazepines and barbiturates, within 30 minutes.  Super-refractory status epilepticus (SRSE) is further defined as SE that remains refractory to therapy with general anesthesia, for 24 hours, using medications such as propofol.  Incidence of refractory epilepsy is surprisingly high despite the development of many anti-epileptic agents and ranges from 20-40% in the literature.  Multi-faceted factors likely contribute to the development of RSE, including: the type of seizure, any underlying health conditions or neurological disorders, patient’s personal seizure history (frequency, duration, medication compliance, etc.), a patient’s genetics impacting drug metabolism (rate of absorption, metabolism, etc), or any prior use of illicit drugs altering brain chemistry (for example recreational MDMA, chronic alcohol or benzodiazepine use), amongst many others.  To prevent cortical disruption and damage, and to prevent morbidity and mortality, early control of SE is desirable.  Patients with development of RSE have high mortality rates (reported to approach 50%), increased hospital stays, poor functional outcomes, and inability to return to pre-admission baseline functional status.

Conventional therapies of acute seizure, SE, refractory and super refractory status epilepticus are heavily reliant on GABA agonist mediated therapies.  GABA_a agonists control excitatory inhibition and spread of excitatory discharge.  Lorazepam and midazolam are listed to have Level A evidence for use as first line anti-seizure medications.  Second line therapies include sodium channel blockers such as phenytoin, fosphenytoin, levetiracetam, lamotrigine, and carbamazepine.  Also studied therapies include barbiturates, valproate, topiramate, and propofol.  Refractory states of SE are theorized to be attributable to alterations in receptors and disruption of molecular transport at the blood-brain barrier.  GABA_a receptors are thought to be down-regulated with prolonged use of GABA_a agonists. GABA_a subunits are thought to undergo structural changes leading to impaired binding of anti-epileptic medications.  In addition, p-glycoprotein molecules are thought to be up-regulated as molecular transporters leading to increased efflux of medications from the brain, in particular phenytoin and phenobarbital.

With prolonged down regulation of GABA_a receptors, an inhibitory function of excitation is lost. With decreased expression of GABA_a receptors, increased expression and mobilization of non-competitive N-methyl-D-aspartate (NMDA) receptors to the cell surface of neurons occurs. Activation of NMDA receptors by glutamate will increase intracellular calcium, cause neuronal excitation, and potentiate refractory seizure physiology. In addition, prolonged treatment of RSE with traditional GABA_a agonists may lead to development of refractory hypotension and other adverse cardiovascular effects. Hypotension in status epilepticus causes further insult to injury as seizures already have potential to cause anoxic damage as cerebral blood flow autoregulation is disrupted during seizures.

For all of these aforementioned reasons, conventional therapies can adversely impact treating SE. Ketamine has been postulated as a novel agent in treatment of RSE and perhaps has a role for early use in SE. Ketamine is a non-competitive NMDA glutamate receptor antagonist. Animal studies have demonstrated that ketamine is effective in control of refractory seizures and is neuroprotective (leading to decreased morbidity and mortality), when compared to control data. A recent systematic review of the literature by Zeiler (2015) summarized data of multiple human case reports and three prospective cohort studies (with an average of 7 patients per study) utilizing ketamine for RSE. Seizure resolution was established in 56% of 110 total adult patients and 63% of pediatrics patients. Most patients were with seizure resolution within 48 hours to 72 hours of start of ketamine. Treatment time ranged from 2 hours to 27 days in adults and 6 hours to 27 days in pediatrics. The literature is low powered and therefore statistically it is difficult to make generalizations to extrapolate its use and benefits for the general patient population. Dosing, duration, and outcomes with use of ketamine in RSE have been reported to vary, as well. Ketamine has sympathomimetic properties preventing hypotension and cardiac depression. It has been found to be especially useful in RSE when other anti-epileptic treatments are causal in cardiac depression or hypotension, eliminating need for pressor support with ketamine infusion. Treatment doses of continuous ketamine infusions range in the literature from 0.12mg/kg/hour to 10mg/kg/hour. At times, patients were initially bolused at doses ranging from 0.3mg/kg to 4.5mg/kg. Ketamine can be administered with low risk to most patients as there are few contraindications or adverse effects. Previous arguments for increased intracranial pressure with use of ketamine have been refuted in the literature, and few population groups exist where ketamine cannot be used safely for RSE. However, the prolonged use of ketamine and its effects have not been studied in the literature.

Prospective studies are required to help establish a role for NMDA antagonists in treatment of routine seizures. In addition, research should consider studying the use of ketamine earlier in treatment of seizure disorder. In one case report by Kramer (2012), ketamine was administered early on in treatment of SE after the patient began to develop worsening hypotension with escalating doses of midazolam and propofol. Ketamine infusion resulted in immediate reduction in prevalence, duration, and amplitude of seizures on EEG. The need for vasopressor support was weaned off and patient's seizures resolved within 12 hours of start of ketamine. Patient was discharged home with return to baseline level of function.

Now we potentially have another reason to use more ketamine!!!

References

Drislane, FW. Convulsive status epilepticus in adults: Classification, clinical features and diagnosis. UptoDate. (2015). http://www.uptodate.com/contents/convulsive-status-epilepticus-in-adults-classification-clinical-features-and-diagnosis?source=search_result&search=status+epilepticus+adult&selectedTitle=2~150

F. A. Zeiler, “Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and

Superrefractory Status Epilepticus,” Critical Care Research and Practice, vol. 2015, Article ID 831260, 5 pages, 2015.

Shorvon S. and Ferlisi M. “The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.” Brain: A Journal of Neurology. 10. (2011):1-17.

Synoweic, et al. “Use of ketamine in the treatment of refractory status epilepticus.' Epilepsy Research. 105. (2013). 183-188.

Williams, et al. “Use of ketamine for control of refractory seizures during the intraoperative period.” Journal of Neurosurgical Anesthesiology. 26. (2014). 412.

Kramer AH. “Early Ketamine to Treat Refractory Status Epilepticus.” Neurocritical Care Society. 16. (2012): 299-305

Let Apneic Oxygenation Reign!

We have talked about this topic briefly in the past but it is extremely important and deserves more dedicated attention.  Past mantra has dictated using a bag-valve mask (BVM) whenever a patient was thought to not be breathing adequately, or even not breathing at all.  Current evidence emphasizes the danger of the BVM and its inappropriate use.  The BVM can be summarized nicely: 1) It increases intrathoracic pressure thus decreasing preload and coronary artery perfusion, 2) opens the lower esophageal sphincter(even if you are good at ventilating) causing a high risk for vomiting from gastric insufflation, 3) causes over-distention of the alveoli resulting in oxygen shunting and decreased capillary PaO2. and 4) decreases cerebral blood flow. So what can we do to ensure oxygenation in those patients who just don’t require a BVM?  Apneic oxygenation!

The most common time the apneic oxygenation strategy will be employed is during the preoxygenation period and peri-intubation period of airway management.  The principles of apneic oxygenation may also be applied to patients who require supplemental oxygen but may not be able to be intubated at the time (i.e., predicted difficult airway or RSI meds are not available).  The goal is to maintain a SpO₂ > 93% without using a BVM.  If the patient is unconscious during preoxygenation, this can be accomplished with a nasopharyngeal airway (NPA), nonrebreather (NRB) and high-flow nasal cannula (HFNC) set to at least 15 Lpm.  To review, the purpose of preoxygenation is to provide nitrogen washout.  As we know, nitrogen is the most common atmospheric gas and also predominates in your lungs.  If you remove the nitrogen by flooding the airway, including the dead space, with 100% O2 you can increase the functional reserve capacity and buy yourself time and reassurance during the apneic period of intubation. 

The best way to provide oxygenation during the apneic period of intubation is obviously to continue oxygenation.  Place an NPA (or two, yes two, NPAs) and passively oxygenate past the tongue through the glottis.  HFNC may actually provide bubbles or assist in visualization of the trachea; voila you have your view!  Through the use of HFNC during the apneic period of intubation the alveoli will continue to take up oxygen despite a lack of diaphragmatic movement or lung expansion.  Ideally the patient should remain in the upright 20 degree position ensuring that the airway remains patent with an NPA, OPA, jaw-thrust, head-tilt-chin-lift or, preferably, a combination to allow oxygen gas to pass down the nasopharynx into the deeper airway structures and then to the alveoli for passive diffusion.

Recent evidence has reviewed the effectiveness of the HFNC when used in the apneic period of intubation using RSI.  The study was conducted by an Australian helicopter emergency medical service (HEMS).  The HEMS service consisted of a physician and paramedic.  Intubation attempts were split evenly between the physician and paramedic in the pre-intervention arm of the study but favored the paramedics during the institution of apneic oxygenation.   They reviewed RSI intubations pre and post implementation of an apneic oxygenation protocol.  They had a significant decrease in desaturation during intubation in the group that received apneic oxygenation (22.6% to 16.5%).  They also noted a decrease in cardiac arrests (5.6% to 1.4%) and episodes of bradycardia (7% to 1.4%) related to desaturation during intubation after apneic oxygenation was implemented.  In conclusion, avoid the BVM whenever possible and always use a HFNC during intubation. 

So here is what I do EVERY TIME I am getting ready to intubate.  (Not in this order)

1. Have a BVM ready with PEEP valve on at all times. 
2. Have suction ready. 
3. Quantitative ETCO₂ ready to place on ETT.  (Remember, it needs to “zero” to the atmosphere first anyway.)
4. Nasal cannula at least 15 LPM or as high as you can go. 
5. Apply NRB at 100% over nasal cannula
6. Bag only if RR<4 and SpO₂ <93%.  If RR>4 and SpO₂ <93% use oxygen for 3 MINUTES to see if saturation will come up.  If it does not come up… you can ventilate with BVM slowly (no more than 6 times per minute)

Bonus:  If systolic BP is less than 90 mmHg, add…

1. IV fluid bolus as fast as possible
2. Push-dose Epi 10 µg/min until SBP >90 mmHg

References

Weingart, SD. “Preoxygenation, Reoxygenation, and Delayed Sequence Intubation in the Emergency Department.” J Emerg Med 2010.

Weingart, SD, Levitan, RM. “Preoxygenation and Prevention of Desaturation During Emergency Airway Management.” Ann Emerg Med 2011.

Wimalesena Y, Burns B, Reid C, Ware S, Habiq K. “Apneic Oxygenation Was Associated With Decreased Desaturation Rates During Rapid Sequence Intubation by an Australian Helicopter Emergency Medicine Service.” Ann Emerg Med 2014. 

Let It Flow! Intraosseous Flow Rates by Insertion Site

Intraosseous (IO) access has become increasingly popular as a ‘safety net’ for failed IV access and has become a go-to procedure in pre-hospital cases of rapidly decompensating patients. Think of the cardiac arrest patient or the hemodynamically unstable trauma patient. The IO has proven a quick and reliable way to gain access to medullary venous plexuses in long bones, which drain into systemic venous circulation. We can basically think of the bone marrow as a vein that will not collapse on us that can be accessed very rapidly, with very little training. We have infused fluids, medications, and blood products successfully through the IO. And now that increased support has grown for the use of IOs prehospitally, the question has become which site is best: Tibia (which many people seem to be most comfortable with due to prominent landmarks and distance from resuscitative efforts), humerus, or sternum. There is literature supporting, and widespread consensus for, proximal tibia as the optimal insertion site in children, but this consensus does not exist in adults. Choice often depends on comfort level of the operator and convenience of the location, but we should also consider the difference in flow rates between sites.

There are few studies comparing IO placement sites but the ones that exist compare proximal to distal tibia, tibia to humerus, and one study which compared IO infusion rates between tibia, humerus and sternum in cadavers. The first study found that IO flow rates in the proximal tibia were significantly faster with and without use of a pressure bag than flow rates the in the distal tibia. The drawback of this study was its small sample size of only 22 patients. Pasley et al did a cadaver study published 1 year ago which utilized 16 cadavers to compare flow rates and found that the sternal site had the highest and most consistent flow rate compared to the humerus and tibia. In fact the average flow rate in the sternum according to this study was 1.6x higher than the humerus and 3.1x higher than the tibia. Additionally, this study showed that the tibia had the greatest number of insertion difficulties (In 3 out of the 16 cadavers, infusion was unsuccessful after insertion and alternate tibia had to be used.) Ong et al did a study in 2009 which had very different results. This study recruited 24 patients who presented to an ED in Singapore, all patients received a tibial IO, and those who needed a second access point were given a humeral IO (which 11 patients received). This study found no significant difference between the flow rates at the tibial and humeral site in contrast to Pasley’s study which did show a significant difference between humerus and tibia with the humeral site achieving a 1.8x greater volume on average than the tibia. Small sample size is an issue in all articles existing on this subject.

It seems that there have been no conclusive studies in human or cadaver studies on best IO insertion site, but, if we believe the most recent study by Pasley et al, the sternal and humeral IO sites, in that order, have better flow rates compared to tibial placement. This higher flow rate could make a difference when rapid fluid resuscitation is imperative and could lead to better survival of our patients. A new device called the FASTResponder was released by Pyng Medical in 2013 to make the sternal IO concept easier. This device is safe on ages 12 years and older and makes site identification easy. Another benefit of the device is, unlike the IO drill system, it requires no batteries, and, anecdotally, there is less pain on fluid delivery compared to other sites. One factor we are still unclear about is if the sternal IO could pose a problem if cervical immobilization is being used in trauma patients, with chest compressions, and for some airway procedures. Pyng Medical advertises on their website that it is “safe” to use in conjunction with cervical immobilization devices and CPR. However, the drill-based EZ-IO is approved for all ages, and many providers are already comfortable with it. According to Pasley’s study, the humeral placement is second best in terms of flow rates and had less insertional difficulties. He also notes that the humeral site had the greatest variability in volumes infused from subject to subject. There doesn’t seem to be enough evidence yet to draw firm conclusions; more studies are needed with a greater number of test subjects to increase reliability.  Furthermore, outcome measures, though often difficult to study, would be nice.

References

Carness J, Russell J, Rodrigo M, et al. Fluid Resuscitation Using the Intraosseous Route: Infusion with Lactated Ringer’s and Hetastarch. Military Medicine 2012; 2:222.

Ong M, Chan Y, Jen J, Ngo A. An observation prospective study comparing tibial and humeral intraosseous access using the EZ-IO. Amer Journal of Emergency Medicine 2009; 27, 8-15. 

Pasley J, Miller C, Dubose J, et al. Intraosseous Infusion Rates under High Pressure: A Cadaveric Comparison of Anatomic Sites. Distribution A: Approved for Public Release 2014: Case Number 88ABW-2014-1139.

Tan B, Chong S, Koh Z, Ong M. EZ-IO in the ED: an observational, prospective study comparing flow rates with proximal and distal tibia intraosseous access in adults. Amer Journal of EM 2012;30(8):1602-6.