Valproic acid and status epilepticus

You are working in trauma when a patient arrives with altered mental status requiring intubation, and a negative work-up who seemingly wakes up after a trial of ativan, trying to grab his endotracheal tube. You consult Neurology with concern for status epilepticus, who suggest a fosphenytoin load. As the patient has systolic blood pressure in the 80s, you consider valproic acid as the next intervention for presumed status epilepticus.

Clincal Question: 

Is VPA an effective next-line therapy for status epilepticus after benzodiazepines?

Literature:

One of the first articles found with a quick pubmed search is from 2006 in Neurology, a small unblinded RCT of 68 patients in status epilepticus as defined as 2 or more convulsive seizures w/o full recovery of consciousness between the seizures or continuous convulsive seizures lasting for more than 10 minutes. Patients were consecutively enrolled then randomized to a VPA group (n=35) which received sodium valproate 30 mg/kg in 100 mL saline infused over 15 minutes, or the PHT group (n=33) which received phenytoin sodium 18 mg/kg in 100 mL saline infused immediately at a rate of 50 mg/minute. They found that SE was aborted by VPA in 23 (66%) and by PHT in 14 (42%) (p = 0.046), and in refractory patients, as a second choice, VPA was effective in 15 of 19 patients (79%), whereas PHT was effective in 3 of 12 patients (25%) (p value = 0.004). As for side effects and relating to my case, 2 patients who received PHT had CV effects (not elaborated) while 0 of the VPA group though this was not significant.

Another article from 2008 by Gilad et al., similarly prospectively enrolled 74 patients in SE (2 or more consecutive clinical seizures, or continued seizure activity >30min) or acute repetitive seizure/acute refractory seizure (ARS) (2 or more w/in 5-6hrs) and gave either VPA as 30mg/kg over 20min in 50mL saline or PHT as 18mg/kg over 20min in 100mL saline. They found seizure discontinued in 43/49 (87.8%) of the VPA patients, with similar results in the PHT group in which seizures of 22/25 (88%) patients were well controlled. They noted that 3 pts had side fx of cardiac arrhythmia, hypoNa, or vertigo in the PHT group, and none in the VPA (p 0.035). This study was certainly small, but I think it should be noted that of the PHT group 12/25 had exposure to PHT in the past while only 11/49 of the VPA group (p = .03).

Furthermore, in April 2014 ACEP released its policy on the valuation and management of adult patients with seizures in the emergency department. Item #4 “In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzo, which agent or agents should be administered next to terminate seizures?” directly applies to my question. As a Level B recommendation, they state “Valproate appears to be safe and effective in refractory status epilepticus and was not associated with hypotension. In conclusion, it appears that IV valproate is an acceptable treatment option for refractory status epilepticus and may work as well as phenytoin.” My last comment is that I was unable to find any studies w/ direct comparison of fosphenytoin vs VPA, and the ACEP literature review did not find any as well. The policy and lit review does cite a number of articles detailing CV effects of both PHT and fosphenytoin.

Take Home: 

In the setting of hypotension, valproic acid may be considered instead of fosphenytoin for the treatment of status epilepticus.

References: 

1) Misra UK1, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study.Neurology. 2006 Jul 25;67(2):340-2.
2) Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, Lampl Y. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.Acta Neurol Scand. 2008 Nov;118(5):296-300
3) American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Seizures:, Huff JS, Melnick ER, Tomaszewski CA, Thiessen ME, Jagoda AS, Fesmire FM. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Seizures. Ann Emerg Med. 2014 Apr;63(4):437-447.

Does a cervical seatbelt sign mandate advanced imaging?

You are working in the emergency department when EMS brings in a middle aged female who was the restrained driver in a low speed head-on MVC. In the emergency department, she is slightly hypertensive and complaining of generalized stiffness. Her physical exam (including C-spine exam and neurologic exam) is unremarkable with the exception of an abrasion to the left side of her neck without surrounding hematoma concerning for a cervical seat belt sign.

Clinical Question:

In this otherwise well appearing patient you wonder – what is the best course of action? Does the physical finding of a cervical seat belt sign warrant additional imaging for vascular injury, such as a CT-A?

Literature:

One study that addressed this question was a retrospective review of patients who received neck CT angiograms based on the presence of a seatbelt sign alone at a Level I trauma center from 2008-2010. Over this time period, 418 patients underwent a CT-A. Eleven patients had positive vascular findings, two with blunt carotid injury (BCA) – giving an overall frequency vascular injury of 2.6%. Importantly, all of the patients who were found to have vascular injuries had a cervical spine fracture, rib fracture, thoracic spine fracture, facial fracture, skull fracture, large hematoma on the neck or a combination of the above injuries. The correlation between seatbelt sign and positive CT-A finding was overall very weak (r = .007). The above findings lead the authors to reasonably conclude that CT-A of the neck vascular injury can be “safely reserved for patients with a seatbelt sign and obvious injuries on physical examination and/or positive findings on standard trauma imaging.”

A second study prospectively evaluated trauma patients with cervical or thoracic seatbelt signs at a level I trauma center over a 17 month period. Out of 131 trauma pts with cervical or thoracic seatbelt signs, four (3%) were found to have carotid artery injuries. The presence of a carotid injury was strongly associated with a GCS < 14 (p< 0.0003), ISS > 16 (p < .0001), and the presence of a clavicle or first rib fracture (p < .0037). No vascular injuries were identified in patients with thoracic-only seatbelt signs. Each of the four patients had at least one identifiable significant injury ranging from scalp laceration + extremity fracture to clavicle + bilateral superior rib fractures. The authors of this study concluded that the cervical-thoracic seatbelt sign combined with an abnormal physical examination is an “effective screening combination for cervico-thoracic vascular injury.”

Take Home:

CT-angiogram is not necessarily indicated based on the finding of a cervical seatbelt sign alone in the absence of significant hematoma, neurologic symptoms, or other traumatic injuries.

References:

1) Dhillon, Ramandeep Singh, et al. "Seatbelt sign as an indication for four-vessel computed tomography angiogram of the neck to diagnose blunt carotid artery and other cervical vascular injuries." The American Surgeon 79.10 (2013): 1001-1004.
2) Rozycki, Grace S., et al. "A prospective study for the detection of vascular injury in adult and pediatric patients with cervicothoracic seat belt signs." The Journal of Trauma and Acute Care Surgery 52.4 (2002): 618-624.

Insulin bolus in DKA?

A middle aged male with a history of IDDM presents with 2 days of nausea and vomiting. He reports running out of his insulin. In triage, FSBS is critical high, FS ketones are 5.0. You start to treat for DKA with bolus of IVF and draw basic labs. You order your insulin infusion and give a 0.10U/kg bolus prior to starting the drip. Your attending questions your actions. 

Clinical Question:

Is there any evidence to support giving an insulin bolus prior to starting a drip in DKA patients?

Literature:

The latest ADA recommendations last updated in 2009 still recommend giving a 0.1U/kg bolus prior to initiating an insulin infusion at 0.1U/kg/hr. This recommendation is based on the theory that DKA represents a significant "insulin resistant" state, and a bolus of insulin is needed to overcome this resistance and effectively reduce serum glucose and suppress gluconeogensis. Much of these recommendations are based on limited studies from the 1980's, measuring active levels of insulin in serum, and none were prospective comparing continuous insulin infusion with and without the bolus. (1) In 2008, Kitbachi Et al performed a randomized prospective study with three arms, those on an insulin infusion at 0.07U/kg/hr with and without a bolus, and those who were only on a infusion at 0.14U/kg/hr. Kitbachi effectively demonstrated that an insulin bolus is unnecessary in those who were started on a infusion at 0.14U/kg/hr. There was no difference in time to optimal glucose, pH, Anion Gap, or bicarbonate. (2) In 2010, Goyal Et al performed a similar study but had two arms, insulin infusion at 0.1U/kg/hr and those with an infusion and a bolus. He showed no difference in length of ED stay or hospital stay, and no difference in time to goal glucose or anion gap closure. (3)

Take Home:

In summary, there appears to be a paucity of evidence supporting the ADA recommendation for an insulin bolus prior to infusion, however there seems to be robust evidence showing at least a noninferiority with insulin infusion alone. Therefore I find there is no reason to continue using an insulin bolus during my standard treatment of DKA.

References:

1) Diabetes in the Emergency Department: Acute Care of Diabetes Patients. Clinical Diabetes April 1, 2011 29:51-59 http://care.diabetesjournals.org/content/32/7/1335.short
2) Kitabchi Et al, Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care. 2008 Nov;31(11):2081-5
3) Goyal Et al, Utility of initial bolus insulin in the treatment of diabetic ketoacidosis. J Emerg Med. 2010 May;38(4):422-7. doi: 10.1016/j.jemermed.2007.11.033. Epub 2008 Jun 2.

Submitted by Louis Jamtgaard, PGY-3

A suspected case of Eczema Herpeticum

Your patient is a 2 y/o with a history of eczema who was brought in by his mother for a new rash x 1 day, associated with fever. The rash is pustular-appearing and in other places vesicular. It covers the arms, legs (including palms and soles), and trunk with relative sparing of the face. There are no oral lesions were noted. In the emergency department, the patient is febrile and tachycardic, but otherwise non-toxic appearing.

You are worried that he might have eczema herpeticum or a staph superinfection. You collect viral and bacterial swabs, and admit him to the pediatrics service. 

Question:

Should you start acyclovir right away, or is it okay to wait until the swab results come back?

Literature: 

Fortunately, an article in Pediatrics aimed at answering this very question. The study was a large, retrospective cohort study conducted between 2001-2010. This study included 1331 children age 2 mo to 17 yrs treated at 42 different centers for eczema herpeticum (identified by their primary discharge diagnosis). The primary objective of the study was to determine whether delayed acyclovir therapy was associated with increased LOS. Secondarily, the study examined the mortality rate (0%), the rate of ICU admission (3.8% ), co-existing bacterial infection (30.3%) and Staph bacteremia (~3.9%). Using multivariable linear regression models, the authors found that a delay in initiation of acyclovir was associated with an increased length of stay. Adjusted increase in LOS was 11% (95 % CI 3-20), 41% (95 % CI 19 - 67), and 98% (95% CI 60-145) for a delay in initiation by 1, 2, and 3-6 days respectively. These results were statistically significant (p <.001). The authors found no significant difference between the administration of acyclovir in IV vs. oral form. Given the above results, the authors concluded that “Patients clinically suspected of having eczema herpeticum should receive empiric therapy with acyclovir because there is a statistically significant time-dependent increase in LOS with every day of delaying in initiating acyclovir therapy". Adverse events from acyclovir therapy were not addressed.


Take Home:

1) If you are admitting a child because you are worried about eczema herpeticum, start acyclovir. Oral form is fine if kid can take it.

2) Send blood cultures and start antibiotics for co-existing Staph infection, especially if the kid is febrile because ~ 30% have co-existing Staph infection and ~4% are bacteremic.


Reference:

Aronson et. al. “Delayed Acyclovir and Outcomes of Children Hospitalized with Eczema Herpeticum.” Pediatrics 2011; 128; 1161.