Pharmacotherapy

If There's a Delay, Consider TXA: On Anti-fibrinolytic Therapy for Management of Aneurysmal Subarachnoid Hemorrhage


Clinical Scenario: While working in a community emergency department you see a middle aged otherwise healthy female who developed a thunderclap headache two hours ago while lifting weights.  She is very nauseated, has intermittent vomiting, but is able to respond to your questions. An emergent Head CT shows subarachnoid hemorrhage involving the suprasellar, interpeduncular, and ambient cisterns with associated ventriculomegaly.  You call the neurosurgeon at the closest tertiary care hospital and he asks whether you considered giving tranexamic acid (TXA) prior to transport.
 
Clinical question: Does TXA improve outcomes for patients with spontaneous subarachnoid hemorrhage? Does it increase the risk for thrombotic event/stroke? 

Literature Review
In people who suffer from aneurysmal subarachnoid hemorrhage, rebleeding is a cause of significant death and disability, peaking in incidence 24 hrs from the initial presenting event [1].   More than a third of rebleeding events occur within 3 hrs and more than half within 6 hrs [2].  It is thought that part of the mechanism of rebleeding is dissolution of the clot at the site of the aneurysm.  While securing the aneurysm via coiling or clipping is the standard of care to prevent rebleeding, in instances where there is an delay of care is unavoidable, it was been postulated that anti-fibrinolytic therapy, which may mitigate this process, may decrease the incidence of rebleeding.

One form of anti-fibrinolytic therapy is TXA, a synthetic analog of the amino acid lysine that works as a hemostatic agent by binding to the lysine binding sites on plasminogen, thereby competitively inhibiting its conversion to plasmin and subsequently fibrin degradation Existing studies suggest that TXA decreases bleeding in menorrhagia and cardiopulmonary bypass, as well as to improves mortality in trauma patients dying of massive hemorrhage [3,4,5,6].  Does this hemostatic benefit apply to spontaneous subarachnoid hemorrhage?

A large number of studies regarding anti-fibrinolytic therapy for aneurysmal subarachnoid hemorrhage have been published.    These were assessed in a 2013 Cochrane meta-analysis aimed at addressing the overall clinical effects of such therapies on rates of rebleeding and overall morbidity/mortality in aneurysmal SAH [7].  This was prompted in part because of concern that even if antifibrinolytics decreased risk of rebleeding, this would be offset by an increased risk of cerebral ischemia, which tends to develop between 4-14 days after initial SAH.  The Cochrane review included only randomized trials that compared antifibrinolytic to placebo vs. control and assessed subsequent outcomes on an intention to treat basis.   Their systematic review included 10 studies [with a pooled patient sample of 1904 who received TXA, 597 placebo, and 348 control].  Nine of these studies used TXA as the antifibrinolytic agent and one used epsilon-amino-caproic acid (39 patients).  These studies were extremely heterogeneous in their anti-fibrinolytic treatment regimens.  One study treated for less than 72 hrs (before onset of potential cerebral ischemia) [8] and others treated up to six weeks (through peak time of cerebral ischemia).  Two of the studies concurrently treated patients with therapy (such as nimodipine) to reduce the risk of cerebral ischemia [8,9].  Their analysis found that that TXA did not affect the overall morbidity (risk of poor outcome was RR 1.02; 95% 0.91-1.15) or mortality (death from all causes RR 1.00; 95% CI 0.85-1.18). Administration of TXA did decrease the risk of rebleeding (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 people), but this was offset by the increased the risk of cerebral ischemia (RR 1.41, 95% CI 1.04 to 1.91; 83 per 1000 people). 




There was was considerable heterogeneity between the older studies and the newer studies, which may be attributed to newer studies using specific treatments to prevent the risk of cerebral ischemia. 

While this overall analysis suggests that TXA may not significantly benefit long term outcome in aSAH, the majority of the studies administered the drug for a prolonged period time of > 10 days, at which point definitive aneurysmal treatment via endovascular or surgical intervention should be achieved.  One study examined short term  (mean of 15.3 +/- 16 hrs) use of an anti-fibrinolytic therapy (E-Aminocaproic acid - EACA) on risk of rebleeding, mortality and favorable neurologic outcome at 3 months [10].  They prospectively studied 248 patients with aSAHPatients were not randomized, but the two groups were similar with regard to baseline characteristics predictive of rebleeding risk and neurologic outcome, including anticoagulation and Hunt-Hess grade (with the exception of blood pressure which was not assessed).  The authors compared the outcomes of 73 patients who received EACA with those of 175 patients who did not.  They found that there was a significant decrease in rebleeding in EACA-treated patients (2.7% vs. 11.4%), as well as a general trend towards favorable neurologic outcome in those who received anti-fibrinolytic therapy.  While we will continue to await randomized, placebo-controlled trials to determine if (and which) antifibrinolytic therapy improves outcome for patients with aSAH, the AHA/ASA guidelines have incorporated anti-fibrinolytic therapy into the recommendations for medical measures to prevent rebleeding [2]:

Current AHA/ASA Guidelines for Medical Management to Prevent Rebleed in Aneurysmal SAH (Ref 2)

  Take home: TXA may reduce the risk of rebleeding in aneurysmal subarachnoid hemorrhage, but current evidence does not strongly support a benefit regarding survival or morbidity.   In studies using prolonged anti-fibrinolytic therapy, the benefit conferred by decreased risk of rebleed was offset by increase in cerebral ischemia.  However, more recent trials of short-term antifibrinolytic therapy have had promising, but far from definitive results.  Current AHA/ASA guidelines encourage its use for patients who will have a delay in aneurysm obliteration.

Submitted by Melissa Kroll, PGY-3
Edited by Maia Dorsett, PGY-4
Faculty Reviewed by Peter Panagos  


References
1.Guo, L. M., Zhou, H. Y., Xu, J. W., Wang, Y., Qiu, Y. M., & Jiang, J. Y. (2011). Risk factors related to aneurysmal rebleeding. World neurosurgery, 76(3), 292-298.
2. Connolly, E. S., Rabinstein, A. A., Carhuapoma, J. R., Derdeyn, C. P., Dion, J., Higashida, R. T., ... & Vespa, P. (2012). Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association. Stroke, 43(6), 1711-1737.
3. Jimenez, J. J., Iribarren, J. L., Lorente, L., Rodriguez, J. M., Hernandez, D., Nassar, I., ... & Mora, M. L. (2007). Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care, 11(6), R117.
4. Lethaby, A., Farquhar, C., & Cooke, I. (2000). Antifibrinolytics for heavy menstrual bleeding (Cochrane Review). The Cochrane Library, (4).
5. Williams-Johnson, J. A., McDonald, A. H., Strachan, G. G., & Williams, E. W. (2010). Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) A randomised, placebo-controlled trial. The West Indian medical journal, 59(6), 612-624.
6. Morrison, J. J., Dubose, J. J., Rasmussen, T. E., & Midwinter, M. J. (2012). Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Archives of surgery, 147(2), 113-119.
7.Baharoglu, M. I., Germans, M. R., Rinkel, G. J., Algra, A., Vermeulen, M., van Gijn, J., & Roos, Y. B. (2013). Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. The Cochrane Library.
8.Hillman, J., Fridriksson, S., Nilsson, O., Yu, Z., Säveland, H., & Jakobsson, K. E. (2002). Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. Journal of neurosurgery, 97(4), 771-778.
9.Roos, Y. B. W. E. M., & STAR Study Group. (2000). Antifibrinolytic treatment in subarachnoid hemorrhage A randomized placebo-controlled trial. Neurology, 54(1), 77-77.
10. Starke, R. M., Kim, G. H., Fernandez, A., Komotar, R. J., Hickman, Z. L., Otten, M. L., ... & Connolly, E. S. (2008). Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke, 39(9), 2617-2621.

Droperidol the psycho dropper or heart stopper?

Clinical Scenario:
You are working a typical EM-1 shift loaded full of psychiatric patients, EMS brings you another agitated male with a history of schizophrenia. He is shouting absurdities and threatening staff members.  The RN glances over at you, 5/2 doc? You're feeling a little different today and order 10mg of droperidol IM. The drug is administered and the patient calms down. With pride you present the patient to your attending. Your attending is alarmed and immediately requests an EKG and places the patient on a cardiac monitor and tells you the patient is in imminent danger of converting into torsades de pointes (TdP) secondary to prolonged QT.  You perform a rapid review of the literature.


Literature Review:
Droperidol is a butyrophenone that has been used since the mid 1970's primarily for acute agitation but it has also found a role in treating nausea, headaches, and abdominal pain. In 2001, droperidol received a black box warning by the FDA because of its association with QT prolongation and potential fatal arrhythmias.
FDA Black Box warning

There is no consensus as to what degree of QT prolongation is clinically significant, but several papers have cited QT longer than 500ms or delta QT of 60ms as at risk for TdP. (1) Mechanistically, in animal models Droperidol has been shown to both block efflux of myocardial potassium and induce early depolarization in cardiac fibers. Human studies have shown varied results, but lean towards droperidol causing some degree of prolonged QT without clinically significant arrhythmias. (2) 

 Lischke et al performed a randomized, double blind study on 40 patients undergoing cardiac surgery that were given either 7 mg,12.5 mg, or 17.5 mg of droperidol prior to surgery. Serial ECGs were obtained and QT prolongation ranged from 37 to 59ms in all groups in a dose dependent manner, however there were no recorded dysrhythmias or fatal events. (3) Again, Guy et al performed a prospective study in 55 patients who received 0.25mg/kg of droperidol prior to surgery, mean QT increased by 24ms, however no arrhythmias were noted. A 2014 prospective study by Calver involved continuous Holter monitoring for 24hrs in patients who had received 10-30mg IM of droperidol for acute agitation. Four out of 46 patients had abnormal QT greater than 480ms, but only one case was temporally associated with droperidol administration.  No arrhythmias were recorded. (4)  Kao et al reviewed decades of published literature including multiple systematic reviews and randomized controlled trials with outcome measures specifically observing for adverse effects of droperidol, and none cited any cases of fatal arrythmias. (1)

 Kao et al reviewed the FDA surveillance data cited by the FDA as cardiac events related to droperidol administrations, and found that the case reports were plagued by confounders and failed to show causation between droperidol administration and fatal arrhythmias.   Many of the European studies cited by FDA used doses of 50 -100mg IM, significantly higher than doses typically used in the US.  
Kao et al FDA surveillance data

Furthermore, similar case studies are described with haloperidol another commonly used antipsychotic.  

Take home points:
Bottom line is there are no randomized trials that demonstrate that droperidol causes fatal arrhythmias, there is data to show the droperidol prolongs QT in a likely clinically insignificant manner. There are rare case reports that suggest cardiac events might be associated with droperidol administration, but most cases involve confounders and cannot demonstrate causation.  Therefore it is likely reasonable to administer droperidol in most cases without any type of cardiac monitoring. However use of droperidol in this manner falls outside of FDA approval, therefore it is likely reasonable to take some precations (EKG or cardiac monitoring) in high risk groups (ESRD, severe cardiac disease) or consider alternative agents.  

Submitted by Louis Jamtgaard PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee


  1. Kao LW Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med. 2003 Apr;41(4):546-58.


  1. JM Guy, X Andre-Fouet, J Porte, et al. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol [in French] Ann Cardiol Angeiol (Paris), 40 (1991), pp. 541–545


  1. V Lischke, M Behne, P Doelken, et al. Droperidol causes a dose-dependent prolongation of the QT interval Anesth Analg, 79 (1994), pp. 983–986

  1. Calver LBr J Clin Pharmacol. 2014 May;77(5):880-6. doi: 10.1111/bcp.12272. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings.



Steroids for recurrent migraine headaches?


Clinical Scenario:
A young female in her 20's  with no significant medical history returns for the 3rd time this week with recurrent migraine headache.  She has had an unremarkable workup in the past including lumbar puncture and head CT.   As you start treatment with your standard migraine cocktail, you wonder if there is a way to prevent recurrence.   While you are not ready to start her on daily long term treatment such as propanolol or amitriptyline from the ED (you have given her neurology follow-up to determine if she needs this),  is there is anything you can give her now to decrease the chance that she will back yet again in the next few days?

Literature Review:
Neurogenic inflammation has been proposed to contribute to migraine recurrence and relapse.  As such, several trials have examined the potential efficacy of steroid administration in the prevention of migraine recurrence.

Based on a meta-analysis published in the British Medical Journal [1], the use of single-dose dexamethasone (range 10 -24 mg IV) compared to placebo in severe migraine headaches reduces recurrence (NNT =9) of headaches within 72 hours (relative risk 0.74, 95% confidence interval 0.60 to 0.90).  Dexamethasone does not provide significant acute pain reduction when compared to placebo (mean difference 0.37, 95% confidence interval -0.20 to 0.94) (see Figure below):

Figure 2 from Colman et. al. BMJ (2008)


In a more recent meta-analysis published in the European Journal of Neurology [2]which included 8 studies (total patients 905) - which significantly overlapped with the studies included in the BMJ study - dexamethasone (10 - 24 mg IV) was compared to placebo and again demonstrated reduction in the rate of moderate to  severe headache recurrence after 24-72 hours of headache evaluation (RR = 0.71; 95% CI = 0.59-0.86).  One study comparing PO (Prednisone 40 mg x 2 days) vs. parenteral steroids, found no statistically significant difference between the two routes of administration.
Figure 2 from Huang et. al. Eur. Journal of Neurology (2013)



Take Home Point:
-While they provide no acute pain reduction, administration of steroids in patients with frequent migraine headaches may prevent return visits in the next 24-72 hrs.

References:
1. Colman I, Friedman BW, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence. BMJ. 2008 Jun 14;336(7657):1359-61.1.
2. Huang Y, Cai X, Song X, Tang H, Huang Y, Xie S, Hu Y. Steroids for preventing recurrence of acute severe migraine headaches: a meta-analysis. Eur J Neurol. 2013 Aug;20(8):1184-90.


Submitted by Lydia Luangruangrong, PGY-3.
Edited by  Steven Hung (@DocHungER), PGY-2 and Maia Dorsett (@maiadorsett), PGY-3
Faculty reviewed by Peter Panagos

IV lidocaine for analgesia in the ED?

Clinical scenario:
You’re in the midst of a busy evening shift, when out of the corner of your eye you think you notice a patient you just took care of a few days ago. You check the board, and sure enough you’re right. She is an unfortunate female in her 20's with a history of SLE complicated by both  ESRD on dialysis and recurrent VTE. She also has chronic recurring chest pain of unclear etiology. She has had several full cardiac workups and CT imaging which have yet to reveal an etiology of her recurring pain. She tells you the pain is identical in character to her prior presentations. It is not associated with SOB, diaphoresis, lightheadedness, palpitations, or N/V. The patient is not interested in further diagnostics, and flat-out refuses admission, further CT imaging, or cardiac testing. She just wants some relief from her pain. In the past, hydromorphone at relatively high doses has been somewhat effective, but your attending is wary of continuing to provide high-dose hydromorphone at frequent intervals during your patient’s repeated ED visits. He suggests IV lidocaine may be effective for your patient.

Clinical question:
Is IV lidocaine a safe and effective parenteral analgesic alternative to narcotic pain control in the ED?


Literature review:

The analgesic properties of lidocaine in the setting of subcutaneous local anesthesia and topical anesthesia are well-appreciated. Additional uses include digital blocks, hematoma blocks, intra-articular injection, and regional nerve blocks. It is not a drug commonly used parenterally, though indications for such use do exist – both as an antidysrhythmic and for localized intravenous analgesia of an extremity exsanguinated by an arterial tourniquet (i.e., a Bier block).

In terms of systemic analgesia, the preponderance of the available literature focuses on the use of parental lidocaine for treatment of refractory neuropathic pain, particularly in the setting of advanced malignancy. There are also numerous case reports and small case series reporting its use for postoperative pain [1,6,8]. Its effectiveness in such cases is plausible based on the results of animal studies, which “suggest a link between spontaneous ectopic discharges of the injured nerve and peripheral mechanisms of neuropathic pain, and such spontaneous discharges can be suppressed by IV lidocaine in a clinically relevant dose range” [1]. Also, oral cogeners of IV lidocaine do exist (e.g., mexiletine), which could provide a possible maintenance therapy for those for whom IV lidocaine was effective. However, concerns over systemic cardiovascular and neurologic effects have thus far prevented the widespread adoption of IV lidocaine as therapy for acute pain, particularly when numerous other analgesic agents without these potential adverse effects exist (i.e., narcotics).

Double-blinded RCTs published in the 1990s first demonstrated efficacy of an IV lidocaine infusion of 5 mg/kg over 30 minutes in treating pain due to numerous neuropathic causes (including diabetic neuropathy), and postherpetic neuralgia [1,6]. One early study did not find lidocaine to be effective for pain due to a peripheral nociceptive origin (i.e., ischemic pain in a limb after blood pressure cuff inflation) [2]. The dose of lidocaine used in published studies to date ranges from 1.5 – 5 mg/kg. At these doses, lidocaine blocks function in actively depolarizing neurons without interfering with the normal function of other motor & sensory neurons [3].

Two cancer pain specialists published a review of IV lidocaine infusion for that purpose in the Journal of Supportive Oncology in 2004 [3]. In the authors’ experience, lidocaine was effective for treatment of visceral or central pain. They describe their protocol as beginning with a “lidocaine test,” consisting of a 1-3 mg/kg dose administered over 20 – 30 minutes to test for efficacy and occurrence of any adverse effects. If effective and safe, an infusion is then begun at the lowest effective dose, anywhere from 0.5 – 2 mg/kg/hr. Initially, the authors checked lidocaine blood levels, and found they were rarely over 3 mg/kg. Toxicity is rare at this dose.

Prior studies of IV lidocaine have found symptoms of toxicity to develop in a sequential and predictable manner based on blood levels [1].

Blood Lidocaine Level
Expected Signs/Symptoms
4 – 6 mg/kg
Lightheadedness
Perioral numbness
Dizziness
Transient HTN
8 mg/kg
Visual/auditory disturbances
Dissociative effects
Muscle twitching
Hypotension
12 mg/kg
Convulsions
16 mg/kg
Coma
20 mg/kg
Respiratory arrest
Cardiovascular collapse

While milder symptoms of toxicity are easily and quickly reversed by stopping the infusion and providing other appropriate supportive care, cardiovascular collapse due to lidocaine toxicity can be rapidly fatal. It is not reversible simply with infusion cessation and often requires lipid emulsion therapy.

In terms of dosage and safety, our faculty toxicologist reviewer had this to say:

"As far as the safety goes, Goldfrank's goes up to 6 mg/kg... However, I was always taught 4-4.5 mg/kg was the toxic amount. I'd be hesitant to go above that. Anecdotally, it probably should be said that we think nothing of giving approx 1.5 mg/kg to ED patients pre-intubation or with a ventricular tachyarrhythmia and do it quite safely. In fact, in ACLS we can give lidocaine twice, so up to 3 mg/kg. As such, I'm not sure why this would be considered unsafe in a pain patient."

A systematic review and meta-analysis of parenteral use of local anesthetics for treatment of neuropathic pain found IV lidocaine to be superior to placebo [6]. The weighted mean difference (WMD) of post-treatment pain ratings along a 100mm visual analog scale was -10.02mm (95% CI -16.51 to -3.54mm, p < 0.002) for those patients receiving IV lidocaine. The combined N of the included studies was 129 patients. The authors also found five trials (total N 206) which compared IV lidocaine (or its oral cogeners) to other drugs – carbamazepine, gabapentin, amantadine, and morphine. There was no significant difference in effect on pain scores, with WMD -0.60mm (95% CI -6.96 to +5.75mm).

From Tremon-Lukats IW, et al. Anesth Analg. 205;101:1738-49.

From Tremon-Lukats IW, et al. Anesth Analg. 205;101:1738-49.

There were more adverse events associated with lidocaine than with placebo, 32.2% vs 11.5%, for an OR of 4.16 (95% CI 2.68 – 6.46). The most common adverse reaction was dizziness, affecting almost 30% of treated patients. Other common reactions included nausea, vomiting, abdominal pain, diarrhea, and perioral numbness. Less frequent side effects were metallic taste, tremor, dry mouth, insomnia, allergic reactions, and tachycardia. There was no significant difference in adverse events reported between IV lidocaine and the other active drugs listed above. Of note, 410 patients were treated with IV lidocaine in the included studies (most commonly at a 5 mg/kg dose), and no serious cardiac dysrhythmia or hemodynamic instability was reported.

Another use for which there is published efficacy of IV lidocaine is for perioperative pain. A systematic review of RCTs comparing perioperative IV lidocaine vs placebo for postoperative pain found significant reductions in postoperative pain scores and opioid consumption [7]. This effect was most pronounced in open laparotomy or laparoscopic abdominal surgeries, for which the authors were able to perform a meta-analysis of 6 RCTs including a total of 250 patients. Among these patients, pain scores at 24 hrs post-op (on a 10-point scale) were significantly lower for those patients that received perioperative IV lidocaine, with a WMD of -5.93 (95% CI -9.63 to -2.23). This effect held true at rest, with movement, and with coughing, for up to 48 hours post-op. Opioid consumption was also reduced up to 85%.

There was significant heterogeneity in the dosages of lidocaine given, though most studies utilized a perioperative infusion rate of 2 – 3 mg/kg/hr. Of note, all of these trials included patients receiving both IV lidocaine and opioids, demonstrating the safety of the co-administration of these agents as no significant adverse events were reported in 395 treated patients. Four patients receiving perioperative IV lidocaine infusions did experience transient bradycardias with preserved stable hemodynamics.

A small case-series published in 2008 reported efficacy of a perioperative IV infusion of 4 mg/min of lidocaine in controlling pain for patients undergoing orthopedic surgery that were unable to be provided the usual regional analgesia for their procedures [8]. The authors report that postoperative pain scores were lower, opioid requirements from a PCA device were reduced, and hospital LOS were shorter for these patients compared with their usual experience in patients undergoing similar procedures.

A Cochrane Review (updated October 2014) investigated the safety & efficacy of IV lidocaine as a means of procedural pain relief in burn patients [4]. The Cochrane group identified only a single eligible study of 45 patients comparing IV lidocaine vs placebo. It was a randomized, double-blind, placebo-controlled, cross-over study. Increase in subjective pain ratings during procedures (e.g., wound care) was lower for the treatment arm. However, no significant clinical or statistical differences were found in terms of opioid requests or consumption, anxiety, or level of satisfaction. This small study was likely underpowered to detect such differences.

Unfortunately, none of these studies are directly applicable to the ED setting. The only study of IV lidocaine analgesia used in the ED setting comes from a study group in Iran [5]. This group studied IV lidocaine vs IV morphine in a prospective, randomized, double-blind clinical trial with 240 patients presenting with renal colic. Initial inclusion into the study was undertaken on the basis of clinical diagnosis (namely appropriate clinical picture and microscopic hematuria on urinalysis), which was later confirmed in all included patients via KUB or ultrasound. Patients were aged 18 – 65 and did not have history of renal, hepatic, or coronary disease.

All patients were initially given 0.15 mg/kg IV metoclopramide. The treatment group was given slow push of 1.5 mg/kg lidocaine dose, with control group receiving slow push of 0.1 mg/kg morphine. The study protocol was considered completed with documented pain scores of < 3 for 30 minutes, or max dose administration of 200mg lidocaine or 10mg morphine. Visual analogue scale pain scores were collected at 5, 10, 15 and 30 minutes after injection.

There were no significant differences in gender, age, prior history of nephrolithiasis, incidence of hydronephrosis, or initial pain scores between the two groups. VAS scores were significantly lower in the lidocaine group across all timepoints. The authors report that 90% of patients in the lidocaine arm and 70% of patients in the morphine arm had a “successful response” (p = 0.0001), though unfortunately they do not describe what criteria they used to determine a successful response. The study authors report that all side effects were “mild and temporary.” In the lidocaine group, 22.5% of patients experienced at least one side effect, consisting of perioral numbness, transient dizziness, and dysarthria. In the morphine group, 23.3% of patients experienced at least one side effect, consisting of vertigo, nausea/vomiting, and hypotension.

Limitations of this study include lack of true placebo arm, small sample size without description of power calculation or other true comparative statistics, lack of clear “gold standard” for diagnosis, and unclear description of primary outcome.

This same group of authors attempted to perform a systematic review of parenteral lidocaine use in the ED [9]. They found evidence for efficacy of IV lidocaine in treatment of renal colic, intractable cancer pain, chronic/refractory headache, and post-herpetic neuralgia. This was largely a descriptive study which simply listed relevant citations and general conclusions from the available literature with no quantitative analysis. Also, despite the study’s stated objectives, the authors inexplicably described multiple studies that included non-ED patients.

Take-home:
- Study of IV lidocaine as acute analgesia in the ED is extremely limited.
- Risk of cardiovascular and neurologic adverse effects cause EPs to be more hesitant in using it compared with opiates, although studies of IV lidocaine in other settings have demonstrated its safety.
- IV lidocaine appears to be most effective in treating neuropathic and visceral pain, with indications of possible efficacy for musculoskeletal pain.
- It may be reasonable to consider a low-end dose of IV lidocaine (≤ 2 mg/kg) in patients with severe neuropathic or visceral pain not adequately controlled with opiates.
- Of note, use of IV lidocaine may be restricted at your facility and may not be allowed for parenteral analgesia.

References:
[1] Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain. 2000;87(1):7-17.
[2] Bath FW, Jensen TS, Kastrup J, et al. The effect of intravenous lidocaine on nociceptive processing in diabetic neuropathy. Pain. 1990;40:29-34.
[3] Ferrini R, Paice JA. How to initiate and monitor infusional lidocaine for severe and/or neuropathic pain. J Support Oncol. 2004;2:90-4.
[4] Wasiak J, Mahar PD, McGuinness SK, et al. Intravenous lidocaine for the treatment of background or procedural burn pain. Cochrane Database Syst Rev. 2014 Oct 17;10:CD005622. [Epub ahead of print].
[5] Soleimanpour H, Hassanzadeh K, Vaezi H, et al. Effectiveness of intravenous lidocaine versus intravenous morphine for patients with renal colic in the emergency department. BMC Urology. 2012:12(13). [Epub ahead of print].
[6] Tremon-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetics to relieve neuropathic pain: A systematic review and meta-analysis. Anesth Analg. 2005;101:1738 –49.
[7] McCarthy GC, Megalla SA, Habib AS. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery, a systematic review of randomized controlled trials. Drugs. 2010;70(9):1149-1163.
[8] Clarke C, McConachie I, Banner R. Lidocaine infusion as a rescue analgesic in the
perioperative setting. Pain Res Manage. 2008;13(5):421-423.
[9] Golzari SE, Soleimanpour H, Mahmoodpoor A, Safari S, Ala A. Lidocaine and pain management in the emergency department: a review article. Anesth Pain Med. 2014 February;4(1):e15444 [ePub ahead of print].

Submitted by Aurora Lybeck, PGY-3.
Edited by C Sam Smith (@CSamSmithMD), PGY-3.
Faculty reviewed by Evan S Schwarz, MD FACEP (@TheSchwarziee)

Oh Shacka - Dantrolene for Neuroleptic Malignant Syndrome?

You are in a community emergency department when a middle-aged woman is brought in by her husband for worsening confusion over the last two days.  The charge nurse comes and asks if it should be a stroke page because the patient has “slurred speech”.   You rush into the room, NIHSS card in hand ready to wheel the patient off to CT and are confronted by a worrisome picture.  The patient is burning man re-incarnate - She is laid out on the stretcher with all 4 limbs stiff and outstretched, is febrile to 39.4 and tachycardic to the 140’s.  Her blood pressure is normal. She can answer some of your questions (says she has trouble “saying” words) but is definitely confused.  You think that this might be good old sepsis, but something about her sets your tox-sense tingling …. and you ask her husband immediately for a medication list which contains a number of pro-serotonergic anti-depressants and a single anti-psychotic. 

Could this be serotonin syndrome?  Could this be NMS?  You  send off a CK level (which comes back at > 1000), initiate a sepsis work-up, get a head CT and phone a friend.  Your tox expert by phone helps you with this by asking a single question:  Well, does she have myoclonus  (SS) or is she rigid (NMS)?  Rigid has it, and you create a mnemonic for future reference:


Oh SHACKA this patient might have NMS:

Now that you think that this is like NMS, how is it best treated?  You have memorized for your board exams that bromocriptine is the treatment for NMS, but your toxicology friend reminds you that bromocriptine can worsen the symptoms of serotonin syndrome [1], and given this patient’s med list and possible mixed-picture, may not be the best idea. What about dantrolene?  Well, what about it?

Clinical question:  What is the mechanism of action for dantrolene? Does dantrolene have any proven effectiveness in the treatment of neuroleptic malignant syndrome? 

Literature Review: 
    Neuroleptic malignant syndrome is a rare, and potentially life-threatening adverse reaction to anti-dopaminergic anti-psychotic medication.  There are multiple established diagnostic criteria - the Levenson Criteria and DSM-IV - that are largely described by the mnemonic above. 

from Guzofski et. al. [2]

The exact pathophysiology of NMS is unknown, but the muscle rigidity (which looks a lot like Parkinsonism) is thought to be secondary to inhibition of dopamine-mediated signalling (as such this can also occur in Parkinson's patients in the setting of dopamine withdrawal).  This muscle rigidity can cause muscle
damage and subsequent rhabdomyolysis.  The hyperthermia may be the result of either (or both) the muscle rigidity or by direct effects of dopamine D2-receptor blockade on the hypothalamus.  Hyperthermia can become life-threatening, and thus the treatment, in addition to cessation of the offending agent, is to pharmacologically relax and cool down the patient.

Bromocriptine, a dopamine agonist, is sometimes used.  But as discussed above, if there is a serotinergic component to the patient's presentation, this could worsen serotonin syndrome.  Benzodiazepines and IV fluids are the mainstay of supportive care. 

            Dantrolene, the mainstay of treatment for malignant hyperthermia, has also been proposed and has been used for the treatment of NMS.  Dantrolene acts as a direct skeletal muscle relaxant by blocking calcium release from the sarcoplasmic reticulum [3].  As such, the main side effect is muscle weakness, but no reports of respiratory or airway compromise have been reported (at least in healthy volunteers) [3].  Given this mechanism, it is unclear why it would be helpful for NMS.  Like most things in toxicology, the majority of data regarding the efficacy (or lack thereof) of dantrolene in the treatment of NMS comes from case series and case reports. In 2007, a study published in Critical Care attempted to pool the results of 271 Case Reports to assess the effectiveness of dantrolene for the treatment of NMS [4].  From these 271 case reports, the authors collected patient data including gender, age, diagnosis, triggering medication, dosage, time of incidence, diagnostic criteria met, other laboratory parameters and whether the patients received dantrolene therapy alone, dantrolene + other medications, only other medications, or only supportive care.  The "other medications" and the scope of "supportive care" was not specified (or necessarily the same) between case reports.  The outcomes of the study were the following: reported improvement within 24 hrs, complete time to remission and overall mortality.  The authors found that dantrolene monotherapy was associated with a higher likelihood of improvement within 24 hrs and shortest time (9.4 +/- 12.7 days) to complete remission than dantrolene+ other medication, other medication or supportive therapy alone.  If this was not confusing enough (for example, why would dantrolene alone be better than dantrolene+other medication), the dantrolene monotherapy also had an overall higher mortality (16.2% vs. 7.3% for d+other, 8.9% for "other", and 2% for supportive care).  Given the innumerable caveats to pooling the data only from case reports and the difficult to interpret results, it is unclear whether dantrolene therapy is effective, helpful or potentially harmful in the treatment of NMS.  It is possible that patients who received dantrolene who were either 1) not very sick and so got better quickly or 2) very sick, in which case they received other medications (therefore the longer time to remission) or mismanaged by giving dantrolene alone leading to higher overall mortality.

Clinical Takehome: Know your hyperthermic toxidromes because they are not made better with antibiotics.  Regarding NMS, dantrolene has unproven effectiveness but lack of rigorous evidence that it causes harm.  Benzodiazepines and fluids will be your mainstay of treatment, give bromocriptine if you are confident in your diagnosis. Boom shaka laka.

References:
[1]Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120.

[2] Peralta, M. D. (2006). Neuroleptic malignant syndrome, with attention to its occurrence with atypical antipsychotic medication: a review. Jefferson Journal of Psychiatry, 20(1), 7.
[3] Krause, T., Gerbershagen, M. U., Fiege, M., Weisshorn, R., & Wappler, F. (2004). Dantrolene–a review of its pharmacology, therapeutic use and new developments. Anaesthesia, 59(4), 364-373.
[4]Reulbach, U., Dutsch, C., Biermann, T., Sperling, W., Thuerauf, N., Kornhuber, J., & Bleich, S. (2007). Managing an effective treatment for neuroleptic malignant syndrome. Crit Care, 11(1), R4.

Submitted by Maia Dorsett [@maiadorsett], PGY-3
Faculty Reviewed by Evan Schwarz [@TheSchwarziee] 

Antibiotics for Mandible Fractures?

Clinical Scenario:

You’re working a busy Saturday overnight, and the traumas are rolling in. You’ve just finished packaging up your patient with an abdominal GSW for the OR, and they’re bringing back a new patient before the stretcher is even flipped over. He’s a 25 year-old male, presenting to the ED after being in an altercation with some friends of friends. He was hit in the face during the fistfight. He is complaining of left-sided jaw pain and facial swelling. He is able to open his jaw to a reasonable degree, but uncomfortably. There is no apparent intra-oral injury. CT max/face shows multiple minimally-displaced fractures of the left mandibular ramus and paramental region.

Luckily for you the ENT consult resident is still in the department from seeing your last patient with a complicated ear lac. She evaluates the patient with her senior and looks over the images. The patient will need surgical repair, but is OK for discharge with close pre-op follow-up next week. They recommend mouthwash, nasal spray, analgesia, and antibiotics.

Clinical question:

When are prophylactic antibiotics indicated in mandibular fractures, and how effective are they are preventing infection?

3D CT recon of minimally-displaced mandible fractures. Image from MD Consult.




Literature review:

The use of antibiotics for mandible fractures has been common practice for some time, based on the assumption that such fractures are at high risk of infection due to contamination with oral flora. However, like many dogmatic practices, it appears the initial evidence upon which the “standard practice” is based is sorely lacking [1]. 

A recent systematic review of 31 studies including a total of 5,437 patients published in the Journal of Oral and Maxillofacial Surgery in 2011 found that the overall evidence to support the use of prophylactic antibiotics in mandible fractures is of poor quality [1]. Only 9 of the included studies were RCTs, including 974 patients. The study author laments numerous methodological shortcomings of these RCTs – all had relatively small cohort sizes, none included power calculations, 7/9 RCTs did not describe randomization method, none reported allocation concealment, only one study reported an intention-to-treat analysis, and none reported NNT figures. 

The author found it impossible to perform any quantitative analysis due to heterogeny of study design and poor quality of included studies. For example: only 10/31 studies included information on time from injury to operative management, 13/31 studies did not describe the type of antibiotic used, half of studies did not describe route of administration of duration of course, and 23/31 studies did not report dose of antibiotic used! Significant heterogeny was also found between the types of fractures included, the types of surgical repairs performed, and the types of antibiotic used.

Five of the 9 included RCTs concluded that antibiotics were effective in preventing infection. However, the rates of infections varied widely between included studies – from 4.5-62% in untreated groups and 1.9-29% in treated groups, limiting applicability of those conclusions.

The study author reports that there may be some signal indicating antibiotics are superior to nothing in terms of preventing infection, but concludes:

“Even then, we are not sure which antibiotic to use, we do not know best route of administration, we are not confident about duration of course, and we have very limited information about the optimal dosage. Even worse, we do not have the slightest idea about how many patients we need to treat with prophylactic antibiotics to prevent a complication, and there is no clue about how much this costs the health care spectrum. Therefore, even in this very optimistic scenario, the available evidence is not sufficient to support a standard protocol for the use of prophylactic antibiotics in the treatment of mandible fracture.”

Recommendations for post-operative antibiotics have also become more conservative in recent years. A study group in Switzerland conducted an RCT comparing 24hrs of post-op IV antibiotics only vs post-op IV antibiotics followed by a 5-day PO antibiotic course [2]. It was designed as a pilot study and only included 59 patients, but they found no significant differences in incidence of infection between the two groups.

Another recent retrospective review of 197 patients who underwent operative repair of mandible fracture, published by a group at St. Louis University, found that advanced patient age was the only statistically significant difference in infected and uninfected groups [3]. Injury severity score, fracture type, duration of antibiotic course, and antibiotic type did not differ significantly between the two groups. One primary limitation of this study is the low rate of the primary outcome (only 9 post-op infections occurred).

Take-home:

- There is insufficient evidence to strongly support or discourage the routine use of prophylactic antibiotics in closed mandible fractures.

- Signal from some studies indicating possible benefit of antibiotics warrants further investigation in the form of a well-designed, adequately-powered, placebo-controlled RCT.

References:

1) Kyzas PA. Use of antibiotics in the treatment of mandible fractures: a systematic review. Journal of Oral and Maxillofacial Surgery 2011;69(4):827-32.
2) Schaller B, Soong PL, Zix J, Iizuka T, Lieger O. The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomized, double-blind, placebo-controlled pilot clinical study. Part 2: mandibular fractures in 59 patients. Br J Oral Maxillofac Surg 2013;51:803-7.
3) Hindawi YH, Oakley GM, Kinsella CR, Cray JJ, Lindsay K, Scifres AM. Antibiotic duration and postoperative infection rates in mandibular fractures. Journal of Craniofacial Surgery 2011;22(4):1375-7.

Submitted by Aurora Lybeck, PGY-3.
Edited by C. Sam Smith, PGY-3.

Faculty reviewed by Chris Brooks. 

Steroids for Acute Chest Syndrome?

Clinical Scenario:

A 41 year-old male with a history of well-controlled sickle cell disease and a remote history of CVA and Acute Chest Syndrome (ACS) presents to the ED with three days of left sided chest, shoulder, and flank pain. The pain was subacute in onset, was not pleuritic, was worse with movement, and was not improved with NSAIDs. He also complained of a dry cough but reported no fevers. He had an oxygen saturation of 88% on room air, but his vital signs were otherwise normal. His physical exam demonstrated clear lungs and pain with palpation of his left shoulder and left anterior chest wall. His EKG showed stable borderline LVH. Labs were notable for a negative troponin and Hgb of 5.8, and a left basilar airspace opacity on lateral chest X-ray. He was given IV fluids, morphine, and IV ceftriaxone & azithromycin to cover for Community-Acquired PNA (CAP) triggering Acute Chest Syndrome.

Clinical Question:

Do steroids have a role in treatment of Acute Chest Syndrome?


Plain CXR showing patchy infiltrates of acute chest syndrome. Image credit from AccessMedicine.




Literature Review:

Several retrospective studies from the late 1990s and early 2000s found conflicting results with regards to the effect of steroids on length-of-stay (LOS) and readmission rates [1]. The first RCT designed to answer this question published results in 1998. This group randomized 43 children with ACS to IV dexamethasone or placebo. The authors found that those receiving steroids were admitted an average of 33 fewer hours and had reduced rate of blood transfusion [2].

retrospective review of over 5,000 hospitalizations for ACS at 32 different hospitals over a four year period was undertaken to try to better answer this question. This group found that pediatric patients admitted with ACS who received corticosteroids had longer LOS (8.0 days vs 5.2 days, p < 0.0001) and higher readmission rates (4.4% vs 1.9%) with an OR of 2.4 (95% CI 1.6-3.5) [1]. This study also found considerable variation in use of steroids among the 32 hospitals reviewed, anywhere from 10-86%. The patients who received steroids seemed to be a sicker cohort, as steroid use was associated with comorbid asthma, use of supplemental oxygen, use of inhaled nitric oxide, ICU admission, need for mechanical ventilation, and higher illness severity score. However, the increased LOS and readmission rate trends remained significant even when the authors attempted to control for these factors with propensity score modeling. Interestingly, in this study only 40% of SCD patients with concomitant asthma who were admitted for ACS were given steroids, though it is unclear from this retrospective review of ICD-9 coding whether or not these patients were having an acute exacerbation of asthma.

There is some concern that the variation in steroid use may be related to concerns of steroids causing other clinical complications in these patients. A retrospective case-control study from 2006, which included patients from St. Louis Children’s Hospital, found an association between sickle cell patients with hemorrhagic strokes and recent corticosteroid use [3]. Other studies have found associations of steroid use with higher rates of avascular necrosis and vaso-occlusive crises (presumably the cause of prolonged LOS and readmit rates seen in some studies) [1,4].

A recent review attempted to summarize the available evidence, but in its conclusions the authors noted: "It is clear that the role of corticosteroid therapy in SCD and its complications is anything but settled" [4]. They admit that wide variation in practice pattern as well as use of different agents, dosages, and routes of administration complicates any attempt at meta-analysis. The authors of both the large retrospective study and the review paper admit that patients with comorbid asthma are likely undertreated due to concerns over adverse effects of steroids [1,4]. Though there is not enough evidence to make any definitive recommendation, the authors suggest following standard guidelines for asthma treatment in patients with comorbid asthma and ACS, with the provision that a low-end dose (max 60 mg/day) be utilized and a slow taper employed to avoid "rebound" vaso-occulsive crisis. 

Take-home:

- There does not appear to be strong evidence supporting the routine use of steroids in SCD patients presenting with ACS.

- If the patient has a concomitant condition for which steroids would usually be indicated, particularly acute asthma exacerbation, then their cautious use is likely warranted.

Further FOAMed reading:

1) "Acute Chest Syndrome" from UMEM Educational Pearls.
2) "Acute Chest Syndrome" on Peds EM Morsels. Excellent summary of diagnosis and management.
3) "Sickle Cell Disease, Answers" on EM Lyceum. Evidence-based review of several clinical issues regarding ED management of SCD patients.
4) "Sickle Cell: 10 Things Every EP Should Know About SCD" from EP Monthly. Addresses several common misconceptions about ED management of SCD.

References:
[1] Sobota A, et al. Corticosteroids for acute chest syndrome in children with sickle cell disease: variation in use and association with length of stay and readmission. Am J Hematol 2010; 85:24.
[2] Bernini JC, et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood 1998; 92:3082.
[3] Strouse JJ, et al. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics. 2006 Nov;118(5):1916-24.
[4] Ogunlesi F, et al. Systemic Corticosteroids in Acute Chest Syndrome: Friend or Foe? Paediatr Respir Rev. 2013 Oct 31.


Submitted by Brendan Fitzpatrick, PGY-3
Edited by C. Sam Smith, PGY-3
Faculty review by Doug Char

Antihistamines for asthmatics?

You walk into the exam room, and find an older female patient complaining of an asthma exacerbation. She reports three days of symptoms consistent with her prior asthma exacerbations, including dry cough, wheezing, increased work of breathing, and exertional dyspnea. She had tried her home MDI and continued her maintenance medications, but her symptoms had gradually worsened to the point that she did not feel she could manage at home.

Her exam is significant for wheezing bilateral full fields, somewhat prolonged expiratory phase but good air exchange. She is speaking in full sentences, and maintaining adequate SpO2 on room air. She is afebrile, and the rest of her VS are stable. The patient's only other complaint is that her "allergies had been acting up lately." The patient appears to have a life-long history of seasonal and recurrent allergic rhinitis, but is not prescribed a daily antihistamine or other anti-allergy therapy.


Clinical Question:

Is there any evidence that antihistamine treatment has a clinically significant effect on asthma symptoms?


The Literature:

A systematic review of the efficacy of 2nd-generation antihistamines in patients with allergic rhinitis (AR) and comorbid asthma was published in the Journal of Asthma in 2011. Epidemiological and histopathological evidence confirms the strong association of AR and asthma. The two conditions share histaminergic mediators released by mast cells & basophils, and the cumulative weight of clinical & laboratory evidence suggests a strong pathophysiologic role.

The study authors performed a comprehensive literature search for double-blind randomized controlled trials in which patients with both asthma & AR were treated with 2nd-gen antihistamines -- cetirizine, loratadine, & fexofenadine being the most common. The authors first summarized the findings of several older trials which did not meet their inclusion criteria (i.e., were not double-blind RCTs). Overall, 1st-gen antihistamines (e.g., diphenhydramine, doxylamine, hydroxyzine, meclizine) have not been shown to have an effect on asthma symptoms except at doses high enough to cause anti-cholinergic and CNS-related ADRs. Some in vitro studies have suggested a steroid-sparing effect or diminished airway hyperreactivity with 2nd-gen antihistamines, but these results are inconsistent in the literature. There is fairly strong evidence in the form of large retrospective studies that effective treatment of AR reduces health-care utilization and improves quality-of-life scores in patients with concomitant asthma, but these cohorts included patients utilizing other AR therapies such as intranasal steroids as well as antihistamines.

A multicenter RCT with N=274 comparing cetirizine-D (cetirizine + pseudoephredine) to placebo found improvement in AR & PM asthma symptoms, but no significant effect on AM symptoms or pulmonary function scores. Another RCT of cetirizine alone had similar results. Several double-blind RCTs comparing the drug desloratadine to placebo, with total N >1100, showed significant reductions in both AM/PM & total asthma sx scores (including specific scores for wheezing & cough) and rescue inhaler use.

As is the case for 1st-gen antihistamines, in vitro data suggests higher doses may be needed to treat asthma as compared with AR. A small RCT (N=28) compared cetirizine 20mg daily to placebo (usual dosing 5-10mg daily), and found significant improvement in reported asthma & AR symptoms without a significant rate of adverse effects compared to placebo. Unfortunately, this dosing regimen has not been compared to standard dosing.


Take home:

- Overall, these studies suggest that antihistamine treatment may improve overall asthma symptom severity in patients with concomitant allergic rhinitis.
- Unfortunately, no study to date has evaluated effects, if any, of antihistamines during acute asthma exacerbation, or if addition of antihistamine prevents ED visits or hospitalizations.
- It seems reasonable to offer these patients antihistamine prescription if they are not already taking them.


Reference:
1) J Asthma, 48(2011):965–973.

Contributed by Sam Smith, PGY-3.

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.