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 aSAH.  Patients 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.

Brought in By Ambulance #5: Chemical Takedown - IM Ketamine for Prehospital Restraint

Clinical scenario: You are working the overnight shift in the Emergency Department (ED) when a pre-arrival for "agitation" pops up on the board.  You see EMS roll by with several police officers and decide that you should follow.  On the stretcher lies a partially clothed, basically unresponsive patient who is maintaining a respiratory rate of 10 and oxygen saturation of 88% on room air.  As you quickly slap on the oxygen, check the patient's response to pain with a sternal rub, see an end-tidal CO2 reading of 35, and contemplate intubation, EMS starts to provide their signout.  The paramedics responded to a call for "altered behavior" and were confronted with a psychotic, agitated, diaphoretic patient who would likely fit the description of Excited Delirium Syndrome (ExDS).  The patient quickly ran at and jumped on a paramedic.  The paramedics, fire department, and police restrained the patient who required multiple doses of Haldol and Ativan to facilitate transport.  As you further assess the patient, you wonder, "is there a better way to chemically restrain a patient that maximizes the safety of EMS providers and patients?".  As the patient's sats improve to 98%, you realize that you have some time to think. You have recently heard about prehospital use of IM ketamine for just this purpose and decide to review the evidence.

Practical exercise:  Calculate the IM Ketamine dose to takedown the Incredible Hulk.

Literature Review:
In 2011, the term "Excited Delirium Syndrome (ExDS)" was coined to describe the clinical syndrome referred to in different venues as "agitated delirium", "excited delirium", or "Sudden Death in Custody Syndrome".   The American College of Emergency Physicians (ACEP) convened a task force to define the spectrum of the syndrome which has the following clinical features [1,2]:

                   - hyper-aggressive or bizarre behavior, including lack of clothing
                   - lack of sensitivity to pain
                   - hyperthermia
                   - diaphoresis
                   - attraction to light or shiny objects

The exact etiology of ExDS is unknown, but there is a strong association with pre-existing psychiatric disease (in particular, schizophrenia) and drugs of abuse (cocaine, methamphetamine, and PCP) [2].

Most importantly,  ExDS conveys a high risk of mortality, in the realm of 10% [1,2].  The exact cause of death is not completely clear, but is thought to arise from severe acidosis or hyperkalemia, and is usually the end result of physical struggle or restraint.  Agitated, combative patients also pose a risk to prehospital providers.  Follow this link to watch a video of ExDS from presentation to death. 

Multiple pharmacologic therapies for chemical restraint of patients with ExDS have been suggested, from anti-psychotics, to benzodiazepines to the dissociative drug, ketamine:

Table 2 from Vilke et. al (Ref 3).

Anti-psychotics and benzodiazepines have long delays to peak effect when given via the IM route, in the realm of 15-30 minutes.  Because of its relatively rapid onset,  there has more widespread  prehospital of IM ketamine for chemical restraint of ExDS.

Several studies have attempted to examine the efficacy of ketamine for prehospital management of ExDS.  Anecdotal evidence for the effectiveness of prehospital ketamine came from initial case series and has been adopted into EMS protocols for extreme agitation [4,5].  These initial case series also highlighted the potential adverse effects of the drug, including hypersalivation, laryngospasm, and hypoxia (at least in the doses used ~ 5 mg/kg IM).

After the initial case series were reported, a pilot, retrospective study of prehospital ketamine for ExDS was published in the Western Journal of Emergency Medicine [6].  In this study, the authors reviewed the paramedic run sheets for 52 violent and agitated patients who were given a single 4 mg/kg dose of IM ketamine  The average time to sedation and medical control was approximately 2 minutes. At the 4 mg/kg IM dosage,  3/52 patients developed respiratory depression, two of whom were intubated.  In each of these cases, the patients had received IV midazolam in conjunction ketamine to prevent emergence reaction.  The authors concluded that "ketamine may be safely and effectively used by trained paramedics following a specific protocol."  A major caveat to this study is that the authors did not examine what happened later in the emergency department.  Interestingly, a previously published case series of 13 patients found that of the three patients who developed respiratory distress, two did so only after arrival to the ED while one patient arrived with ventilation being assisted by EMS [5].  In none of these cases was the impending respiratory distress documented in the prearrival note, suggesting that 6% may be a gross underestimation of the true incidence of respiratory complications. 

Another outcome measure for respiratory complication is by examining incidence of intubation after the patients arrive in the emergency department.  A recent retrospective study published in the American Journal of Emergency Medicine examined the correlation between ketamine dosage and need for intubation [7].  They reviewed the prehospital and emergency department records for 51 consecutive patients who were administered ketamine for prehospital chemical restraint.  Fourteen (29%) of patients required intubation.  Of note, none of these patients were intubated in the field.  Patients who were intubated were administered a significantly higher ketamine dose (6.16 +/- 1.62 mg/kg) than those who were not (4.90 +/- 1.54 mg/kg).  It is not clear what proportion of patients were intubated as a side-effect of the ketamine as opposed to facilitation of  medical care in the emergency department.  It was specifically noted that two of the patients were intubated because of "recurrent agitation and need for additional sedation" and one patient was intubated to facilitate medical workup (a lumbar puncture).  The mortality rate for these patients was not documented, but 71% of the patients were admitted to the hospital, primarily on medical (55%) rather than psychiatric (14%) services.

A final consideration is whether ketamine interacts at all with the psychiatric disorders that underlie some cases of ExDS.  Ketamine acts as an NMDA-receptor antagonist, thereby causing a deficiency in glutamate-mediated

Ketamine chemical structure (wiki)

neurotransmission [8] .   Because PCP and ketamine-abuse can model some aspects of schizophrenia, some have postulated that some aspects of schizophrenia are due to defects in glutamate-mediated neurotransmission.  Indeed, in one study they found that CSF from schizophrenic patients had lower glutamate content when compared with controls [9].  While the "glutamate hypothesis of schizophrenia" remains controversial, because a subset of ExDS syndrome patients have psychotic disorders, one might be concerned that ketamine could have an adverse effect on the underlying psychiatric disease, although this does not appear to have been directly studied anywhere and there are no reports in the limited literature regarding ketamine administration for chemical restraint.

Take Home Points:  ExDS is a syndrome with a high rate of mortality. IM Ketamine is a promising treatment for the prehospital realm because of its rapid time of onset (~2-5 min).  Providers administering ketamine need to have heightened awareness and ability to handle potential respiratory complications, including respiratory depression and laryngospasm.  The long-term effects of single dose ketamine administration in patients with underlying psychiatric diagnoses is unclear.

Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by H. Phil Moy

References:
1. Vilke, G. M., DeBard, M. L., Chan, T. C., Ho, J. D., Dawes, D. M., Hall, C., ... & Bozeman, W. P. (2012). Excited delirium syndrome (ExDS): defining based on a review of the literature. The Journal of emergency medicine, 43(5), 897-905.
2. Vilke, G. M., Payne-James, J., & Karch, S. B. (2012). Excited delirium syndrome (ExDS): redefining an old diagnosis. Journal of forensic and legal medicine, 19(1), 7-11.
3. Vilke, G. M., Bozeman, W. P., Dawes, D. M., DeMers, G., & Wilson, M. P. (2012). Excited delirium syndrome (ExDS): treatment options and considerations. Journal of forensic and legal medicine, 19(3), 117-121.
4. Ho, J. D., Smith, S. W., Nystrom, P. C., Dawes, D. M., Orozco, B. S., Cole, J. B., & Heegaard, W. G. (2013). Successful management of excited delirium syndrome with prehospital ketamine: two case examples. Prehospital Emergency Care, 17(2), 274-279.
5.Burnett, A. M., Salzman, J. G., Griffith, K. R., Kroeger, B., & Frascone, R. J. (2012). The emergency department experience with prehospital ketamine: a case series of 13 patients. Prehospital Emergency Care, 16(4), 553-559.
6. Scheppke, K. A., Braghiroli, J., Shalaby, M., & Chait, R. (2014). Prehospital use of IM ketamine for sedation of violent and agitated patients. Western Journal of Emergency Medicine, 15(7), 736.
7. Burnett, A. M., Peterson, B. K., Stellpflug, S. J., Engebretsen, K. M., Glasrud, K. J., Marks, J., & Frascone, R. J. (2014). The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. The American journal of emergency medicine.
8. Murray, R. M., Paparelli, A., Morrison, P. D., Marconi, A., & Di Forti, M. (2013). What can we learn about schizophrenia from studying the human model, drug‐induced psychosis?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 162(7), 661-670.
9.  Kim, J. S., Kornhuber, H. H., Schmid-Burgk, W., & Holzmüller, B. (1980). Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neuroscience letters, 20(3), 379-382.

Steroids for recurrent migraine headaches?

Clinical Scenario:

A young female in her 20's  with no significant medical history returns for the 3^rd 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