Pharmacotherapy

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.

Brought in by Ambulance, #4: Pour Some Sugar on Me

Case Scenario: 
Your unit is responding on the quiet to a 36 year-old F with chief complaint of “sick.”  You arrive to find a cachectic woman (BMI 16) who suffers from lifelong anorexia. She complains of shortness of breath, abdominal pain and general malaise. She walks herself to the ambulance and after her vitals are taken, a FSBS is 56.  According to your protocol, this should be treated in the following manner: the EMT-B administers 15 gm oral glucose solution and repeat as needed, while the EMT-P administers 25 gm D50W IV/IO or D10W IV/IO, or glucagon 1 mg IM if no IV/IO access available.  The medic asks your opinion and as the patient was symptomatic, you suggested starting with oral glucose solution. However, this made her feel nauseated. Once again, the medic asks you whether to give D10W or D50W. You elected for D10W, but you admittedly have no evidence for doing so. After an uneventful ride to the hospital, the patient’s repeat blood glucose was 254 mg/dL.

Clinical Question:
What is the best way to treat hypoglycemia in the prehospital environment?

Literature Review:  
Most common sources define hypoglycemia as less than 60-70 mg/dL. According to the Endocrine Society’s Clinical Practice Guidelines, hypoglycemia should only be treated and investigated in patients showing signs of "Whipple’s triad" -- signs and symptoms of hypoglycemia, a low plasma glucose reading, and resolution of symptoms with elevation of plasma glucose concentration [1]. The signs and symptoms of hypoglycemia are quite vague and nonspecific; they can include shakiness, anxiety, headaches, and weakness, progressing to seizures and unconsciousness [2]. Severe symptoms typically occur with serum glucose values less than 40 mg/dL [3]. It seems obvious that seizures and unconsciousness attributed to hypoglycemia should be treated, but any of the minor signs and symptoms could easily be appreciated on almost any primary scene response. Therefore the vast majority of hypoglycemic patients encountered by EMS providers are most likely going to be treated.

Once we have decided to treat prehospital hypoglycemia, we must determine the optimum modality for doing so. We could find no published work doing a heads-up comparison of oral versus intravenous carbohydrate administration, but there has been work related to D10W versus D50W. An EMS system in California published data from their experience replacing 50mL D50W with 100mL D10W as the standard treatment for hypoglycemia [7]. In 164 treated patients, the median pretreatment glucose was 38 mg/dL, and at 8 minutes after treatment was 98 mg/dL.Twenty-nine patients required an additional dose, and one patient required a third. There were no adverse events reported. The authors conclude these results demonstrate the feasibility, safety, and efficacy of D10 as an alternative to D50.

One unblinded randomized controlled trial compared D10W to D50W in prehospital hypoglycemic patients with GCS < 15 (approx. 25 pts in each group) with regards to the ability of the solutions to raise glucose to normal values and the time to reach a GCS of 15 [4]. The mean repeat glucose value in these groups was 112 and 169 in the D10W and D50W groups, respectively (p = 0.003). The authors note that the average D10 given was 10g (100 mL) and D50 given was 25g (50 mL) (p < 0.001). There were no significant differences between the groups in median time to recovery, median post-treatment GCS, or number of patients experiencing another hypoglycemic episode within 24 hours. The authors conclude that due to the efficacy of treatment with lower risk of hyperglycemia, D10 should be the preferred agent.
   
Not only is D50 more likely to cause hyperglycemia after administration, but it also carries with it the risk of hypertonicity and tissue necrosis. D50 has an osmolarity of 2,525 mOsm/L and a pH between 3.5 and 6.5. This is in contrast to D10 which has an osmolarity of 506 mOsm/L and is pH neutral. Usual IV therapy recommendations state that solutions with osmolarity greater than 900 mOsm/L should be administered through central access. There have also been several case reports of extremity amputation after dextrose extravasation [5,8].

To illustrate the difficulty in administering D50, one of our toxicology faculty compared the injection of D50 to injecting maple syrup. This is not a facetious analogy, as a simple look at the nutrition label of a bottle of syrup reveals:



Note that D50 = 50g of sugar per 100mL of soluion. Each "amp" of D50 contains 25g of sugar in 50mL. Compare that to Aunt Jemima's, which contains 32g of sugar in 60mL solution.

The primary EMS agency bringing patients to our facility recently updated their protocols to make D10 the preferred agent for treating hypoglycemia prehospital. The Medical Director of this agency reiterated the preferable safety profile of D10 compared with D50, and remarked on another important advantage of D10 -- it does not need to be diluted for use in pediatric patients.

In the absence of IV/IO access, evidence exists for the efficacy of IM glucagon in treating prehospital hypoglycemia [9]. The response to glucagon may take longer than when oral or IV glucose solutions are used [10, 11], though may cause a greater increase in blood glucose levels than 10g of glucose solution [12].
   
Take-home:
- If mental status allows, hypoglycemic patients should first be offered oral glucose -- preferably 15gm of a standard glucose formula, but syrup, juice, or honey can also be used. (Note that honey has a lower glycemic index than most juices or glucose solution and thus theoretically may not be as effective.) 
- The next line of therapy should probably be IV D10, as there is good evidence to suggest efficacy on par with that of D50 but with a more favorable safety profile.
- If no IV/IO access is available and oral glucose is unable to be administered, it is reasonable to administer 1mg IM glucagon.

References:
[1] Evaluation and management of adult hypoglycemic disorders.  J Clin Endocrinol Metab, 2009, 94(3), 709.
[2] American Diabetes Association.  Diabetes.org
[3] National Diabetes Information Clearinghouse.  Diabetes.niddk.nih.gov
[4] Moore and Woolard. Emerg Med J, 2005, 22, 512-515.
[5] Kumar et al. ANZ Journal of Surgery, 2001, 71, 285-289.
[6] Is D50 Too Much of a Good Thing?  Stephen Wood, 2007, m.jems.com/article/patient-care
[7] Kiefer et al. Prehosp Disaster Med2014, 29(2), 190-194.
[8] Lawson et al. Am J Emerg Med, 2013, 31(5), 886:e3-5.
[9] Vukmir et al. Ann Emerg Med, 1991, 20(4), 375-9.
[10] Howell et al. J Accid Emerg Med, 1997, 14(1), 30-2.
[11] Carstens and Sprehn. Prehosp Disaster Med, 1998, 13(2-4), 44-50.
[12] Vermeulen et al. Diabetes Care, 2003, 26(8), 2472-3.

Submitted by Chris Miller, PGY-2.
Edited by C. Sam Smith (@CSamSmithMD), PGY-3.
Faculty reviewed by Hawnwan P. Moy.