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November 2016

Ketamineâ&#x20AC;&#x2122;s Effect on Post Traumatic Stress Disorder

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Sheri Harvey, Shar Graphics

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November 2016

November 2016 Vol.2 Issue 11

Ketamine’s Effect on Post Traumatic Stress Disorder

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Ketamine’s Effect on Post Traumatic Stress Disorder Victoria Zolkewsky RN, BSN, SRNA Andrea D’Agostino RN, BSN, SRNA Dr. Greg Bozimowski CRNA, DNP Funding/Conflict of Interest Disclosure: None

Learning Objectives Participants will be able to.. 1. Identify accepted ketamine dosage to administer intraoperatively for patients with PTSD 2. Explain the effect of intraoperative ketamine use for patients diagnosed with PTSD 3. Differentiate between negative perceptions about intraoperative ketamine use on PTSD patients and evidenced-based outcomes 4. Describe anesthetic implications of ketamine administration in patients with PTSD Background Ketamine is a useful drug well known to anesthesia practitioners but interest in its application has been seen in the management of post-traumatic stress disorder (PTSD). Its known side effect of emergence delirium has raised concern for its administration in PTSD victims. This literature review sought to examine the effects of ketamine in that population. The literature revealed evidence to suggest that when ketamine was administered to patients with PTSD, a reduction in symptoms occurred. The literature also suggests that ketamine reduces the signs of depression in patients who suffer other psychiatric disorders. These findings offer promise in the management of PTSD and future research to determine optimal dosing and protocols is warranted. Introduction Ketamine is a N-methyl-D aspartate (NMDA) antagonist drug useful in a variety of settings but most particularly in anesthesia. It was first developed in 1962 for use as a rapid acting general anesthetic.1 In 1970, it was approved by the Food and Drug Administration (FDA) and was initially considered a battlefield anesthetic1 Ketamine was associated with illicit use in the 1970’s and 1980’s, which may have attributed to the negative association sometimes applied to this pharmacological agent.1 It has the ability to quickly induce general anesthesia and 4

provide analgesia while maintaining hemodynamic stability. However, due to its phencyclidine derivative structure, its use may produce a dissociative state causing hallucinations, delusions and an overall distorted perception of sight and sound. Emergence delirium, a state of psycho-motor agitation during awakening from general anesthesia, affects a portion of the population. The combination of emergence delirium from general anesthesia and ketamine’s known dissociative state has made anesthetists fearful to use ketamine as an adjunct anesthetic for individuals with mental instability, including posttraumatic stress disorder (PTSD). Recent studies, however, have begun to re-explore the use of ketamine and further address the concern that its use may exacerbate PTSD.2 PTSD, common in war veterans, is characterized by over-stimulated brain activity.2 It is “a mental health condition that’s triggered by a terrifying event — either experiencing it or witnessing it”.3 PTSD can develop in anyone who experiences a frightening event in which the fight or flight response is triggered, which is a normal reaction that is meant to protect a person from harm4. PTSD develops when a person does not recover from the traumatic event but rather continues to feel scared or stressed, despite the passing of the original danger.4 Symptoms usually include flashbacks of the triggering event, avoiding people and places, anger, disengagement, and hyper-arousal. Patients with PTSD can also experience anxiety and depression. The symptoms of the disorder can range from mild to severe.3, 4 Literature Review A retrospective review of the literature was conducted utilizing the PICOT format approach as it identifies the population studied, the intervention performed, the comparison made between groups, the outcomes examined, and the time or duration studied. The review sought to answer the following question; What is the effect of ketamine as part of the anesthetic for a patient affected by PTSD? CRNA Today

The research databases used were CINHAL, Pubmed, the side effects of ketamine. No surgical procedure was performed at this time.7 Pre-induction, the patient Cochrane, and Science Direct. The key search terms received 3 mg of midazolam (0.04 mg/kg). For included: PTSD, post-traumatic stress disorder, induction the patient received 30 mg of lidocaine and ketamine, ketalar, NDMA antagonist, post-traumatic, emergence delirium, and veterans. The articles chosen 70 mg of propofol (1 mg/kg). After a hypnotic state was noted, a 20 minute infusion of 30 mg of propofol were primarily published from the year 2012 to 2014 (20 mcg/kg/min) and 35 mg of ketamine (0.5 mg/kg) in order to assure relevance to current practice. One were administered. These doses were derived from article was published in 2008, but the evidence was a published protocol of a clinical trial pertaining to strong and appropriate, despite its earlier publication. 7 A common population studied to assess for correlation ketamine and its effect on PTSD. No emergence delirium was noted. One hour post-infusion, the between ketamine and PTSD were burned service patientâ&#x20AC;&#x2122;s mentality and overall demeanor was members in the military. In six research articles improved. For the next two weeks, the patient reported ketamine was shown to reduce PTSD in burned being free of anxiety and depression, had improved service members who were undergoing medical sleep patterns, and no longer experienced nightmares. 2 treatment. This finding was noted despite the fact After two weeks, the patient began to develop signs of that the patients who received perioperative ketamine depression, indicating relapse.7 had a higher injury severity score, underwent more

operations and spent more time in the intensive care unit (ICU). The mechanism was unclear, but the authors theorized it was the result of better pain control, neuronal protection and antagonism of the NMDA receptor.2 In a follow up retrospective study in 2014, the authors concluded that patients in a similar population did not screen positive for PTSD at a different rate than those who did not receive ketamine, and their symptoms did not worsen.5 The authors concluded that there was no association between ketamine and worsening PTSD.5 Active duty Army anesthesia providers were surveyed on their perceptions about characteristics associated with emergence delirium; ketamine and PTSD were common variables.6 PTSD was the most common reported psychological factor believed to be related to emergence delirium. The active duty army aesthesia providers who were administered surveys consisted of 156 certified registered nurse anesthetists (CRNAs) and 98 anesthesiologists. The results from the survey showed that primarily anesthetic agents, and secondly ketamine, were believed to be associated with emergence delirium.6 Anesthesia providers reported through the survey the perception that the administration of a benzodiazepine and talking to the patient during a PTSD episode were helpful interventions to alleviate emergence delirium.6 A case study of a 26-year-old male combat veteran received a ketamine infusion as a treatment modality for severe PTSD and chronic major depressive disorder. This treatment plan was initiated by the patientâ&#x20AC;&#x2122;s psychiatrist who consulted with an anesthesia practitioner to formulate a plan in efforts to reduce November 2016

A randomized double-blind control trial, which compared ketamine to midazolam tested the safety and efficacy of a single dose of ketamine for treatment of PTSD and associated depressive symptoms. The interventions were either ketamine hydrochloride (0.5 mg/kg) or midazolam (0.045 mg/kg).8 The authors reported that when assessed 24 hours after infusion, the use of a ketamine was associated with a significant reduction in PTSD symptom severity as compared to midazolam, and greater reductions of PTSD symptoms were also noted in the long term.8 The ketamine infusion was associated with reduction in co-morbid depressive symptoms with overall improvement in clinical presentation. Ketamine was tolerated well without clinically significant persistent dissociative symptoms.8

In answering the research question the literature revealed supporting evidence to suggest that when ketamine was administered to patients with preexisting PTSD, a reduction in symptoms occurred. The literature also suggests that ketamine reduces the signs of depression in patients who suffer other psychiatric disorders. A majority of the studies reviewed were conducted on either U.S Army veterans and/or burn victims due to their high prevalence of PTSD. While this limits the ability to generalize results to other populations, it also limits the additional variables that could potentially skew the results. The sample sizes were small and were only based in the United States. There is limited research specific to only PTSD; many studies include depressive disorders. Despite these limitations, there was evidence to conclude that ketamine is safe to 5

use in PTSD patients and has been shown to reduce PTSD symptoms and have an overall improvement in clinical presentation.2,4,5,6,7,8,9 Future Research The evidence presented suggests that ketamine may be beneficial in treating PTSD. Current research calls for developing pharmacologic approaches in treating patients with PTSD with a drug of similar class or different formulation (i.e. sublingual or nasal spray). Since ketamine has been used as a multi-modal pain therapy, and PTSD can be exacerbated by pain, this correlation should be further explored. Future research is also warranted for ketamineâ&#x20AC;&#x2122;s effect on other psychiatric disorders such as anxiety, bipolar disorder and schizophrenia. The safety and efficacy of ketamine use with other psychotropic drugs needs to be tested, especially since there is limited knowledge in the exact mechanism with which ketamine reduces PTSD. Finally, more insight into varying doses of ketamine needs to be explored to determine at which dose ketamine treatment is therapeutic without causing adverse effects. Implications for Clinical Practice CRNAs have diverse views on the use of ketamine as a part of their anesthetic plan. Many are hesitant to use ketamine for the fear of the hallucinatory side effects. Some reserve its use as a last resort for difficult sedation cases, limited airway access or obese patients in hopes of avoiding apnea. Others use it as an opioid adjunct for patients with chronic pain or for lengthy orthopedic cases to reduce opioid requirements. The literature suggests that in individuals with a history of PTSD, ketamine use does not worsen the severity of PTSD and may in fact relieve symptoms. Due to the dissociative state seen with ketamine there is often reluctance to administer it to patients with any type of psychiatric history or substance abuse. These patients can be difficult to manage from an anesthesia standpoint. As a result of the polypharmacy therapy

approach they are often treated with, acute and chronic pain may not be responsive to opioid therapy. Ketamine, which does not rely solely on effects at opiate receptors, can be an effective complementary treatment in managing these patients. Ketamine may not be a permanent solution to PTSD, but the literature has provided evidence that the beneficial properties exist to help these patients. The recommended dose most supported by the research is 0.5 mg/kg.7, 9 Most studies infused this dose over a variable amount of time from 20-45 minutes. The analgesia and sedation dose of ketamine ranges from 0.2-0.8 mg/kg over 2-3 minutes, followed by a continuous ketamine infusion (5-120 mcg/kg/min).10. A dose of 10-20 mg can offer preemptive analgesia.10 The dose recommended from the studies of 0.5 mg/ kg is comparable to the normal analgesia dose that is not outside of the norm for usual intraoperative administration.7,9 After administration of a single dose, full reorientation to person, place and time takes place in 15-30 minutes.10 The incidence of emergence reactions in the general population is approximately 12%.10 It is most commonly seen in female patients over 16 years of age who have received large doses of ketamine in a short period of time.11 The emergence reactions are the result of visual, auditory, proprioceptive, and confused illusions.10 Benzodiazepines have been found to significantly decrease the incidence of these reactions.10 In regards to other psychiatric disorders, a few studies comparing ketamine for major depression, using the same dose of 0.5 mg/kg of a ketamine infusion showed a significant improvement compared to baseline depression.9 Unfortunately, the extent and duration of the antidepressant effect has not been explored or well documented at this time. Ketamine has been shown to have an early effect on reducing suicidal thoughts.9 Some adverse effects from these studies included transient headaches, dizziness, changes in vital signs, euphoria, confusion and dissociative effects.9

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References

1. Ketamine. Center for Substance Abuse Research 2013. Available at: http://www.cesar.umd.edu/cesar/ drugs/ketamine.asp. Accessed March 6, 2016. 2. Mcghee LL, Maani CV, Garza TH, Slater TM, Petz LN, Fowler M. The intraoperative administration of ketamine to burned U.S. service members does not increase the incidence of post-traumatic stress disorder. Military Medicine 2014;179(8S):41–46 3. Post-traumatic stress disorder (PTSD). Mayo Clinic. Available at: http://www.mayoclinic.org/diseasesconditions/post-traumatic-stress- disorder/basics/definition/con-20022540. Accessed March 6, 2016 4. Post-Traumatic Stress Disorder. National Institute of Mental Health. Available at: http://www.nimh.nih. gov/health/topics/post-traumatic-stress-disorder- ptsd/index.shtml#part_14537. Accessed March 6, 2016 5. Mcghee LL, Maani CV, Garza TH, Gaylord KM, Black IH. The Correlation between ketamine and posttraumatic stress disorder in burned service members. The Journal of Trauma: Injury, Infection, and Critical Care 2008;64 (Supplement). 6. Wilson J.T. Pharmacologic, physiologic, and psychological characteristics associated with emergence delirium in combat veterans. AANAJ. 2014;82(5):355–362. 7. Womble AL. Effects of ketamine on major depressive disorder in a patient with posttraumatic stress disorder. AANAJ 2013;81(2):118–119 8. Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder. JAMA Psychiatry. 2014. 71(6):681. 9. Howland RH. Ketamine for the treatment of depression. J Psychosoc Nurs Ment Health Serv. 2013. 51(1):11– 14. 10. Nagelhout JJ. Intravenous Induction Agents. In: Nurse Anesthesia. Nagelhout JJ, Plaus KL. St. Louis, MO: Saunders/Elsevier; 2014: 113-117. 11. Ouellette RG, Joyce JA. Pharmacology For Nurse Anesthesiology. Sudbury, MA: Jones & Bartlett Learning; 2011

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Study/Authors

Design, Purpose and Sample

Study #1 Title: The correlation between Ketamine and Posttraumatic Stress Disorder in Burned Service Victims 2008 Authors: McGhee, L.L., Maani, C.V., Garza, T.H., Gaylord, K.M., and Black, I.H.

Design: clinical trial comparing PTSD correlation coefficients for operative patients (ketamine, TBSA, ISS, ICU days, morphine equivalents/operation, total morphine equivalents in OR). Purpose: To determine a correlation between ketamine and posttraumatic stress disorder in burned service victims using a screening tool for comparison. Sample: 147 total soldiers tested positive for PTSD and required an operation for burns. 119 of these patients received ketamine, 28 did not. Level of Evidence: II

Study #2 Title: The Intraoperative Administration of Ketamine to Burned U.S Service Members Does Not Increase the Incidence of Post- Traumatic Stress Disorder Authors: McGhee, L.L., Maani, C.V., Garza, T.H., Slater, T.M., Petz, Fowler, M.

Design: A retrospective chart review study. Purpose: To revisit the relationship between PTSD and ketamine in U.S. servicemen who have experienced burns using a larger sample size. Sample: 289 subjects total; 189 received ketamine and 100 did not. The population consisted of burned U.S service members treated at the U.S Army Institute of Surgical Research. The patients had to have received a screening test for PTSD at least 30 days after the burn to be included in the study. Level of Evidence: IV

Study #3 Title: Pharmacologic, Physiologic, and Psychological Characteristics Associated with Emergence Delirium in Combat Veterans Authors: Wilson, J.T.

Design: Descriptive correlational study. Purpose: To explore medical providersâ&#x20AC;&#x2122; perceptions of pharmacologic, physiologic and psychological characteristics associated with emergence delirium seen in veterans. Ketamine and PTSD were used as common variables. Sample: Convenience sampling of active duty Army personnel consisting of 156 CRNAs and 98 anesthesiologists. Of the 254 people included, 89 responded to the survey and 2 of those 89 responses were discarded due to incompleteness; therefore, there were a final number of 87 respondents (34% response rate). Level of Evidence: VI

Study #4 Title: Effects of Ketamine on Major Depressive Design: Case study Disorder in a Patient with Posttraumatic Stress Disorder Purpose: To evaluate the use of a ketamine infusion as a treatment modalAuthors: Womble, A.L. ity for PTSD. Sample: One 26-year-old male combat veteran presenting with severe PTSD and chronic major depressive disorder. Level of Evidence: VI

Study #5 Title: Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder: A Randomized Clinical Trial Authors: Feder, A., Parides, M.K., Murrough, J.W., Perez, A.M., Morgan, J.E., Saxena, S., Kirkwood, K., Aan Het Rot, M., Lapidus, K.A.B., Wan, L.B., Iosifescu, D., & Charney, D.S.

Design: Randomized, double-blind, crossover trial Purpose: To test the efficacy and safety of a single intravenous dose of ketamine for treatment of PTSD and association of depressive symptoms in patients with chronic PTSD. Sample: 41 patients with moderate to severe chronic PTSD to a range of trauma exposures that were recruited with advertisements Level of Evidence: II

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Results and Conclusions

Critique of Strengths and Weakness

Result: Patients receiving ketamine demonstrated a lower prevalence of PTSD (32/119 = 26.9%) compared to those who did not receive ketamine (13/28= 46.4%). There were no statistical differences in the age of patients or the amount of morphine per surgical procedure. Conclusions: Perioperative low-dose ketamine use in burned soldiers undergoing surgery seems to decrease the prevalence of PTSD. The mechanism is unclear, but may be due to better pain control, neuronal protection, and antagonism of the NMDA receptor.

Strengths: The study used a screening questionnaire, which was used to develop a PTSD baseline. It is an objective tool that could be repeated in other populations and studies. Weakness: Unequal, small sample sizes and different characteristics within patients (ketamine patients had a larger burn size). For PTSD itself, there is not a mechanism to predict its development, but despite this weakness, other studies have shown that burn size does not correlate with PTSD development. The study was from 2008, making it nearly eight years old and possibly not as relevant.

Result: Patients who received ketamine during treatment, did not screen positive for PTSD at a rate different than those who did not receive ketamine. PTSD scores and symptom severity were similar between groups. Conclusions: Although this study does not show a benefit of ketamine on PTSD development that was identified in previous work with a smaller sample number, it does support the conclusion that ketamine does not increase PTSD development in burned service members.

Strengths: The study had a larger population than previously studied. No subjects were lost during this follow-up. Other variables, such as patient demographics and opioid usage, were thoroughly investigated. Due to previously collected data, there was more direction in the type of data to collect. Weakness/Limitations: This was a retrospective study using a small sample size. Changes in practice and personnel occurred during study time, which may have contributed to differences. There was little consistency in the time post-burn at which the patient was screened using the screening tool, leading to the possibility of under-reporting the incidence of PTSD. Other mental health disorders were not evaluated. Each patient also received multiple other drugs during the hospital stay and the dose of ketamine each patient received was not included

Result: 68 respondents had experience with emergence delirium. Of those 68 people, 44 believed that the type of anesthesia influenced emergence delirium with ketamine being the second most commonly reported anesthetic agent to be perceived as the cause. 88% of respondents thought that PTSD was a psychological factor that was related to emergence delirium. Conclusions: The survey indicated that an overwhelming amount of anesthesia providers believed that ketamine was related to emergence delirium despite previous research findings.

Strengths: A pilot study was initially performed to test the reliability and validity of the study, and allowed time to make changes prior to the studyâ&#x20AC;&#x2122;s final release. The study included automated question-answer format, as well as the opportunity to provide comments. Weaknesses: The study was based on surveyed opinions and views, therefore only providing subjective data. Some prospective subjects did not have access to the Internet.

Result: 15 minutes after the infusion was stopped, the patient was arousable and responding to verbal stimuli. At this time, the patient was also reported to be in an amorous state, and was witnessed smiling and joking with staff as well has having positive interactions with his wife. The first 2 weeks after infusion consisted of complete resolution of anxiety, depression and nightmares. He also experienced normal sleep patterns. After 2 weeks, relapse occurred and pre-infusion depression symptoms returned. Conclusions: Warrants further investigation as a treatment for PTSD. Offers promise that ketamine can be used safely in patients with PTSD.

Strengths: The case study was valuable in providing how a patient would benefit from a ketamine infusion intraoperatively. Provided a timeline with when the patient started to relapse. Weaknesses: Additional case studies need to be reported and further information needs to be provided on what happens after 14 days of study. Other medications were administered at the time of the ketamine infusion, which may influence the results. Other ketamine formulations need to be compared to intravenous infusions for efficacy.

Result: 24 hours after the infusion, ketamine was associated with a significant reduction of PTSD symptom severity on a measurable scale. Ketamine was also associated with reduction in co-morbid depressive symptoms and with overall improvement in clinical presentation. Conclusions: This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. It was generally well tolerated, without clinically significant persistent dissociative symptoms. Further studies are needed for replication and to examine the efficacy and safety of ketamine administration beyond a single infusion for patients with chronic PTSD.

Strengths: The enrollment of patients with moderate to severe PTSD symptom levels. Also, the use of the active placebo control midazolam, which strengthened the blind (compared to saline solution) because midazolam can also induce psychoactive effects. Finally, the shielding of the primary outcome rater from adverse effects occurring during the day of infusion Weakness/ Limitations: Several patients did not receive a second infusion, but in half of these patients, this second infusion was prevented per protocol because of sustained reduction in PTSD symptom levels 2 weeks after ketamine infusion. The study does not address the important question of safety or efficacy of ketamine in combination with other psychotropic medications in PTSD.

November 2016

Questions: POST TEST 1. What is an appropriate dose for ketamine use to reduce symptoms for a patient with a history of PTSD? A. 0.01 mg/kg B. 0.5 mg/kg C. 5 mg/kg D. 0.6 mcg/kg 2. What drug classification is believed to be most effective in reducing emergence delirium associated with ketamine? A. benzodiazepine B. phenothiazine C. phencyclidine D. piperidine

4. What are symptoms of Post Traumatic Stress Syndrome? A. Euphoria progressing to delusional behavior and uncharacteristic mood elevation B. flashbacks of the triggering event, anxiety, depression, anger, and hyper arousal C. extreme depression often accompanied by suicidal thoughts and catatonia D. hallucinations and paranoia to external environmental changes 5. In which of the following patient history assessment findings might ketamine be beneficial? A. substance abuse B. a history of PTSD

3. Which of the following describes post-traumatic stress disorder (PTSD)? A. A condition in which a preexisting schizophrenia recurs despite triggering events B. A manic episode that is characterized by delusions of grandeur and uncharacteristic spending of large amounts of money C. A condition that is triggered by a terrifying event, where a patient continues to experience symptoms following the event D. An ill-defined syndrome in which patients report bizarre hallucinations and exhibit swings of mood between mania and depression

C. long-term use of opiates for chronic pain D. All of the above 6. Which of the following patients is most likely to have a history of PTSD? A. a war veteran who recently returned from deployment B. a 16 year old girl with a history of depression and anxiety C. a 26 year old male with a history of illicit IV drug abuse D. a 32 year old female with post-partum depression

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7. Which of the following best describes ketamineâ&#x20AC;&#x2122;s mechanism of action?

1.) In what psychiatric population is ketamine administration shown to be beneficial?

A. GABA-ergic

A. depression

B. NMDA antagonist

B. mania

C. Opiate receptor mixed agonist

C. personality disorders

D. Serotonin enhancer

D. schizophrenia

8.) Which of the following best describes emergence delirium A. a state of confusion exhibited in pre-op and continuing into PACU B. psycho-motor agitation during awakening from general anesthesia C. euphoria whenawakeningfrom general anesthesia D. amnestic sedation upon awakening from general anesthesia 9. What contributes to CRNA reluctance to administer ketamine to patients with a psychiatric history? A. fear of the possible hallucinatory side effects B. concern for the potential to increase recovery time and hospital costs C. fear of causing relapse of depression or other psychiatric symptoms D. Unknown 10.) What is the theorized mechanism with which ketamine reduces symptoms of PTSD? A. Through its interaction as a cholinergic receptor agonist

12.) Which of the following have been shown to exacerbate PTSD? A. hypoxia B. pain C. temperature extremes D. virus 13.) TRUE or FALSE: Ketamine was initially considered a battlefield anesthetic 14.) TRUE or FALSE: Witnessing, rather than being victim of a traumatic event can trigger PTSD 15.) TRUE or FALSE: Even in sub-therapeutic dose ketamine is free of negative side effects 16.) TRUE OR FALSE: Ketamine effects on depression typically last between 6 months and 1 year. 17.) TRUE OR FALSE: The incidence of emergence reactions in the general population is approximately 12%

B. The ability to decrease the dissociation of GABA from the GABA receptor

18.) TRUE OR FALSE: Ketamine has been shown to have an early effect on reducing suicidal thoughts

C. Through the result of improved pain control, neuronal protection and NDMA antagonism

19.) TRUE or FALSE: Recent literature suggests that over time ketamine worsens symptoms of PTSD.

D. By inding to the sodium channel in its inactive state 1

20.) TRUE or FALSE: CRNAs widely agree that it is beneficial to administer Ketamine to a patient suffering from PTSD

Test questions must be completed online, visit CRNAToday.com November 2016

1. American Heart Association (AHA) http://www.heart.org/HEARTORG/Conditions/Arrhythmia/ AboutArrhythmia/What-is- Atrial-Fibrillation-AFib-or-AF_UCM_423748_Article.jsp#.VkFLu4Tl7zI. Retrieved on Nov 9, 2015.

London (2011) CRNA Hall, JE, and AC Guyton. “Textbook of Medical TODAY Physiology.” Saunders TM

3. Silbernagl, S, and A Despopoulos. “Color Atlas of Physiology.” Thieme (2009) 4. Narouze, S, HT Benzon et al. “Interventional Spine and Pain Procedures in Patients on Antiplatelet and Anticoagulant Medications” Reg Anesth Pain Med 40.3 (2015): 182-212.

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