Cord Cunningham, MD, MPH Lieutenant Colonel, US Army 1 st Air Cav Flight Surgeon EMS Physician

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1 Cord Cunningham, MD, MPH Lieutenant Colonel, US Army 1 st Air Cav Flight Surgeon EMS Physician

2 Opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the Department of the Army or the Department of Defense. No conflicts except my concern and drive to reduce prehospital/battlefield morbidity & mortality This reflects the work of many others with special thanks to Major Andy Fisher, MPAS Salviens Vita, Serviens Bellatorum

3 Describe the mechanism of action of Ketamine List the reasons why treating prehospital pain is important Identify the types of pain and settings that Ketamine is better suited than opioids Explain the safety and efficacy of Ketamine in the current medical literature List and describe the complications attributed to Ketamine and their proof Discuss the Tactical Combat Casualty Care Triple Option Analgesia Protocol Salviens Vita, Serviens Bellatorum

4 Discussing benefits of Ketamine outside of analgesia such as for Excited Delirium and Drug Assisted Intubation The policy changing road map to overcome existing hurdles of state or facility restrictions on Ketamine use Salviens Vita, Serviens Bellatorum

5 Ketamine has great utility in EMS Ketamine is very safe Dosing range determines effect and duration Salviens Vita, Serviens Bellatorum

6 About me Importance of pain treatment Background & PK of Ketamine Terminology & Sedation Spectrum Safety and Efficacy Military Ketamine Uses/Data Conclusion/Discussion Salviens Vita, Serviens Bellatorum

7 Board Certified Emergency Physician 1 of 5 Active Army EMS Subspecialty Board Certified 5 Deployments to Iraq/Afghanistan with 75 th Ranger Regiment & USSOCOM Medical Director of 15 Air Ambulance Unit and Fort Hood MSTC Involvement in many DoD Prehospital initiatives CoERCCC, MHS Genesis, medical monitor FDP & USAISR CCC research Salviens Vita, Serviens Bellatorum

8 Don t get dead(create another cax) Make the blood go round & round Make the air go in and out Treat pain and ease suffering Hand off better than you found it Salviens Vita, Serviens Bellatorum

9 Adequate analgesia reduces DVT/PE, catabolic stress response, immunosuppression(malchow, Crit Care Med) Early analgesia linked to lower rates of PTSD(Holbrook, NEJM) Easing suffering(as part of beneficence) is a fundamental tenet of medicine Morphine and similar opioids have been the de facto battlefield analgesic agent since the Civil War era Newer agents have less adverse effects, faster onset time, and more reliable hemodynamic support: LDK, Fentanyl, and OTFC Salviens Vita, Serviens Bellatorum

10 The psychological responses associated with uncontrolled pain: Anger Increased anxiety Sensitivity to external stimuli Withdrawal from interpersonal contact Self-absorption Depression and despair

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12 Ketamine first described in Regular clinical use in the 1970s. Classified as a dissociative anesthetic, but also a analgesic in sub-anesthetic doses. DEA Schedule III Traditionally used in the perioperative setting and emergency department setting. Very low-cost medication; generic: 10cc vial average cost <$7 Salviens Vita, Serviens Bellatorum

13 SOF Tactical Protocols review by Black & McManus ideal battlefield analgesic(&mci) Ranger Medic Protocols 2009 June 2011 DHB for DoD evaluation as prehospital analgesic 14&15 Nov 2011 discussed at the DHB Feb 2012 deliberated and recommended to TC3 w/ TBI and eye injury restriction Salviens Vita, Serviens Bellatorum

14 March 2012 ASDHA Approval Memo Initial recommendation was only to advanced providers(sof & flight paramedics) Oct 2013 Triple Analgesia Option CoTCCC approved Feb 2016 placed in MES Combat Medic Salviens Vita, Serviens Bellatorum

15 NMDA receptor antagonist-binds at the phencyclidine site Racemic solution (S-ketamine more active) Binds mu-receptor(it really is an analgesic) At higher doses causes corticothalamic dissociation Inhibits the reuptake of catecholamines Bioavailability 100% IV, 93% IM, 45% IN, 30% PR/SL, 20% PO Salviens Vita, Serviens Bellatorum

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17 Anesthesia: Loss of sensation resulting from pharmacologic depression of nerve function or from neurological dysfunction. Analgesia: A neurological or pharmacologic state in which painful stimuli are so moderated that, though still perceived, they are no longer painful. Sedation: The act of calming, especially by administration of a sedative. Fleisher, Lee A.; Miller, Ronald D.; Eriksson, Lars I.; Wiener-Kronish, Jeanine P.; Young, William L. ( ). Anesthesia E-Book: 2-Volume Set (Kindle Locations ). Elsevier Health. Kindle Edition. Salviens Vita, Serviens Bellatorum

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20 A large meta-analysis found no dose related adverse events across the standard dosing range, with only unusually high IV doses (ie, initial dose 2.5 mg/kg or total dose 5.0 mg/kg) increasing the risk of vomiting and slightly increasing the risk of apnea and recovery agitation. Salviens Vita, Serviens Bellatorum

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24 Combined prospective and retrospective, observational study of 1,022 ketamine administrations over 9 years in 2 EDs Most common indications fracture reduction, lac repair Salviens Vita, Serviens Bellatorum

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27 Hypersalivation occurred in 17 patients (1.7%) 7 were suctioned All received atropine 14 patients in study did not receive atropine None experienced hypersalivation Salviens Vita, Serviens Bellatorum

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29 Prospectively data collection via Quality Assurance (QA) database 191 administrations by 6 nurses All for procedural sedation All were non-anesthestist nurses Only one was an RN (rest were equivalent of LPN) Most common indication was abscess drainage Salviens Vita, Serviens Bellatorum

30 *None of which required more than supplemental O2 or very transient BVM Salviens Vita, Serviens Bellatorum

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32 Case series of 9 inadvertent overdoses for procedural sedation in one pediatric ED 5x intended dose (n=3) 10x intended dose (n=5) All experienced prolonged sedation (3 to 24hrs) Salviens Vita, Serviens Bellatorum

33 5x the intended dose (n=3) Two with transient O2 desaturations that resolved with O2 supplementation None required BVM 10x the intended dose (n=5) Two experienced desaturations and received <10 minutes of BVM 1 was prophylactically intubated at the providers discretion (no respiratory depression noted) 4 were discharged home from the ED (including the one that got intubated) 1 was admitted for observation Salviens Vita, Serviens Bellatorum

34 100x the intended dose (n=1) Nurse mistook vial that was 100 mg/ml for 1 mg/ml Prophylactically intubated (no respiratory depression noted) Admitted to the PICU for observation All patients were neurologically normal at discharge 8 patients available for follow-up and were neurologically normal Only patient not available was discharged home from the ED without sequelae Salviens Vita, Serviens Bellatorum

35 Inpatient to Outpatient self adminstered 25mg IN vs 2mg Versed IN Focused on aura Limited study 30 total No serious adverse events Ketamine reduced severity p=0.032 Salviens Vita, Serviens Bellatorum

36 The greater the ignorance, the greater the dogmatism. Salviens Vita, Serviens Bellatorum

37 Get your facts first, then you can distort them as you please Salviens Vita, Serviens Bellatorum

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40 Prospective, observational before and after study of mechanically ventilated pediatric patients with intracranial hypertension Hemodyanmics, ICP and CPP were measured before and after ketamine administration Salviens Vita, Serviens Bellatorum

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45 Multicenter, randomized, double-blinded trial of narcotic-naïve patients with VAS >60mm Patients were given 0.2 mg/kg of ketamine or equivalent placebo Then given morphine 3mg every 5min until VAS <30 achieved Primary endpoint was total morphine required to achieve VAS goal Salviens Vita, Serviens Bellatorum

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48 Secondary safety end-points No difference in vital signs at T30 No difference in level of sedation via RASS at T30 Rates of vomiting were the same between both groups Ketamine group experienced more neuropsychological effects (12 vs 1) Hallucinations (4) Dizziness (6) Double vision (2) Dysphoria (6) None of which required intervention Salviens Vita, Serviens Bellatorum

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50 mg/kg IV <20mg IV & 25mg IM No major adverse events (apnea,laryngospasm,mi, HTN emergency) Dysphoria & psychomimetic effects with LDK Salviens Vita, Serviens Bellatorum

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54 Prospective, randomized, controlled, open-label trial of 135 patients receiving prehospital analgesia Both arms received an initial 5mg dose of IV morphine Patients were then randomized to 10mg IV morphine versus 10-20mg of IV ketamine Doses of 5mg morphine or 10mg ketamine were then given every 5 minutes until They were pain free, or An serious adverse event occurred, or They arrived at the hospital Almost all patients also received inhaled methoxyflurane Salviens Vita, Serviens Bellatorum

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56 Adverse events were similar to previously reported studies No major adverse events in either arm Addition of inhaled gas anesthetic not done in US EMS but adverse events still small Salviens Vita, Serviens Bellatorum

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58 Randomized, double-blinded, controlled trial Primary outcome is the maximal change in pain scores via NRS from baseline over 120 minutes Convenience sample, ages with moderate-to-severe abdominal, flank, back or extremity pain Randomized to 0.3 mg/kg ketamine (max 25 mg) or 0.1 mg/kg morphine (max 8 mg) Patients could request repeat dose of study medication after 20 minutes Salviens Vita, Serviens Bellatorum

59 45 subjects (morphine 21, ketamine 24) Demographics were similar Age (29, 30) Gender (male 58%, 42%) Baseline vitals NRS baseline scores (7.1, 7.1) Salviens Vita, Serviens Bellatorum

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65 Retrospective review of injured Navy-Marine personnel brought to level 1 (equivalence) in Navy or Marine AO over 36 months Patients were stratified based on AIS and ISS from data entered prospectively into Navy- Marine CTR EMED system at level 3 Diagnosis of PTSD was made based on DSM-IV criteria at 1-24 months post-injury Patients divided into 2 groups received morphine at level 1 versus those that did not Salviens Vita, Serviens Bellatorum

66 61% were diagnosed with PTSD in the early pain treatment arm versus 76% in the arm lacking pain treatment Remained significant even after stratification by ISS and AIS Salviens Vita, Serviens Bellatorum

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68 Reviewed records of 603 patients that were burned during OIF/OEF from PTSD Military Checklists were available for 241 of the 603 Of those 241, 147 underwent surgery 119 received ketamine intra-op versus 28 that did not Patients grouped based on TBSA <20% versus >20% Salviens Vita, Serviens Bellatorum

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71 25mg IM Ketamine vs 10mg IM Morphine w/ placebo arm Tests include M9/M4 simulated marksmanship, malfunctions, target discrimination, MOPP(NBC) & commo Greater reported unpleasant side effects nausea, dizzy, blurred vision, and decreased concentration Task time slowing No significant task completion/error Salviens Vita, Serviens Bellatorum

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75 PJ Experience: Nine patients Blast (6)-25mg IV (2), 25mg IM (2), 50mg IM (2) *all received opioids prior GSW (2) 50mg IM (2) *all received opioids prior DNBI (1) 25mg IM, repeat x1 Salviens Vita, Serviens Bellatorum

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77 Providing a battlefield analgesia option that does not cause respiratory depression or exacerbate hemorrhagic shock. TCCC battlefield analgesia recommendations need to be simplified there are too many options Decrease the amount of opioids medications because they are contraindicated in hemorrhagic shock. Salviens Vita, Serviens Bellatorum

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84 Ketamine IV 30 seconds Ketamine IM 3-4 minutes Morphine IV 5 minutes Morphine IM minutes Fentanyl IV 1-2 minutes Fentanyl IM 7-15 minutes Fentanyl OTFC 3-15 minutes Salviens Vita, Serviens Bellatorum

85 Severe pain. Amputation, Long bone fracture, Tourniquet, severe pain Ketamine mg IV; 300 mg IM/IN. Consider Midazolam mg IV; 2 mg IM. Wounded and in pain. Ketamine mg/kg IV; 0.5 mg/kg IM/IN. Minor to moderate pain Consider Midazolam 0.5 mg IV; 2 mg IM.

86 EMR/EMT/AEMT/NRP Minimum psychomotor skills EMT=NPA/OPA, PO Glucose/ASA 68W requires approx 212 hrs to AEMT 68W/EMT giving Ketamine!? Salviens Vita, Serviens Bellatorum

87 Ketamine has great utility in EMSlarge dose range, shelf stable, multiple routes of admin Ketamine is very safe-fewer major adverse events than opoids Dosing range determines effect and duration-caution about LDK psychomimetic effects(disarm/safe) Salviens Vita, Serviens Bellatorum

88 We succeed only as we identify in life, or in war, or in anything else, a single overriding objective, and make all other considerations bend to that one objective. -GEN Dwight D. Eisenhower cord.w.cunningham.mil@mail.mil Salviens Vita, Serviens Bellatorum