Objectives. History of Ketamine First synthesized at Parke Davis Alternative to phencyclidine Veterinary medicine. Mechanism. Mechanism 9/13/2016

Transcription

1 Objectives Keeping Things Calm and Cool: A Pharmacotherapy Update Describe the pharmacology and recognize the adverse effects of ketamine Select an appropriate patient to sedate with ketamine to facilitate mechanical ventilation Demonstrate an understanding of the different pharmacologic options available to prevent shivering in patients receiving targeted temperature management Christine M. Groth, Pharm.D., BCPS September 19 th, 2016 History of Ketamine 1962 First synthesized at Parke Davis Alternative to phencyclidine Veterinary medicine Ketamine as an Adjunctive Sedative Agent to Treat Pain and Agitation in Mechanically Ventilated Patients mid 1970 s Tested in prisoners Approved First used in Vietnam War Illicit use first reported in literature (Special K) 1999 Becomes controlled substance in US (Schedule III) Potter DE, Choudhury M. Drug Discov Today Mechanism Mechanism Dissociative anesthetic Cataleptic state Eyes remain open, sensory input is suppressed Tone of pharyngeal and laryngeal muscles is maintained Cardiopulmonary drive is maintained Non competitive antagonist at NMDA receptors Activity at norepinephrine, muscarinic, serotonergic, and opioid receptors Analgesia at sub anesthetic doses (nociceptive, neuropathic) Psychotomimetic effects at high doses Sympathetic stimulant Decreases catecholamine uptake Anti inflammatory effects Bronchodilator Potter DE, Choudhury M. Drug Discov Today 2014 Potter DE, Choudhury M. Drug Discov Today

2 Pharmacokinetics Adverse Effects Route IV/IM SC PO Onset (minutes) Duration (minutes) hours Half life (hours) Ketamine: 1 3 Norketamine (active): 12 Metabolism Ketamine: Demethylation CYP 3A4, 2B6, 2C8/9 Norketamine: Hydroxylation, Conjugation CNS: hallucinations, delirium, vivid dreams, emergence phenomenon, increased muscle tone/purposeless movement, increased ICP/IOP Pulmonary: laryngospasm, increased secretions CV: hypertension, tachyarrhythmias, negative inotrope in heart failure patients (hypotension) GI/GU: nausea/vomiting, hepatic damage (long term use), ulcerative cystitis (long term use) Elimination Renal: Norketamine Kronenberg RH et al. J Pain Pall Care Pharmacother 2002;16:27-35 Domino EF et al. Clin Pharmacol Ther 1965;6: Emergence Phenomenon Increased ICP Hallucinations, depersonalization, illusions More often described in adults than pediatrics 10 20% of patients receiving ketamine for procedural sedation Treatment strategies benzodiazepines used most commonly Pre dissociation Pre emergence PRN Little is known about the impact of ketamine on delirium Monitor for worsening delirium, especially with prolonged use Delirium may actually improve if able to keep patient more awake and calm on ketamine 1970 s reports of elevated intracranial pressure Large increases up to 1600 mmh20 accompanied by bradycardia, apnea Branded ketamine with a contraindication Misinterpretations in the early studies Largest ICP elevations and all sequelae occurred in patients with preexisting hydrocephalus (ICP <20) CPP is maintained or improved despite absolute increases in ICP Many recent studies show no effect on ICP Strayer RJ et al. Am J Emerg Med 2008;26: Green SM et al. Ann Emerg Med 2014 pii: S (14) Cohen L et al. Ann Emerg Med 2014 pii: S (14) Question What adverse effects should be closely monitored for when using ketamine? A. Hemodynamic instability (hypertension, tachyarrhythmias, or hypotension) B. Increased secretions C. Hallucinations and delirium D. All of the above Ketamine Use for ICU Sedation and Analgesia Mechanically ventilated Patient populations Opioid tolerant Reduced need for other sedatives and analgesics Hemodynamic instability Increase MAP and decrease vasopressor use Bronchospasm Increase chest wall compliance and decrease airway resistance Reduced peak inspiratory pressures Increased PaO2 and decreased PaCO2 Decreased wheezing and bronchodilator use 2

3 Ketamine Use for ICU Sedation and Analgesia Very little supporting literature Mostly case reports and retrospective case series Small number of patients Mostly short term use Limit to specific situations Limit duration of therapy NYS Regulations for Nursing Administration: Sedation/Analgesia for Mechanically Ventilated NYS memorandum on IV anesthetic agents from board of nursing Anesthetic agents should only be administered by An anesthesia trained provider Nurse who is deemed competent through education SMH interpretation A nurse can administer and titrate a continuous infusion of ketamine for the purpose of sedation and analgesia in a MECHANICALLY VENTILATED patient after completing competency and education SMH ICU Pain and Sedation Guidelines Ketamine can be used as an adjunctive sedative/analgesic agent in MECHANICALLY VENTILATED patients DOES NOT require an acute pain service/palliative care consult Use should be discussed with an ICU attending DOES NOT apply for the treatment of intractable pain in NON INTUBATED patients This indication does require acute pain service/palliative care consult SMH ICU Pain and Sedation Guidelines Clinical situations where ketamine may be appropriate: Opioid tolerance Status asthmaticus/copd Hemodynamic instability USE WITH CAUTION: Patients with hypertension, tachycardia, decompensated heart failure, pulmonary hypertension Patients with or at risk for delirium/psychiatric illness Patients with seizure disorders Patients with increased intraocular pressure SMH ICU Pain and Sedation Guidelines Usual dose for sedation/analgesia in MECHANICALLY VENTILATED patients: Bolus: mg/kg Starting infusion rate: mg/kg/hr Usual range: mg/kg/hr Opioid sparing doses are typically mg/kg/hr Dose can be increased by mg/kg/hr every 30 minutes to achieve a SAS of 4 or NVPS 3 Consider slower titration of 0.1 mg/kg/hr if using lower doses Safety and Monitoring Monitoring Level of consciousness Increased secretions Increases in HR and BP Decreases in BP in catecholamine depleted Emergence reaction/delirium Withdrawal with prolonged use 3

4 Safety and Monitoring Two RNs should verify dose and program pump Standard concentration: 2 mg/ml Wild card option with dose limits Occasionally a non standard concentration of 10 mg/ml may be required to reduce fluid volume in patients with increased weight or dose requirements 31 yof was admitted to the ICU for respiratory failure due to community acquired pneumonia and acute respiratory distress syndrome requiring intubation and ECMO She had a prolonged ICU stay requiring large doses of fentanyl (250 mcg/hr) and midazolam (8 mg/hr) as well as chemical paralysis with atracurium Once removed from ECMO sedation weaning was attempted with transitioning from midazolam to propofol Titration of the propofol was limited by soft blood pressures and she continued to have oxygen desaturations, SAS scores > 4, and positive delirium screenings Propofol was transitioned back to midazolam with increasing doses (6 mg/hr) which was hindering her ability to wean from the ventilator and causing further delirium and she remained on fentanyl (250 mcg/hr) Would ketamine be a good option for this patient? Why or why not? If yes, what would be a reasonable starting dose and titration? Ketamine was started at 1 mg/kg/hr and titrated by 0.5 mg/kg/hr to achieve a goal SAS of 4 Her hemodynamics and oxygenation improved She was more awake and able to follow commands Delirium improved over the next few days Ketamine was titrated down to 0.5 mg/kg/hr and then shut off prior to extubation Scenarios Would this patient be appropriate for sedation with ketamine? A 54 yom with chronic opioid use (240 oxycodone tablets a month) being weaned from the ventilator after resolving pneumonia requiring fentanyl 250 mcg/hr, propofol 20 mcg/kg/min, and dexmedetomidine 1.5 mg/kg/hr (SAS 5 6, positive for delirium, MAP 50, HR 60) 4

5 Scenarios Would this patient be appropriate for sedation with ketamine? A 25 yof with severe bronchospasm from status asthmaticus requiring 200 mcg/hr of fentanyl and 8 mg/hr of midazolam to facilitate mechanical ventilation (SAS 2 3, unable to assess for delirium, frequent desats) Scenarios Would this patient be appropriate for sedation with ketamine? A 75 yof with HFrEF, COPD, Afib, DM, and hypothyroidism admitted for COPD vs CHF exacerbation requiring fentanyl 100 mcg/hr and midazolam 1 mg every 3 to 8 hours PRN for agitation (SAS 3 6, negative for delirium, MAP 60, HR ) Scenarios Would this patient be appropriate for sedation with ketamine? A 42 yom with history of HTN, Afib, and heroin abuse admitted after a MVC without head injury requiring fentanyl 300 mcg/hr and midazolam 10 mg/hr to facilitate mechanical ventilation (SAS 6 7, positive for delirium, MAP 70, HR ) Anti Shivering Methods in Targeted Temperature Management Targeted Temperature Management (TTM) Actively cooling patients to a target temperature between 32 and 36 C Recommended by the American Heart Association for any unconscious patient following return of spontaneous circulation after cardiac arrest Out of hospital ventricular fibrillation (1B) Out of hospital pulseless electrical activity (2B) In hospital any rhythm (2B) Cool for 24 hours Target temperature is debatable? Targeted Temperature Management (TTM) Brain Trauma Foundation suggests hypothermia is associated with better clinical outcomes in severe traumatic brain injury (level III) Recent evidence suggests hypothermia is equivocal to normothermia Best to avoid hyperthermia Reserve for refractory intracranial pressure elevation Peberdy MA, et al. Circulation 2010;122:S BTF guidelines. J Neurotrama 2007;24:S

6 Proposed Benefits of Hypothermia Proposed Benefits of Hypothermia Neuroprotective Reduced CNS edema (improved BBB) Reduced cerebral blood flow Reduced metabolism (oxygen consumption) For every 1 C fall in temperature, the cerebral metabolism falls by 8% Interrupted apoptosis Improved energy balance Reduced cerebral metabolism for O 2 and glucose Net increase in ATP Anti epileptic effect Decreased duration, amplitude, and frequency of ictal discharges Increased time between depolarizations Decreased synthesis and release of glutamate Corry JJ. World J Crit Care Med. 2012;1(4) Saigal S, et al. Indian J Crit Care Med. 2015;19(9) Corry JJ. World J Crit Care Med. 2012;1(4) Saigal S, et al. Indian J Crit Care Med. 2015;19(9) Outcomes Associated with Therapeutic Hypothermia vs. Normothermia Hypothermia after Cardiac Arrest Trial 2002 Bernard SA, et al Study group OHCA presenting as VF C vs normothermia OHCA presenting as VF 33 C vs normothermia Number 273 patients over 5 years 77 patients over 3 years Hypothermia duration At least 24 hours At least 12 hours ROSC and initiation of cooling 105 minutes Within 2 hours Mortality at 6 months Good neurological outcome at 6 month 41% hypothermic 55% normothermic p= % hypothermic 39% normothermic p= % hypothermic 68% normothermic p= % hypothermic 26% normothermic p=0.046 Outcomes Associated with Therapeutic Hypothermia vs. Normothermia Targeted Temperature Management after Cardiac Arrest Trial patients in 36 centers in Europe and Australia with OHCA with VF/VT or asystole Outcome Randomized to 33 C either Group 33 C 36 C or Group 36 C Hazard/Risk for at least Ratio 28 p value (95% CI) hours and on fever reduction for 72 hours postarrest end of Primary outcome: 235/473 (50%) 225/466 (48%) 1.06 ( ) 0.51 Death at trial Secondary outcomes: Neurologic function at follow up CPC of 3 5 MRSS of 4 6 Death at 180 days 251/469 (54%) 245/469 (52%) 226/473 (48%) 242/464 (52%) 239/464 (52%) 220/466 (47%) 1.02 ( ) 1.01 ( ) 1.01 ( ) CPC: Cerebral Performance Category Scale; MRSS: Modified Rankin Scale Score Hypothermia after Cardiac Arrest Study Group.N Engl J Med Feb 21;346(8): Nielsen N, et al. N Engl J Med Dec 5;369(23): Bernard SA, et al. N Engl J Med Feb 21;346(8): Outcomes Associated with Therapeutic Hypothermia vs. Normothermia Targeted Temperature Management after Cardiac Arrest Trial 2013 Phases of TTM and Potential Complications Adverse Events 33 C 36 C p value Any adverse event 93% 90% p=0.086 Hypokalemia 19% 13% p=0.018 Shivering 30% 34% p=0.20 Suppl. to Nielsen N, et al. N Engl J Med Dec 5;369(23): Andresen, M, et al. Scand J Trauma Resusc Emerg Med Jun 5;23:42. Nunnally ME, et al. Crit Care Med. 2011;39(5):

7 Shivering Shivering Autonomic response to reduced body temperature Regulated through the hypothalamus Shivering response maximal at 35.5 C Typically ceases at 33.5 C Fever increases the shivering threshold Causes thermal discomfort and autonomic activation Significant impact on Systemic oxygen consumption Tissue ischemia Brain tissue oxygenation Intracranial pressure Shown to be a good prognostic sign Polderman KH. Crit Care Med 2009;37:S Bedside Shivering Assessment Scale (BSAS) 0 None: no shivering noted on palpation of the masseter, neck, or chest wall 1 Mild: shivering localized to the neck and/or thorax only 2 Moderate: shivering involves gross movement of the upper extremities (in addition to neck and thorax) 3 Severe: shivering involves gross movements of the trunk and upper and lower extremities. Goals of Anti shivering Agents Treat and prevent shivering Reducing the shivering threshold Prevent shivering induced neuronal injury Helps to achieve goal temperature Badjatia N, et al. Stroke 2008;39(12):3243 Properties of a Good Anti shivering Agent Quick onset High degree of anti shivering activity Minimal sedation Short duration of sedation Anti shivering Agents (Preventative Therapy) Acetaminophen Inhibits cyclooxygenase mediated prostaglandin synthesis Lowers hypothalamic set point Reduces shivering threshold by C Reduced absorption with hypothermia Buspirone Acts on the 5 HT 1A (serotonin) receptor Lowers shivering threshold by C Synergistic when added to other anti shivering interventions Reduced absorption with hypothermia 7

8 Anti shivering Agents (Preventative Therapy) Magnesium sulfate Increases comfort and decreases the time to goal temperature Effects on peripheral vasodilation 2 3 g boluses given over 5 10 minutes Continuous infusion g/hr Titrated to goal Mg + level of 3 4 mg/dl Anti shivering Agents (Opioids) Meperidine Kappa receptor opioid agonist Alpha 2B adrenoreceptor agonist Lowers shivering threshold by up to 2 C Works synergistically with buspirone and dexmedetomidine Caution: May also lower the seizure threshold, risk of serotonin syndrome with buspirone Fentanyl Opioid with weak anti shivering effects Lowers shivering threshold by 0.2 C Sedative impact Zweifler RM, et al. Stroke 2004;35: Anti shivering Agents (Sedatives) Dexmedetomidine Centrally acting alpha 2 receptor agonist Decreases vasoconstriction and shivering thresholds by > 0.9 C Caution: Bradycardia and hypotension Propofol GABA agonist Reduces shivering threshold by 0.6 C High doses necessary to have impact on shivering Caution: Hypotension MAP <75 80 mmhg may be associated with poor outcome Hypothermia increases serum concentrations/reduces clearance Anti shivering Agents (Sedatives) Midazolam GABA agonist Minimal anti shivering properties Half life is prolonged in hypothermia Increase in plasma concentrations/reduced clearance with CYP 3A4 inhibitors (propofol, diltiazem, macrolides) Anti shivering Agents (Paralytics) Non depolarizing neuromuscular blockers Neuromuscular relaxation prevents muscular shivering response Need to heavily sedate/loss of neuro exam Mask status epilepticus Prolonged weakness Train of four is not reliable Titrate to shivering is recommended Prolonged effects with hypothermia Dose reduce by 20 25% Non pharmacological Methods for Shivering Prevention Skin counter warming Skin temperature contributes ~20% to the input back to hypothalamus about body temperature A4 C increase in skin temperature can compensate for a 1 C decrease in core temperature Hands, feet, and face contain high concentrations of temperature sensors Variable benefits in clinical trials Badjatia N, et al. Crit Care Med 2009;37: Polderman KH. Crit Care Med 2009;37:S

9 Question Which of the following is false regarding antishivering medications? A. Anti shivering medications are use to prevent and treat shivering induced neuronal injury B. Most agents only lower the shivering threshold by < 1 C C. Hypothermia can shorten the duration of action of anti shivering medications D. Anti shivering medications shorten the time to reaching goal temperature SMH Therapeutic Hypothermia Protocols Therapeutic Hypothermia for Post Cardiac Arrest Therapeutic Hypothermia for Refractory ICP Normothermia Clinical Practice Guidelines/Critical Care Guidelines %20Approved%20Policies%20and%20Guidelines/Forms /AllItems.aspx SMH Anti shivering Protocols Columbia Anti shivering Protocol Continuous Paralysis Approach Sedate patient to goal BIS Fentanyl infusion ( mcg/hr) Midazolam infusion ( mg/hr) Prior to initiating hypothermia Bolus atracurium 0.5 mg/kg IV x1 Continuous infusion (5 20 mcg/kg/min) Titrate to train of four 2/4 Columbia Anti shivering Protocol Does not require initial sedation Prior to initiating hypothermia Start preventative medications Skin counter warming Up titration of medications based on BSAS score Paralysis is used last line for refractory shivering Given prn instead of continuous Step Intervention Dose 0 Baseline Acetaminophen Buspirone Magnesium sulfate Skin counterwarming 1 Mild sedation Dexmedetomidine or Opioid 2 Moderate sedation Dexmedetomidine + Opioid mg q 4 6 hr 30 mg q 8 hr g/h IV Goal (3 4 mg/dl) 43 C/MAX Temp mcg/kg/hr Fentanyl starting dose 25 mcg/hr Meperidine mg IM or IV Doses as above 3 Deep sedation Propofol mcg/kg/min 4 Neuromuscular blockade Vecuronium Atracurium -Score of 2 or more on BSAS requires step-up therapy 0.1 mg/kg IV 0.5 mg/kg IV A patient undergoing TTM received appropriate baseline interventions yet still earned a 3 on the BSAS (heart rate has been persistently in the 40 50s bpm) Per the Columbia anti shivering protocol, what would be the best initial intervention (Step 1)? A. Fentanyl B. Dexmedetomidine C. Propofol D. Atracurium A patient undergoing TTM received appropriate baseline interventions and was started on a fentanyl infusion at 25 mcg/hr. BSAS scores are still 3, and the patient is hemodynamically stable. Which of the following would be the next step per the Columbia anti shivering protocol? A. Try meperidine 50 mg IV x1 B. Add dexmedetomidine 0.2 mcg/kg/hr C. Change fentanyl to propofol with rapid titration to 50 mcg/kg/min D. Increase fentanyl infusion to 50 mcg/hr 9

10 55 10