ANALGESIA AND SEDATION IN MECHANICAL VENTILATION Erik Stoltenberg, MD Abbott Northwestern Hospital February 27, 2018 DISCLOSURE Nothing to disclose AllinaHealthSystem 1
OBJECTIVE To apply knowledge of the pharmacology of analgesics and sedatives to better care for patients requiring mechanical ventilation to decrease the duration of mechanical ventilation and improve patient survival. Case: 55 year old man with sepsis from pneumonia traditional management Past Medical History Smoking Diabetes On multiple neuroactive home medications (citalopram, PRN hydrocodone-acetaminophen, trazodone) ED Course Initial VBG ph 7.15 pco 2 55mmHg HCO 3 19mEq/L, placed on BiPAP CVC placed, given 8L IV crystalloid, ceftraixone ICU Course Arrives to ICU, RR has increased to 40, FiO2 100%, intubated Intensivist writes sedation orders (morphine gtt, lorazepam gtt), no clear RASS goal Continues on morphine 4mg/h and lorazepam 2mg/hour AllinaHealthSystem 2
Case: 55 year old man with sepsis from pneumonia traditional management ICU Day 2: ABG is ph 7.33 pco 2 45mmHg O 2 70mmHg HCO 3 24 meq/l, patient is occasionally breathing over the set ventilator rate and is occasionally dyssynchronous with the ventilator Physician determines patient is not ready yet and continues morphine and lorazepam infusions at 4mg/h and 2mg/h ICU Day 3: ABG improved to normal, infusions are decreased (but not stopped) ICU Day 5: Patient wakes enough to follow commands intermittently, but is confused, clonazepam per feeding tube is started for benzodiazepine withdrawal ICU Day 6: Despite confusion, spontaneous breathing trial (SBT) is attempted and patient fails Case: 55 year old man with sepsis from pneumonia traditional management ICU Day 7: Sedation infusions changed to intermittent dosing Patient passes a spontaneous breathing trial and is extubated Continued to struggle with delirium ICU Day 9: Eventually able to transfer to acute care floor, weaning clonazepam AllinaHealthSystem 3
Outline PAD Framework Pain analgesia Agitation sedation Delirium numerous strategies Sedation pharmacology Selected evidence to support a different sedation paradigm Recommended strategy within PAD Framework Purpose of analgesia and sedation in the ICU To Reduce discomfort Increase tolerance of intubation and mechanical ventilation Prevent accidental removal of instrumentation Decrease metabolic demands during cardiorespiratory instability NOT to Provide sleep Decrease unpleasant memories Avoid/treat tachypnea Decrease nursing workload* AllinaHealthSystem 4
Pain in the ICU Common the majority of ICU patients have pain Post-cardiac surgery, women experience more pain then men Negative patient-centered effects Significant source of stress (sometimes the MOST significant source) Can increase risk of PTSD Decrease quality of life of ICU survivors Can lead to chronic pain Negative physiologic effects Increase plasma catecholamine levels Increase myocardial oxygen demand Increase oxygen consumption Increase vasoconstriction Objective Pain Assessments (CPOT) AllinaHealthSystem 5
Objective Pain Assessments (BPS) Multi-modal Analgesia AllinaHealthSystem 6
Opioids Opioid IV dose (mg) PO dose (mg) Time to Peak effect Duration of effect Infusion rate Elimination half life Notes Morphine 5 15 30 min (IV) 3-4 h 2-30 mg/h 1.5-2 h Histamine release may be important from a cardiovascular and pulmonary perspective. Caution in renal failure. Hydromorphone 0.7 4 30 min (IV) 4-5 h 0.5-3 mg/h 2-3 h Accumulation with hepatic dysfunction. Fentanyl 0.05 N/A <5 min 30-60 min 25-300+ mcg/hr 3-4 h Significant increase in contextsensitive half-time with infusions >12h. Remifentanil N/A N/A <3 min <10 min 0.05-0.3 mcg/kg/hr 10-20 min Abrupt discontinuation of analgesia. Oxycodone N/A 10 <1h 3-4 h N/A 3-4 h Oxycodone is a prodrug Methadone (variable) 10-20 min (IV), 30-60 min (PO) 3-6 h (longer with repeat dosing) N/A 8-59 h NMDA receptor-antagonist, unpredictable pharmacokinetics (risk for accumulation). Multiple drug-drug interactions. Can prolong qtc Context-Sensitive half time https://www.e-jnc.org/journal/figure.php?xn=jnc-8-2-53.xml&id=f1-jnc-8-2-53&number=199&p_name=0333_199 AllinaHealthSystem 7
Analgesic Adjunct Medications Drug IV or PO dose Half-life Metabolism Notes Ketamine IV: 0.1-0.5mg/kg bolus, then 0.05-0.4mg/kg/hr 2-3h CYP450: 2B6, 2C9, 3A4, urinary excretion Attenuates opioid-induced hyperalgesia, may decrease persistent postoperative pain Acetaminophen IV/PO: 650-1000 mg q4-6 h (<4000 mg per day) 2-4 h CYP450: 1A2, 2E1, urinary excretion Use caution in hepatic impairment Ketorolac IV: 15-30 mg q6 h up to 5 days 2.4-8.6 h CYP450. Less than 50% metabolized. 90% excreted in the urine, 6% in bile/ feces Avoid use in patients with aspirin allergy. Caution with renal dysfunction, patients at high risk for bleeding, and in elderly patients. Ibuprofen PO: 400 mg q 4 h 1.8-2.5 h CYP450: 2C9, urinary excretion Same caution as with ketorolac, IV formulation also available. Gabapentin PO: 100 mg TID, can titrate up to maximum dose 1800 mg/day Pregabalin PO: 50 mg TID, may increase to 100mg TID Lidocaine IV: 1.5 mg/kg loading dose, 1-2 mg/kg/h 5-7 h Minimal. Excreted intact in urine. 5.5-6.7 h Minimal metabolism (2%). Renally excreted. 1.5-2 h Hepatic CYP450 (1A2 and 3A4), 10% unchanged in the urine May cause sedation. Abrupt discontinuation may cause seizures. Active metabolites may accumulate in hepatic or renal failure Principles of Sedation The first step in treatment of agitation assess the cause Pain, delirium, hypoxemia, hypoglycemia, hypotension, withdrawal from substances Use an objective scale Use non-pharmacologic methods first Analgesia, re-orientation, re-positioning, normalize sleep Choice of sedative is extremely important Myth: doses of sedation infusions are constant for each patient over time AllinaHealthSystem 8
Richmond Agitation Sedation Scale (RASS) Benzodiazepines Pharmacodynamics via GABA A receptors in the brain Anxiolysis Sedation Hypnosis Anticonvulsant effect Paradoxical agitation in elderly Midazolam Pharmacokinetics Long and variable context-sensitive half-time (especially in elderly) Hepatic metabolism: caution in liver dysfunction and with cp450 inhibitors (common) AllinaHealthSystem 9
Benzodiazepines Myths Myth: BZDs protect patients from bad memories Myth: BZD sedation is required in all patients in the ICU Propofol Pharmacodynamics unknown! (probably GABA A ) Sedation Hypnosis Amnesia Anticonvulsant Anti-emetic no analgesia! Adverse effects Hypotension Vasodilation and myocardial depression Potentially allergenic Egg (lecithin) Soybean oil Propofol Infusion Syndrome (PRIS) Hypertriglycerideemia, rhabdomyolysis, ECG changes, cardiovascular collapse AllinaHealthSystem 10
Dexmedetomidine (Precedex) Unique pharmacodynamics α 2 adrenergic receptor agonist Similar to clonidine, but 8x more specific for CNS Decreases sympathetic tone Mild analgesia Potentially ideal ICU sedative Light sedation (with apparent ceiling) Minimal respiratory depression FDA approved at doses up to 0.7 μg/kg/hr for 24h Compared with other sedatives, decreased ventilator days Adverse effects Hypotension (at rates similar to propofol!) Bradycardia (asystole with bolus dosing) Withdrawal can be a problem (little literature on this) Chen K, Lu Z, Xin YC, Cai Y, Chen Y, Pan SM. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD010269. DOI: 10.1002/14651858.CD010269.pub2. Ketamine N-methyl D-asparate (NMDA) antagonist Historically a dissociative anesthetic Only analgesic effects at low doses Can avoid chronicization of pain Adverse effects Tachycardia, hypertension Salivation Hallucinations AllinaHealthSystem 11
Sedation Options Drug IV Loading Dose Infusion rate Midazolam 0.01-0.05 0.02-0.1 mg/kg mg/kg/hr Lorazepam 0.02-0.04 mg/kg Propofol 0.1-0.3 mg/kg Dexmedetomidine 1 μg/kg over 10 min 0.01-0.1 mg/kg/hr 5-50 μg/kg/min 0.2-0.7 μg/kg/hr Time to Onset Elimination Half-life* Active Metabolites Notes 2-5 min 1.7-2.6 h Yes (α- Active metabolites especially hydroxy- important in renal failure; adverse midazolam and effects hypotension, respiratory conjugated α- depression hydroxymidazolam) 15-20 min 11-22 h No Propylene glycol (carrier solution) can cause acidosis; adverse effects hypotension, respiratory depression 1-3 min 4-23 h No Soybean oil and lecithin carrier (avoid with egg allergy) Adverse effects: hypotension, respiratory depression, propofol-related infusion syndrome (PRIS), pain on injection, hypertriglyceridemia, pancreatitis 5-10 min 1.8-3.1 h No Adverse effects bradycardia and hypotension, hypertension with loading dose; difficult to achieve deep sedation Context-Sensitive half time https://www.e-jnc.org/journal/figure.php?xn=jnc-8-2-53.xml&id=f1-jnc-8-2-53&number=199&p_name=0333_199 AllinaHealthSystem 12
Key Study Point #1: Turn the Sedation OFF Kress Trial (2000) Sedation Vacations or SATs Sedation turned OFF (used to be called DSI daily sedation interruption) Restarted at half the dose Control group patients only followed commands on 9% of patient days! ICU length of stay decreased by 3.5 days Mechanical ventilation decreased by 2.4 days Key Study Point #2: Pair Sedation Vacations (SAT) with Spontaneous Breathing Trials (SBTs) ABC (Awakening and Breathing Controlled trial)trial (2008) Paired SATs and SBTs Safety screens for SAT and SBT were important Control group underwent SBTs 1 year morality decreased from 58% to 44% (NNT 7) Multidisciplinary teams work! AllinaHealthSystem 13
Key Study Point #3: Lighter Sedation is Safe, and May be Equal to Sedation Vacations (SATs) Light vs. deep sedation (2010) Goal RASS 0 to -3 Similar ICU LOS Similar self-extubation rate Similar delirium rate Daily sedation interruption increased: 1. Total midazolam dose 2. Total fentanyl dose 3. Sense of nursing workload Key Study Point #4: PRN Opioids Alone can be OK Protocol: PRN morphine IV + 1:1 sitter Restraints were never used PRN haloperidol for delirium Results 4 fewer days with mechanical ventilation No differences in accidental extubation AllinaHealthSystem 14
Studies are well and good, but this is reality in the ICU, and physicians need nurses help! AllinaHealthSystem 15
Selected Sedation Myths Myth: But our patients aren t deeply sedated! many intensive-care practitioners have the perception that their patients are not oversedated, even though observational studies in Europe and the US found that nearly half of intensive-care patients are deeply sedated and unarousable. Myth: lighter sedation leads to more re-intubations Although in one study it increased risk of self-extubation Girard, T. D. et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 371, 126 134 (2008). In summary, lighter sedation Decreased ICU LOS Decreased ventilator time Decreased disturbing memories Decreased PTSD Decreased nursing workload (compared to daily sedation interruptions) Decreased mortality (when paired with SAT/SBT) AllinaHealthSystem 16
Delirium Assessment and Management Delirium definition: syndrome with acute onset change in baseline mental status, inattention, disorganized thinking and/or altered level of consciousness. Hallucinations and delusions are not required Affects up to 80% of patients with mechanical ventilation Overall Management: Predict Prevent Detect Treat Use a validated screening tool Intensive Care Delirium Screen Checklist (ICDSC) Confusion Assessment Method for ICU (CAM-ICU) Non-pharmacologic methods Risks Age Benzodiazepines (lorazepam) Consequences 3x higher mortality Longer mechanical ventilation time Delirium Risks AllinaHealthSystem 17
Delirium is Frustrating There are no well-validated treatments to reduce the duration of delirium Quetiapine may reduce duration, but it was in one small study (36 patients) There is severe, but rare, risk with antipsychotic medications Antipsychotic medications are therefore not recommend to prevent delirium Synthesizing Sedation into Modern Critical Care: ABCDEF AllinaHealthSystem 18
ABCDEF Result from PAD Guidelines (Barr 2013) Recommended sedation strategies instead of agents After implementation of this ABCDEF bundle, mortality decreased approximately 10% for each bundle element followed AllinaHealthSystem 19
Pain, Agitation and Delirium Guidelines Pain Assess main in ICU patients using an objective behavioral pain scale (BPS, CPOT) Do not use vital signs alone to assess pain, but can them as use a cue for pain assessment. Treat chest tube removal pain pre-emptively with analgesic and/or non-pharmacological therapy Use opioids as first-line therapy for treatment of nonneuropathic pain For neuropathic pain, use gabapentin or carbamazepine Use epidural analgesia in patients under going open AAA repair. Sedation Use an objective sedation scale (RASS and SAS) Titrate to a light level of sedation rather than a deep level, unless contraindicated Use a multidisciplinary approach to sedation management Routinely assess delirium using an objective scale (CAM-ICU or ICDSC) Mobilize ICU patients early to reduce delirium Promote sleep in ICU patients with non-pharmacologic means. ***Note: NO recommendation supporting therapy of delirium with any medication Barr, J. et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. in 41, 263 306 (2013). Case: 55 year old man with sepsis from pneumonia modern management PMH and ED course the same (DM, smoking, pneumonia) ICU Course Arrives to ICU, RR has increased to 40, FiO2 100%, intubated Intensivist writes sedation orders (fentanyl gtt, propofol gtt), RASS goal -1 to -2 ICU Day 2: ABG is ph 7.33 pco 2 45 HCO 3 24 meq/l, patient is occasionally breathing over the set ventilator rate and is occasionally dyssynchronous with the ventilator SBT is done, patient takes TV 500mL with RR in the 20s Becomes anxious off propofol and RR increases to 40, placed back on full vent support Dexmedetomidine started AllinaHealthSystem 20
Case: 55 year old man with sepsis from pneumonia modern management ICU Day 3: Repeat SBT in the morning on dexmedetomidine results in patient with RASS -1, is not anxious with SBT, and is extubated ICU Day 4: Transferred to the acute care floor. Effect of Improving Sedation Practices: Victims of our own success Paradigm shifts in ICU care especially sedation have significantly improved patient outcomes This has resulted in numerous negative trials This lack of difference can be explained by lower-than-expected mortality, a phenomenon we can all be proud of Trial Expected Mortality Observed Mortality ProCESS 30-46% 18.9% ARISE 38% 18.8% ProMISe 40% 30% AllinaHealthSystem 21
More Multidisciplinary Victories Infection Sepsis bundles VAP Bundles Antibiotic Stewardship CVC Bundles Nutrition Early Enteral nutrition Enteral over TPN Mechanical Ventilation SAT/SBT NIPPV Monitoring Less reliance on invasive catheters Others Increased intensivist staffing More restrictive blood product management Early rehabilitation/mobility Lighter Sedation Appropriate DVT prophylaxis Checklists Multidisciplinary Practice Myths, compiled Benzodiazepine sedation is required in the ICU Deep sedation protects patients from bad memories Doses of sedation infusions are constant for each patient Lighter sedation increases nursing workload Lighter sedation leads to more re-intubations AllinaHealthSystem 22
Pearls, compiled Many patients in the ICU have pain which requires treatment Context-sensitive half time = drug infusions build up Sedation is directly related to mechanical ventilation The primary reason for sedation is for mechanical ventilation tolerance Pair sedation strategy (or sedation vacations) with SBTs Light sedation without sedation vacations is probably equal to light sedation with sedation vacations (and decreases nurses sense of workload) In selected ICU patients with appropriate staffing, opioid-only sedation may be safe and desirable Summary Appropriate sedation techniques saves lives! Objective assessments are required to individualize treatment Use an analgesia-first approach Remember the context-sensitive half-time Optimal PAD care requires multidisciplinary teamwork Nurses, physicians, CNSs, NPs, RTs, PT, OT, SLP, rehab physicians Nurses are the tip of the spear Nurses input should always be welcome (and is essential) Appropriate treatment of PAD is arguably the most important work we can do! AllinaHealthSystem 23
REFERENCES Barr, J. et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. in 41, 263 306 (2013). Sessler, C. N. et al. The Richmond Agitation Sedation Scale. Am J Respir Crit Care Med 166, 1338 1344 (2012). Ely, J. et al. Monitoring Sedation Status Over Time in ICU Patients: Reliability and Validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 289, 2983 2991 (2003). Stoltenberg, E. et al. Analgesia, Sedation, and Neuromuscular Blockade in Critical Care / John M. Oropello, Stephen M. Pastores, Vladimir Kvetan, editors. McGraw Hill Medical (2017). Strøm, T., Martinussen, T. & Toft, P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet 375, 475 480 (2010). Pandharipande, P. et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 104, 21 26 (2006). Girard, T. D. et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 371, 126 134 (2008). REFERENCES Mehta, S. et al. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA: The Journal of the American Medical Association 308, 1985 1992 (2012). Treggiari, M. M. et al. Randomized trial of light versus deep sedation on mental health after critical illness. Critical Care Medicine 37, 2527 2534 (2009). Jakob, S. M. et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA: The Journal of the American Medical Association 307, 1151 1160 (2012). Barnes-Daly, M. A., Phillips, G. & Ely, E. W. Improving Hospital Survival and Reducing Brain Dysfunction at Seven California Community Hospitals: Implementing PAD Guidelines Via the ABCDEF Bundle in 6,064 Patients. Critical Care Medicine 45, 171 178 (2017). Kress, J. P., Pohlman, A. S., O'Connor, M. F. & Hall, J. B. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342, 1471 1477 (2000). Pun, B. T., Balas, M. C. & Davidson, J. Implementing the 2013 PAD guidelines: top ten points to consider. Semin Respir Crit Care Med 34, 223 235 (2013). PRISM Investigators. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta- Analysis. N Engl J Med 376, 2223 2234 (2017). AllinaHealthSystem 24
TO CONTACT ME Erik.Stoltenberg@allina.com AllinaHealthSystem 25