Sedation and Pain Management in Acute Neurological Disease

ABSTRACT

The optimum provision of pharmacological sedation of the critically ill neurological patient requires defining the underlying etiology of agitation or need for sedation to determine the optimal agent: pain management, anxiolysis, or treatment of delirium. An appropriate regimen can then be decided upon based on the profiles of action of the several common classes of sedative agents. Methods to both evaluate the efficacy of sedation as well as titration to a predefined clinical goal are important tools toward safe administration of drugs that often have serious adverse effects. Recognition of an individualized approach is also necessary as patients will vary considerably with respect to the kinetics and pharmacodynamics of sedative therapy. The drug classes often selected for sedation in an intensive care unit will be reviewed as well as the metrics by which physicians can achieve their objectives in a safe manner.

KEYWORDS

Sedation - scales - pharmacokinetics - intensive care unit - toxicity

REFERENCES

• 1 Payen J F, Chanques G, Mantz J et al.. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study.  Anesthesiology. 2007;  106 687-695
• 2 Phillips D M. JCAHO pain management standards are unveiled. Joint Commission on Accreditation of Healthcare Organizations.  JAMA. 2000;  284 2317-2318
• 3 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. 2000;  342 1471-1477
• 4 Hogarth D K, Hall J. Management of sedation in mechanically ventilated patients.  Curr Opin Crit Care. 2004;  10(1) 40-46
• 5 Mirski M A, Muffelman B, Ulatowski J A, Hanley D F. Sedation for the critically ill neurologic patient.  Crit Care Med. 1995;  23 2038-2053
• 6 Siffleet J, Young J, Nikoletti S, Shaw T. Patients' self-report of procedural pain in the intensive care unit.  J Clin Nurs. 2007;  16 2142-2148
• 7 Li D, Puntillo K, Miaskowski C. A review of objective pain measures for use with critical care adult patients unable to self-report.  J Pain. 2008;  9 2-10
• 8 Mateo O M, Krenzischek D A. A pilot study to assess the relationship between behavioral manifestations and self-report of pain in postanesthesia care unit patients.  J Post Anesth Nurs. 1992;  7 15-21
• 9 Payen J F, Bru O, Bosson J L et al.. Assessing pain in critically ill sedated patients by using a behavioral pain scale.  Crit Care Med. 2001;  29 2258-2263
• 10 Gelinas C, Fillion L, Puntillo K, Viens C, Fortier M. Validation of the critical-care pain observation tool in adult patients.  Am J Crit Care. 2006;  15 420-427
• 11 Odhner M, Wegman D, Freeland N, Steinmetz A, Ingersoll G. Assessing pain control in nonverbal critically ill adults.  Dimens Crit Care Nurs. 2003;  22 260-267
• 12 Puntillo K A, Miaskowski C, Kehrle K, Stannard D, Gleeson S, Nye P. Relationship between behavioral and physiological indicators of pain, critical care patients' self-reports of pain, and opioid administration.  Crit Care Med. 1997;  25 1159-1166
• 13 Labus J S, Keefe F J, Jensen M P. Self-reports of pain intensity and direct observations of pain behavior: When are they correlated?.  Pain. 2003;  102 109-124
• 14 Ely E W, Siegel M D, Inouye S. Delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction.  Semin Respir Crit Care Med. 2001;  22 115-126
• 15 Thomason J W, Shintani A, Peterson J F et al.. Intensive care delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients.  Crit Care. 2005;  9 R375-R381
• 16 Ramsay M A, Savege T M, Simpson B R, Goodwin R. Controlled sedation with alphaxalone-alphadolone.  BMJ. 1974;  2 656-659
• 17 Riker R R, Picard J T, Fraser G L. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients.  Crit Care Med. 1999;  27 1325-1329
• 18 Riker R R, Fraser G L, Simmons L E, Wilkins M L. Validating the Sedation-Agitation Scale with the Bispectral Index and Visual Analog Scale in adult ICU patients after cardiac surgery.  Intensive Care Med. 2001;  27 853-858
• 19 Devlin J W, Boleski G, Mlynarek M et al.. Motor Activity Assessment Scale: a valid and reasonable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit.  Crit Care Med. 1999;  27 1271-1275
• 20 Sessler C N, Gosnell M S, Grapp M J et al.. The Richmond Agitation-Sedation Scale. Validity and reliability in adult intensive care unit patients.  Am J Respir Crit Care Med. 2002;  166 1338-1344
• 21 De Jonghe B, Cook D, Griffith L et al.. Adaptation to the Intensive Care Environment (ATICE): development and validation of a new sedation assessment instrument.  Crit Care Med. 2003;  31 2344-2354
• 22 Avripas M B, Smythe M A, Carr A, Begle R L, Johnson M H, Erb D R. Development of an intensive care unit bedside sedation scale.  Ann Pharmacother. 2001;  35 262-263
• 23 Ely E W, Truman B, Shintani A et al.. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).  JAMA. 2003;  289 2983-2991
• 24 de Lemos J, Tweeddale M, Chittock D. Measuring quality of sedation in adult mechanically ventilated critically ill patients: the Vancouver Interaction and Calmness Scale.  J Clin Epidemiol. 2000;  53 908-919
• 25 Weinert C, McFarland L. The state of intubated ICU patients. Development of a two-dimensional sedation rating scale for critically ill adults.  Chest. 2004;  126 1883-1890
• 26 Jacobi J, Fraser G L, Coursin D B et al.. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.  Crit Care Med. 2002;  30 119-141
• 27 Park K S, Hur E J, Han K W, Kil H Y, Han T H. Bispectral index does not correlate with observer assessment of alertness and sedation scores during 0.5% bupivacaine epidural anesthesia with nitrous oxide sedation.  Anesth Analg. 2006;  103 385-389
• 28 Sackey P V, Radell P J, Granath F, Martling C R. Bispectral index as a predictor of sedation depth during isoflurane or midazolam sedation in ICU patients.  Anaesth Intensive Care. 2007;  35 348-356
• 29 Tukenmez B, Memis D, Pamukcu Z. The addition of haloperidol, propofol, or midazolam to sufentanil for intravenous sedation in the intensive care unit using bispectral index.  J Opioid Manag. 2008;  4 34-40
• 30 Gutstein H B, Akil H. Opioid analgesics. In: Hardman JG, Limbird LE Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York; McGraw-Hill 2001: 569-619
• 31 Pan Y X, Xu J, Bolan E, Moskowitz H S, Xu M, Pasternak G W. Identification of four novel exon 5 splice variants of the mouse mu-opioid receptor gene: functional consequences of C-terminal splicing.  Mol Pharmacol. 2005;  68 866-875
• 32 Muellejans B, López A, Cross M H, Bonome C, Morrison L, Kirkham A J. Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial.  Crit Care. 2004;  8 R1-R11
• 33 Rao T LK, Mummaneni N, El-Etr A A. Convulsions: an unusual response to intravenous fentanyl administration.  Anesth Analg. 1982;  61 1020-1021
• 34 Murkin J M, Moldenhauer C C, Hug C C et al.. Absence of seizures during induction of anesthesia with high-dose fentanyl.  Anesth Analg. 1984;  63 489-494
• 35 De Conno F, Caraceni A, Martini C et al.. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine.  Pain. 1991;  47 337-339
• 36 Flacke J W, Flacke W E, Bloor B C, Van Etten A P, Kripke B J. Histamine release by four narcotics: a double-blind study in humans.  Anesth Analg. 1987;  66 723-730
• 37 Charney D S, Mihic S J, Harris R A. Hypnotics and sedatives. In: Hardman JG, Limbird LE Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York; McGraw-Hill 2001: 399-427
• 38 Greenblatt D J, Divoll M, Abernathy D R et al.. Clinical pharmacokinetics of the newer benzodiazepines.  Clin Pharmacokinet. 1983;  8 233-252
• 39 Hoffman E J, Warren E W. Flumazenil: a benzodiazepine antagonist.  Clin Pharm. 1993;  12 641-656
• 40 Sanchez-Izquierdo-Riera J A, Caballero-Cubedo R E, Perez-Vela J L, Ambros-Checa A, Cantalapiedra-Santiago J A, Alted-Lopez E. Propofol versus midazolam: safety and efficacy for sedating the severe trauma patient.  Anesth Analg. 1998;  86 1219-1224
• 41 Forster A, Juge O, Morel D. Effects of midazolam on cerebral hemodynamics and cerebral vasomotor responsiveness to carbon dioxide.  J Cereb Blood Flow Metab. 1983;  3 246-249
• 42 Ely E W, Inouye S K, Bernard G R et al.. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU).  JAMA. 2001;  286 2703-2710
• 43 Bergeron N, Dubois M J, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool.  Intensive Care Med. 2001;  27 859-864
• 44 Pandharipande P, Jackson J, Ely E W. Delirium: acute cognitive dysfunction in the critically ill.  Curr Opin Crit Care. 2005;  11 360-368
• 45 Claassen J, Hirsch L J, Emerson R G, Bates J E, Thompson T B, Mayer S A. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus.  Neurology. 2001;  57 1036-1042
• 46 Neale B W, Mesler E L, Young M, Rebuck J A, Weise W J. Propylene glycol-induced lactic acidosis in a patient with normal renal function: a proposed mechanism and monitoring recommendations.  Ann Pharmacother. 2005;  39 1732-1736
• 47 Barnes B J, Gerst C, Terrell A R, Mullins M E. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation.  Pharmacotherapy. 2006;  26 23-33
• 48 Dobrydnjov I, Axelsson K, Samarutel J, Holmstrom B. Postoperative pain relief following intrathecal bupivacaine combined with intrathecal or oral clonidine.  Acta Anaesthesiol Scand. 2002;  46 806-814
• 49 Iskandar H, Guillaume E, Dixmerias F et al.. The enhancement of sensory blockade by clonidine selectively added to mepivacaine after midhumeral block.  Anesth Analg. 2001;  93 771-775
• 50 Venn R M, Grounds R M. Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions.  Br J Anaesth. 2001;  87 684-690
• 51 Khan Z P, Munday I T, Jones R M, Thornton C, Mant T G, Amin D. Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions.  Br J Anaesth. 1999;  83 372-380
• 52 Tulen J H, van de Wetering B J, Kruijk M P et al.. Cardiovascular, neuroendocrine, and sedative responses to four graded doses of clonidine in a placebo-controlled study.  Biol Psychiatry. 1992;  32 485-500
• 53 Pandharipande P P, Pun B T, Herr D L et al.. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial.  JAMA. 2007;  298 2644-2653
• 54 Szumita P M, Baroletti S A, Anger K E, Wechsler M E. Sedation and analgesia in the intensive care unit: evaluating the role of dexmedetomidine.  Am J Health Syst Pharm. 2007;  64 37-44
• 55 Elbaradie S, El Mahalawy F H, Solyman A H. Dexmedetomidine vs. propofol for short-term sedation of postoperative mechanically ventilated patients.  J Egypt Natl Canc Inst. 2004;  16 153-158
• 56 ter Minassian A, Beydon L, Decq P, Bonnet F. Changes in cerebral hemodynamics after a single dose of clonidine in severely head-injured patients.  Anesth Analg. 1997;  84 127-132
• 57 Aryan H E, Box K W, Ibrahim D, Desiraju U, Ames C P. Safety and efficacy of dexmedetomidine in neurosurgical patients.  Brain Inj. 2006;  20 791-798
• 58 Talke P, Richardson C A, Scheinin M, Fisher D M. Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine.  Anesth Analg. 1997;  85 1136-1142
• 59 Riker R. The Precedex ICU Long Term Sedation Trial Results. Paper presented at: the Society of Critical Care Medicine 37th Critical Care Congress February 2–6, 2008 Honolulu, HI;
• 60 Baldessarini R J, Tarazi F I. Drugs and the treatment of psychiatric disorders: psychosis and mania. In: Hardman JG, Limbird LE Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York; McGraw-Hill 2001: 485-520
• 61 Misfeldt B B, Jorgensen P B, Spotoft H, Ronde F. The effects of droperidol and fentanyl on intracranial pressure and cerebral perfusion pressure in neurosurgical patients.  Br J Anaesth. 1976;  48 963-968
• 62 Lischke V, Behne M, Doelken P, Schledt U, Probst S, Vettermann J. Droperidol causes a dose-dependent prolongation of the QT interval.  Anesth Analg. 1994;  79 983-986
• 63 Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome.  Intensive Care Med. 2003;  29 1417-1425
• 64 Alkire M T, Haier R J. Correlating in vivo anaesthetic effects with ex vivo receptor density data supports a GABAergic mechanism of action for propofol, but not for isoflurane.  Br J Anaesth. 2001;  86 618-626
• 65 Tsuchiya H. Structure-specific membrane-fluidizing effect of propofol.  Clin Exp Pharmacol Physiol. 2001;  28 292-299
• 66 Greenblatt D J. Intravenous anesthetic agents. Pharmaco-kinetic-pharmacodynamic relationships.  Clin Pharmacokinet. 1981;  6 89-105
• 67 Perrier N D, Baerga-Varela Y, Murray M J. Death related to propofol use in an adult patient.  Crit Care Med. 2000;  28 3071-3074

APPENDIX: SPECIFIC SEDATION SCALES USED IN THE INTENSIVE CARE UNIT

Motor Activity Assessment Scale

Score	Description	Definition
0	Unresponsive	Does not move with noxious stimulus[*]
1	Responsive only to noxious stimuli	Opens eyes OR raises eyebrows OR turns head toward stimulus OR moves limbs with noxious stimulus*
2	Responsive to touch OR name	Opens eyes OR raises eyebrows OR turns head toward stimulus OR moves limbs when touched or name is loudly spoken
3	Calm and cooperative	No external stimulus is required to elicit movement AND patient is adjusting sheets or clothes purposefully and follows commands
4	Restless and cooperative	No external stimulus is required to elicit movement AND patient is picking at sheets or tubes OR uncovering self and follows commands
5	Agitated	No external stimulus is required to elicit movement AND attempting to sit up OR moves limbs out of bed AND does not consistently follow commands (e.g., will lie down when asked but soon reverts back to attempts to sit up or move limbs out of bed)
6	Dangerously agitated, uncooperative	No external stimulus is required to elicit movement AND patient is pulling at tubes or catheters OR thrashing side to side OR striking at staff OR trying to climb out of bed AND does not calm down when asked

1 Noxious stimulus, suctioning, OR 5 seconds of vigorous orbital, sternal, or nail bed pressure. Adapted from Devlin et al.[19]

Riker Sedation-Agitation Scale (SAS)

Score	Category	Description
7	Dangerous agitation	Pulling at endotracheal tube, trying to remove catheters, climbing over bedrail, striking at staff, thrashing side-to-side
6	Very agitated	Does not calm despite frequent verbal reminding of limits, requires physical restraints, biting endotracheal tube
5	Agitated	Anxious or mildly agitated, attempting to sit up, calms down on verbal instructions
4	Calm, cooperative	Calm, easily aroused, follows commands
3	Sedated	Difficult to arouse, awakens to verbal stimuli or gentle shaking but drifts off again, follows simple commands
2	Very sedated	Arouses to physical stimuli but does not communicate or follow commands, may move spontaneously
1	Unarousable	Minimal or no response to noxious stimuli, does not communicate or follow commands
Adapted from Riker et al.[17]

Richmond Agitation-Sedation Scale

Score	Term	Description
+4	Combative	Overtly combative or violent; immediate danger to staff
+3	Very agitated	Pulls on or removes tube(s) or catheter(s) or has aggressive behavior toward staff
+2	Agitated	Frequent nonpurposeful movement or patient–ventilator dyssynchrony
+1	Restless	Anxious or apprehensive, but movements not aggressive or vigorous
0	Alert and calm
-1	Drowsy	Not fully alert, but has sustained (> 10 seconds) awakening, with eye contact, to voice
-2	Light sedation	Briefly (< 10 seconds) awakens with eye contact to voice
-3	Moderate sedation	Any movement (but no eye contact) to voice
-4	Deep sedation	No response to voice, but any movement to physical stimulation
-5	Unarousable	No response to voice or physical stimulation
Adapted from Sessler et al.[20]

AVRIPAS: Revised Sedation Scale

Agitation	Alertness
1. Unresponsive to command/physical stimulation	1. Difficult to arouse, eyes remain closed
2. Appropriate response to physical stimuli/calm	2. Mostly sleeping, eyes closed
3. Mild anxiety/delirium/agitation (calms easily)	3. Dozing intermittently, arouses easily
4. Moderate anxiety/delirium/agitation	4. Awake, calm
5. Severe anxiety/delirium/agitation	5. Wide awake, hyperalert
Respiration
1. Intubated, no spontaneous effort
2. Respirations even, synchronized with ventilator
3. Mild dyspnea/tachypnea, occasional asynchrony
4. Frequent dyspnea/tachypnea, ventilator asynchrony
5. Sustained, severe dyspnea/tachypnea
Patient Classification	Sedation Goal
Acutely ill (weaning not a goal)	5–9
Ventilated patient being weaned	7–10
Chronic ventilated patient (weaning not a goal)	6–9
Nonventilated patient	7–9
Adapted from Avripas et al.[22]

Procedure for Scoring the Minnesota Sedation Assessment Tool (MSAT)

1. Record the highest level of unstimulated spontaneous motor activity observed in the last 10 minutes.

2. Walk to the right shoulder and observe eye opening and/or tracking.

3. If no eye opening, call first name and “open your eyes!”

4. If no eye opening yet, shake right shoulder firmly, call first name and “open your eyes!”

5. Choose the arousal scale category appropriate for the patient's response to procedures 2 to 4.

6. Judge the current quality of the sedation therapy as “adequate,” “oversedated,” or “undersedated.” Use any clinical information available to you in addition to the scale levels.

MOTOR ACTIVITY SCALE

• Movement of central muscle group (back or abdominal muscles)

• Movement of proximal limbs (hip or shoulder)

• Movement of distal limbs or head and neck muscles

• No spontaneous movement

Note: Disregard respiratory efforts, cough, swallowing, eye movement, or isolated tiny muscle contractions.

AROUSAL SCALE

• Eyes open spontaneously with tracking

• Eyes open spontaneously, but not tracking

• Eyes closed, but open to sound of voice

• Eyes closed, but open to shoulder shake plus sound of voice

• Eyes stay closed, but other patient movement observed in response to stimulation

• Eyes stay closed and no patient movement observed in response to stimulation

Adapted from Weinert and McFarland.[25]