4. 2 Sedation and Analgesia Guideline Introduction

4.2 Sedation and Analgesia Guideline
Introduction
Critically ill patients are routinely mechanically-ventilated, undergo repeated bedside procedures, and are likely to have anxiety and pain ^1. Thus, a variety of sedatives and analgesics are employed in the ICU to provide patient comfort, amnesia, reduce hemodynamic instability, and to blunt the stress response. Recent investigations have shown that continuous intravenous sedation is associated with prolonged mechanical ventilation and increased morbidity ^2, and that daily interruption of sedation via a protocol of daily awakening trials improves patients’ outcomes dramatically ^{3, 4}.

Another area of concern associated with sedation is the problem of delirium and long-term cognitive impairment. Recent studies have shown that delirium occurs in over 80% of mechanically ventilated patients and that this is a major independent determinant of length of stay, cost of care, and 6-month mortality ^5-7.

Sedation selection in the ICU and goal directed therapy

Sedation and analgesia strategies in the ICU are usually comprise of a combination of benzodiazepines and narcotics ^8. A number of investigators have shown that nurse implemented sedation protocols in the ICU, as well as goal directed levels of sedation, resulted in shorter ventilator times, decreased length of stay, and decreased ICU costs ^{4, 9-13}. Based on these studies, the Society of Critical Care Medicine (SCCM), recently published guidelines for the use of sedatives, analgesics, and neuromuscular blockers in the critically ill.^13

SCCM recommendations^13

The SCCM guidelines offer evidence-based drug recommendations depending on the duration of sedation and co-morbid conditions in critically ill patients. They also emphasize the need for protocolized sedation strategies as well as recommend goal-directed therapy based on sedation scales.

• Analgesia

• hemodynamically stable: morphine

• hemodynamically unstable: fentanyl or hydromorphone

• Anxiety

• Acute agitation: midazolam

• Short-term sedation: midazolam or propofol

• Long-term sedation: lorazepam

• For patients with elevated intracranial pressures and compromised cerebral perfusion pressure, propofol is recommended with frequent reevaluation

• Delirium

• haloperidol

The Maricopa Medical Center Goals

• To implement a reliable, reproducible, and validated scale to guide drug usage as a means to minimize pain, anxiety, and delirium in critically ill patients (SCCM Grade A recommendation).

Monitoring analgesia

Patients in the ICU are evaluated for pain either by a Numerical Rating Scale (NRS) or by Behavioral & Physiological Indicators (BPI). Often we are utilizing the BPI since our patients are unable to communicate their pain due to their co-morbid conditions, sedation or mental status.

Monitoring sedation – The Richmond Agitation Sedation Scale (RASS)

To date, there are 25 scales developed for assessing sedation.^10 Only 3 have been validated in ICU patients. Of those validated scales, the Ramsay Scale and the Riker –Agitation scale (SAS)/ Motor agitation Scale (MAAS)^14 do not differentiate between verbal and motor stimulus. Additionally the SAS and MAAS are difficult to memorize since they don’t have precise discriminating factors.

The Richmond Agitation Scale^15 was developed in 1998 and validated at the Medical College of Virginia by Curt Sessler, MD, and a multidisciplinary team. It differentiates between motor and verbal stimuli and each category has very precise definitions, making it easy for communication of sedation goals between various care providers. Since the original validation study, this scale has been re-validated and shown to be a reliable instrument in a large cohort study at Vanderbilt University.^16

Richmond Agitation Sedation Scale (RASS)

Score Category Description
+4 Overtly combative, violent, immediate danger to staff

+3 Pulls or removes tube(s) or catheter(s); aggressive

+2 Frequent non-purposeful movement, fights ventilator

+1 Anxious but movements not aggressive or vigorous

0 Alert and calm
-1 Not fully alert, but has sustained awakening

(eye-opening and eye contact) to voice (>10 seconds)

-2 Briefly awakens with eye contact to voice (<10 seconds)

-3 Movement or eye opening to voice (but no eye contact)

-4 No response to voice, but movement or eye opening to

physical stimulation

-5 No response to voice or physical stimulation

Procedure for RASS Assessment

1. 
   Observe patient
   

a. Patient is alert, restless, or agitated. (score 0 to +4)

2. 
   If not alert, state patient’s name and say to open eyes and look at speaker.
   

b. Patient awakens with sustained eye opening and eye contact. (score -1)

c. Patient awakens with eye opening and eye contact, but not sustained. (score -2)

d. Patient has any movement in response to voice but no eye contact. (score -3)

3. 
   When no response to verbal stimulation, physically stimulate patient by
   shaking shoulder and/or rubbing sternum.
   

e. Patient has any movement to physical stimulation. (score -4)

f. Patient has no response to any stimulation. (score -5)

Monitoring delirium – The Confusion Assessment Method for the ICU (CAM-ICU)

Delirium

DSM IV criteria: a disturbance of consciousness with inattention accompanied by a change in cognition or perceptual disturbance that develops in a short period of time (hours to days) and fluctuates over time.

• Changes in cognition: memory impairment, disorientation and rambling or irrelevant speech

• Perceptual changes: hallucinations (usually visual), illusions and delusions.

Delirium Subtypes^{5, 17}

• Hyperactive delirium: seen in <1% of delirious patients; agitation, restlessness, pulling catheters or tubes, hitting, biting, and emotional lability; at risk for self-extubation and subsequent reintubation

• Hypoactive delirium: seen in about 35% of delirous patients, and associated with the worst prognosis; withdrawal, flat affect, apathy, lethargy and perhaps even unresponsiveness; often unrecognized due to these “quiet” symptoms; at risk for aspiration, pulmonary embolism, decubitus ulcers, and other complications related to immobility

• Mixed: combination (~ 64%)

Delirium in the ICU

Until recently delirium was considered an unavoidable occurrence of ICU stay and no significant attempts had been made to quantify delirium and its implications in the critically ill. Recent work by Ely et al. using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) has shown that delirium is extremely common in mechanically ventilated ICU patients and is associated with prolonged hospital stays, ongoing neuropsychological deficits, higher costs, and increased mortality ^{6, 7}. Guidelines for the use of sedatives and analgesics in the critically ill adult from the SCCM have emphasized that the study of delirium and other forms of cognitive impairment in mechanically ventilated patients after ICU care may be an important advancement in the monitoring and treatment of critically ill patients ^13.
Confusion Assessment Method for the ICU (CAM-ICU)

I. Acute onset or fluctuating course	Absent		Present
Is there evidence of an acute change in mental status from the baseline? OR Did the (abnormal) behavior fluctuate during the past 24 hours (i.e., tend to come and go, or increase then decrease in severity) as evidenced by fluctuation on a sedation scale (e.g. RASS), GCS, or previous delirium assessment?
II. Inattention	Absent		Present
Did the patient have difficulty focusing attention as evidenced by scores less than 8 on either the auditory or visual component of the Attention Screening Examination (ASE)? Auditory: The rater explains to the patient that he or she will be reciting 10 letters with intermixed “A”s, and the patient should squeeze the raters hand when he/she hears the letter ‘A’. The rater then recites slowly the following 10 letters (SAVE A HAART). Score 1 point for every appropriate response either a hand squeeze for the ‘A’ or no squeeze for the other letters. Usually the auditory test is all that is required to document inattention Visual: The patient is shown 5 simple pictures at 3-second intervals and asked to remember them. They are then immediately shown 10 subsequent pictures and asked to nod “yes” or “no” according to whether or not they have or have not just seen each of the pictures. Since 5 pictures have been shown to them already (correct nod = Yes), and five others are new (correct nod = No), patients are scored perfectly if they achieved 10 correct yes or no “nods.”
III. Disorganized thinking	Absent		Present
Is there evidence of disorganized or incoherent thinking as evidenced by incorrect answers to 3 or more of the 4 questions and/or inability to follow the commands? Questions: Will a stone float on water? Are there fish in the sea? Does one pound weigh more than two pounds? Can you use a hammer to pound a nail? Commands: Are you having any unclear thinking? Hold up this many fingers. (Examiner holds two fingers in front of patient) Now do the same thing with the other hand. (Not repeating the number of fingers)
IV Altered Level of Consciousness	Absent		Present
Is the patient’s level of consciousness anything other than alert such as vigilant, lethargic, or stupor (e.g., RASS other than “0” at time of assessment)? Alert: spontaneously fully aware of environment and interacts appropriately Vigilant: hyperalert Lethargic: drowsy but easily aroused, unaware of some elements in the environment, or not spontaneously interacting appropriately with the interviewer; becomes fully aware and appropriately interactive when prodded minimally Stupor: becomes incompletely aware when prodded strongly; can be aroused only by vigorous and repeated stimuli, and as soon as the stimulus ceases, stuporous subject lapse back into the unresponsive state
Overall CAM-ICU (“YES” to Features 1 and 2 and either Feature 3 or 4):		Yes	No

Feature 1 Acute onset of changes or fluctuations in the course of mental status

AND

Feature 2 Inattention

Feature 4

Altered level of consciousness

Feature 3

Disorganized thinking

AND EITHER



OR

DELIRIUM

Figure 1- Flow Diagram of CAM-ICU (note: patients are delirious if they have Feature 1 and Feature 2, and either Feature 3 or Feature 4)

Pharmacology of commonly used drugs

Anxiolytics and sedatives

Lorazepam is a benzodiazepine of intermediate duration of action and may be administered as an infusion or by intermittent bolus injection. Like other benzodiazepines, it has anticonvulsant properties. Given its terminal elimination half life (10 20 hr), it is the benzodiazepine of choice for prolonged sedation. It depends on glucoronidation and not the cytochrome p450 mechanism for metabolism in the liver, so is not significantly altered in hepatic insufficiency. It is still prudent to decrease lorazepam doses in the patient with liver disease. Propylene glycol is used as a solvent for production of intravenous lorazepam, and at high doses can accumulate causing metabolic acidosis. Patients with renal or hepatic dysfunction, as well as, receiving ≥ 10mg/hr for ≥ 48 hours, should be closely monitored. Another advantage is no change in elimination half life in renal disease.

Midazolam is a short acting, hydrophilic benzodiazepine that becomes a lipophilic compound in the blood. It is metabolized in the liver to α-hydroxymidazolam that has some sedative activity. Accumulation of the parent drug and its metabolite can produce a longer than expected duration, particularly in critical illness or hepatorenal dysfunction.

Propofol is an alkylphenol which is formulated in 10% Intralipid^®. It is properly classified as an anesthetic, as it does not possess the ceiling effect of the above sedatives. Therefore, it is more appropriately used to sedate intubated, mechanically ventilated patients. In those patients who are ready to do so, it allows more rapid weaning from the mechanical ventilator than benzodiazepines due to its short duration of action and lack of accumulation. For the same reasons, of all currently used sedatives it can most easily be titrated to a desired level of consciousness. At anesthetic doses, it can cause hypotension secondary to vasodilation and, to a lesser degree, direct myocardial depression. Although a cerebral vasodilator, propofol reduces intracranial pressure and has anticonvulsant properties; it may provide cerebral protection in the head-­injured patient (providing hypotension is avoided). Its formulation in Intralipid^® mandates that intravenous tubing be changed every day, that strict aseptic technique be adhered to in handling the drug, and that preferably a dedicated infusion port be utilized and that total parenteral nutrition be adjusted for lipid content.

Dexmedetomidine (Precedex) is a selective alpha-2 receptor agonist that has sedative, analgesic, and anesthetic properties when given as a slow infusion. It undergoes rapid distribution with the half-life being only 6 minutes. It is indicated for short-term sedation in the ICU. It has no respiratory depression and so can be used for hemodynamically unstable patients, or for patients who need sedation for a short period but cannot afford to have respiratory depression. A bolus of 1 mcg/kg is given over 10 minutes followed by an infusion of 0.2 – 0.7 mcg/kg/hr. Rapid administration of the bolus can cause severe bradycardia, hypotension, or hypertension
Analgesics

Morphine is suitable when given by infusion or patient controlled intravenous analgesia. It is particularly appropriate when administered by infusion over several days, because of its relatively low volume of distribution and rapid hepatic clearance. However, caution is exercised in the patient with renal insuffiency as its water soluble metabolites (morphine 3  and 6 glucuronide) have analgesic efficacv and are dependent on renal elimination.
Fentanvl possesses one hundred times the potency of morphine, but has similar efficacy. Because of its high lipophilicity, it is rapidly acting and widely distributed. It has high accumulative potential secondary to both its high volume of distribution and slow hepatic clearance. As a result, its half life increases progressively from 30 minutes to 9 16 hrs with continuous infusion, and care must be taken to adjust infusion rate with time. Fentanyl is suitable for patients with morphine allergy and established renal insufficiency. Unlike morphine, it does not cause histamine release and is purported to afford greater hemodynamic stability as a result. However, all sedatives and analgesics cause hypotension usually by sympatholysis, and must be used with caution in those patients with hypovolemia, cardiac failure, and cardiac tamponade.
ANTIDELERIUM DRUGS

Haloperidol is a useful drug for the treatment of delirium. It is particularly safe in non intubated patients because it rarely causes respiratory depression. It may cause exacerbation of parkinsonism and should be used with caution when combined with other centrally acting antidopaminergics, including metoclopramide. Haloperidol causes QT prolongation, which may be exacerbated in the presence of class III antiarrhythmics, hypocalcemia, and intracranial hypertension. It is a mild α-adrenergic antagonist. Its safety has been questioned in acute head injury, as animal studies suggest worsening of secondary brain injury by the central antidopaminergic effect.

References

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2. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. Aug 1998;114(2):541-548.

3. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. May 18 2000;342(20):1471-1477.

4. Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. Dec 1999;27(12):2609-2615.

5. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). Jama. Dec 5 2001;286(21):2703-2710.

6. Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. Dec 2001;27(12):1892-1900.

7. Milbrandt E, Deppen S, Harrison P. ICU Delirium: A Costly Complication in Critically Ill Patients. AJRCCM. 2003;(abstract).

8. Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ. Sedation in the intensive care unit: a systematic review. Jama. Mar 15 2000;283(11):1451-1459.

9. Brattebo G, Hofoss D, Flaatten H, Muri AK, Gjerde S, Plsek PE. Effect of a scoring system and protocol for sedation on duration of patients' need for ventilator support in a surgical intensive care unit. Bmj. Jun 8 2002;324(7350):1386-1389 Order.

10. De Jonghe B, Cook D, Appere-De-Vecchi C, Guyatt G, Meade M, Outin H. Using and understanding sedation scoring systems: a systematic review. Intensive Care Med. Mar 2000;26(3):275-285.

11. Mascia MF, Koch M, Medicis JJ. Pharmacoeconomic impact of rational use guidelines on the provision of analgesia, sedation, and neuromuscular blockade in critical care. Crit Care Med. Jul 2000;28(7):2300-2306.

12. Slomka J, Hoffman-Hogg L, Mion LC, Bair N, Bobek MB, Arroliga AC. Influence of clinicians' values and perceptions on use of clinical practice guidelines for sedation and neuromuscular blockade in patients receiving mechanical ventilation. Am J Crit Care. Nov 2000;9(6):412-418.

13. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. Jan 2002;30(1):119-141.

14. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. Jul 1999;27(7):1325-1329.

15. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. Nov 15 2002;166(10):1338-1344.

16. Ely EW, 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. Jun 11 2003;289(22):2983-2991.

17. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. Jul 2001;29(7):1370-1379.