SEDO-ANALGESIA in ICU

Prof. Dr. Sait KarakurtMarmara University Medical School

Pulmonary and Critical Care Medicine

ANALGESIA

• The primary goal of analgesia is optimizing patient comfort

• The secondary goals are attenuation of the negative physiologic responses to pain including – hypermetabolism– increased oxygen consumption– hypercoagulability– alterations in immune function

TO ASSESS PAIN• Assessment of pain in

conscious and interactive patients– VRS (Verbal Rating Scale)– VAS (Visual Analogue Scale)– NRS (Numeric Rating Scale)– Behavioral-Physiological Scale

• Assessment of pain is more complicated in semiconscious or noncommunicative patients. Pain should be suspected in the presence of signs of discomfort (eg, grimacing, writhing) or sympathetic activation (eg, tachycardia, hypertension).

The critically ill patient may not be able to adequately communicate their level of pain and, as such, pain control in the critical care setting is often inadequate.

The degree of pain often is underestimated and the clinician should err on the sideof assuming the patient is in pain.

Visual analog pain scale

For conscious patients, a pain rating of 3 or less out of 10, or 2 or less out of 5, has been suggested as a desirable goal of analgesia. However, analgesic goals are patient-specific and depend upon the clinical situation, and patient tolerance of pain and side effects. Some patients may prefer to tolerate some pain to maintain a degree of alertnesswhereas others will not.

NONPHARMACOLOGIC THERAPY

•To prevent sleep deprivation •To treat anxiety and delirium•Nonpharmacologic interventions include minimizing irritating stimuli (eg, traction on the endotracheal tube) and uncomfortable positioning. •Complementary therapies – relaxation techniques– music therapy (based upon the gate control theory of

pain)

ANALGESIA• Analgesics reduce the sensation

of pain by– altering perception of pain in the

central nervous system (eg, opiate analgesics, acetaminophen)

– inhibiting local pain mediator production (eg, blockade of prostaglandin synthesis by nonsteroidal antiinflammatory drugs)

– interrupting neural impulse in the spinal cord (eg, neuraxial block)

• In critically ill patients, alleviation of pain is predominantly accomplished via central mechanisms

Opioid analgesics Loading dose

Maintenance dose Onset (min) Duration of intermittent dose (min)

Morphine sulfate 2-10 mg 2 to 4 mg every 1 to 2 hours intermittentAND/OR 2 to 30 mg/hour infusion

5-10 240-300

Hydromorphone 0.5-2 mg 0.2 to 0.6 mg every 1 to 2 hours intermittent AND/OR 0.5 to 3 mg/hour infusion

5-10 240-300

Fentanyl 1 to 2 mcg/kg 0.35 to 0.5 mcg/kg every 0.5 to 1 hour intermittent AND/OR 0.7 to 10 mcg/kg/hour infusion

<1-2 30-60

Remifentanil 1.5 mcg/kg 0.5 to 15 mcg/kg/hour infusion 1-3 5-10

Nonopioid analgesics (adjunctive or opiate sparing)Paracetamol none 325 to 1000 mg every 4 to 6 hours (oral, rectal)

650 mg IV every 4 hours to 1000 mg IV, every 6 hours (IV), or 15 mg/kg every 6 hours for patients weighing <50 kg, Maximum ≤4 g/day

30-60 (oral)Variable (rectal)5-10 (IV)

240-360

Ibuprofen none 400 mg orally every 4 hours (maximum 2.4 g/day chronic)400 to 800 mg IV every 6 hours (maximum 3.2 g/day acute)

25 (oral) 240-360

Ketorolac Optional:30mg IV once

Age <65 years and weight ≥50 kg: 15 to 30 mg IV every 6 hours; maximum 120 mg/day for up to 5 daysAge ≥65 years or weight <50 kg: 15 mg IV every 6 hours; maximum 60 mg/day for up to 5 days

10 360-480

Gabapentin none Initially 100 mg orally three times per dayMaintenance dose 900 to 3600 mg orally per day in 3doses

variable -

ANALGESIAFor parenteral analgesia, fentanyl, morphine, or hydromorphone are most commonly used.●Fentanyl or hydromorphone are recommended instead of morphine for patients with renal insufficiency or hemodynamic instability (IIB).

●Fentanyl may be preferred to morphine in patients with acute bronchospasm.

●Morphine or hydromorphone are preferred to fentanyl for intermittent bolus therapy due to their longer duration of action.

●Remifentanil may be selected for patients with multiple organ dysfunction due to metabolism that is not dependent upon hepatic or renal function. It is generally used in mechanically-ventilated patients due to the high incidence of respiratory depression

Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit , CCM 2013

Intravenous opiates ●Bolus intravenous injections

-moderate pain, with doses titrated to analgesic requirements and avoidance of respiratory depression and hemodynamic instability.

-bedside procedures that may cause pain with additional dosing given during the procedure, as needed.

●Continuous intravenous infusions -moderate-to-severe pain that is poorly controlled with repeated bolus

injections

●Patient-controlled analgesia (PCA) may be preferable in conscious patients, particularly in the postoperative setting. This technique allows self-dosing with opiates up to a predetermined limit set by the clinician.

Fentanyl

• A synthetic derivative of morphine and approximately 100 times more potent

• More lipid-soluble than morphine improved penetration of the blood-brain barrier a more rapid onset of action and a shorter half-life (two to three hours) than morphine

• Clinically significant histamine release rarely occurs with fentanyl dosages up to 50 mcg/kg and, thus, fentanyl may be preferred in the presence of hemodynamic instability or bronchospasm

Remifentanil

• Analgesic potency approximately equal to fentanyl

• An ultra-short acting opioid metabolized by nonspecific plasma esterases to inactive metabolites

• The rapid onset and offset and lack of accumulation with renal and hepatic dysfunction are potential advantages

• Despite the unique pharmacokinetic properties, in a meta-analysis of

eleven trials, remifentanil was not associated with reduced mortality, duration of mechanical ventilation, length of intensive care unit stay, or agitation

ANALGESIA

• Other parenteral agents that may become useful for controlling pain in intensive care unit patients include ketamine and paracetamol.

• Intravenous NSAIDs can be used in some patients as a short-term adjunct to other analgesic agents.

• However, NSAIDs are associated with an increased risk

of cardiovascular thrombotic events and gastrointestinal complications including gastritis, bleeding, ulcers and perforation.

Indications of Sedation

• Mechanical ventilation• Invasive procedures• Acute interventions• Decrease O2 requirement• Prevent self damage• Paralysis• Adjunction of analgesia• End of life period• Control and measure physiological parameters

Causes of anxiety/agitation

• Cardiovascular (angina pectoris, myocardial infarction, hypertension…)

• Pulmonary(asthma, COPD, respiratory failure…)

• Endocrine/metabolic(adrenal insufficiency, hypocalcemia, hypercalcemia, hyperkalemia, hypoglysemia….)

• Neurologic(serebral tumor/trauma, convulsion…)

• Some organic diseases(anemia, carcinoid syndrome…)

• Drugs(ACEI, analgesics, fluoroquinolone….)

Selection of an agent• No sedative-analgesic agent is sufficiently superior to other agents to

warrant its use in all clinical situations. Selection of an agent must be individualized according to patient characteristics and the clinical situation.

• The Society of Critical Care Medicine guidelines favor nonbenzodiazepine agents (propofol or dexmedetomidine) due to evidence of shorter duration of mechanical ventilation (+2B).

• Important considerations when selecting a sedative-analgesic agent include – the etiology of the distress – expected duration of therapy– clinical status of the patient– potential interactions with other drugs

Selection of an agent-Etiology of the distress

– Dyspnea or pain opioids– Delirium antipsychotics (haloperidol)– Anxiety benzodiazepines

– More than one cause combination therapyAs an example, a benzodiazepine plus an opioid is appropriate for a patient whose agitation is due to anxiety and pain.

– For patients who are intubated and mechanically ventilated and not able to clearly communicate the source of agitation, analgesia should always be provided first

BenzodiazepinsLoading dose Maintenance dose

Onset (min)

Duration of intermittent dose(min)

Midazolam 0.01 to 0.05mg/kg(0.5-4 mg)

0.02-0.1mg/kg/hour2 to 8mg/hour

2-5 30

Lorazepam 0.02 to 0.04mg/kg1-2 mg

0.02 to 0.06 mg/kg every 2 to 6 hours intermittentAND/OR 0.01 to 0.1 mg/kg/hour infusion (0.5 to 10 mg/h)

15-20 360-480

Diazepam 0.05 to 0.2 mg/kg(5 to 10 mg)

0.03 to 0.1 mg/kg every 0.5 to 6 hours intermittentContinuous infusion is not recommended

2-5 20-60

Anesthetic-sedative

Propofol 5 micrograms/kg/minute 5 to 50 micrograms/kg/minuteTitrate every 5 to 10 minutes in increments of 5 to 10 micrograms/kg/minute

<1-2 3-10

Ketamin 0.1 to 0.5 mg/kg 0.05 to 0.4 mg/kg/hour 0.5 10

Central alpha-2 agonistDexmedetomidine

Optional 1 microgram/kg over 10 minutes if hemodynamically stableUsually not give

0.2 to 0.7 micrograms/kg/hourInitiate at 0.2 micrograms/kg/hour and titrate every 30 minutes

5-10 15 (without loading d)

60-120

Antipsychotics

Haloperidol 0.03 to 0.15 mg/kg 0.03 to 0.15 mg/kg every 30 minutes to 6 hours 30-60 30-360

Olanzapine 5 to 10 mg IM,may repeat every 2 to 4 hours if needed (maximum total 30 mg)

Initially 5 to 10 mg orally once daily; increase every 24 hours as needed by 5 mg increments up to 20 mg per day

15-45 >120

Quetiapine None Initially 50 mg orally every 12 hours; increase every 24 hours as needed up to 400 mg per day

60 (initial)≥24 hours (full effect)

6-12

Ziprasidone 10 mg IMmay repeat every 2 hours if needed (maximum 40 mg)

10 to 40 mg orally every 12 hours 30 >90

DEXMEDETOMIDINEADVANTAGES

• Central alpha-2 agonist

• Moderate anxiolytic and analgesic

• A good choice for short and long-term sedation in critically ill patient without relevant cardiac condition

• No significant effect on respiratory drive

• Easily awakened patient

DISADVANTAGES• Potentially significant

hypotension and bradycardia that do not resolve quickly upon abrupt discontinuation

• Dose reduction recommended with renal/hepatic insufficiency

• Rapid administration of loading dose may be associated with cardiovascular instability, tachycardia, bradycardia, heart block

RAMSEY SEDATION SCALELevel/score Clinical description

1 Anxious, agitated, restless

2 Cooperative, oriented, tranquil

3 Responds only to verbal commands

4 Asleep, brisk response to light stimulation

5 Asleep, sluggish response to stimulation

6 Unarousable

Avoid excess sedation

• Intermittent infusions• Daily interruption

Daily interruption

p=0.02 p<0.001

John P. Kress et al.Daıly ınterruptıon of sedatıve ınfusıons ın crıtıcally ıll patıents undergoıng mechanıcal ventılatıon, N Engl J Med 2000;342:1471-7.

Daily sedative interruption vs standart sedation

• A meta-analysis of nine trials – Reductions in the duration of mechanical ventilation

(13 percent), – Reductions in ICU and hospital length of stay (10 and

6 percent, respectively)– No difference • in risk of death• Rate of accidental endotracheal tube removing• New onset delirium• Doses of sedative

Burry L, Rose L, McCullagh IJ, et al. Daily sedation interruption versus no daily sedation İnterruption for critically ill adult patients requiring invasive mechanical ventilation. Cochrane Database Syst Rev 2014; 7:CD009176.

Early Intensive Care Sedation Predicts Long-TermMortality in Ventilated Critically Ill Patients

Yahya Shehab et al. Am J Respir Crit Care Med Vol, 2012, 186, Iss. 8, pp 724–731

Time to extubationSurvival

Deep sedation within 4 hours of commencing ventilation as an independent negative predictor of the time to extubation, hospital death, and 180-day mortality. The early phase of ICU sedation is usually unaccounted for in randomized controlled trials due to late randomization.

WITHDRAWAL

• The analgesics should be tapered last

• Abrupt discontinuation is acceptable – a short duration (≤7 days). – greater than 7 days who are deeply sedated from prolonged

accumulation of medication.

• However, a gradual reduction (~10 to 25 percent per day) is necessary – if the sedative-analgesic agent has been administered for >7 days– the patient exhibits evidence of tachyphylaxis,

WITHDRAWAL

Benzodiazepine withdrawal symptoms include – agitation, confusion,

anxiety, tremors, tachycardia, hypertension, and fever.

– Seizures may also occur. – The administration of

intermittent IV or oral lorazepam (0.5-1 mg, every 6 to 12 hours)

Opiate withdrawal symptoms include – agitation, anxiety, confusion,

rhinorrhea, lacrimation, diaphoresis, mydriasis, piloerection, stomach cramps, diarrhea, tremor, nausea, vomiting, chills, tachycardia, hypertension, and fever.

– To preventing opioid withdrawal, including • de-escalating the dose• converting to a longer acting oral

equivalent • converting to a long-acting

barbiturate (eg, phenobarbital), and adding an alpha-2-agonist (clonidin, dexmedetomidine, 0.7 mcg/kg/hr (with or without a loading dose)

Conclusions1-Nonpharmacologic therapy should be firstly used

2-Scales should be used for objective assessment

3-For parenteral analgesia, fentanyl, morphine, or hydromorphone are most commonly used

4-Intravenous NSAIDs can be used in some patients as a short-term adjunct to other analgesic agents

5-The Society of Critical Care Medicine guidelines favor nonbenzodiazepine agents (propofol or dexmedetomidine) due to evidence of shorter duration of mechanical ventilation (+2B)

6-No sedative-analgesic agent is sufficiently superior to other agents

7-The analgesics should be tapered last