Washington Manual Summary
"Analgesia should precede sedation. The majority of ICU agitation is pain-driven. Treating pain first and adding sedation only when necessary is the foundation of modern ICU analgesia-first care."
Washington Manual of Critical Care, 4th Ed. (Kollef & Witt, eds.) Wolters Kluwer 2023.Clinical Synopsis
- Prevalence: Unrelieved pain is the most frequently cited stressor in ICU — Marino (Ch.6): surveys of ICU survivors show anxiety and unrelieved pain as dominant recollections. About 50% experience pain at rest even without noxious stimulation.
- PADIS 2018 framework: Pain → Agitation/Sedation → Delirium → Immobility → Sleep. Address in this order.
- ABCDEF Bundle: Integrative, evidence-based approach. Implementing all 6 elements together reduces mortality, delirium duration, mechanical ventilation time.
- Target sedation: RASS −1 to 0 for most ventilated patients. Deeper sedation (RASS −2 to −3) only for specific indications (ARDS proning, raised ICP, NMB).
- Delirium: Affects 60–80% of ventilated patients. Associated with higher mortality, prolonged MV, long-term cognitive impairment.
Marino Physiology — Pain and the ICU
"Contrary to popular perception, our principal function is not to save lives (since this is impossible on a consistent basis), but rather to relieve pain and suffering, and the ICU is the flagship of pain and suffering in hospitalized patients."
Marino PL. The ICU Book, 5th Ed. Chapter 6: Analgesia and Sedation in the ICU, p.103. Wolters Kluwer; 2025.Step 1 — The ICU Pain Experience
Marino identifies three key facts about ICU pain:
- The sensation of pain is magnified in critically ill patients (hypernociception) — a minor event becomes a painful experience
- A common source of pain is the simple act of being turned in bed — about 50% of patients experience pain at rest, in the absence of a noxious stimulus
- The heightened pain sensation is attributed to systemic inflammation (prostenoids) and prolonged immobility
Clinical implication: Failure to recognise the exaggerated pain sensation in ICU patients is a source of inadequate pain control. Use validated pain assessment tools routinely.
Step 2 — The Opioid Pharmacology (Marino Table 6.2)
Marino's ICU opioid comparison table (actual data from Ch.6):
| Property | Morphine | Hydromorphone | Fentanyl |
|---|---|---|---|
| Onset | 5–10 min | 5–15 min | 1–2 min |
| Bolus dose | 2–4 mg q1–2h | 0.2–0.6 mg q1–2h | 0.35–0.5 mcg/kg q0.5–1h |
| Infusion rate | 2–30 mg/hr | 0.5–3 mg/hr | 0.7–10 mcg/kg/hr |
| Active metabolites | YES (M6G, M3G) | Yes (minor) | No |
| Histamine release | YES | No | No |
| Renal failure dose | ↓ 50% or AVOID | No change | AVOID† (accumulates) |
Marino (p.106): "Morphine has active metabolites that accumulate in renal failure. M3G can produce agitation with myoclonus and seizures; M6G has more potent analgesic effects than the parent drug." Morphine also promotes histamine release → hypotension.
Step 3 — Pain vs Vital Signs
"There is a tendency to look for changes in heart rate or blood pressure as evidence of pain, but this practice should be abandoned, because there is a poor correlation between pain intensity (as reported by patients) and changes in any of the vital signs." — Marino, p.105
Use validated tools: Numerical Ranking Scale (1–10) for patients who can self-report; Behavioral Pain Scale (BPS) or CPOT for intubated/sedated patients unable to self-report.
PADIS 2018 Recommendations
A. Analgesia First (eCASH)
B. Sedation Targets
Daily SAT (Spontaneous Awakening Trial): pause all sedation, reassess — pair with SBT (Spontaneous Breathing Trial) for liberation from MV.
C. Sedative Drug Choice
D. Delirium
E. ABCDEF Bundle
Full bundle compliance: ↓ ICU mortality, ↓ delirium, ↓ mechanical ventilation, ↓ physical/cognitive impairment at 1 year.
Sedative & Analgesic Drug Reference
Sedatives
| Drug | Loading | Maintenance | Onset/Duration | Advantages | Cautions |
|---|---|---|---|---|---|
| Propofol | None (causes hypotension) | 5–50 mcg/kg/min (0.3–3 mg/kg/hr) | 30–60s / Short | Rapid on/off; anticonvulsant; RASS easy to control | PRIS if >4mg/kg/hr × 48h; hypotension; check TG |
| Dexmedetomidine | 0.5–1 mcg/kg over 10–20 min (optional) | 0.2–1.5 mcg/kg/hr | 5–10 min / rapid offset | Light sedation; communicable; less delirium; extubate on infusion | Bradycardia/hypotension; avoid in heart block; expensive |
| Midazolam | 1–2.5 mg IV boluses | 0.02–0.1 mg/kg/hr | 2–5 min / accumulates | Cheap; anticonvulsant; anxiolytic | Accumulates in hepatic/renal failure; ↑ delirium; avoid as 1st choice |
| Ketamine | 0.5–2 mg/kg IV | 0.1–0.5 mg/kg/hr | Seconds (IV) / short | Preserves BP and airway reflexes; bronchodilator; excellent analgesia | Emergence phenomena (give low-dose BZD); ↑ secretions; relative CI in raised ICP |
Opioids (Marino Table 6.2, Ch.6, p.106)
| Drug | Bolus | Infusion | Renal Failure | Key Note |
|---|---|---|---|---|
| Fentanyl | 25–50 mcg IV q0.5–1h | 25–200 mcg/hr | SAFE — preferred | No active metabolites; no histamine; first choice in AKI |
| Morphine | 2–4 mg IV q1–2h | 2–30 mg/hr | AVOID (M6G accumulates) | Active metabolites; histamine release → hypotension; avoid in AKI |
| Hydromorphone | 0.2–0.6 mg IV q1–2h | 0.5–3 mg/hr | Minor accumulation; use cautiously | 5× potency of morphine; useful alternative when morphine not tolerated |
| Remifentanil | — | 0.05–0.2 mcg/kg/min | SAFE (plasma esterases) | Ultra-short; organ-independent metabolism; hyperalgesia on stopping |
Delirium Management
| Drug | Dose | Use | Evidence |
|---|---|---|---|
| Haloperidol | 2.5–5 mg IV/IM q8–12h | Agitated delirium; QTc monitoring (<500ms) | MIND-USA: no mortality benefit but comfort use acceptable; avoid in PD, Lewy body |
| Quetiapine | 25–100 mg PO/NGT q12h | Hypoactive delirium; sleep disturbance | May reduce delirium duration; weak evidence; QTc monitoring |
| Dexmedetomidine | 0.2–1.5 mcg/kg/hr IV | Agitated delirium on MV; BZD-associated delirium | MENDS trial: less delirium vs midazolam; SEDCOM: similar delirium reduction |
| Melatonin | 2–10 mg PO/NGT at 9pm | Sleep promotion; circadian rhythm | Well tolerated; may reduce delirium duration; minimal drug interactions |
Sedation/Analgesia Management — Step by Step
Assess Pain FIRST (q4–8h)
If patient can self-report: NRS 0–10. If sedated/intubated: CPOT score (0–8). CPOT ≥3 = significant pain. Marino: vital signs do NOT reliably indicate pain — never use HR/BP as your only pain assessment. Treat pain even without noxious stimulus (50% have pain at rest).
Analgesic-First (eCASH)
Give IV opioid analgesia (fentanyl preferred in AKI). Titrate to CPOT 0–2 before adding sedation. Reassess in 30 min. If agitation persists AFTER adequate analgesia → then consider sedation. Never skip the pain step.
Add Sedation if Needed (lightest effective)
Target RASS −1 to 0 most patients. Propofol or dexmedetomidine preferred over benzodiazepines. Titrate in small increments. Perform Daily SAT: pause all sedation each morning, reassess RASS. Pair SAT with SBT. Document plan: "target RASS −1 to 0."
Assess Delirium (q8–12h) — CAM-ICU
CAM-ICU positive if: Feature 1 (acute/fluctuating) + Feature 2 (inattention) + Feature 3 (altered LOC) or Feature 4 (disorganised thinking). Non-pharm first: reorientation, sleep hygiene (ear plugs, eye masks, dim lights 10pm–6am), remove restraints, vision/hearing aids, early mobility.
ABCDEF Bundle — Daily Checklist
- A: Pain assessed and treated?
- B: SAT + SBT today?
- C: Sedation lightest effective? BZD avoided?
- D: Delirium screened? Non-pharm prevention in place?
- E: PT/OT mobilisation today?
- F: Family at bedside? Included in rounds?
Monitor & Prevent Propofol Infusion Syndrome (PRIS)
If propofol >4 mg/kg/hr or >48h: check TG, CK, lactate, pH daily. PRIS signs: metabolic acidosis + ↑ lactate + rhabdomyolysis + ↑ TG + cardiac failure. If suspected: STOP propofol immediately, switch to dexmedetomidine + midazolam rescue.
Common Mistakes
Marino (Ch.6): "Unrelieved pain is the most frequently cited stressor in the ICU." Most ICU agitation is pain-driven. Adding propofol to a patient in pain treats the symptom (agitation) while ignoring the cause. Treat pain first with adequate opioid analgesia (CPOT ≤2), then reassess the need for sedation.
Marino (Ch.6, p.105): "There is a poor correlation between pain intensity and changes in any of the vital signs." A normal HR and BP do NOT mean your patient is comfortable. Use CPOT for ventilated patients or NRS for communicative patients every 4–8h.
PADIS 2018: RASS −1 to 0 for most patients. Deep sedation (RASS −3 to −5) independently associated with worse outcomes, longer MV, more delirium. Use deep sedation only for: ARDS proning, NMB, status epilepticus, raised ICP. Document target daily.
Marino (Table 6.2): Morphine has active metabolites (M6G, M3G) that accumulate in renal failure — cause prolonged sedation, respiratory depression, seizures. Use fentanyl (no active metabolites, safe in AKI) or hydromorphone. NEVER use morphine infusion in AKI without dose reduction.
MIND-USA (2018): haloperidol and ziprasidone did NOT reduce 28-day mortality or ventilator-free days. Antipsychotics are for comfort (agitation control), not delirium cure. Non-pharmacological prevention is mandatory and must be tried first. Identify and treat reversible causes: pain, constipation, urinary retention, metabolic derangements.
Kress (NEJM 2000): daily sedation interruption reduced ICU stay and mechanical ventilation duration. The SAT+SBT combination (Girard 2008): reduced mortality, ICU days, MV days. Every ventilated patient should have SAT + SBT assessment every morning unless specific contraindications exist.
Exam Pearls
Q: What is eCASH? What does Marino say about the ICU experience?
eCASH = early Comfort using Analgesia, minimal Sedatives, maximal Humane care. Marino (Ch.6, p.103): "Our principal function is not to save lives but to relieve pain and suffering, and the ICU is the flagship of pain and suffering." Analgesia must precede sedation.
Q: What did Marino (5th Ed) say about vital signs as pain indicators?
"There is a tendency to look for changes in heart rate or blood pressure as evidence of pain, but this practice should be abandoned, because there is a poor correlation between pain intensity and changes in any of the vital signs." (Marino Ch.6, p.105). Use CPOT or NRS.
Q: Which opioid is preferred in ICU patients with AKI and why?
Fentanyl — no active metabolites (metabolised to inactive compounds), no histamine release, fastest onset (1–2 min), safe in all degrees of renal failure. Morphine has M6G (potent opioid effect, accumulates in AKI) and M3G (agitation, myoclonus, seizures). (Marino Table 6.2, Ch.6, p.106)
Q: PADIS 2018 — sedation target in mechanically ventilated patients?
RASS −1 to 0 (drowsy to alert/calm) for most mechanically ventilated patients. RASS −2 to −3 only for: ARDS proning, high ventilator support, NMB, raised ICP, status epilepticus. Deep sedation (RASS −4 to −5) independently associated with worse outcomes.
Q: MIND-USA trial (2018) — what did it show about haloperidol?
Haloperidol and ziprasidone did NOT reduce 28-day mortality or ventilator-free days in ICU delirium. Antipsychotics are used for patient safety and comfort (agitation control) but NOT as primary delirium treatment. Non-pharmacological strategies are mandatory first-line.
Q: PRIS (Propofol Infusion Syndrome) — features, risk factors, treatment?
Features: metabolic acidosis + ↑ lactate + rhabdomyolysis + ↑ CK + ↑ TG + cardiac failure + renal failure. Risk: dose >4 mg/kg/hr AND duration >48h + steroids + catecholamines + critical illness. Treatment: STOP propofol immediately, switch sedation, aggressive supportive care.
References
- Marino PL. Marino's The ICU Book, 5th edition. Chapter 6: Analgesia and Sedation in the ICU (pp.103–124). Philadelphia, PA: Wolters Kluwer; 2025. ISBN: 978-1-975176-71-6.
- Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS 2018). Crit Care Med. 2018;46(9):e825–e873.
- Girard TD, Exline MC, Carson SS, et al. (MIND-USA). Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018;379(26):2506–2516.
- 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. 2000;342(20):1471–1477.
- Riker RR, Shehabi Y, Bokesch PM, et al. (SEDCOM). Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients. JAMA. 2009;301(5):489–499.
- Pandharipande PP, Pun BT, Herr DL, et al. (MENDS). Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients. JAMA. 2007;298(22):2644–2653.
- Ely EW, Inouye SK, Bernard GR, et al. Delirium in Mechanically Ventilated Patients: Validity and Reliability of the Confusion Assessment Method for the ICU (CAM-ICU). JAMA. 2001;286(21):2703–2710.
- Vincent JL, Shehabi Y, Walsh TS, et al. Comfort and Patient-Centred Care without Excessive Sedation: The eCASH Concept. Intensive Care Med. 2016;42(6):962–971.
- Washington Manual of Critical Care, 4th Edition. Kollef MH, Witt CA (eds). Wolters Kluwer; 2023.
- Oh TE (ed). Oh's Intensive Care Manual, 8th edition. Chapter: Pain, Agitation and Delirium. Elsevier; 2018.