Treat pain first, sedate lightly, and wake the patient every day. PADIS 2018 makes “treat pain before considering a sedative” a good practice statement and suggests light over deep sedation for mechanically ventilated adults. A sedative started for agitation that is really pain, or delirium, buys a longer ventilator course. Scope: adult, intubated, mechanically ventilated ICU patients. Doses are adult and are ranges for titration to an assessed target, not orders. Several are off-label or beyond labeled duration; confirm against your institutional protocol.
Infusion Lookup
Agent
Usual adult infusion range
The trap
Fentanyl
0.7-10 mcg/kg/h (PAD 2013). Start low and titrate to CPOT/BPS.
Lipophilic. After ~12 h, and with end-organ dysfunction, the context-sensitive half-life rises unpredictably; it accumulates in hepatic impairment. Boxed warning: CYP3A4 inhibitors (e.g., azoles, macrolides, protease inhibitors) raise levels; stopping an inducer does too.
Hydromorphone
0.5-3 mg/h (PAD 2013)
Accumulates in hepatic and renal impairment (PAD 2013). Lower the dose in renal failure; it is not renal-neutral just because it is not morphine.
Morphine
2-30 mg/h (PAD 2013)
Avoid as an infusion in renal failure. Active 3- and 6-glucuronides accumulate with renal impairment. Histamine release causes hypotension.
Remifentanil
Load 1.5 mcg/kg, then 0.5-15 mcg/kg/h (PAD 2013). Use IBW if weight >130% IBW.
Ester-metabolized: no accumulation in hepatic or renal failure, and offset in minutes. That cuts both ways: start a longer-acting analgesic before you stop it, or the patient wakes in pain.
Start 5 mcg/kg/min; titrate by 5-10 mcg/kg/min no faster than q5 min. Maintenance 5-50 mcg/kg/min (label).
Label ceiling: do not exceed 4 mg/kg/h (~67 mcg/kg/min) unless benefit outweighs risk. PRIS risk with >5 mg/kg/h for >48 h, but it can occur at lower doses (PAD 2013). Hypotension, hypertriglyceridemia, and 1.1 kcal/mL of lipid calories.
Label: optional load 1 mcg/kg over 10 min, then 0.2-0.7 mcg/kg/h, ≤24 h. Practice and trials: up to 1.5 mcg/kg/h, for days.
Bradycardia and hypotension; skip the load in unstable patients. Patients arouse to stimulation by design, so it will not deliver deep sedation alone. Tolerance after 24 h; withdrawal after abrupt stop.
Load 0.01-0.05 mg/kg, then 0.02-0.1 mg/kg/h (label)
Active metabolite accumulates in renal failure; CYP3A4 inhibitors, liver dysfunction, and low cardiac output delay clearance. Benzodiazepines are a modifiable delirium risk factor.
Analgesic adjunct: 0.5 mg/kg IV once, then 1-2 mcg/kg/min (0.06-0.12 mg/kg/h) (PADIS 2018). Sedative doses run roughly 10-20 times higher (below).
The units trap: analgesic orders are often in mcg/kg/min, sedative orders in mg/kg/h. Tachycardia, hypertension, hypersalivation, emergence reactions.
Ranges are adult values from the 2013 SCCM PAD guideline pharmacology tables (Barr et al.) or current FDA labeling, as marked. PADIS 2018 and its 2025 update did not republish dosing tables. Underlined agents jump to detail below.
Targets, Tools, and the Daily Wake-Up
Domain
What to use and the target
Pain, can self-report
Self-report is the reference standard; 0-10 NRS (PADIS 2018).
Pain, cannot self-report
CPOT (0-8; pain likely at >2) or BPS (3-12; pain likely at >5). PADIS 2018 names BPS, BPS-NI, and CPOT as the most valid tools. Vital signs alone are not valid pain indicators.
Sedation depth
RASS or SAS. Light sedation for most ventilated adults (PADIS 2018, conditional). Trials operationalized light as RASS -2 to 0 (MENDS2) or -2 to +1 (A2B). Individualize: neuromuscular blockade, refractory hypoxemia, or raised ICP may need deep sedation.
Delirium
Assess regularly with a validated tool such as CAM-ICU or ICDSC (PADIS 2018). Management is out of scope here; see the Practice Signal linked below.
Daily SAT, paired with an SBT
Stop sedatives (up to 4 h in the ABC trial), keep analgesia needed for active pain, then go straight to an SBT if the patient passes. ABC (Lancet 2008, n=336): ventilator-free days 14.7 vs 11.6 and 1-year mortality 44% vs 58% versus SBT alone; self-extubation 10% vs 4%.
Skip the SAT if
Sedation is treating active seizures or alcohol withdrawal; sedation is escalating for ongoing agitation; neuromuscular blockade; myocardial ischemia within 24 h; raised ICP (ABC trial screen).
SAT failed
Sustained anxiety, agitation, or pain; RR >35 or SpO2 <88% for ≥5 min; new arrhythmia; or ≥2 signs of respiratory distress. Restart at half the prior dose and titrate (ABC protocol). Reassess the next morning.
Analgesia-First: Multimodal Adjuncts
Adjunct
Dose
PADIS 2018 position
Acetaminophen, scheduled
Max ≤4 g/day, oral or IV (PAD 2013 table). Caution in significant hepatic dysfunction.
Suggested as an opioid adjunct to lower pain and opioid use (conditional, very low certainty). IV costs more; enteral absorption can be unreliable.
Label: risk with >5 mg/kg/h (≈83 mcg/kg/min) for >48 h. PAD 2013 cites >70 mcg/kg/min but notes it can occur with low-dose infusions; the label also reports it after large-dose, short-term infusions. Signs: unexplained metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, renal failure. Stop propofol immediately when they appear.
Triglycerides
Label: monitor patients at risk of hyperlipidemia. Hypertriglyceridemia developed in 45% of ICU patients staying ≥4 days in one prospective cohort, tracking propofol dose; the authors advise checking at least twice weekly on propofol (Devaud, Intensive Care Med 2012). No guideline sets a stop threshold; that is institutional.
Calories
1.1 kcal/mL (0.1 g fat/mL). Example: 20 mL/h × 24 h = 528 kcal/day. Tell the dietitian and cut lipid in the nutrition prescription.
Other label points
Diprivan contains EDTA: consider a drug holiday after 5 days for zinc replacement. Discard tubing and drug 12 h after spiking. Not indicated for pediatric ICU sedation.
Load 1 mcg/kg over 10 min (optional; may not be needed when converting from another sedative), maintenance 0.2-0.7 mcg/kg/h, not to exceed 24 h. Consider lower doses in hepatic impairment and age >65.
Practice
Up to 1.5 mcg/kg/h for longer than 24 h (PAD 2013 footnote; SPICE III and MENDS2 both titrated to 1.5; A2B capped at 1.4). Off-label in dose and duration.
Hemodynamics
SPICE III: bradycardia 5.1% vs 0.5%, hypotension 2.7% vs 0.5%, asystole 0.7% vs 0.1% versus usual care. A2B: severe bradycardia ~60% more often than propofol. Transient hypertension occurs during the load.
Will it work alone?
Often not. SPICE III: 64% of dex patients also got propofol. A2B: propofol co-administered on 77% of dex patient-days, and agitation was more frequent with dex.
Age signal
SPICE III post hoc analysis: higher 90-day mortality in patients ≤65 years (OR 1.26, 95% CrI 1.02-1.56), most marked in nonoperative patients. EU product information added a warning in 2022.
Stopping it
Label: withdrawal events in 5% within 24 h of stopping (nausea, vomiting, agitation; tachycardia and hypertension). See tapering below.
PADIS 2018 suggests propofol or dexmedetomidine over benzodiazepines for sedation of ventilated adults (conditional, low certainty). The 2025 update found insufficient evidence to recommend benzodiazepines for anxiety. They remain reasonable when the indication itself is alcohol withdrawal or seizures.
⚠️
Lorazepam propylene glycol. Each mL of injection is 0.18 mL polyethylene glycol 400 in propylene glycol (label). In a prospective ICU study, propylene glycol accumulation (anion gap ≥15 with osmol gap ≥10) appeared in 6 of 9 patients on ≥10 mg/h by 48 h (mean 0.16 mg/kg/h); the osmol gap was the best predictor of serum propylene glycol (Arroliga, Crit Care Med 2004). Get a baseline osmol gap and trend it on any sustained infusion.
⚠️
Midazolam accumulation. Active metabolites prolong sedation, especially in renal failure (PAD 2013). The label advises cutting the rate 10-25% every few hours to find the minimum effective dose.
Off-label. A multicenter ICU cohort started at ≥0.5 mg/kg/h; median 1.3 mg/kg/h (IQR 0.96-1.8) in the first 24 h (Pendleton, 2022).
Retrospective and case-series level. A 2023 scoping review found no high-quality trials. Not addressed in PADIS 2025.
⚠️
Pump programming error. In that cohort, one cardiac arrest followed a pump set in mL/h instead of mg/h, roughly doubling the dose. Build analgesic and sedative ketamine as separate orderables with fixed units.
What the Evidence Says
Source
Bottom line
PADIS 2018
Analgesia first; light over deep sedation; propofol or dex over benzodiazepines; protocolized, assessment-driven management (conditional, moderate). Dex for agitated delirium that is blocking extubation.
SPICE III (NEJM 2019, n=4000)
Early dex as primary sedative vs usual care: 90-day mortality 29.1% in both arms. More bradycardia and hypotension; heavy supplemental propofol use.
MENDS2 (NEJM 2021, n=438)
Dex vs propofol in sepsis, light sedation target: no difference in days alive without delirium or coma (10.7 vs 10.8), ventilator-free days, 90-day death (38% vs 39%), or 6-month cognition.
PADIS focused update (CCM, Feb 2025)
Suggests dex over propofol when light sedation or less delirium is the priority (conditional, moderate). Suggests melatonin over none for sleep (conditional, low). No recommendation for or against antipsychotics or benzodiazepines (anxiety). Suggests enhanced mobilization. Ketamine is not addressed.
A2B (JAMA, May 2025, n=1437)
Dex- or clonidine-based vs propofol, RASS -2 to +1: no faster extubation (dex HR 1.09, 95% CI 0.96-1.25; median 136 vs 162 h). More agitation and severe bradycardia with alpha-2 agonists; delirium similar.
💡
The 2025 documents disagree. The PADIS update favoring dex over propofol was published before A2B, the largest head-to-head trial, which found no benefit and more agitation and bradycardia. A reasonable reading: either agent is acceptable for light sedation; choose on hemodynamics, depth needed, and cost, and do not expect dex to shorten ventilation.
Iatrogenic Withdrawal and Tapering
Question
Answer
How common
13.6-49.5% across adult ICU opioid and opioid-hypnotic studies (Moisa, scoping review 2025). No validated adult assessment tool; WAT-1 was 50% sensitive in adults.
Who is at risk
Higher fentanyl exposure (>1200 mcg/day flagged in one study; duration ≥72 h gave conflicting results); weaning fentanyl by ≥50 mcg/h (OR 9.66); concomitant lorazepam (OR 3.02). Dex: peak >0.8 mcg/kg/h or cumulative >12.9 mcg/kg/day; 64% incidence after infusions >72 h in one cohort.
Taper rate
No adult critical care society gives a taper rate (Moisa 2025). Practice borrows from pediatrics: after ≥5 days of around-the-clock exposure, taper rather than stop (AAP clinical report 2025). Steps of about 10-20% every 24-48 h are the commonly cited pediatric approach; adjust to signs of withdrawal. This is extrapolation, not adult evidence.
Bridge options
Enteral methadone during opioid weaning: no change in withdrawal frequency but faster successful extubation in a 68-patient RCT (Wanzuita 2012). Enteral clonidine to bridge off prolonged dex: feasible in small studies. Use the Opioid Conversion Quick Card to move infusion totals to enteral doses.
Running propofol into PRIS. High dose plus long duration (>5 mg/kg/h for >48 h) is the labeled setup. A new unexplained metabolic acidosis, rising potassium, rhabdomyolysis, or lipemic blood on propofol is PRIS until proven otherwise. The label says discontinue immediately; do not titrate down and wait.
☠️
Morphine infusion in renal failure. Glucuronide metabolites accumulate and prolong sedation and respiratory depression long after the drip is off. Switch to fentanyl or a dose-reduced hydromorphone.
☠️
High-dose or prolonged lorazepam drips. At ≥10 mg/h, or a rising osmol gap with an anion-gap acidosis, suspect propylene glycol. Lower rates are not safe by default: renal toxicity has been reported at 2-28 mg/h with long infusions (Yaucher, Pharmacotherapy 2003). Stop or switch agents.
☠️
Dex load in an unstable patient. The label load causes transient hypertension, then bradycardia and hypotension; sinus arrest has occurred in patients with high vagal tone. Skip the load in shock or heart block and start the infusion alone.
☠️
Opioid plus benzodiazepine without a reason. Opioid labeling carries a boxed warning for profound sedation and respiratory depression with benzodiazepines. In a ventilated patient that harm shows up as oversedation, a skipped SAT, and more ventilator days. Each drip needs its own indication and its own target.
Delirium
Benzodiazepine use is a modifiable delirium risk factor (PADIS 2018). For antipsychotics, dexmedetomidine for agitated delirium, and the MIND-USA and AID-ICU evidence, see the Antipsychotics for ICU Delirium Practice Signal.