Overview and Clinical Relevance
Withdrawal syndromes are among the most under-recognised and potentially lethal complications managed in Australian and New Zealand intensive care units. They arise when a substance that chronically suppresses or augments a neurotransmitter system is abruptly reduced or ceased, the resulting rebound neurological and autonomic excitation can be fatal if mismanaged. In the ICU context, three main categories require structured management:
- Alcohol withdrawal, the most acutely dangerous, with seizure and delirium tremens (DTs) risk
- Opioid withdrawal, rarely immediately life-threatening but causes profound distress, autonomic instability, and impairs ventilator weaning
- Iatrogenic sedative/analgesic withdrawal, a consequence of prolonged ICU drug exposure, increasingly recognised as a contributor to post-ICU syndrome
Understanding the receptor-level mechanisms underpinning each syndrome is the foundation for rational pharmacological management.
1. Physiological and Pharmacological Framework
1.1 The Central Mechanism: Neuroadaptation and Rebound Excitation
All clinically significant withdrawal syndromes share a unifying mechanism: receptor upregulation and/or functional uncoupling in response to chronic agonist exposure, followed by a rebound hyperexcitable state when the agonist is removed.
GABAergic-glutamatergic balance is the central axis for alcohol and benzodiazepine withdrawal. The brain operates a tonic inhibition:excitation balance mediated primarily by:
- $\gamma$-aminobutyric acid (GABA) at GABA$_A$ receptors, the principal inhibitory neurotransmitter
- Glutamate at N-methyl-D-aspartate (NMDA) receptors, the principal excitatory neurotransmitter
Chronic ethanol:
- Potentiates GABA$_A$ (allosteric modulation at a site overlapping with benzodiazepines and neurosteroids)
- Inhibits NMDA receptors (at the Mg$^{2+}$ binding site)
With prolonged exposure:
- GABA$_A$ receptors downregulate (reduced density and reduced sensitivity, involving subunit trafficking away from the synapse)
- NMDA receptors upregulate (increased NR2B subunit expression, increased receptor density)
On abrupt cessation, the brain is left with:
- Insufficient GABAergic inhibitory tone
- Excessive glutamatergic excitatory drive
The clinical result is central nervous system and autonomic hyperexcitability, seizures, hallucinations, agitation, tachycardia, hypertension, diaphoresis, and hyperthermia.
1.2 Opioid Withdrawal Mechanism
Opioids act on mu ($\mu$), kappa ($\kappa$), and delta ($\delta$) opioid receptors, all coupled to inhibitory G$_i$ proteins. Sustained activation leads to:
- Receptor internalisation and downregulation
- Compensatory upregulation of adenylyl cyclase (cAMP rebound)
- Upregulation of the locus coeruleus (LC) noradrenergic system, the primary generator of opioid withdrawal symptoms
The LC is responsible for noradrenergic arousal. Chronic opioid suppression of LC firing leads to compensatory LC upregulation; on cessation, LC hyperactivity drives the classical withdrawal syndrome: anxiety, agitation, piloerection, mydriasis, lacrimation, rhinorrhoea, yawning, tachycardia, hypertension, diarrhoea, myalgia.
The cAMP superactivation hypothesis (Nestler and Aghajanian, 1997) explains the neurochemical basis: each opioid receptor normally inhibits adenylyl cyclase; with chronic exposure, the cAMP system adapts upward; withdrawal unmasks this amplified cAMP signalling.
1.3 Alcohol vs. Benzodiazepine Withdrawal, Why They Are Similar but Not Identical
Both cause GABA$_A$/NMDA dysregulation and cross-tolerate each other. Key differences:
| Feature | Alcohol Withdrawal | Benzodiazepine Withdrawal |
|---|---|---|
| Timeline of onset | 6-24 h after last drink | Hours (short-acting) to weeks (long-acting) |
| Seizure risk peak | 12-24 h | Variable, often 1-2 weeks for long-acting agents |
| Severity scale | CIWA-Ar | CIWA-B (less validated in ICU) |
| Treatment backbone | Benzodiazepines | Long-acting benzodiazepine taper |
| Cross-tolerance | Full cross-tolerance with BZDs | Full cross-tolerance with alcohol |
1.4 Iatrogenic Opioid/Benzodiazepine Withdrawal in the ICU
Prolonged ICU infusions of midazolam, lorazepam, or opioids (fentanyl, morphine) cause the same receptor adaptations as chronic community drug use. The Tolerance, Dependence, and Withdrawal triad becomes clinically significant after approximately 5-7 days of continuous infusion or high cumulative dose exposure.
Risk factors for iatrogenic withdrawal:
- Duration of infusion > 5-7 days
- High cumulative opioid dose (fentanyl equivalent > 2.5 mg/kg or morphine equivalent > 60 mg/kg)
- High cumulative benzodiazepine dose
- Young children (extrapolating from PICU literature, less robust in adults)
- Abrupt rather than gradual weaning
2. Alcohol Withdrawal Syndrome
2.1 Clinical Stages and Timeline
| Stage | Onset | Clinical Features |
|---|---|---|
| Stage 1 (Minor withdrawal) | 6-24 h | Tremor, anxiety, diaphoresis, tachycardia, hypertension, insomnia |
| Stage 2 (Hallucinations) | 12-48 h | Visual > auditory > tactile hallucinations; orientation preserved |
| Stage 3 (Seizures) | 12-48 h | Usually brief GTCS; status epilepticus uncommon |
| Delirium Tremens | 48-96 h | Global confusion, agitation, autonomic instability, fever; mortality 5-25% untreated |
Seizures and DTs can overlap. Approximately 5% of alcohol withdrawal progresses to DTs, but ICU patients (often with comorbidities, nutritional depletion, concurrent illness) are over-represented.
2.2 Assessment: CIWA-Ar
The Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) is the standard validated tool.
- 10 items: nausea/vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, visual disturbances, auditory disturbances, headache/fullness in head, orientation/clouding of sensorium
- Each item scored 0-7; maximum score 67
- Score < 8: mild withdrawal, consider oral medications or observation
- Score 8-15: moderate, pharmacotherapy indicated
- Score > 15: severe, IV medications, consider ICU admission or escalation
Limitation in ICU: CIWA-Ar requires patient participation. Mechanically ventilated patients cannot complete the scale. Modified versions exist but lack robust ICU validation. Clinical judgement and objective autonomic parameters (HR, BP, temperature, pupil size) are used in intubated patients.
2.3 Pharmacological Management: Mechanism and Agents
Benzodiazepines, First-Line
Mechanism: Allosteric GABA$_A$ potentiators, they restore the GABAergic inhibitory tone lost with alcohol removal. They are cross-tolerant with ethanol.
Symptom-triggered therapy (dosed to CIWA-Ar thresholds) is superior to fixed-schedule dosing in most non-ICU settings, demonstrated in the landmark GWIS (Saitz 1994) study, showing reduced benzodiazepine use and shorter treatment duration.
In ICU, front-loading (large initial dose titrated to light sedation, then observed for re-escalation) is frequently used for severe withdrawal or DTs. This exploits the long half-lives of diazepam and its active metabolites.
| Agent | Dose Approach | Advantages | Disadvantages |
|---|---|---|---|
| Diazepam (preferred) | 5-10 mg IV q5-10 min until calm; then PRN | Long-acting; self-tapering via active metabolites (desmethyldiazepam t½ 36-200 h); oral bioavailability near 100% | Accumulates in hepatic failure; sedation overshoot |
| Lorazepam | 1-4 mg IV q15-30 min; infusion in DTs | No active metabolites; predictable in liver disease | Propylene glycol toxicity with prolonged infusion; shorter duration requires more frequent dosing |
| Midazolam | Infusion in intubated patients | Rapid onset; titratable | Very short half-life; poor choice for seizure prevention; significant accumulation with prolonged use |
| Oxazepam (oral) | 15-30 mg q6h scheduled | Safe in liver disease (direct glucuronidation); no active metabolites | Oral only; slow onset |
| Chlordiazepoxide (oral) | 25-100 mg q6h with taper | Traditional agent; long-acting | Unpredictable absorption |
ANZ Context: Diazepam is the standard first-line agent in most Australian ICUs for severe alcohol withdrawal. Lorazepam infusion is used for mechanically ventilated patients with DTs when high doses are required. Chlordiazepoxide oral regimens are used for ward-based mild-moderate cases.
Benzodiazepine-Refractory Delirium Tremens
A critical scenario. Defined as persistent agitation/seizures despite adequate benzodiazepine dosing (typically > 40 mg diazepam equivalent in first 2 hours without response).
Phenobarbital
Mechanism: At low doses, GABA$_A$ allosteric modulator (similar to BZDs but binds separately at the barbiturate site). At higher doses, direct chloride channel opener (GABA-independent). Also inhibits AMPA/kainate glutamate receptors. This dual mechanism makes phenobarbital effective even when GABA$_A$ receptors are downregulated to the point where benzodiazepine binding is insufficient.
- Dose: 130-260 mg IV q20 min titrated to sedation (loading up to 10-15 mg/kg); maintenance 30-60 mg q8h
- Key advantages: very long half-life (~80-120 h), providing a self-tapering effect; effective in BZD-refractory cases
- Risk: respiratory depression, requires ICU monitoring
A retrospective cohort by Gold et al. (2007) and subsequent work suggest phenobarbital loading early (even as adjunct) may reduce ICU admission rates and BZD requirements. Prospective RCT data remain limited but observational data are consistent.
Propofol
Mechanism: GABA$_A$ potentiator and direct activator at high concentrations; also inhibits NMDA, sodium channels, and calcium channels. Provides rapid sedation.
- Used for intubated patients with refractory DTs
- Appropriate when the patient requires mechanical ventilation for airway protection
- Risk: Propofol infusion syndrome (PRIS) with high doses/prolonged use, monitor triglycerides, CK, lactate, urine colour
- Limit infusion duration/rate: < 4 mg/kg/h for < 48 h in most guidelines
Dexmedetomidine
Mechanism: Highly selective $\alpha_2$-adrenergic agonist, acts on presynaptic $\alpha_2$ receptors in the LC to suppress noradrenergic output. Reduces sympathetic overdrive. Does not treat the GABA/NMDA imbalance directly but addresses the autonomic component.
- Evidence from Tolonen et al. (2013) and several small RCTs suggests dexmedetomidine as adjunct reduces BZD requirements and cardiovascular instability in alcohol withdrawal
- DeCarolis et al. (2007), retrospective data showing shorter ICU stay with dexmedetomidine adjunct
- Muzyk et al. (2011), dexmedetomidine reduced BZD requirements; not powered for clinical outcomes
- Dose: 0.2-1.5 mcg/kg/h infusion; no bolus dose for this indication
- Limitation: does not prevent seizures, must be combined with GABAergic agents for seizure-prone patients
Ketamine
Mechanism: NMDA receptor antagonist, directly blocks the upregulated excitatory glutamate receptor in withdrawal. Increasingly used as adjunct.
- Emerging evidence from small series (Pizon 2018, Kolinsky 2019), reduces BZD requirements in refractory DTs
- Not standard of care in Australia currently but used in some centres as salvage
- Dose for agitation adjunct: subanesthetic infusion 0.1-0.3 mg/kg/h
2.4 Adjunctive Management
- Thiamine: 300 mg IV/IM TDS for minimum 3-5 days before switching to oral (prevents/treats Wernicke encephalopathy, which can co-present with or be exacerbated by alcohol withdrawal). Always before dextrose in malnourished patients.
- Magnesium: hypomagnesaemia common in heavy drinkers; lowers seizure threshold; replace IV
- Phosphate and potassium: replete aggressively
- Folate: 5 mg daily oral
- Seizure management: BZDs are first-line; phenytoin/levetiracetam do NOT treat alcohol withdrawal seizures (they act on sodium channels, not GABA) and are not indicated unless a structural seizure cause is identified
3. Opioid Withdrawal Syndrome
3.1 Clinical Features and Scoring
The Clinical Opiate Withdrawal Scale (COWS) is the validated tool:
- Items include: pulse, diaphoresis, restlessness, pupil size, bone/joint aches, rhinorrhoea/lacrimation, GI distress, tremor, yawning, anxiety/irritability, gooseflesh
- Score 5-12: mild; 13-24: moderate; 25-36: moderately severe; > 36: severe
In the ICU, COWS can be supplemented with the Withdrawal Assessment Tool-1 (WAT-1) (derived from PICU but adapted) and objective autonomic measures.
3.2 Pharmacological Management
Clonidine
Mechanism: $\alpha_2$-adrenergic agonist, suppresses the hyperactive locus coeruleus. Addresses autonomic symptoms (tachycardia, hypertension, diaphoresis, anxiety) but does not treat the opioid receptor deprivation directly.
- Oral dose: 75-150 mcg three to four times daily (up to 1.2 mg/day), titrated to effect, monitoring for hypotension and bradycardia
- Transdermal patch (clonidine TTS-2 or TTS-3): steady delivery over 7 days, useful for patients with evolving oral access
- Taper over 1-2 weeks in community; in ICU, typically a 3-7 day course during opioid taper
- ANZ context: widely used as adjunct during opioid weaning in ICU
Methadone Bridge
Mechanism: Long-acting full $\mu$-opioid agonist. Substitutes for short-acting opioids, providing receptor occupancy with prolonged plasma half-life (24-36 h), allowing once or twice daily dosing and gradual taper without significant peak-trough fluctuation.
Indications in ICU:
- Transitioning patients with known opioid use disorder from IV fentanyl/morphine infusion
- Preventing withdrawal during protracted weaning
- Patients on methadone maintenance therapy (MMT) pre-admission, always continue, verify dose with prescribing clinic (Telehealth)
ICU Dosing Protocol:
- Convert current IV opioid infusion to oral morphine equivalents per 24 h
- Estimate methadone dose: ratio approximately 3:1 to 10:1 (morphine:methadone) depending on total morphine equivalent dose, higher ratios at very high doses
- Start methadone at conservative equivalent, divide into twice daily dosing
- Continue short-acting IV opioid for 24-48 h overlap, then wean
- Reduce methadone by 5-10% per day or every 2-3 days
Cautions:
- QTc prolongation, baseline and monitoring ECG required
- Drug interactions with CYP3A4/2D6 (many ICU drugs)
- Accumulation risk with renal/hepatic impairment
- Respiratory depression risk if dose calculated too high
Buprenorphine
Partial $\mu$-agonist / $\kappa$-antagonist. Long t½. Used increasingly for induction of opioid agonist therapy. Generally not started de novo in the ICU unless working with addiction medicine. Pre-existing buprenorphine (Suboxone, Subutex) should be continued if at all possible, abrupt cessation causes severe withdrawal in dependent patients.
Other Adjuncts for Opioid Withdrawal
| Agent | Mechanism | Role |
|---|---|---|
| Loperamide | Peripheral $\mu$-opioid agonist | Diarrhoea control |
| Ondansetron | 5-HT$_3$ antagonist | Nausea/vomiting |
| NSAIDs | COX inhibition | Myalgia/arthralgia |
| Dicyclomine | Anticholinergic | Cramping |
| Dexmedetomidine | $\alpha_2$ agonist | Autonomic stabilisation, anxiolysis |
4. Benzodiazepine Withdrawal After Prolonged ICU Sedation
4.1 The Iatrogenic Problem
This is a purely iatrogenic syndrome arising from the pharmacological consequences of standard ICU care. With the shift toward lighter sedation strategies (driven by ABCDEF bundle and the MIND-USA, SPICE-III, ROSE, and ACURASYS evidence frameworks), prolonged deep benzodiazepine sedation should be less common, but it persists in patients requiring:
- Prolonged neuromuscular blockade
- ARDS with prone positioning
- Refractory ICP management
- Severe burns
- Status epilepticus
4.2 Recognition
No validated ICU-specific benzodiazepine withdrawal scale exists for adult ICU. Features include:
- Agitation, anxiety, tremor
- Diaphoresis, tachycardia, hypertension
- Myoclonus
- Seizures, particularly with abrupt weaning of high-dose midazolam
- Perceptual disturbances (hypnagogia, visual phenomena)
- Insomnia
Onset depends on the half-life of the agent:
- Midazolam: active metabolite (1-hydroxymidazolam glucuronide) accumulates in renal failure; withdrawal onset within hours of cessation
- Lorazepam: t½ 10-20 h; onset within 24-48 h
- Diazepam: prolonged action via desmethyldiazepam; withdrawal may be delayed 5-7 days
4.3 Weaning Protocol
The fundamental principle: substitute a long-acting benzodiazepine and taper slowly.
Step 1, Convert:
- Calculate 24-hour midazolam infusion dose
- Convert to oral diazepam equivalent (approximately 1 mg midazolam IV ≈ 2-2.5 mg diazepam oral)
- Diazepam preferred for its long-acting metabolites providing intrinsic taper
Step 2, Initiate taper:
- Divide diazepam dose into 2-4 daily doses
- Reduce by 5-10% of original dose per week (slow taper) OR
- Reduce by 10% every 1-2 days in ICU under close monitoring (faster tolerated with supervision)
- Switch to oral or enteral route as early as feasible
Step 3, Adjuncts:
- Clonidine 75 mcg TDS, $\alpha_2$ agonism blunts autonomic features
- Carbamazepine, GABA and sodium channel effects; reduces withdrawal seizure risk; 200 mg TDS, particularly for ambulatory post-ICU tapering
- Gabapentin/pregabalin, modulates $\alpha_2\delta$ subunit of voltage-gated calcium channels; reduces neuronal hyperexcitability; increasingly used as BZD taper adjunct
- Propranolol, peripheral $\beta$-blockade; addresses tachycardia and tremor but does NOT prevent seizures
Step 4, Duration:
- For high-dose prolonged exposure, the full taper may take 4-12 weeks post-ICU discharge
- Liaison with community GP, outpatient psychiatry, or addiction medicine service essential
4.4 Relationship to Post-Intensive Care Syndrome (PICS)
Iatrogenic withdrawal contributes to cognitive, psychological, and physical components of PICS:
- Anxiety, PTSD features, cognitive impairment in the early post-ICU period may partly represent unrecognised BZD withdrawal
- Lighter sedation practices (SPICE-III: dexmedetomidine-based sedation, reduced benzodiazepine use) reduce this burden
- ICU follow-up clinics (now established in several ANZ centres) should include withdrawal screening
5. Evidence Base, Key Trials
Alcohol Withdrawal
| Trial/Study | Year | Key Finding | ANZ Relevance |
|---|---|---|---|
| GWIS (Saitz et al.) | 1994 | Symptom-triggered BZD therapy superior to fixed-schedule in non-ICU AW | Basis for CIWA-Ar guided therapy |
| Gold et al. | 2007 | Phenobarbital loading reduced ICU admission rates for severe AW | Informs phenobarbital loading protocols |
| Muzyk et al. | 2011 | Dexmedetomidine adjunct reduced BZD requirements in AWS | Supports adjunct use in refractory DTs |
| Amato et al. Cochrane | 2010 | BZDs reduce seizure risk compared to other agents in AW | Supports BZDs as standard of care |
Opioid Withdrawal and ICU Sedation
| Trial | Year | Key Finding | ANZ Relevance |
|---|---|---|---|
| SPICE-III (Djaiani et al.; Shehabi et al.) | 2019 | Dexmedetomidine-based sedation did not reduce 90-day mortality vs usual care but reduced delirium duration | Reduces BZD exposure → less iatrogenic withdrawal |
| ACURASYS (Papazian et al.) | 2010 | Early NMB in ARDS → better outcomes; context of prolonged sedation burden | Highlights iatrogenic exposure risk in ARDS |
| ROSE (PETAL Network) | 2019 | Did not confirm ACURASYS benefit; combined sedation exposure data important | Contextualises depth of sedation in ARDS |
| MIND-USA (Skrobik et al./Girard et al.) | 2018 | Haloperidol/ziprasidone did not reduce delirium duration in ICU, but informs overall sedation management | Delirium vs withdrawal distinction important |
| AID-ICU (Andersen et al.) | 2022 | Haloperidol vs placebo for delirium in ICU, no mortality benefit | Distinguishes delirium management from withdrawal |
| PAC-Man/SEDCOM | 2009 | Dexmedetomidine vs midazolam, less delirium and faster extubation | Reduces BZD burden; less iatrogenic withdrawal |
Benzodiazepine Tapering
No landmark RCTs specifically address ICU benzodiazepine withdrawal tapering. Most evidence extrapolated from:
- Community benzodiazepine withdrawal studies (Ashton protocol basis)
- PICU withdrawal trials (PATCH trial, SBS scoring systems)
- Expert consensus (Society of Critical Care Medicine PADIS Guidelines 2018)
6. Practical ANZ ICU Application
6.1 Alcohol Withdrawal, Clinical Decision Pathway
Admission assessment: Last drink, quantity, prior DTs/seizures, AUDIT score
↓
CIWA-Ar assessment q4-8h (if able) or objective autonomic monitoring
↓
CIWA < 8: → Observe, thiamine, electrolytes, oral chlordiazepoxide PRN
CIWA 8-15: → Diazepam 5-10 mg PO/IV q2h PRN to CIWA, thiamine IV
CIWA > 15 or DTs: → Diazepam 10 mg IV q5-10 min to target calm (not obtunded)
+ Thiamine 300 mg IV TDS
+ ICU admission for monitoring
↓
Refractory (> 40 mg diazepam, still agitated):
→ Phenobarbital 260 mg IV q20-30 min (max 15 mg/kg)
→ Consider intubation if airway at risk
→ Post-intubation: propofol infusion ± dexmedetomidine adjunct
→ Add ketamine infusion if available and per local protocol
Monitoring parameters in ICU during AWS:
- HR, BP, temperature q1h minimum
- CIWA-Ar or RASS (if intubated) q4h
- BGL q6h (thiamine before glucose)
- Electrolytes (K, Mg, PO4) daily
- LFTs, coagulation in suspected hepatic failure
- EEG if seizures develop or if diagnosis uncertain
6.2 Opioid Withdrawal, ICU Management Checklist
- [ ] Identify patients at risk: > 5 days opioid infusion, high cumulative dose, known opioid use disorder
- [ ] Verify pre-admission opioid agonist therapy (methadone, buprenorphine) and contact prescribing service
- [ ] Begin COWS scoring when weaning infusion
- [ ] Initiate clonidine 75-150 mcg TDS enteral when COWS > 8
- [ ] For community opioid-dependent patients: early methadone bridging (liaison with addiction medicine)
- [ ] Calculate morphine equivalent daily dose before converting to methadone
- [ ] ECG before methadone, if QTc > 500 ms, discuss risk/benefit with cardiology
- [ ] Plan post-discharge opioid management before transfer from ICU
6.3 Iatrogenic Benzodiazepine and Opioid Withdrawal, Prevention Framework
Prevention is superior to treatment. The ABCDEF Bundle (Awakening, Breathing, Coordination, Delirium, Early mobility, Family engagement) provides the structure:
- A (Awakening trials): Daily spontaneous awakening trials (SATs), reduces cumulative BZD dose
- B (Breathing trials): SBTs paired with SATs, reduces ventilator duration and sedation exposure
- C (Choice of agents): Prefer non-benzodiazepine sedation in appropriate patients (dexmedetomidine, propofol), supported by SPICE-III, SEDCOM, MENDS-2 data
- D (Delirium monitoring): Distinguish withdrawal from delirium, treatment differs fundamentally
- E (Early mobility): Reduces overall sedation requirement
Risk stratification for iatrogenic withdrawal:
| Risk Factor | Threshold Associated with Withdrawal Risk |
|---|---|
| Fentanyl infusion | Cumulative dose > 1.5 mg/kg total |
| Midazolam infusion | Duration > 5 days; cumulative dose > 50 mg/kg |
| Morphine infusion | Duration > 5 days; cumulative dose > 60 mg/kg |
| Combined opioid + BZD | Synergistic risk, any prolonged dual infusion |
6.4 Monitoring Tools Summary
| Syndrome | Validated Scale | ICU Limitation |
|---|---|---|
| Alcohol withdrawal | CIWA-Ar | Requires patient participation; cannot use if intubated |
| Opioid withdrawal | COWS; WAT-1 | WAT-1 PICU-derived; COWS requires participation |
| Iatrogenic withdrawal | No validated adult scale | Clinical + autonomic parameters + SAS/RASS discordance |
| Delirium (differential) | CAM-ICU; ICDSC | Important to differentiate from withdrawal |
Distinguishing delirium from withdrawal in ICU:
| Feature | Delirium | Withdrawal Syndrome |
|---|---|---|
| Onset | Fluctuating; multifactorial | Temporally related to dose reduction/cessation |
| Autonomic features | May be present | Prominent and consistent |
| Tremor | Rare | Common (especially BZD, alcohol) |
| Seizure risk | Low | High (AWS, BZD withdrawal) |
| Response to BZD | May worsen | Improves |
| Response to antipsychotic | May improve | Little effect on core syndrome |
7. Key Numbers Block
KEY NUMBERS, CICMF_SEDATION_6
Alcohol Withdrawal
- CIWA-Ar > 15: severe withdrawal, pharmacotherapy escalation required
- 5-10%: proportion of AW progressing to DTs
- 5-25%: mortality of untreated DTs (reduced to < 5% with treatment)
- Thiamine: 300 mg IV TDS minimum 3-5 days (before any dextrose)
- Phenobarbital loading: up to 10-15 mg/kg IV (typical single doses 130-260 mg q20 min)
- Seizure peak: 12-24 h after last drink
- DT peak: 48-96 h after last drink
Opioid Withdrawal
- COWS > 13: moderate withdrawal, pharmacotherapy indicated
- LC noradrenergic system: primary driver of withdrawal symptoms
- Clonidine oral: 75-150 mcg TDS (max ~1.2 mg/day); caution BP
- Morphine:methadone conversion ratio: 3:1 (low dose) to 10:1+ (high dose)
- Methadone QTc threshold for caution: > 500 ms
Iatrogenic BZD Withdrawal
- Risk threshold: > 5-7 days continuous infusion
- Fentanyl equivalent threshold: > 1.5 mg/kg cumulative
- Midazolam:diazepam conversion: 1 mg IV midazolam ≈ 2-2.5 mg oral diazepam
- Taper rate: 5-10% per week (slow) or 10% per 1-2 days (supervised ICU)
- Dexmedetomidine: 0.2-1.5
Sources