Part 2: Prone Positioning and Neuromuscular Blockade
Indications, protocols, and evidence for prone positioning in ARDS based on the PROSEVA trial, procedural checklists and contraindications, neuromuscular blockade evidence from ACURASYS and ROSE trials, train-of-four monitoring, and current recommendations.
5. Prone Positioning in ARDS
5.1 Physiological Rationale
Prone positioning (placing the patient face-down) improves oxygenation and reduces mortality in severe ARDS through several complementary mechanisms:12
Improved ventilation-perfusion matching: In the supine position, the dependent (dorsal) lung regions are compressed by the weight of the heart, mediastinum, and abdominal contents, causing atelectasis and shunt. When prone, gravitational redistribution allows recruitment of these dorsal regions while perfusion remains relatively uniform, improving V/Q matching.
More homogeneous ventilation distribution: The prone position reduces the transpulmonary pressure gradient from ventral to dorsal lung, leading to a more uniform distribution of tidal volume and reducing overdistension of ventral regions and cyclic atelectasis of dorsal regions.
Reduced ventilator-induced lung injury: By distributing ventilation more evenly, prone positioning decreases regional lung strain and stress, directly reducing VILI.
Improved secretion drainage: Gravitational repositioning facilitates mobilization and drainage of secretions from dependent airways.
Reduced cardiac compression: In the prone position, the heart rests on the sternum rather than compressing the left lower lobe, which is a common site of atelectasis in the supine position.
Improved chest wall mechanics: The anterior chest wall becomes relatively splinted by the bed surface, redirecting ventilation to the more compliant posterior regions.
5.2 Evidence: The PROSEVA Trial
The landmark multicenter randomized controlled trial (2013) definitively established the mortality benefit of prolonged prone positioning in severe ARDS.1
PROSEVA Trial Design:
- 466 patients with severe ARDS (PaO2/FiO2 <150 mmHg with FiO2 ≥0.6 and PEEP ≥5 cmH2O) after a 12–24 hour stabilization period on lung-protective ventilation
- Randomized to prone positioning for ≥16 consecutive hours per day or supine positioning
- All patients received lung-protective ventilation (VT 6 mL/kg IBW, Pplat ≤30 cmH2O)
- Patients were eligible if severe ARDS persisted after 12–24 hours of stabilization, not immediately at intubation
Results:
| Outcome | Prone Group | Supine Group | Significance |
|---|---|---|---|
| 28-day mortality | 16.0% | 32.8% | p < 0.001 |
| 90-day mortality | 23.6% | 41.0% | p < 0.001 |
| Duration of ventilation (survivors) | 17 days | 18 days | NS |
| Complications (pressure sores, accidental extubation) | No significant increase | — | — |
| Number needed to treat (28-day) | 6 | — | — |
This represents one of the largest mortality reductions demonstrated by any single intervention in ARDS, with a 50% relative reduction in 28-day mortality and a number needed to treat of only 6.1
Key methodological points:
- Patients were stabilized on lung-protective ventilation for 12–24 hours before randomization; transient oxygenation improvement during this period did not exclude patients
- Proning was initiated only if PaO2/FiO2 remained <150 after stabilization
- The treatment effect was robust across multiple subgroups
- Prior negative trials of prone positioning (Gattinoni 2001, Guerin 2004, Mancebo 2006, Taccone 2009) used shorter proning durations (6–8 hours), less stringent enrollment criteria (included mild ARDS), and less consistent use of lung-protective ventilation2
5.3 Indications for Prone Positioning
Based on the evidence from the landmark multicenter trial and subsequent meta-analyses, prone positioning is indicated in the following clinical scenario:123
| Criterion | Requirement |
|---|---|
| ARDS severity | Severe (PaO2/FiO2 ≤150 mmHg) |
| PEEP level | ≥5 cmH2O (typically ≥10 cmH2O in practice) |
| FiO2 | ≥0.6 |
| Stabilization period | After 12–24 hours of optimized lung-protective ventilation in the supine position |
| Lung-protective ventilation | Must be on VT 6 mL/kg IBW with Pplat ≤30 cmH2O |
When to consider proning earlier or with less severe criteria:
- Rapidly deteriorating oxygenation despite optimal supine management
- Trending toward rescue therapy consideration (ECMO, inhaled vasodilators)
- Some centers initiate prone positioning for PaO2/FiO2 <200 based on the physiological rationale, though the strongest mortality evidence is for PaO2/FiO2 <150
5.4 Contraindications
| Contraindication | Type | Notes |
|---|---|---|
| Spinal instability | Absolute | Unstable cervical, thoracic, or lumbar fractures |
| Open abdomen | Absolute | Laparostomy, open surgical wounds |
| Unstable pelvic or long bone fractures | Absolute | Active skeletal traction |
| Pregnancy (late trimester) | Relative | Case reports of successful proning with abdominal support; requires multidisciplinary decision |
| Anterior chest burns or wounds | Relative | Risk of wound compromise |
| Massive facial or anterior neck edema/surgery | Relative | Airway management concerns |
| Recent sternotomy (<48 hours) | Relative | Risk of sternal dehiscence; varies by institutional practice |
| Hemodynamic instability requiring escalating vasopressors | Relative | Brief transient hypotension during turning is common and expected; sustained instability is concerning |
| Elevated intracranial pressure | Relative | Prone positioning can increase ICP; may be used with ICP monitoring in select cases |
| Anterior chest tube with active air leak | Relative | Ensure secure fixation; may proceed with close monitoring |
5.5 Prone Positioning Protocol
5.5.1 Pre-Prone Checklist
| Item | Action |
|---|---|
| Team assembly | Minimum 3 persons for turn (5 recommended for larger patients): 1 at head managing airway, 2–4 at sides for body |
| Airway security | Verify ETT position (depth at lip, document); confirm secure tape or commercial ETT holder; suction oropharynx and ETT |
| Enteral feeding | Stop tube feeds 1–2 hours before turn; aspirate gastric residual; clamp or cap NG/OG tube |
| Eyes | Apply lubricant ointment; tape eyelids closed |
| Lines and tubes | Verify adequate length and security of all central lines, arterial lines, urinary catheters, chest tubes; disconnect non-essential monitoring temporarily |
| Hemodynamics | Ensure MAP is stable (≥65 mmHg) and vasopressor infusions are secure |
| Sedation | Adequate sedation (RASS −4 to −5); consider bolus of sedative and/or analgesic before turn |
| ECG electrodes | Move to posterior/lateral chest or use disposable anterior electrodes that can be left in place |
| Pressure injury prevention | Place foam cushions or gel pads at forehead, chin, chest (bilateral), iliac crests, and knees; use specialty prone positioning system if available |
| Ventilator circuits | Ensure adequate circuit length; verify that the ventilator circuit will not pull with position change |
| Code cart accessible | Ensure resuscitation equipment is at bedside |
5.5.2 Turning Procedure
- Pre-oxygenate: Increase FiO2 to 1.0 for 5 minutes before the turn
- Position patient at edge of bed: Slide the patient to the side of the bed opposite to the direction of the turn
- Turn the patient:
- The airway manager controls the head and endotracheal tube throughout the turn, ensuring the ETT does not migrate or become dislodged
- On command, the team rotates the patient laterally and then into the prone position in one smooth motion
- The “swimming position” is achieved: one arm raised above the head and one at the side, with the head turned toward the raised arm
- Arm positions are alternated every 2 hours
- Post-turn verification:
- Confirm bilateral breath sounds and EtCO2
- Verify ETT depth (should match pre-turn measurement)
- Check all lines, tubes, and drains
- Re-establish monitoring (ECG, SpO2, invasive blood pressure)
- Obtain a blood gas within 30–60 minutes
- Return FiO2 to the previous setting
5.5.3 Care During Prone Positioning
| Aspect | Protocol |
|---|---|
| Duration | ≥16 consecutive hours per session (PROSEVA protocol); most centers target 16–20 hours1 |
| Head position | Turn head to alternating sides every 2 hours; ensure ear and face are not compressed |
| Arm position | Alternate “swimmer’s position” every 2 hours (arm raised/lowered on alternating sides) |
| Pressure injury assessment | Inspect face, chest, and pressure points at each repositioning |
| Enteral feeding | May be resumed at low rate (10–20 mL/hr) with head of bed elevated 25–30 degrees in reverse Trendelenburg position; some centers hold feeds during proning |
| Hemodynamic monitoring | Transient hypotension during the turn is expected and usually resolves within minutes; sustained hypotension warrants evaluation |
| Suctioning | Suction ETT as needed; secretion drainage often increases in the prone position |
| Ventilator adjustments | Oxygenation typically improves within 1–2 hours; do not make PEEP/FiO2 changes in the first hour post-turn |
5.5.4 Criteria for Supinating (Returning to Supine)
After each 16–20 hour prone session, the patient is returned to the supine position for assessment and care. Proning sessions should be repeated daily until:12
| Criterion for Stopping Prone | Detail |
|---|---|
| Sustained oxygenation improvement | PaO2/FiO2 ≥150 mmHg with FiO2 ≤0.6 and PEEP ≤10 cmH2O, maintained for ≥4 hours after supination |
| Clinical improvement | Decreasing FiO2 and PEEP requirements over 24–48 hours |
| Complication requiring supination | Cardiac arrest (initiate CPR in prone if unable to supinate immediately), unplanned extubation, ETT obstruction not relieved by suctioning, massive hemoptysis, anterior chest tube placement needed |
Assessment of response:
- Check PaO2/FiO2 ratio 1 hour after supination
- If PaO2/FiO2 decreases below 150 after supination, return to prone position
- Non-responders (no improvement in PaO2/FiO2 after prone positioning) should still be considered for continued proning, as the mortality benefit in the landmark trial was not limited to oxygenation responders — the benefit may be mediated through reduced VILI rather than solely through oxygenation improvement
5.6 Complications and Risk Mitigation
| Complication | Incidence | Prevention/Management |
|---|---|---|
| Pressure injuries (face, chest, iliac crests) | 20–30% | Foam/gel padding; frequent repositioning of head and arms; specialty mattress systems |
| Peripheral nerve injury (brachial plexus) | 1–5% | Proper arm positioning; avoid hyperabduction; alternate swimmer position every 2 hours |
| Accidental extubation | 0.5–2% | Secure ETT before turning; dedicated airway manager during turn; verify post-turn |
| Loss of vascular access | <1% | Verify line security pre-turn; ensure adequate length |
| Periorbital/facial edema | Common | Elevate head slightly (reverse Trendelenburg 10–15 degrees); usually resolves 12–24 hours after supination |
| Cardiac arrest during proning | Rare | Initiate posterior CPR (compressions between scapulae) if unable to supinate immediately; supinate as soon as possible |
| Hemodynamic instability | Transient in 5–10% | Pre-optimize volume status; ensure vasopressors are running; brief pauses during turn if needed |
| Enteral feed intolerance | Variable | Hold feeds 1–2 hours before turn; may resume at low rate in prone with reverse Trendelenburg |
5.7 Prone Positioning: Summary of Practice Points
- Prone positioning should be initiated early (within first 12–36 hours) in patients with severe ARDS (PaO2/FiO2 <150 with FiO2 ≥0.6 and PEEP ≥5) who have been stabilized on lung-protective ventilation13
- The recommended duration is ≥16 hours per session, repeated daily until sustained improvement1
- The mortality benefit is large (NNT = 6) and represents the strongest level of evidence for any adjunctive therapy in ARDS1
- The clinical practice guidelines from the major critical care societies provide a strong recommendation for prone positioning in severe ARDS3
- Safe execution requires a trained multidisciplinary team, a standardized protocol, and attention to pressure injury prevention
6. Neuromuscular Blockade in ARDS
6.1 Rationale for Neuromuscular Blockade
Neuromuscular blocking agents (NMBAs) may benefit ARDS patients through several mechanisms:45
- Prevention of patient-ventilator dyssynchrony: Eliminates spontaneous breathing efforts that can generate excessive transpulmonary pressures and cause pendelluft (redistribution of gas from non-dependent to dependent regions)
- Reduction of oxygen consumption: Paralysis eliminates the metabolic demand of respiratory and skeletal muscles
- Reduced biotrauma: Controlled ventilation without patient effort may reduce inflammatory mediator release
- Improved chest wall compliance: Eliminating muscle tone allows more predictable ventilator mechanics
- Facilitation of lung-protective ventilation: Prevents the generation of large spontaneous tidal volumes (patient self-inflicted lung injury, or P-SILI) that can occur even during assisted ventilation
6.2 Evidence: ACURASYS Trial (2010)
The initial landmark trial evaluated early continuous neuromuscular blockade in moderate-to-severe ARDS.4
ACURASYS Trial Design:
- 340 patients with early ARDS (PaO2/FiO2 <150 with PEEP ≥5 and FiO2 ≥0.6) within 48 hours of onset
- Randomized to cisatracurium besylate continuous infusion (15 mg bolus then 37.5 mg/hr) vs. placebo for 48 hours
- All patients received deep sedation (targeting no visible spontaneous movements)
- Primary outcome: 90-day mortality (adjusted for baseline PaO2/FiO2 and Simplified Acute Physiology Score II)
Results:
| Outcome | Cisatracurium | Placebo | Significance |
|---|---|---|---|
| 90-day mortality (adjusted HR) | 31.6% | 40.7% | HR 0.68 (95% CI 0.48–0.98), p = 0.04 |
| 28-day mortality | 23.7% | 33.3% | p = 0.05 |
| Ventilator-free days (28-day) | 10.6 | 8.5 | p = 0.04 |
| Barotrauma | 4% | 12% | p = 0.01 |
| ICU-acquired weakness at day 28 | No significant difference | — | — |
6.3 Evidence: ROSE Trial (2019)
The subsequent, larger multicenter trial re-evaluated early neuromuscular blockade in moderate-to-severe ARDS using a different control group sedation strategy.5
ROSE Trial Design:
- 1,006 patients with moderate-to-severe ARDS (PaO2/FiO2 <150 with PEEP ≥8) within 48 hours of onset
- Randomized to cisatracurium continuous infusion with heavy sedation (RASS −5) for 48 hours vs. light sedation without NMB (target RASS 0 to −1)
- Key difference from ACURASYS: the control group used light sedation, not deep sedation
- Stopped early for futility at the second interim analysis
Results:
| Outcome | NMB + Deep Sedation | Light Sedation Alone | Significance |
|---|---|---|---|
| 90-day mortality | 42.5% | 42.8% | p = 0.93 |
| Ventilator-free days (28-day) | 15.3 | 16.1 | p = 0.40 |
| ICU-acquired weakness | 7.3% | 5.1% | Not statistically significant |
| Cardiovascular adverse events | 14.0% | 8.6% | p = 0.01 |
| Barotrauma | No difference | — | — |
6.4 Reconciling ACURASYS and ROSE
The apparently conflicting results of these two trials are best understood through consideration of their differing control group strategies:56
| Factor | ACURASYS | ROSE |
|---|---|---|
| Control group sedation | Deep sedation (RASS −5) | Light sedation (RASS 0 to −1) |
| Comparison being tested | NMB vs. deep sedation without NMB | NMB + deep sedation vs. light sedation alone |
| Implication | NMB may be beneficial compared to deep sedation alone | NMB + deep sedation is NOT beneficial compared to light sedation |
Interpretation: The ROSE trial suggests that the benefit seen in ACURASYS may have been driven by the harmful effects of deep sedation in the control group rather than a direct benefit of neuromuscular blockade. When the comparator is light sedation (which is now the standard of care), routine NMB does not improve outcomes and may increase cardiovascular adverse events.56
6.5 Current Recommendations for Neuromuscular Blockade
Based on the totality of evidence:36
Routine early NMB is NOT recommended in moderate-to-severe ARDS.
| Situation | Recommendation |
|---|---|
| Routine use in all moderate-severe ARDS | Not recommended; no mortality benefit when compared to light sedation |
| Refractory patient-ventilator dyssynchrony | Consider NMB when dyssynchrony compromises lung-protective ventilation despite optimizing sedation and ventilator settings |
| Persistent ventilator dyssynchrony causing double-triggering | NMB may prevent patient self-inflicted lung injury (P-SILI) |
| Refractory hypoxemia on maximum settings | Consider NMB as part of a bundle with prone positioning |
| Facilitation of prone positioning | Consider NMB for the turning procedure and initial prone period if patient is agitated or at risk for accidental extubation |
| PaO2/FiO2 <80 despite optimal ventilation and prone positioning | NMB may be reasonable as a temporizing measure while arranging rescue therapy |
6.6 Neuromuscular Blocking Agents in ARDS
| Agent | Mechanism | Dosing | Advantages | Disadvantages |
|---|---|---|---|---|
| Cisatracurium | Benzylisoquinolinium; organ-independent Hofmann degradation | Bolus: 0.1–0.2 mg/kg; Infusion: 1–3 mcg/kg/min (typically 37.5 mg/hr for 70 kg patient) | No hepatic/renal metabolism; predictable duration regardless of organ failure; no histamine release; most studied in ARDS | Cost; limited availability in some settings |
| Atracurium | Benzylisoquinolinium; Hofmann degradation + ester hydrolysis | Bolus: 0.4–0.5 mg/kg; Infusion: 5–10 mcg/kg/min | Similar organ-independent metabolism; alternative to cisatracurium | Greater histamine release; laudanosine metabolite (theoretical seizure risk at high doses) |
| Rocuronium | Aminosteroid; hepatic metabolism | Bolus: 0.6–1.2 mg/kg; Infusion: 5–15 mcg/kg/min | Rapid onset; can be reversed with sugammadex | Organ-dependent metabolism (accumulation in hepatic/renal failure); may prolong ICU-acquired weakness |
| Vecuronium | Aminosteroid; hepatic metabolism | Bolus: 0.08–0.1 mg/kg; Infusion: 0.8–1.7 mcg/kg/min | Widely available; lower cost | Hepatic metabolism with active metabolites; unpredictable duration in organ failure; associated with prolonged weakness |
Preferred agent: Cisatracurium is the preferred NMBA in the ICU setting due to its organ-independent metabolism via Hofmann degradation and the absence of active metabolites, making its pharmacokinetics predictable regardless of hepatic and renal function.45
6.7 Monitoring Neuromuscular Blockade
6.7.1 Train-of-Four (TOF) Monitoring
| Parameter | Detail |
|---|---|
| Technique | Apply peripheral nerve stimulator over the ulnar nerve at the wrist (or facial nerve, posterior tibial nerve); deliver four supramaximal stimuli at 2 Hz (0.5 seconds apart) |
| Response assessment | Count the number of visible or palpable twitches (0/4 to 4/4) of the adductor pollicis (thumb adduction) |
| Target during NMB infusion | 1–2 out of 4 twitches (TOF 1–2/4); ensures adequate blockade while avoiding over-paralysis |
| Frequency | Every 4–6 hours during continuous infusion |
| Drug holiday | Interrupt NMB infusion daily (after 48 hours if used beyond the initial period) to assess depth of blockade and attempt to wean |
6.7.2 Sedation During Neuromuscular Blockade
| Requirement | Detail |
|---|---|
| Mandatory deep sedation | NMB eliminates all motor response; without adequate sedation, the patient may be awake and aware but unable to move or communicate — this constitutes a medical emergency |
| Sedation target | RASS −4 to −5 (no response to voice, response to physical stimulation only, or no response) |
| BIS monitoring | Bispectral index (BIS) monitoring may be considered to assess sedation depth during NMB, targeting BIS 40–60; however, BIS accuracy is limited in the ICU setting and should not be relied upon as the sole guide |
| Analgesic requirement | Concurrent opioid infusion is essential; NMB does not provide analgesia |
6.8 Complications of Neuromuscular Blockade
| Complication | Risk | Mitigation |
|---|---|---|
| ICU-acquired weakness | May be increased with prolonged (>48 hours) use, especially with concurrent corticosteroids | Limit NMB duration to shortest necessary period; daily drug holidays; avoid aminosteroid agents when possible |
| Awareness during paralysis | Devastating psychological trauma | Ensure adequate sedation and analgesia before and during NMB; BIS monitoring if available |
| Impaired clinical assessment | Loss of neurological exam, cough reflex assessment | Document pre-NMB neurological status; minimize duration |
| Cardiovascular events | ROSE trial showed increased cardiovascular events in NMB group (14% vs. 8.6%) | Hemodynamic monitoring; cautious fluid management |
| Mesenteric ischemia | Rare but reported | Monitor abdominal exam (limited during NMB); lactate trends |
| Diaphragm atrophy | Contributes to ventilator-induced diaphragm dysfunction | Limit duration; facilitate early liberation |
6.9 Neuromuscular Blockade: Summary Algorithm
Moderate-to-Severe ARDS (P/F <150)
|
Optimize lung-protective ventilation
Consider prone positioning
|
Assess for ventilator dyssynchrony
|
+-----+------+
| |
No dyssynchrony Dyssynchrony present
P/F improving or refractory hypoxemia
| |
Continue current Optimize sedation first
management (target RASS −2 to −3)
|
+-----+------+
| |
Resolved Persistent
| |
No NMB needed Consider NMB
Cisatracurium
48-hour course
TOF monitoring 1-2/4
Daily reassessment
References
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Papazian L, Forel JM, Gacouin A, et al. “Neuromuscular blockers in early acute respiratory distress syndrome (ACURASYS).” N Engl J Med, 363(12), 1107-1116, 2010. doi:10.1056/NEJMoa1005372. https://doi.org/10.1056/NEJMoa1005372 ↩︎ ↩︎ ↩︎
National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, et al. “Early neuromuscular blockade in the acute respiratory distress syndrome (ROSE).” N Engl J Med, 380(21), 1997-2008, 2019. doi:10.1056/NEJMoa1901686. https://doi.org/10.1056/NEJMoa1901686 ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Grasselli G, Calfee CS, Camporota L, et al. “ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies.” Intensive Care Med, 49(7), 727-759, 2023. European Society of Intensive Care Medicine (ESICM). doi:10.1007/s00134-023-07050-7. https://doi.org/10.1007/s00134-023-07050-7 ↩︎ ↩︎ ↩︎