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Trial Summaries & Critiques

DESIGNATION

Image: Shutterstock / Kaan Yetkin Toprak

Intubated patient undergoing an operation

Publication

  • Title: Intraoperative Driving Pressure–Guided High PEEP vs Standard Low PEEP for Postoperative Pulmonary Complications
  • Acronym: DESIGNATION (Driving Pressure During General Anesthesia for Open Abdominal Surgery)
  • Year: 2026
  • Journal published in: JAMA
  • Citation: Writing and Steering Committees for the DESIGNATION–Investigators. Intraoperative Driving Pressure–Guided High PEEP vs Standard Low PEEP for Postoperative Pulmonary Complications. JAMA. 2026;335(8):693-702.

Context & Rationale

  • Background
    • Postoperative pulmonary complications (PPCs) are frequent after major surgery, particularly open abdominal procedures, and are associated with morbidity, mortality, and increased healthcare utilisation.
    • Lower tidal volume (“lung-protective”) intraoperative ventilation reduced pulmonary and extrapulmonary complications in abdominal surgery, but later trials isolating individual ventilatory components (particularly PEEP and recruitment manoeuvres) produced inconsistent effects on PPCs.1
    • Large perioperative RCTs comparing higher PEEP (often with recruitment manoeuvres) versus lower PEEP during low tidal volume ventilation did not reduce PPCs and increased haemodynamic complications (notably hypotension and vasopressor use).23
    • Individual patient data meta-analysis linked higher intraoperative driving pressure (ΔP) to increased PPCs, supporting ΔP as a plausible physiological target for “individualised PEEP” strategies aiming to reduce lung stress/strain.4
    • DESIGNATION prospectively tested whether ΔP-guided individualised higher PEEP plus repeated recruitment manoeuvres could translate physiological improvements into fewer clinically relevant PPCs; the protocol was prepublished and feasibility/safety data supported deliverability across centres.56
  • Research Question/Hypothesis
    • In adults at increased risk of PPCs undergoing open abdominal surgery, does intraoperative ventilation with ΔP-guided higher PEEP plus recruitment manoeuvres reduce PPCs within 5 postoperative days compared with standard low PEEP without recruitment manoeuvres?
  • Why This Matters
    • Individualised higher PEEP titration and repeated recruitment manoeuvres are commonly advocated on physiological grounds, but may impose haemodynamic risk and workflow burden if not clinically beneficial.
    • The trial directly tests whether ΔP is a valid intraoperative therapeutic target (not merely a prognostic marker) for reducing clinically important PPCs.
    • Findings inform pragmatic perioperative ventilation practice in a large, high-risk surgical population.

Design & Methods

  • Research Question: In adults at increased risk for PPCs undergoing open abdominal surgery, does intraoperative ΔP-guided higher PEEP with recruitment manoeuvres (vs standard low PEEP without recruitment) reduce PPCs within 5 postoperative days?
  • Study Type: International, multicentre, investigator-initiated, parallel-group, superiority randomised clinical trial with concealed allocation and blinded postoperative outcome assessment; conducted in operating theatres at 29 sites across 5 European countries (April 2019 to December 2024; final follow-up March 2025).
  • Population:
    • Key inclusion: Adults ≥18 years; open abdominal surgery under general anaesthesia; ARISCAT score ≥26; BMI ≤40 kg/m2.
    • Key exclusions: Planned laparoscopic/robotic surgery; open abdominal surgery combined with intrathoracic procedures; prone/lateral positioning; <12 hours “reflection time” for consent; ventilation >30 minutes within prior 30 days; expected postoperative ventilation in ICU/post-anaesthesia care unit; persistent haemodynamic instability/intractable shock; severe cardiac disease (NYHA III–IV, acute coronary syndrome, or persistent ventricular tachyarrhythmias); prior major lung surgery; history of ARDS; severe COPD (GOLD III/IV or requiring home oxygen/home ventilation); absence of written informed consent.
    • Randomisation strata: Site and BMI category (≤30 vs >30), using variable block sizes (maximum 8).
  • Intervention:
    • Ventilation platform: Volume-controlled ventilation with tidal volume 8 mL/kg predicted body weight (PBW); other parameters per protocol guidance (e.g., I:E 1:2; respiratory rate titrated to end-tidal CO2 targets; FiO2 titrated to oxygenation).
    • Recruitment + decremental PEEP titration: Recruitment manoeuvre with respiratory rate set to 15/min; PEEP increased every 15 seconds from 5 to 20 cm H2O in steps of 5, then decreased every 20 seconds in steps of 2 cm H2O down to 6 cm H2O; ΔP calculated at each step (plateau pressure − PEEP) and plotted; the PEEP associated with the lowest ΔP was selected (if no minimum, PEEP set to 12 cm H2O).
    • Repetition/delivery: Recruitment manoeuvres performed before and after titration, after any ventilator disconnection, and within 1 hour prior to extubation; selected PEEP maintained until extubation; all intraoperative trial interventions delivered manually by the attending anaesthetist.
  • Comparison:
    • Volume-controlled ventilation with tidal volume 8 mL/kg PBW.
    • Fixed PEEP 5 cm H2O throughout surgery; no recruitment manoeuvres; no decremental PEEP trial.
  • Blinding: Anaesthetists were not blinded (intervention delivery required); postoperative outcome assessors were blinded to allocation; outcome definitions prespecified in the published protocol.5
  • Statistics: Assuming 34% PPC incidence in the low PEEP group and 2% dropout, 1468 patients provided 80% power to detect a 20% relative risk reduction with two-sided α=0.05; primary analysis used a modified intention-to-treat population (randomised patients who did not drop out before intervention start) analysed by assigned group; mixed-effect generalised linear models (identity link) estimated absolute risk differences with site as a random effect; multiplicity correction was prespecified for secondary outcomes.
  • Follow-Up Period: Primary outcome assessed through postoperative day 5; additional outcomes included ICU use and in-hospital outcomes to discharge.

Key Results

This trial was not stopped early. It completed the planned enrolment (n=1468) with final follow-up in March 2025.

Outcome Driving pressure–guided high PEEP Standard low PEEP Effect p value / 95% CI Notes
Postoperative pulmonary complications (composite within 5 postoperative days) 142/718 (19.8%) 125/717 (17.4%) Absolute difference 2.5% 95% CI −1.5 to 6.4; P=.23 Primary outcome; prespecified composite
Severe respiratory failure 13/718 (1.8%) 10/717 (1.4%) Absolute difference 0.4% 95% CI −0.9 to 1.7; P=.53 Component of primary composite
Atelectasis 87/718 (12.1%) 75/717 (10.5%) Absolute difference 1.7% 95% CI −1.5 to 5.0; P=.30 Component of primary composite
Pleural effusion 87/718 (12.1%) 77/717 (10.7%) Absolute difference 1.5% 95% CI −1.7 to 4.8; P=.36 Component of primary composite
Intraoperative desaturation 6/716 (0.8%) 20/716 (2.8%) Absolute difference −2.0% 95% CI −3.3 to −0.6; P=.005 Secondary outcome (SpO2 <92% for >1 min)
Intraoperative hypotension 382/708 (54.0%) 317/704 (45.0%) Absolute difference 9.0% 95% CI 4.7 to 13.4; P<.001 Secondary outcome (>20% mean arterial pressure decrease for >3 min)
Use of vasoactive agents 224/700 (32.0%) 130/690 (18.8%) Absolute difference 13.2% 95% CI 9.0 to 17.4; P<.001 Secondary outcome
Unplanned admission to ICU 9/718 (1.3%) 18/717 (2.5%) Absolute difference −1.3% 95% CI −2.7 to 0.1; P=.07 Secondary outcome
All-cause hospital mortality 25/698 (3.6%) 23/703 (3.3%) Absolute difference 0.3% 95% CI −1.6 to 2.2; P=.75 Secondary outcome
  • The primary PPC composite was not reduced with ΔP-guided higher PEEP (19.8%) versus standard low PEEP (17.4%); absolute difference 2.5% (95% CI −1.5 to 6.4; P=.23).
  • The strategy reduced intraoperative desaturation (0.8% vs 2.8%; absolute difference −2.0% [95% CI −3.3 to −0.6]; P=.005) but increased hypotension (54.0% vs 45.0%; P<.001) and vasoactive agent use (32.0% vs 18.8%; P<.001).
  • Prespecified subgroup: planned ICU/HDU admission showed higher PPC incidence with high PEEP (75/221 [33.9%] vs 48/203 [23.6%]; absolute difference 10.1% [95% CI 1.7 to 18.7]; P for interaction=.007), whereas patients without planned ICU/HDU admission showed no signal of benefit (absolute difference −1.5% [95% CI −5.8 to 2.7]).

Internal Validity

  • Randomisation and allocation: Concealed, computer-generated randomisation with stratification by site and BMI category (≤30 vs >30) and variable block sizes (maximum 8), supporting low risk of selection bias.
  • Dropout/exclusions: 1468 patients were randomised; 1435 (98%) formed the primary analysis population (718 high PEEP vs 717 low PEEP), reflecting a low post-randomisation attrition rate (33/1468, 2.2%) due to dropout before intervention start.
  • Performance/detection bias: Anaesthetists were unblinded; postoperative outcome assessors were blinded; the primary outcome was a composite with protocolised definitions, but some components (e.g., radiographic diagnoses) can vary in ascertainment intensity across centres.
  • Protocol adherence: High feasibility and clear separation in the intended ventilatory exposure were achieved intraoperatively.
  • Baseline comparability: Groups were well balanced (median age 66 years; 52% female; ARISCAT median 38; high-risk ARISCAT ≥45: 44.1% vs 42.4%; BMI median 27.5 vs 27.7 kg/m2), supporting exchangeability.
  • Separation of the variable of interest (mechanistic separation):
    • Recruitment manoeuvres delivered: 711/718 (99.0%) vs 1/717 (0.1%); median number of manoeuvres 3 (3 to 3) vs 0; absolute difference 3.0 (3.0 to 3.0).
    • PEEP after first hour: 10 (10 to 12) vs 5 (5 to 5) cm H2O; absolute difference 5.0 (5.0 to 5.0).
    • ΔP after first hour: 8 (7 to 10) vs 10 (8 to 12) cm H2O; absolute difference −2.0 (−2.4 to −1.6).
    • Tidal volume after first hour: 7.9 (7.8 to 8.0) vs 7.9 (7.8 to 8.0) mL/kg PBW; absolute difference 0 (no separation), indicating the strategy primarily altered mechanics via PEEP/recruitment rather than tidal volume.
  • Crossover: PEEP was adjusted for clinical reasons in 61/718 (8.5%) vs 12/717 (1.7%); despite this, between-group PEEP and ΔP separation remained large, suggesting limited dilution of exposure contrast.
  • Timing and dose: The intervention was applied intraoperatively from early after intubation and maintained through the final intraoperative measurement, consistent with the intended exposure window for prevention of ventilator-associated perioperative lung injury.
  • Statistical rigour: The planned sample size was achieved; mixed-effect modelling accounted for centre-level clustering; the observed PPC incidence was lower than expected, reducing precision for smaller effect sizes.

Conclusion on Internal Validity: Overall, internal validity appears strong given concealed randomisation, minimal attrition, and substantial separation of the ventilatory strategy, with the main threats being unavoidable clinician unblinding and reliance on a composite PPC outcome with potentially variable ascertainment across sites.

External Validity

  • Population representativeness: Applicable to adults at moderate-to-high PPC risk undergoing open abdominal surgery in high-resource European centres; median age 66 and substantial ARISCAT high-risk representation support relevance to common high-risk surgical pathways.
  • Key exclusions limiting generalisability: Minimally invasive surgery, BMI >40 kg/m2, severe COPD/home ventilation, severe cardiac disease, and those expected to remain ventilated postoperatively (ICU/PACU) were excluded.
  • Intervention feasibility: Requires ability to perform repeated recruitment manoeuvres and short decremental PEEP titration steps with plateau pressure measurement; this is feasible in many modern theatres but may be constrained by staffing, monitoring, or haemodynamic instability.
  • Cross-setting applicability: The haemodynamic trade-off (increased hypotension/vasopressor use) is likely to generalise to similar patients/settings, making local haemodynamic management capacity a key determinant of implementation risk.

Conclusion on External Validity: Generalisability is moderate: findings translate well to high-risk open abdominal surgery in resourced perioperative environments, but extrapolation to minimally invasive surgery, extreme obesity, severe cardiopulmonary disease, and settings with limited haemodynamic/ventilator monitoring is uncertain.

Strengths & Limitations

  • Strengths:
    • Large, international, multicentre randomised trial with concealed allocation and blinded postoperative outcome assessment.
    • High protocol deliverability with substantial physiological separation (PEEP +5 cm H2O and ΔP −2 cm H2O at 1 hour) and near-universal delivery of recruitment manoeuvres in the intervention arm.
    • Pragmatic perioperative setting and broad open abdominal surgery case-mix increase relevance to real-world practice.
    • Prespecified protocol and analysis framework published prior to database lock.5
  • Limitations:
    • Primary composite outcome included PPCs with heterogeneous clinical importance and potentially variable detection/diagnostic thresholds across centres.
    • Observed PPC incidence was lower than assumed in sample-size planning, reducing precision for modest but potentially clinically relevant differences.
    • Clinician unblinding was unavoidable and could influence co-interventions (e.g., fluid/vasopressor management) that may interact with pulmonary outcomes.
    • Findings do not directly generalise to minimally invasive surgery, BMI >40, severe cardiopulmonary disease, or patients expected to remain ventilated postoperatively.

Interpretation & Why It Matters

  • Clinical practice
    In high-risk open abdominal surgery managed with low tidal volumes, routine intraoperative ΔP-guided higher PEEP with repeated recruitment manoeuvres did not reduce PPCs and increased haemodynamic instability (hypotension and vasopressor exposure).
  • Physiology vs outcomes
    Physiological benefits (higher PEEP, lower ΔP, fewer desaturations) did not translate into fewer PPCs, supporting caution in using intraoperative mechanics as a surrogate for clinically meaningful postoperative outcomes.
  • Targeting and selection
    The subgroup signal of harm in patients planned for ICU/HDU admission emphasises the need to consider haemodynamic vulnerability and perioperative phenotype when applying higher PEEP/recruitment strategies.

Controversies & Subsequent Evidence

  • Event rate and precision: The PPC incidence (17.4% in low PEEP) was substantially lower than the 34% assumed for power calculations, narrowing the ability to detect smaller effect sizes and shifting interpretation towards “no clinically relevant benefit” rather than proof of equivalence.
  • Composite outcome interpretability: The primary endpoint combined PPCs with varying severity and clinical impact; this can dilute signal if the intervention affects only a subset of components or if ascertainment varies between centres.
  • Physiological mechanism vs clinical translation: The intervention achieved the intended mechanical separation (PEEP +5 cm H2O; ΔP −2 cm H2O at 1 hour) yet did not improve postoperative outcomes, reinforcing that ΔP can function as a risk marker without being a sufficient standalone therapeutic target.4
  • Haemodynamic trade-off aligns with prior large RCTs: Increased hypotension/vasopressor exposure with higher PEEP/recruitment is consistent with earlier perioperative trials (open abdominal surgery and obesity cohorts), strengthening the inference that haemodynamic cost is reproducible across populations.23
  • Subgroup signal (planned ICU/HDU admission): The interaction (P=.007) suggests that sicker phenotypes may be more vulnerable to the haemodynamic downsides of higher PEEP/recruitment; however, subgroup estimates are imprecise and should be treated as hypothesis generating.
  • Subsequent and parallel evidence:
    • Perioperative “open lung” strategies incorporating intraoperative and postoperative components (e.g., iPROVE) have been evaluated, leaving open the possibility that isolated intraoperative optimisation is insufficient without postoperative lung expansion/respiratory support elements.7
    • Patient-level and trial-level meta-analyses have not supported routine higher intraoperative PEEP with recruitment manoeuvres (on a background of low tidal volume ventilation) as a universal strategy to reduce PPCs, consistent with DESIGNATION’s neutral primary outcome and increased haemodynamic events.89
    • The IMPROVE-2 multicentre pragmatic trial in emergency abdominal surgery similarly found that a driving pressure–targeted “highest PEEP” strategy did not reduce postoperative respiratory failure or death and increased reintubation/curative non-invasive ventilation, reinforcing concerns about harm without clear benefit in high-risk phenotypes.11
  • How this reshapes guidance: International expert consensus recommendations endorse lung-protective intraoperative ventilation principles, but do not support routine high PEEP/recruitment in unselected patients; DESIGNATION provides direct large-scale RCT evidence supporting a cautious, haemodynamics-aware approach to PEEP individualisation.10
  • High-end commentaries: Editorial and “What’s New” scholarship around perioperative ventilation and ΔP emphasises that driving pressure is best interpreted within a broader framework (lung size, elastance, mechanical power, haemodynamic tolerance) and that future trials should integrate perioperative bundles and phenotype-driven targeting rather than isolated intraoperative mechanics.1213
  • Further Reading (Randomised trials):
    • IMPROVE: low tidal volume vs higher tidal volume (abdominal surgery).1
    • PROVHILO: higher vs lower PEEP during low tidal volume ventilation (open abdominal surgery).2
    • PROBESE: higher vs lower PEEP with recruitment (obese patients undergoing surgery).3
    • iPROVE: perioperative open-lung approach vs standard protective ventilation (abdominal surgery).7
    • IMPROVE-2: driving pressure-targeted PEEP strategy vs fixed PEEP 5 (emergency abdominal surgery).11
    • Driving pressure-guided PEEP RCT (abdominal surgery).14
    • Driving pressure-guided PEEP RCT (laparoscopic/robotic surgery).15
  • Further Reading (Systematic reviews and meta-analyses):
    • Driving pressure and PPCs (individual patient data meta-analysis).4
    • Higher vs lower intraoperative PEEP with recruitment (patient-level meta-analysis).8
    • Individualised PEEP in abdominal surgery (systematic review and meta-analysis).9
  • Further Reading (Guidelines and consensus statements):
    • International expert panel-based consensus recommendations for lung-protective ventilation in surgical patients.10
  • Further Reading (Protocol, feasibility, and commentaries):
    • DESIGNATION protocol (Trials).5
    • DESIGNATION interim feasibility/safety analysis (J Clin Med).6
    • Editorial on driving pressure as a target in perioperative strategies (IMPROVE-2 lessons).12
    • “What’s New” synthesis on intraoperative ventilator setting principles.13

Summary

  • In 1435 high-risk adults undergoing open abdominal surgery, ΔP-guided higher PEEP with repeated recruitment manoeuvres did not reduce PPCs within 5 postoperative days versus fixed PEEP 5 without recruitment (19.8% vs 17.4%; P=.23).
  • The intervention achieved strong mechanical separation (PEEP +5 cm H2O and ΔP −2 cm H2O after 1 hour) but increased hypotension (54.0% vs 45.0%) and vasopressor use (32.0% vs 18.8%).
  • Intraoperative desaturation was less frequent with ΔP-guided higher PEEP (0.8% vs 2.8%), illustrating improved oxygenation without downstream PPC reduction.
  • A prespecified subgroup showed a signal of harm in patients planned for ICU/HDU admission (interaction P=.007), emphasising haemodynamic vulnerability as a potential effect modifier.
  • Alongside prior large perioperative trials, DESIGNATION supports avoiding routine higher PEEP/recruitment strategies in unselected surgical patients and prioritising haemodynamics-aware, phenotype-driven approaches.

Overall Takeaway

DESIGNATION is a landmark multicentre perioperative ventilation trial because it rigorously tested a physiologically compelling strategy (ΔP-guided higher PEEP with recruitment) and demonstrated no reduction in postoperative pulmonary complications despite clear improvements in intraoperative mechanics and oxygenation. The consistent haemodynamic cost (more hypotension and vasopressor use) shifts the balance away from routine application of this strategy and towards pragmatic low PEEP ventilation with careful patient selection for rescue lung recruitment.

Overall Summary

  • ΔP-guided higher PEEP + recruitment did not reduce PPCs after open abdominal surgery.
  • Physiological improvements came with reproducible haemodynamic harm (hypotension/vasopressors).
  • Routine use of higher PEEP/recruitment in unselected patients is difficult to justify; targeting may be best reserved for rescue or phenotype-selected strategies.

Bibliography