"PROTECT-ICU: Impact of an Educational Intervention on the Implementation of an Expanded ABCDEF Bundle and Its Effect on Post-Intensive Care Syndrome - A Multicenter Cluster Randomized Clinical Trial."
Phase: NA
Conditions: Post Intensive Care Syndrome (PICS), Critical Illness
Sponsor: Carola Giménez-Esparza Vich

OFFICIAL TITLE OF THE STUDY:   
   
PROTECT-ICU:  Impact of a Formative 
Training Intervention on the Implementation 
of an Expanded ABCDEF Care Bundle and  
Its Effect on  PICS: a Multicenter Cluster-  
Randomized Pre-Post Clinical Trial with 
Post-ICU  Follow-up   NCT NUMBER: Not 
yet assigned   
DOCUMENT TYPE:   
Study Protocol with Statistical Analysis Plan     
DOCUMENT DATE (most recent approved 
version):26/10/2025]   
Protocol Version: 1.0     
     
  
   
1. INTRODUCTION     
Survival following intensive care has steadily improved over the past decade, 
but a significant percentage of patients develop post-intensive care syndrome 

(SPCI), with physical, cognitive, and psychological sequelae that substantially 
impact quality of life, return to activity, and use of healthcare resources. The 
frequency and severity of PICS vary greatly depending on the evaluation time 
point (1, 3, 6, or 12 months), the population type (medical/surgical, 
COVID/noCOVID), and the instruments used to measure each domain, with 
significant heterogeneity among studies and meta-analyses. In large cohorts 
and recent reviews, this variability is described and the need for standardized 
and longitudinal evaluations is emphasized to adequately interpret the evolution 
of PICS in clinical practice.     
The ABCDEF bundle (analgesia/light sedation; spontaneous breathing trials; 
choice/monitoring of sedation; detection and management of delirium; 
mobilization; family involvement) is associated with process improvements (less 
deep sedation, less delirium, more mobilization, and family participation) and, 
potentially, better intermediate outcomes. However, adherence to the bundle is 
uneven between centers, and evidence of its direct relationship with PICS at 3–    
12 months in multicenter and routine-practice settings is limited and 
methodologically heterogeneous. Meanwhile, post-discharge follow-up 
strategies (e.g., post-ICU clinics) have shown heterogeneous results and 
sometimes no benefit in clinically relevant outcomes; therefore, focusing 
interventions within the ICU and measuring their implementation with robust 
methods emerges as a priority improvement approach.     
Standardized training of personnel is a key factor in optimizing the 
implementation of complex care. Structured programs — with homogeneous 
materials, coverage verification, and mini-comprehension audits — have been 
shown to be feasible and transferable in multicenter networks (e.g., “Zero”-type 
initiatives), although their specific impact on PICS has not been consistently 
measured in Spanish-speaking settings. Similarly, there is interest in expanded 
components to the core ABCDEF bundle (e.g., nutrition, sleep, discharge 
planning, rehabilitation, psychosocial support, etc.) that could provide 
incremental benefit; their comparative evaluation against the classic bundle 
remains necessary and should be approached with an exploratory framework.     

In the present study, in addition to the “classic package of measures” 
recommended in intensive care (ABCDEF), a series of additional interventions 
have been incorporated that, according to available scientific evidence, could 
contribute to improving the quality of life of critically ill patients and reducing the 
incidence of post-intensive care syndrome (SPCI), called the “expanded 
measures package” (G–Z). The development of these complementary measures 
has involved the collaboration of all Working Groups of the Spanish Society of 
Intensive, Critical, and Coronary Medicine (SEMICYUC), each contributing 
specific proposals related to the comprehensive care of the critically ill patient 
according to their field of expertise. This multidisciplinary approach enriches and 
expands the framework of the ABCDEF bundle, with the aim of providing more 
comprehensive, patient-centered care and targeting the reduction of medium- 
and long-term complications, including PICS.     
In this context, PROTECT-UCI proposes to evaluate, under real clinical practice 
conditions and using a multicenter methodology, whether a standardized training 
program that reinforces the implementation of the ABCDEF bundle (with 
expanded components) improves ICU adherence and translates into a lower 
incidence of PICS measured at 3 months post-hospital discharge, maintaining 
follow-up at 1, 6, and 12 months.     
2.- HYPOTHESES     
• 
(Primary) An increase in ABCDEF bundle adherence achieved through a 
standardized training program is associated with a clinically significant 
reduction in PICS at 3 months (target: an absolute reduction of ~20 
percentage points, from 50% to 30%).     
• 
(Process) The training intervention significantly and sustainably 
increases overall and component adherence to the ABCDEF bundle in 
participating ICUs.     
• 
(Exploratory) The expanded components of the ABCDEF bundle 
provide additional incremental benefit on PICS compared to the core 
bundle.     

3.- OBJECTIVES     
3.1. Primary     
Evaluate the effect of a training intervention directed at ICU healthcare staff 
focused on adherence to the “classic” ABCDEF package of measures on the 
incidence of post-intensive care syndrome (SPCI) at 3 months post-hospital 
discharge.     
3.2. Secondary     
3.2.1. Process outcomes (ICU bundle):     
1. Evaluate whether the training intervention modifies adherence to the classic 
ABCDEF package of measures and its components.     
2. Evaluate whether the training intervention modifies adherence to the 
expanded ABCDEF package of measures and its components.     
3. Determine whether implementation of the training program for the classic 
and expanded package of measures leads to a reduction in the incidence of 
delirium in ICU patients.     
4. Evaluate the change in overall adherence in each center and the proportion 
of ICUs that experience a ≥20 point improvement in compliance after 
training.     
3.2.2. Patient outcomes (post-ICU follow-up clinics):     
5.- Evaluate the effect of a training intervention directed at ICU healthcare staff 
focused on adherence to the expanded ABCDEF package of measures on the 
incidence of post-intensive care syndrome (SPCI) at 3 months post-hospital 
discharge.     
6.- Determine whether implementation of the classic and expanded ABCDEF 
package of measures, overall and by components, reduces the incidence of    
PICS at 1 month, 6 months, and 1 year post-hospital discharge in ICU patients.   

7.- Determine whether implementation of the standard and expanded ABCDEF 
care bundles, overall and by individual components, improves health-related 
quality of life measured by SF-12 and EQ-5D at 1,3,  6, and 12 months after 
hospital discharge in ICU patients. 
4. MÉTHODS    
4.1 Design and setting of the study     
Type: Cluster-randomized clinical trial, multicenter, pre-post with two sequential 
time points (PRE vs POST) and longitudinal follow-up at 1, 3, 6, and 12 months 
post-hospital discharge.     
Intervention: Standardized training program for ICU professionals.     
Process measurement: Compliance with the CLASSIC and EXPANDED 
ABCDEF bundle with daily data collection (case report form) for 21 days or until 
ICU discharge/death if it occurs earlier.     
4.2. Population and selection criteria     
4.2.1. Population     
• 
Setting: Adult ICUs in Spain and participating Spanish-speaking 
countries.     
• 
Primary analysis population: Patients discharged alive from the 
hospital, scheduled for post-ICU follow-up, from both the PRE and POST 
periods.     
4.2.2. Criteria (classic and expanded ABCDEF bundle)     
• 
Inclusion:     
o Patients ≥ 18 years old. o ICU stay ≥ 48 hours.     
o Informed consent: obtained from the patient (if decision-making 
capacity remains) or, if not, from their legal/family representative, 
to participate in the study, in accordance with current regulations.     

• 
Exclusion:     
o Limitation of life support treatment, defined as the clinical and 
ethical decision, agreed by the medical team and, when possible, 
with the patient or their representatives, not to initiate, escalate, or 
withdraw certain advanced life support measures (e.g., invasive 
mechanical ventilation, prolonged noninvasive ventilation, 
vasopressor/inotropic drugs, renal replacement therapies, CPR, 
ECMO, or other extracorporeal support).     
o Imminent discharge < 24 hours from the cut-off point.     
o Inability for in-person follow-up (e.g., not reachable, language 
barrier, transfer to/from another hospital, inability to attend 
consultation).     
o Life expectancy < 3 months.     
o Severe cognitive impairment or serious pre-existing mental illness. 
o Severe traumatic brain injury or severe neurological, 
degenerative, or traumatic diseases that impede functional and 
cognitive assessment.     
4.2.3. Criteria for post-ICU follow-up clinic     
• 
Inclusion: Patients meeting criteria in section 4.2.2 and without 
exclusion criteria, discharged alive from ICU.     
• 
Exclusion: Same as in section 4.2.2.     
4.3. Study groups     
Once the ICUs that will participate in the study have been recruited and the 
baseline phase of data collection on the degree of implementation of the 
expanded measures package (A–Z) is completed, two groups of ICUs will be 
formed by stratified randomization by geographic area (Spain and Latin  
America) and size (ICUs with <16 beds vs. ≥16 beds). Two ICU groups will be 

formed: A and B. Group A will implement the classic bundle, and group B will 
implement the classic and expanded bundles.     
• 
Group A (“classic bundle”): measures A through F.     
• 
Group B (“expanded bundle”): measures A through Z.     
4.4. Development and validation of the CRF by Delphi method     
After the initial proposal of items prepared by the expert group of SEMICYUC 
Scientific Committees, based on scientific evidence, recommendations, and 
consensus guidelines, a Delphi method will be used to refine and reach 
agreement on the contents of the CRF for the classic and expanded ABCDEF 
bundle (A–Z). The aim will be to reach expert consensus on the relevance, 
clarity, and feasibility of each CRF item, and to estimate its content validity.     
A multidisciplinary panel (15–20 participants) will be formed, with diversity in 
professional background: intensivist physicians (7–8), ICU nursing (4–5), 
physiotherapy/rehabilitation (2–3), hospital pharmacy (1–2), psychology/social 
work/ethics (1–2), and post-ICU patients/families (2). Criteria: ≥5 years of 
experience or participation in ABCDEF/Zero/post-ICU; geographic diversity 
(different regions of Spain and Latin America); role balance (no one group >1/3); 
commitment to 2–3 rounds. Study coordinators will not be part of the panel (to 
avoid bias); they will act as a scientific committee (design, analysis, and writing).     
Delphi procedure: Rounds: 2 (with the possibility of a third if consensus is not 
reached). Rating scale (Likert 1–9) for each item in three domains: clinical 
relevance, clarity/writing, and feasibility of daily collection. Consensus criterion 
(a priori): Include if median 7–9 and ≥70% of scores are 7–9; Review if median 
4–6; Exclude if median 1–3 or ≥70% of scores 1–3. Structured and anonymized 
feedback between rounds will be provided (aggregated statistics + qualitative 
comments).     

Delphi results: The results will consist of the assessment of the validity of each  
CRF item and of the entire set, as well as agreement among experts, recording 
response rates and changes made to each item. This will yield the final version of 
the CRF v1.0 with mandatory and optional fields, clear definitions, and completion 
rules, together with a user manual including the variable dictionary to be used in 
the PRE and POST phases of the study. An approximate duration of 3 to 4 weeks 
is estimated, including one week for recruitment, one week for the first round, 3–
5 days for analysis, one week for the second round, and, if necessary, a third 
round of one week. Responses will be collected via online questionnaires on a 
secure platform, anonymously, with encrypted storage and supervised by the 
principal investigator in accordance with current data protection regulations.     
5. STATISTICAL ANALYSIS  
5.1 Sample size calculation     
5.1.1 Hypotheses and comparison objectives: The primary objective is to 
evaluate if a training intervention reduces the incidence of PICS at 3 months.     
Three groups are proposed:     
• 
Baseline (pre-intervention): expected prevalence = 50%.     
• 
Intervention A: reduction to 30%.     
• 
Intervention B: reduction to 20%.     
Two primary comparisons will be made (Baseline vs A and Baseline vs 
B). To control the overall type I error, a Bonferroni correction will be 
applied, setting the significance level at α = 0.025 (two-sided) for each 
comparison.     
5.1.2 Power and initial calculation: With 90% power and using a two-sided 
test for comparison of proportions for the most demanding contrast (50% vs 
30%), the required sample size without multicenter adjustment is 147 evaluable 
subjects per group.     

5.1.3 Adjustment for design effect (multicenter): As a multicenter study, an 
inflation factor is applied to account for correlation between patients within the 
same hospital. The design effect (DE) is calculated as:     
DE = 1 + (m – 1) × ICC     
• 
Intracluster correlation coefficient (ICC): 0.02.     
• 
Average cluster size (m): evaluables per group divided by number of 
centers in that group.     
Since center randomization is 1:1 after the baseline phase, the number of 
centers per group is: Baseline: 57 centers (all); A: 28 centers; B: 29 centers.     
Calculation per group (n₀ = 147; ICC = 0.02):     
• 
Baseline (C = 57): n ≈ 151.9 → 152 evaluable.     
• 
A (C = 28): n ≈ 161.0 → 161 evaluable.     
• 
B (C = 29): n ≈ 160.3 → 160 evaluable.     
To ensure both comparisons (Baseline vs A and Baseline vs B) have the 
required power, we take the worst case (largest n). The worst case is group A 
with 28 centers, so 161 evaluable subjects per group is adopted.     
5.1.4 Adjustment for losses: A 47% loss rate is expected (mortality and 
nonattendance to follow-up). This means only 53% of scheduled patients will be 
evaluable. To guarantee 161 evaluable per group, approximately 304 patients 
per group need to be enrolled.     
5.1.5 Final sample size: The final sample size will be 304 patients per group,     
i.e., 912 in total (304 Baseline, 304 A, 304 B).     
5.1.6 Distribution by hospital: With 57 hospitals and 1:1 center randomization 
after the baseline phase (28 in A and 29 in B):     
• 
Baseline (57 hospitals): 304/57 ≈ 5–6 patients per hospital.     
• 
A (28 hospitals): 304/28 ≈ 10–11 patients per hospital.     

• 
B (29 hospitals): 304/29 ≈ 10–11 patients per hospital.     
In total, each hospital will contribute around 16 patients (5–6 in the baseline 
phase and 10–11 in the assigned group).     
5.1.7 Sensitivity analysis: Alternative scenarios were considered:     
• 
If ICC = 0.01 (lower), ~154 evaluable (289 scheduled) needed.     
• 
With ICC = 0.02 (reference), 161 evaluable (304 scheduled) needed.     
• 
With ICC = 0.03 (higher), ~169 evaluable (320 scheduled) needed. 
Varying the number of centers yields a range of 152–164 evaluable, so 
304 scheduled per group provides sufficient statistical assurance.     
5.1.8 Contingency for center dropout: If the number of active hospitals differs 
from planned (either before study start or due to dropout after the PRE phase), 
the planned sample per group will be recalculated automatically using an 
adaptive rule based on the actual number of active hospitals per group (H), 
maintaining assumptions (power 90%, α = 0.025, ICC = 0.02, losses 47%). 
Quotas will be redistributed proportionally among the active ICUs in the same 
group until the new target is reached.     
5.2 Analysis of variables     
Quantitative variables will be expressed as mean ± standard deviation or 
median (interquartile range), and categorical as absolute and relative 
frequencies. Comparison between categorical variables will be performed using 
Pearson’s Chi-squared test, linear trend Chi-squared, or Fisher’s exact test. 
Comparison between quantitative variables and a binary categorical variable will 
be performed using Student’s t-test or the Mann–Whitney U test. To analyze 
independent predictive variables of PICS development, a multivariate binary 
logistic regression with stepwise forward method (PIN<0.10; POUT<0.05) will be 
used. Clinically relevant variables and those with p<0.20 in the univariate 
analysis will be included. Odds ratios (OR) with 95% confidence intervals will be 
calculated.     

5.3 Propensity score analysis     
A propensity score matching will be performed (nearest neighbor 1:1, no 
replacement). Each patient in the pre group will be matched with one in the post 
group based on the variables: hospital, age, sex, SAPS III, SOFA on admission, 
Charlson index, ARDS, septic shock, delirium, need for MV/VMI/NIV >48h, deep 
sedation, and ICU length of stay. Balance will be checked using standardized 
mean differences (<0.1 indicates adequate balance). Comparisons of the 
matched groups will be done using McNemar and Wilcoxon tests. The adjusted 
difference in 3-month PICS incidence, the number needed to treat (NNT), and 
the adjusted OR with 95% confidence interval will be calculated.     
5.4 Subgroup analysis     
The effect of the intervention will be explored in subgroups defined by: gender, 
age (<65 vs ≥65 years), need for mechanical ventilation ≥48h, presence of 
ARDS, delirium, septic shock or cardiac arrest, and ICU stay ≥5 days.     
5.5 Additional sensitivity analyses     
Sensitivity analyses will be performed excluding patients from units with bundle 
item completion <70% and by geographic regions.     
5.6 Interim analysis     
An interim analysis will be conducted when half of the patients have completed 
the 3-month post-ICU consultation.     
5.7 General considerations     
All tests will be two-sided and p≤0.05 will be considered statistically significant. 
Analyses will be performed with SPSS version 27 (IBM, Armonk, NY) and R 
version 4.5.1 (R Foundation for Statistical Computing).     

6.- ETHICAL CONSIDERATIONS     
• 
Ethical approval: The protocol will be reviewed and approved by the 
Drug Research Ethics Committee (CEI) of Hospital Universitario Vega 
Baja, and subsequently by the CEI of each participating center before 
study initiation.     
• 
Informed consent: Written informed consent will be obtained from each 
patient or, if not possible, from their legal representative before inclusion 
in the study and for the post-ICU follow-up (Phase 4). Participants can 
withdraw their consent at any time without affecting the quality of care 
received.     
• 
Risks and benefits: The study is an interventional observational study 
(training and standardized care bundle), without additional invasive 
procedures beyond standard clinical practice. No significant added risks 
beyond usual ICU care are anticipated. The potential benefit is the 
improvement of care and reduction in the incidence of post-intensive care 
syndrome.     
• 
Data protection: All data will be anonymized using a numeric code 
irreversibly dissociated from personal identity. The correspondence file 
will be securely held by the Principal Investigator. Data processing will 
comply with the EU General Data Protection Regulation (GDPR     
2016/679) and the Spanish Data Protection Law (LOPDGDD 3/2018).     
• 
Confidentiality: Only authorized investigators will have access to the 
data. Results will be reported in aggregate form without the possibility of 
identifying participants.     
• 
Nature of the study: This study is part of quality improvement and 
training projects and does not involve procedures outside standard care 
practices.     
7.- MONITORING AND QUALITY CONTROL PLAN     
An internal monitoring plan will be carried out with periodic review of the Case    

Report Forms (CRFs), data consistency checks, and random data audits. The   
Principal Investigator and the Coordinating Committee will supervise the quality 
and completeness of the recorded information, ensuring the reliability and validity 
of the obtained results.     
8.- DISSEMINATION PLAN     
The study results will be disseminated at national and international scientific 
conferences and published in indexed peer-reviewed journals. International 
reporting guidelines will be followed (e.g., CONSORT for clinical trials and 
STROBE for observational studies). Patient confidentiality will be maintained at 
all times, and results will be presented only in aggregate form.