Fentanyl Versus Hydromorphone as First Line Strategy in Patients on Mechanical Ventilation, a Pilot Pragmatic Randomized Superiority Clinical Trial: the FenHydro Trial
Phase: PHASE2
Conditions: Mechanical Ventilation, Sedation and Analgesia, Critical Care, Intensive Care
Sponsor: Beth Israel Deaconess Medical Center

Fentanyl versus Hydromorphone as First Line Strategy in Patients on 
Mechanical Ventilation, a pilot pragmatic cluster randomized superiority 
clinical trial: the FenHydro Trial 
 
Protocol Version 1.32 
Date 4/15/2026 
 
Authors: 
Eduardo Messias Hirano Padrao1,2,3, MD 
Adrian Wong2,4, pharmD, MPH 
Margaret Hayes1,2, MD 
David M. Furfaro1,2, MD 
Mehrnaz Sadrolashrafi2,4, pharmD 
Gabrielle Cozzi2,4, pharmD 
Alexandra Sopuch2,3,5, MD 
Alper Gulluoglu2,3,5, MD 
Maria Alejandra Alape2,3,5, MD 
Anne Thu Nguyen6, pharmD 
Kevin Nguyen6, MPH, MS 
Sammantha Harrison, MS2,3,5 
Krystal Capers, MPH2,3,5 
Valerie M. Banner-Goodspeed2,3,5, MPH 
Guanqing Chen2,3,5, phD 
Victor Novack2,3,5, MD, PhD 
Daniel Talmor2,3,5, MD 
Elias Baedorf Kassis1,2,3, MD 
 
Affiliations: 
1. Department of Pulmonary and Critical Care, Beth Israel Deaconess Medical Center, 
Boston, MA, USA 
2. Harvard Medical School, Boston, MA, USA 
3. Center for Anesthesia Research Excellence, Beth Israel Deaconess Medical Center, 
Boston, MA, USA 
4. Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA 
5. Department of Anesthesia, Pain and Critical Care, Beth Israel Deaconess Medical 
Center, Boston, MA, USA 
6. Beth Israel Deaconess Needham Hospital, Boston, MA, USA 
 
 
 
 
 
 
 

Table of Contents 
0. Summary of Changes ............................................................................................................ 3 
1. Study Summary ..................................................................................................................... 4 
2. Trial Design ............................................................................................................................ 8 
3. Background ............................................................................................................................ 8 
4. Inclusion Criteria ...................................................................................................................12 
5. Exclusion Criteria ..................................................................................................................12 
6. Study Sites ............................................................................................................................12 
7. Study Population ...................................................................................................................14 
8. Enrollment .............................................................................................................................14 
9. Consent ................................................................................................................................14 
10. Randomization ....................................................................................................................15 
11. Blinding ...............................................................................................................................17 
12. Study Procedures................................................................................................................17 
13. Safety Monitoring ................................................................................................................27 
14. Data Collection ....................................................................................................................27 
15. Outcomes Measures ...........................................................................................................34 
16. Statistical Analysis Plan ......................................................................................................36 
17. Benefits and Possible Risks ................................................................................................40 
18. Study Withdrawal and Discontinuation ................................................................................42 
19. Privacy ................................................................................................................................42 
20. Study Chart Retention .........................................................................................................43 
21. Roles and Responsibilities ..................................................................................................43 
22. Funding ...............................................................................................................................43 
23. Conflicts of Interest .............................................................................................................43 
24. References..........................................................................................................................45 
 
 
 

0. Summary of Changes 
October 30th, 2025 (v1.1) 
0. Added a retrospective data collection to 30 patients admitted to the ICU prior to trial initiation 
to compare the accuracy of automated versus manual data extraction (14. Data Collection) 
 
February 2nd, 2026 (v1.2) 
1. Added an anonymous survey to gather feedback from health care providers (nurses, 
advanced practice providers (APPs) and attendings involved in the care of patients during this 
trial on their experience with fentanyl versus hydromorphone infusions in mechanically 
ventilated patients. This will be presented as a separate research and it’s protocol will be 
presented elsewhere. 
 
April 6th, 2026 (v1.30) 
1. Added to the protocol our institutional approach to analgosedation and recommended doses 
of each sedative 
2. Added a summary of the current interventions to improve adherence of providers to our 
study 
3. Explained in more details the rationale for sample size calculation 
4. Clarified if alternate and crossover opioids will be included in the analysis 
5. Added a sensitivity analysis for different MME conversion formulas 
 
April 10th, 2026 (v1.31) 
1. Harmonized the data analysis by planning to use GLMM for both primary and secondary 
outcomes to account for random effects 
 
April 14th, 2026 (v1.32) 
1. Extended the duration of the trial by 1 week to achieve similar sample sizes between both 
groups (still within the pre-planned 6 months) 
 
 

1. Study Summary 
This protocol was written in accordance with Standard Protocol Items: Recommendations for 
Interventional Trials (SPIRIT) guidelines. Any amendment to the protocol after the study is 
initiated will be registered.  
 
1.11 Title: Fentanyl versus Hydromorphone as First Line Strategy in Patients on Mechanical 
Ventilation, a pilot pragmatic cluster randomized superiority clinical trial (FenHydro Trial) 
 
1.12 Study Purpose: 
The final purpose of this study is to evaluate whether analgosedation of mechanically 
ventilated patients with fentanyl or hydromorphone infusion as first line strategy will lead to a 
difference in:  
1. daily MME required during mechanical ventilation 
2. all-cause mortality at 28 days 
3. days alive free of the ICU at 28 days 
4. days alive and free of mechanical ventilation at 28 days 
5. days alive and free of vasopressors at 28 days 
6. ventilatory mechanics during mechanical ventilation 
7. daily morphine-milligram equivalent required during the first 28 days 
8. incidence of opioid withdrawal 
9. daily average number of bowel movements through ICU stay 
10. percentage of time without coma and delirium during the ICU stay 
11. days alive and free of restraints at 28 days 
12. need for tracheostomy during hospital stay 
 

 
As a pilot study, the trial purpose is also to evaluate: 
1. The recruitment rate of patients 
2. The contamination rate between the interventions, adherence and compliance to the study 
protocol 
3. Intracluster correlation coefficient  
4. Challenges with data collection and follow-up in the setting of a pragmatic trial 
5. Other logistics of a pragmatic cluster randomized trial in the ICU 
 
1.13 Overall study design:  
We plan to perform a prospective, pragmatic, single center, multiple ICU, cluster 
randomized, cross-over, open label trial comparing fentanyl to hydromorphone as analgesia in 
mechanically ventilated patients        
 
1.14 Research question:  
Hypothesis: We hypothesize that there is a difference in total morphine-milligram 
equivalent (MME) between patients receiving fentanyl and those receiving hydromorphone 
 
1.21 Inclusion Criteria 
Admitted to a either MICU A, B, C or FICU at Beth Israel Deaconess Medical Center (Boston, MA, 
USA) requiring mechanical ventilation, and opioid infusion for analgosedation 
 
1.22 Exclusion Criteria 
Age < 18 years old, medical team discretion that a specific opioid would be more appropriate for 
the patient, do not intubate orders, comfort measures or and true immunologic allergy to fentanyl 
or hydromorphone 
 

1.31 Interventions 
Intervention 1: Fentanyl continuous infusion will be the first choice as opioid analgesia for 
mechanically ventilated patients in the ICU randomized to this intervention group.  
 
Intervention 2: Hydromorphone continuous infusion will be the first choice as opioid analgesia for 
mechanically ventilated patients in the ICU randomized to this intervention group.  
 
Following 3 months of the intervention, the cluster will be changed to receive the second protocol. 
 
Decision regarding titration, initial dosing, additional boluses of the intervention drug will be at the 
discretion of the healthcare provider. The study will not impact other sedative medications, 
additional analgesic medication, weaning of sedation, mechanical ventilation liberation and other 
ICU management. These will follow-up current guidelines and our ICU policies. 
 
1.41 Sample Size Calculation 
There is no trial comparing fentanyl to hydromorphone for analgosedation in critically ill 
mechanically ventilated patients. One randomized trial performed in Oceania compared morphine 
and fentanyl. They found that the mean total MME for the morphine group was 747 ± 1131 mg 
and for the fentanyl group was 1274 ± 1928 mg. Considering  a daily MME dose while on 
mechanical ventilation in the fentanyl group of 270 ± 250 mg and 450 ± 500 mg in the 
hydromorphone group based on the data from two months of our MICU A, B, C and FICU, group 
sample sizes of 137 patients would achieve 80% power to detect a difference of 180 MME at a 
significance level (alpha) of 0.05 using a two sided Mann-Whitney Test. These results are based 
on 500 Monte Carlo samples from the null distributions: WeibullMS (450 500) and WeibullMS 
(450 500), and the alternative distributions: WeibullMS (450 500) and WeibullMS (270 250). 

Considering eventual losses to follow-up and contamination it will be required a sample size in 
each group of 150 patients. 
Therefore, considering recruitment of 50 patients per month, it will be required 6 months to obtain 
the sample size. 
 
 
1.51 Outcomes and Follow-up 
Primary Outcome: difference in daily MME during mechanical ventilation 
 
Secondary Outcomes:  
- 
All-cause mortality on day 28 
- 
Days alive and ICU free days at 28 days 
- 
Days alive and free of vasopressors at 28 days 
- 
Days alive and free of ventilator at 28 days 
- 
Requirement of adjunctive analgesia or sedation medications 
- 
Difference in average daily dose of MME required during the first 28 days 
- 
Percentage of days with delirium in the ICU 
- 
Need for tracheostomy 
- 
Incidence of opioid withdrawal 
- 
Daily Average number of Bowel Movements through ICU stay 
- 
Respiratory system mechanics and ventilator synchrony 
- 
Adverse effects 
 
1.61 Follow-up duration: 28 days after enrollment or hospital discharge, whatever comes first 
 
1.71 Planned date of first enrollment: November 3rd, 2025 

 
1.81 IRB approval: The protocol was approved by the institutional review board of the center (IRB 
2005P000456), and written informed consent was waived.  
 
1.82 Data Sharing Statement: deidentified data, data dictionary and analytical code will be made 
available to researchers whose proposed use of the data has been approved by the lead trial 
investigators for any purpose that facilitates advancement of the field. It will require investigator 
support and IRB approval, after approval of a proposal, with a signed data access agreement 
 
1.91 Funding: None. This is an investigator initiated study with no trial sponsor and funder 
 
2. Trial Design 
 
This is a cluster randomized, pragmatic, pilot and feasibility superiority clinical trial to 
compare two standard-of-care analgosedation medications, fentanyl and hydromorphone, in 
mechanically ventilated patients in the ICU. 
 
3. Background 
Patients with respiratory failure who require mechanical ventilation are not only at risk of 
death, but also of complications of prolonged ICU stay [1,2]. Patients may have significant 
functional decline, impact in quality of life, develop psychiatric disorders and at long-term can lead 
to significant cost to society [3-5]. Although sedation and analgesia are considered only supportive 
therapy, several studies have shown that in patients on mechanical ventilation, different 
approaches can have significant impact on patient centered outcomes [6-8]. However, to date, 

randomized clinical trials on critically ill patients have mostly evaluated the sedative agent but not 
the analgesic agent [9-11]. Although morphine and its derivates are the most common used opioid 
analgesic agents in the critical care setting [12], only some prospective study compared them 
head-to-head (ramifentanyl versus morphine and fentanyl versus morphine) [13,14]. Current 
guidelines recommend choosing the analgesic agent based on pharmacokinectics, physician 
experience and side-effects profile [15]. 
 
3.2 Equipoise Between Approaches, Rationale and Significance for the Study 
3.21 Equipoise between approaches 
Fentanyl is a synthetic derivate of morphine that is 100 times more potent than morphine, 
has a great lipid solubility leading to fast onset (one to two minutes), has a short half-life (up to 
three hours) and limited histamine release [16,17]. It is metabolized by the liver and its excretion 
is not affected by the kidneys [18]. Those characteristics allow fentanyl to be versatile and be 
used in many different scenarios in the ICU [15]. Despite those advantages, concerns have been 
raised regarding adipose tissue accumulation, tachyphylaxis, CYP3A4 interaction and chest wall 
rigidity, particularly when on high doses [16,19,20].  
Hydromorphone is an alternative analgesic agent. It is a semisynthetic morphine derivate 
that can be five to ten times more potent than morphine [21]. It also has a fast onset (up to 10 
minutes), a short half-life (up to three hours) and is less renally excreted than morphine [21]. 
Some concerns have been raised regarding the accumulation of hydromorphone metabolites 
including hydromorphone-3-glucuronide, which can lead to neuroexcitatory effects and delirium 
[22,23]. A few retrospective studies compared fentanyl and hydromorphone in the critical care 
setting [24,25,26]. Due to the retrospective nature, small size of the studies and several 
imbalances in the groups, no significant conclusion can be drawn regarding the benefits and risks 
of fentanyl versus hydromorphone [24,25]. However, the largest and most recent retrospective 

study, showed no difference in 28-day mechanical ventilation free days and death during 
mechanical ventilation [26]. 
Opioids currently used for analgosedation in mechanically ventilated ICU patients include 
morphine, fentanyl and hydromorphone. Currently, at BIDMC, fentanyl and hydromorphone 
represent standard-of-care for providing analgosedation and both are considered by healthcare 
providers as similar or equal. The selection of a specific agent as standard-of-care is determined 
by primary ICU team preference and experience. At BIDMC, based on our data, fentanyl is the 
most commonly used option, due to familiarity. However, the practice varies from institution to 
institution with hydromorphone is considered as first choice.  Although provider experience and 
unit policy are usually the most common reason to choose one over the other, some clinical 
characteristics may influence the decision. As mentioned, both medications have fast onset of 
action, and similar half-lives. Although small differences may affect the decision of one over the 
other, dosage reduction and close monitoring are used rather than switching to an alternative in 
most cases [26]. Whether or not either of these agents afford additional meaningful clinical 
benefits, advantages or contribute to meaningful clinical outcomes has not been fully established 
in available literature and represents the basis for performing this clinical pilot study. Since the 
study will not limit the ability of the provider to choose which medication is used for their patient 
or cross over medications in any situation, the randomization of the unit to a specific opioid agent 
as the recommended first choice will not add any additional risk to the patients. 
We propose to study the use of fentanyl and hydromorphone in the critically ill population 
on mechanical ventilation due to the paucity of data comparing both medications head-to-head 
and their widespread use. 
 
3.21 Previous studies comparing Fentanyl versus Hydromorphone 
 
To our knowledge, only three studies [24,25, 26] have compared the use of fentanyl versus 
hydromorphone in the ICU setting.  

 
Choi et al. performed a single center retrospective study comparing both medications 
titrated to CPOT [24]. Patients on mechanical ventilation for more than 24 hours from different 
ICUs (medical, surgical and cardiac) were included. They included 177 patients, 103 in the 
fentanyl group and 74 in the hydromorphone group. Group imbalances included a higher 
proportion of patients on neuromuscular blockade on the hydromorphone group (25.68% versus 
10.68%), higher levels of sedation in the hydromorphone group and higher use of 
dexmedetomidine in the fentanyl group. Despite the imbalances, the ICU length of stay was non-
statistically significant (seven days, IQR 5 - 11 in the hydromorphone group versus eight days, 
IQR 4 - 15 in the fentanyl group, p = 0.11). The median time on mechanical ventilation was 146.47 
hours (IQR 64.55 - 279.69) in the fentanyl group versus 122.33 hours (IQR 70.27 - 204.98) in the 
hydromorphone group, p = 0.31. The study found that the CPOT was different between the two 
groups (two in the hydromorphone group versus zero in the fentanyl, p < 0.001). Also, the need 
for restraints was statistically higher in the hydromorphone group. 
 
Martin et al. performed a single center retrospective study comparing our intervention 
medications on patients requiring veno-venous or veno-arterial extracorporeal membrane 
oxygenation (ECMO) [25]. A total of 52 patients were included in the analysis. In their study, 
patients on fentanyl were more commonly in veno-venous ECMO (28.1% versus 20%). They also 
had more prolonged time on ECMO (95.8 hours versus 66 hours) and on mechanical ventilation 
(seven versus five). They found that subjects receiving hydromorphone had less MME 
requirement than those on fentanyl (168 mg, IQR 80–281 versus 325 mg, IQR 270–449, p-value 
<0.01). They also found that patients on hydromorphone had less daily utilization of opioids (94 
mg versus 172 mg). This could be explained by the fact that more patients on fentanyl were on 
veno-venous ECMO, which in their study required more MME than veno-arterial ECMO. Also, it 
is unclear if this would apply to our study, since it is known that ECMO circuits can sequester 
medications, particularly fentanyl [27,28]. 

 
Finally, one recent study performed at Lahey clinic showed higher dose of opioids used 
with fentanyl, however with no difference in mechanical ventilation duration (22, 0-25 days in the 
fentanyl group versus 21, 0-25 days in the hydromorphone group, p = 0.356) [26]. The median 
days alive and free of mechanical ventilation were also similar among the two groups, with a 
median of 24 (21-26) days in the fentanyl group and a median of 24 (20.75-26) days in the 
hydromorphone group (p = 0.751). The cumulative dose of opioids in fentanyl equivalent was 
higher in the fentanyl group with 4241 (1817-8146) mcg and 2448 (1012-4926) mcg in the 
hydromorphone group (p < 0.001). 
 
4. Inclusion Criteria 
- 
Admitted to either MICU A, B, C or FICU at Beth Israel Deaconess Medical Center, 
requiring mechanical ventilation, and opioid infusion for analgosedation 
 
5. Exclusion Criteria 
- 
Age < 18 years old 
- 
Contraindication to fentanyl or hydromorphone (prior true immunological reaction or at 
medical team discretion) 
- 
Do not intubate orders 
- 
Comfort measures only 
 
6. Study Sites 
Participating ICUs included at Beth Israel Deaconess Medical Center 

- 
MICU A and B (Rosenberg 6) - 13 beds 
- 
MICU C (Rosenberg 6) - 8 beds 
- 
FICU (Finard 4) - 14 beds 
 
Both MICU A/B and C are medical ICUs on the same floor of the Rosenberg building (West 
Campus) but physically separated and run by different teams with no overlap. Physicians, nurses 
and respiratory therapists do not manage patients in both ICUs during the same shift, except in 
rare circumstances. FICU is the Finard ICU, a 14 ICU bed with medical, oncological and surgical 
patients located in other building (East Campus).  
Medical teams in the MICU A and B are composed of Critical Care attending, 
internal/emergency medicine residents and interns, physician assistants or nurse practitioners. 
MICU A has an average annual admission average of patients requiring mechanical ventilation of 
80-100 patients while MICU B has an average annual admission rate of patients requiring 
mechanical ventilation of 210-250. 
Medical teams in the MICU C are composed of a Critical Care attending, a Pulmonary and 
Critical Care Fellow and internal medicine residents. MICU C has an average annual admission 
rate of patients requiring mechanical ventilation of 170-200. 
The Finard ICU teams are components of a Critical Care attending, a Critical Care Fellow 
and internal medicine residents. FICU has an average annual admission rate of patients requiring 
mechanical ventilation of 220-270 
 

7. Study Population 
All patients admitted to MICU A, B, C or FICU requiring mechanical ventilation at Beth 
Israel Deaconess Medical Center during the study period will be enrolled unless they meet any of 
the exclusion criteria.  
We will also assess health care providers’ perceptions of continuous fentanyl versus 
hydromorphone infusions in mechanically ventilated patients by surveying all ICU nurses, APPs 
and attendings who participated in the care of the patients during the study period. 
 
8. Enrollment 
Since this is a cluster randomized trial, all patients requiring mechanical ventilation 
admitted to the trial ICUs will be included in the study if no exclusion criteria. 
Based on previous years, our MICU A, B, C and FICU patients requiring mechanical 
ventilation comprise an average of 700 to 820 in a year. Therefore, based on our sample size 
calculation we will need 6 months for a total of 300 patients to be enrolled in the study. 
 
9. Consent 
The study satisfies all 4 or 5 conditions required by the U.S. Department of Health and 
Human Services Office for Human Research Protections: 
- 
The study does not involve additional risk to subjects 
- 
The research could not be carried out practicably without the waiver 
- 
The waiver will not adversely affect the rights and welfare of the subjects 
- 
Where appropriate, the subjects will be provided with additional information about 
their participation 

- 
The research will not involve identifiable private information or identifiable 
biospecimens 
 
Fentanyl and hydromorphone intravenous infusions are the most common opioids 
prescribed for analgesia in mechanically ventilated patients at Beth Israel Deaconess Medical 
Center. Currently, the choice between them is solely based on provider preference since there is 
no randomized clinical trial or evidence-based guidelines to recommend one over the other. 
Expert recommendations [15] defer the choice of the analgesic opioid to the bedside provider 
based on pharmacokinetics and pharmacodynamics of the drug. We believe that until now, 
despite small differences, there is clear equipoise between hydromorphone and fentanyl without 
any current evidence to suggest that one is superior to the other. Since there is no known 
difference in risks or benefits between both medications a waiver of informed consent was 
requested. Considering equipoise among interventions, the use of a cluster randomized trial 
design with waived consent would be the only way to complete this study, allow sufficient 
recruitment, potentially reduce treatment contamination (since the randomization of the ICU 
occurs prior to enrolment of the individual patient), improve perceived external validity, potentially 
decrease bias caused by the open-label nature of the study, increase adherence to the allocated 
intervention and allow a low implementation costs [29]. The main risk will be inadvertent 
disclosure of PHI but will be minimized using safeguards for data security and collecting only the 
minimum necessary information to conduct the study. 
 
10. Randomization 
Randomization will occur at the level of the ICU, rather than for each individual patient. 
Cluster I (MICU A, B, C) and cluster II (FICU) will be randomized to start from a period with fentanyl 

or hydromorphone and after 3 months will be crossed over to the other group. Cluster cross-over 
are planned to be 3 months to avoid seasonal variability. We plan to start enrollment in the middle 
of a season, so that the clusters have 1.5 months of each season. No washout period is planned. 
 
Table 1. Randomization per ICU, cross-over design 
ICU 
3 months  
3 months 
MICU A/B/C 
Intervention 1 
Intervention 2 
FICU 
Intervention 2 
Intervention 1 
 
 
Figure 1. Planned Cross-Over according to seasonality 
 

 
11. Blinding 
This will be an open-label study. Due to small differences in pharmacokinetics and 
pharmacodynamics, an open-label study will be more appropriate regarding safety. The data 
analyst will be blinded to the intervention groups when performing statistics. 
 
12. Study Procedures 
12.1 Groups: 
12.1.1 Fentanyl infusion  
Fentanyl infusion will be used as first-line therapy for analgosedation, when clinically warranted. 
The unit automated dispensing cabinet will be loaded with fentanyl, except in circumstances 
where the provider believes that hydromorphone is the preferred opioid. This will be 
communicated to the medical teams taking care of patients in this geographic location and study 
period. ICU pharmacists will also communicate to other ICU pharmacists what the randomized 
opioid is. 
 
Suggested initial continuous infusion 
-Route: Intravenous 
-Dose: 0-200 mcg/hr (max 1,440 MME/day) 
-Initial dose: 50mcg/hr 
-Concentration: 50 mcg/mL 
-Bolus: 50-200mcg up to every 5 minutes as needed 

-Continuous infusion adjustment: Increase in the continuous infusion if sedation not at goal after 
3 bolus doses, increase by 25 mcg/hr every 60 minutes 
 
12.1.2 Hydromorphone infusion 
Hydromorphone infusion will be used as first-line therapy for analgosedation, when clinically 
warranted. The unit automated dispensing cabinet will be loaded with hydromorphone, except in 
circumstances where the provider believes that fentanyl is the preferred opioid. This will be 
communicated to the medical teams taking care of patients in this geographic location. ICU 
pharmacists will also communicate to other ICU pharmacists what the randomized opioid is. 
 
Suggested initial continuous infusion 
-Route: Intravenous 
-Dose: 0-3 mg/hr (max 1,440 MME/day) 
-Initial dose: 0.5mg/hr 
-Concentration: 0.2 mg/mL 
-Bolus: 0.5-2mg up to every 5 minutes as needed 
-Continuous infusion adjustment: Increase in the continuous infusion if sedation not at goal after 
3 bolus doses, increase by 0.25 mg/hr every 60 minutes 
 
12.2 Patient management correlated with the intervention 
Decision regarding titration, initial dosing, additional boluses of the intervention drug will 
be at the discretion of the healthcare provider. The goal sedation level will be set by the medical 
team according to patient requirements. The Richmond Analgesia and Sedation Scale (RASS) 
will be used to titrate sedation. The critical care pain observation tool (CPOT) will be used to titrate 
pain management. 

The study will not impact the use of sedative medications such as dexmedetomidine, 
propofol, benzodiazepines, antipsychotics and ketamine. Weaning of sedation will be driven per 
nursing protocol and/or at the discretion of the health care provider. Figure 2 show details of the 
suggested approach of analgosedation currently used in our institution. 
 
Figure 2. Suggested analgosedation approach 
 
 
 
In our instution, the suggested sedation doses are as follows: 
 
12.2.1 Propofol: 
Infusion 
- 
Initial dosing allowed: 5-10 mcg/kg/min 
- 
Increase: 5-10 mcg/kg/min every 5 minutes. 
- 
Decrease: 5-10 mcg/kg/min every 5 minutes. 
 

Bolus 
- 
May repeat 10mg every 1 minute x 2 doses. Do not exceed a total of 30mg 
supplemental dose in any one hour.  
- 
Consider using adjusted body weight in patients with a BMI greater than 30 kg/m2 
 
12.2.2 Ketamine 
Infusion 
- 
Usual dosing for Pain/Analgesia: 0.1-0.4 mg/kg/h 
- 
Usual dosing for Sedation: 0.4-2.5 mg/kg/h 
- 
Usual dosing for Generalized Convulsive Status Epilepticus: 1-7 mg/kg/h 
- 
Initial dosing allowed: 0.05 mg/kg/h, 0.1 mg/kg/h, 0.2 mg/kg/h, 1.2mg/kg/h 
- 
Increase: 0.1 mg/kg/h every 30 min 
- 
Decrease: 0.1 mg/kg/h every 30 min 
 
Bolus 
- 
0.2 mg/kg every 30 minutes PRN if agitation not at goal specified in titration order. 
Consider using adjusted or ideal body weight in patients with a BMI greater than 40 kg/m2. 
 
12.2.3 Dexmedetomidine 
Infusion 
- 
Usual dosing for Sedation: 0-1.5mcg/kg/h 
- 
Initial dosing allowed: 0.2-0.4 mcg/kg/h 
- 
Increase: 0.2 mcg/kg/h every 30 minutes. 
- 
Decrease: 0.2 mcg/kg/h every 30 minutes. 
 
12.2.4 Midazolam 

Infusion 
- 
Usual dosing for Sedation: 0-5 mg/h 
- 
Initial dosing allowed: 0.5-2mg/h 
- 
Increase: If not still at goal after 3 bolus doses, increase by 0.5 mg/hr every 60 
minutes. 
- 
Decrease: 50% of the current hourly infusion rate every 60 minutes. 
 
Bolus 
- 
Administer whichever is greater, 2 mg or 50% of current continuous infusion rate 
Q5min PRN agitation not at goal specified in titration order. 
- 
Must give at least 3 boluses within 60 minutes before increasing the infusion rate. 
If patient requires 3 boluses within 30 minutes, contact provider. 
 
Liberation from mechanical ventilation will be driven per respiratory therapist and nursing 
protocols or at discretion of the health care provider. Spontaneous breathing trials (SBT) will be 
performed per protocol with 0 to 8 cmH2O of inspiratory pressure augmentation and 0 to 5 cmH2O 
of PEEP. Variations on the SBT will be allowed at discretion of the health care provider. 
Once a patient is liberated from mechanical ventilation, the study intervention medication 
will be discontinued. However, if at any time during the study period, the patient will receive the 
drug assigned to the cluster at the time of the first institution of mechanical ventilation, if possible. 
Enrolled patients who remain in the ICU through the crossover time will continue with the same 
drug intervention. 
 
12.3 Interventions to improve adherence 

 
Our records show that fentanyl is the more prevalently analgosedation opioid used in our 
units, however hydromorphone is used in around 20-25% of patients. Given the potential for 
contamination, we implemented several strategies to minimize accidental crossover: 
1. 
Randomization at the building level rather than by individual ICU  
2. 
Weekly email reminders to ICU intensivists and nocturnists  
3. 
Weekly announcements during multidisciplinary rounds specifying the assigned 
opioid of the unit 
4. 
Signage indicating the randomized opioid in easily accessible locations, including 
on the automated dispensing cabinets  
5. 
Patients who had been assigned an opioid within 28 days prior to crossover and 
remained in the unit continued on the same opioid unless a clinical change was deemed 
necessary by the primary team 
 
 
 

Table 2. Participant timeline: Schedule of enrollment, interventions, and assessments 
 
 
 
 

12.4 Pragmatic Intervention Approach 
The goal of the trial is to evaluate fentanyl versus hydromorphone as a first line strategy 
for analgosedation in mechanically ventilated patients in a pragmatic randomized trial. We 
decided to perform a feasibility and pilot trial in order to understand not only clinical outcomes but 
also improve and obtain outcomes regarding the logistics of such a type of study. To evaluate 
and aid with the trial development we performed the PRECIS-2 prior to the trial initiation. The 
PRECIS-2 is a tool developed to aid trialists to evaluate whether design decisions match their 
intended purpose.  
 
Table 3. PRECIS-2 evaluation 
# 
Domain 
Score 
Rationale 
1 
Eligibility 
5 
Inclusion criteria: “Admitted to either MICU A, B, C or FICU at Beth 
Israel Deaconess Medical Center, requiring mechanical ventilation, 
and opioid infusion for analgosedation” 
Very broad inclusion criteria with appropriate safety exclusion 
(medical team discretion, contraindication to the agent, DNI, CMO) 
2 
Recruitment Path 
5 
No specific recruitment limitation. All patients are admitted to the 
ICU on MV, both medical and mixed (medical and surgical) ICU. We 
are not excluding transfers within the hospital neither from outside 
hospitals. 
3 
Setting 
2 
Since this is single center academic tertiary hospital, we reduced 
the score by 3. This may limit generalizability to smaller or 
secondary hospitals. 
4 
Organization 
5 
Care will not change among two interventions except by the 
medication themselves. All decisions will follow usual care. No extra 
training of staff will be required since both medications are routinely 
used in the ICU. 

5 
Flexibility 
of 
experimental 
intervention – Delivery 
5 for both 
The delivery of the randomized medication follows our regular ICU 
policy (developed years prior to the trial) and dosing, titration can be 
changed at any moment by preference of the team. 
6 
Flexibility 
of 
experimental 
intervention 
– 
Adherence 
Individual: NA 
  
Cluster: 4 
Individual Intervention: Patients are sedated and participants do not 
need to adhere to the trial. 
Cluster intervention: we provided signage to ICU team and 
meetings to remind them about the trial, but always making them 
aware that the decisions are defined by the primary team. Cross-
over was allowed without restriction. 
7 
Follow-up 
5 
No additional follow-up than usual care and no additional data 
collection than usual care 
8 
Outcome 
2 
The use of daily MME during ICU stay, although not patient-
centered, it is a useful surrogate. Also, the measurement of 
outcome is pragmatic, not requiring any additional measurement. 
9 
Analysis 
5 
Intention-to-treat analysis including all patients in the trial 
 
 
 

Figure 3. PRECIS-2 
 
 
 
 

13. Safety Monitoring 
Assuring patient safety is primordial for this protocol. Although patients would already 
require an opioid infusion for analgesia if not participating in the trial, the protocol will address 
safety through: 
- 
Exclusion of patients with any contraindication to the intervention drugs, as 
determined by the medical team 
- 
Since this study is performed in the ICU, all patients will be monitored with 
telemetry, SpO2, mechanical ventilator monitor, and a high level of laboratory 
monitoring. Patients will also have a high number of medical staff required in the 
ICU including nurses, respiratory therapists, pharmacists and physicians.  
 
Since both interventions are standard of care and our protocol does not involve any 
additional change in our hospital policy, the IRB waived the need for a Data Safety Monitoring 
Board. 
 
Routine monitoring of adverse events will be performed during intensive care department, 
nursing leadership and pharmacy meetings. 
 
 
14. Data Collection 
14.1 Preliminary data collection validation 
Data will be collected from the patient's electronic medical record using SQL. The automated data 
Extraction will be compared to the manual data extraction by two independent team members 
prior to the trial initiation. Data will be collected from 30 patients to achieve at least 10% of the 
predicted sample size and at the same time enough power to obtain an expected intraclass 
correlation coefficient of 0.95 and a minimum accepted of 0.99. Data that cannot be extracted 

using SQL will be collected manually for the study data set. The accuracy of the data collection 
will be published elsewhere. 
 
The data collected will be entered into REDcap, an online and secure database. 
 
Our study will not require any additional studies besides the ones required for medical care and 
the decision to order the studies will be at discretion of the medical ICU team.  
 
14.2 Data Collection at the time of enrollment 
For laboratory, radiographic, and vital signs, we will consider data available up to 12 hours prior 
to 12 hours after enrollment, if more than one value available, we will prioritize the one prior to 
randomization. We present the data that will be collected, but not restricted to: 
- 
Medical Record Number (only for initial identification, patients will be assigned a study 
number and data for analysis will be unidentified) 
- 
Admission date (MM/DD/YYYY and time in military system), admission indication, ICU 
admission date (MM/DD/YYYY and time in military system), location when inclusion 
criteria met (ED, floor, ICU), ICU indication 
- 
Transfer from outside hospital or other within system ICU 
- 
Intubation date (MM/DD/YYYY and time in military system) 
- 
Demographic data  
- 
Age (years) 
- 
Sex assigned at birth (Male or Female) 
- 
Race (Caucasian, Hawaiian, African American, Asian, American Indian, Alaska 
Native, not defined) 
- 
Height (cm) 
- 
Measured Weight (kg) 

- 
Ideal Weight (men = 50 kg + 2.3 * [height (in) – 60], women = 45.5 kg + 2.3 * [height 
(in) – 60]) 
- 
Body mass index (BMI, kg/m²) 
- 
Comorbidities 
- 
Laboratory results (creatinine, estimated GFR, BUN, sodium, potassium, chloride, 
glucose, bicarbonate, lactic acid, ALT, AST, alkaline phosphatase, WBC, hemoglobin, 
hematocrit, platelet count, INR) 
- 
Vital signs including  
- 
Heart rate (bpm) 
- 
Blood pressure (mmHg) 
- 
Temperature (°C) 
- 
SpO2 (%) 
- 
Respiratory Rate (rpm) 
- 
Support therapy including: 
- 
Vasopressors (norepinephrine, vasopressin, phenylephrine, angiotensin 2, 
epinephrine, dobutamine), rates (data collected in usual rate presentation, but will 
be adjusted to norepinephrine equivalents, when possible), daily total dose 
- 
Sedation medication (propofol, ketamine, midazolam, dexmedetomidine) and 
rates (data collected in usual rate presentation, but will be adjusted to propofol 
equivalents, when possible), daily total dose 
- 
Neuromuscular blockade (cisatracurium or rocuronium) (Y/N), daily total dose 
- 
Mechanical ventilation settings (PEEP [cmH2O], inspiratory pressure [cmH2O], 
tidal volume [mL], inspiratory time [s], driving pressure  [cmH2O], peak pressure  
[cmH2O], resistive pressure  [cmH2O], plateau pressure  [cmH2O], respiratory rate 
[ipm], minute ventilation [L/min], FiO2 [%]) 

- 
Prior to randomization intervention medication rate (fentanyl or hydromorphone) 
converted to MME and total MME received 
- 
SOFA (PaO2, FiO2, need for mechanical ventilation, platelets, glasgow coma scale, 
bilirubin, mean arterial pressure, creatinine) 
 
14.3 Data Collection during the time of intervention 
The data collection during intervention will be performed daily. For numerical data, the lowest, the 
highest and the morning (7:00 am) values will be collected. For continuous interventions such as 
presence or absence of mechanical ventilation, use of vasoactive drugs, neuromuscular 
blockade, continuous renal replacement therapy and others we will consider as “Yes” if the 
intervention was present at 7:00 am and “No” if absent. For laboratory work-up we will consider 
the closest value to 7:00 am, on the same day. 
- 
Patient alive (Y/N) 
- 
Daily Laboratory results (creatinine, estimated GFR, BUN, sodium, potassium, chloride, 
glucose, bicarbonate, lactic acid, ALT, AST, alkaline phosphatase, WBC, hemoglobin, 
hematocrit, platelet count, INR) 
- 
Venous blood gas or arterial blood gas if available (pH, pCO2, pO2). 
- 
Daily vital signs. We will consider the highest value for temperature, heart rate, respiratory 
rate and the lowest value for blood pressure and oxygen saturation. 
- 
Heart rate (bpm) 
- 
Blood pressure (mmHg) 
- 
Temperature (°C) 
- 
SpO2 (%) 
- 
Respiratory Rate (rpm) 
- 
Days requiring mechanical ventilation, accidental extubation (Y/N), planned extubation 
(Y/N) 

- 
Daily mechanical ventilation settings (PEEP [cmH2O], inspiratory pressure [cmH2O], tidal 
volume [mL], inspiratory time [s], driving pressure  [cmH2O], peak pressure  [cmH2O], 
resistive pressure  [cmH2O], plateau pressure  [cmH2O], respiratory rate [ipm], minute 
ventilation [L/min], FiO2 [%]) and tracings, if possible. 
- 
Fluid net, intakes and outputs (in mL) 
- 
Number of daily bowel movements 
- 
Sedation medication (propofol, ketamine, midazolam, dexmedetomidine) and rates (data 
collected in usual rate presentation, but will be adjusted to propofol equivalents, when 
possible), daily total dose 
- 
Daily RASS 
- 
Intervention medication rate (fentanyl or hydromorphone) and MME. 
- 
Vasopressors and inotropes (Y/N), type (norepinephrine, vasopressin, phenylephrine, 
angiotensin 2, epinephrine, dobutamine) and rates (data collected in usual rate 
presentation, but will be adjusted to norepinephrine equivalents, when possible), daily total 
dose 
- 
Neuromuscular blockade (Y/N), type and rate 
- 
Renal replacement therapy (Y/N) 
- 
Presence of delirium in the day (as diagnosed by the medical team, from the primary team 
note, or CAM-ICU positive by nurse evaluation) (Y/N) 
- 
Presence of opioid withdrawal (as diagnosed by the medical team, from the primary team 
note or COWS by nurse evaluation) (Y/N) 
- 
Need for tracheostomy (Y/N and time to event - MM/DD/YYYY and time in military system) 
- 
Additional analgesic medication used (Y/N and type), rate and/or dose 
- 
Daily need for restraints 
- 
Adverse Events as explained in “17. Benefits and possible Risks” 
 

14.4 Data at the time of termination 
At termination of the patient inclusion we will collect 
- 
Patient alive at 28 days (Y/N) 
- 
Patient is discharged from the ICU at 28 days (Y/N), ICU transfer date (MM/DD/YYYY and 
time in military system) 
- 
Patient is discharged from the hospital at 28 days (Y/N), hospital discharge date ( 
MM/DD/YYYY and time in military system) 
 
Table 3. Retrospective Data Collection timepoints details 
Data 
Enrollment 
Daily Routine 
Extubation 
day 
ICU discharge 
Day 28 or Discharge 
Demographic data 
X 
 
 
 
 
Comorbidities 
X 
 
 
 
 
Intubation data 
X 
 
 
 
 
SOFA 
X 
 
 
 
 
APACHE 
X 
 
 
 
 
Intervention total dose 
(type and daily MME) 
X 
X 
 
 
 
Other sedatives *type 
and dose) 
X 
X 
X 
X 
X 
Other analgesics (type 
and dose) 
X 
X 
X 
X 
X 
Neuromuscular 
 
X 
 
 
 

blockade (Y/N) 
Vital Signs and Is/Os 
X 
X 
 
 
 
Bowel Movements (Y/N 
and n) 
 
X 
 
 
 
Vasopressors (type, 
total dose) 
X 
X 
 
 
 
RRT (Y/N) 
 
X 
 
 
 
Mechanical Ventilation 
Data 
X 
X 
 
 
 
Adverse Events (type 
and Y/N) 
 
X 
 
 
 
COWS (Y/N) 
 
X 
X 
X 
 
Extubation data (day 
and time) 
 
 
X 
 
 
Tracheostomy (Y/N) 
 
 
 
 
X 
Use of opioids (daily 
MME) 
X 
X 
 
 
X 
CAM-ICU (Y/N) 
 
X 
X 
X 
 
Mechanical Ventilation 
Day (Y/N) 
 
X 
 
 
X 
ICU Day (Y/N) 
 
X 
 
 
X 
Death (Y/N) 
 
X 
 
X 
X 
 

15. Outcomes Measures 
15.1 Primary Outcome:  
- Difference in daily MME dose received during mechanical ventilation period. The daily MME 
dose will be calculated using all the opioid doses received during the day. The outcome will be 
obtained from the days patients were on mechanical ventilation. It will include not only the 
intervention medication, but also the additional boluses and alternate opioids, including cross-
over drug. The doses will be converted into MME [30]. 
 
15.2 Secondary Outcomes:  
- All cause mortality on day 28 - patients who were discharged prior to 28 days will be assumed 
to be alive. If they are readmitted to our hospital system before day 28, we will use the that 
admission information 
- Days alive and free of MV at day 28 (VFD) - the ventilator free days will be counted as 28 minus 
the duration of mechanical ventilation in days for those patients who survived the 28 days. 
Patients discharged prior to 28 days will be assumed to be free of mechanical ventilation. Patients 
who died before 28 days will be assumed to have zero VFD. 
- Days alive and free of ICU at day 28: counted as 28 minus the days alive in the ICU. Patients 
discharged prior to 28 days will be assumed to be out of the ICU. Patients who died before 28 
days will be assumed as zero ICU free days. 
- Days alive and free of vasopressors at day 28: counted as 28 minus the days alive with 
intravenous vasopressors. Patients discharged prior to 28 days will be assumed to be off of 
vasopressors. Patients who die before 28 days will be assumed as zero vasopressors free days. 
- Days alive and free of hospitalization at day 28: counted as 28 minus the days alive in hospital. 
Patients discharged prior to 28 days will be assumed to be out of the hospital. Patients who die 
before 28 days will be assumed as zero hospital free days. 

- Total morphine-milligram equivalent doses required: will be calculated based on total dose at 28 
days of the intervention drug and other opioids received during hospital admission [30]. The dose 
of opioids used on the comfort measures period for those patients that were transitioned to 
comfort measures will not be considered for the outcome analysis. 
- Difference in average daily dose of morphine milligram equivalent required during hospital stay. 
Will be calculated based on total dose at 28 days of the intervention drug and other opioids 
received during hospital admission. The dose of opioids used on the comfort measures period for 
those patients that were transitioned to comfort measures will not be considered for the outcome 
analysis. Patients discharged prior to 28 days of enrollment will be considered to have 0 morphine 
milligram equivalent per day after discharge. 
- Difference in total daily dose of vasopressor in norepinephrine equivalents. Calculated based on 
total dose at 28 days of all the vasopressors (norepinephrine, epinephrine, dobutamine, 
vasopressin, angiotensin II, phenylephrine). Patients discharged prior to 28 days of enrollment 
will be considered to have 0 dose per day after discharge. 
- Requirement of adjunctive analgesia or sedation medications: total dose and medications used 
at 28 days in propofol equivalent dose 
- Patient-ventilator mechanics, measure by weighted average of the following outcomes: PEEP, 
plateau, driving pressure and compliance through the first 3 and 7 days 
- Incidence of opioid withdrawal: using daily COWS measure during 28 hospital days or until 
discharge 
- Daily Average number of Bowel Movements through ICU stay: Will be measured by the number 
of bowel movements per day during the ICU stay. In patients with rectal tube, 1 bowel movement 
will be considered to have least 50mL and a maximum of 250mL of stools.  
- Percentage of time without coma and delirium during the ICU stay: assessed daily by RASS and 
CAM-ICU by nurses at the bedside. A positive day for coma is RASS of -3 or less and delirium is 

considered as RASS of 3 or more or positive CAM-ICU. The value obtained will be divided by the 
number of days in the ICU. 
- 28 day free of restraints: counted as 28 minus the days alive with need for restraints. Patients 
discharged prior to 28 days will be assumed to be off of restraints. Patients who die before 28 
days will be assumed as zero restraints free days. 
- Need for tracheostomy during hospital stay 
- Mean difference in total MME dose received during the first 24 hours, first 3 days, 7 days and 
total hospital stay 
 
16. Statistical Analysis Plan 
To enhance transparency and reproducibility, the statistical analysis plan will be available, pre-
specified and every update will be time-marked.  
 
16.1 Sample Size Calculation 
There is no trial comparing fentanyl to hydromorphone for analgosedation in critically ill 
mechanically ventilated patients. Considering a daily MME dose while on mechanical ventilation 
in the fentanyl group of 270 ± 250 mg and 450 ± 500 mg in the hydromorphone group based on 
the data from two months of our MICU A, B, C and FICU, group sample sizes of 137 patients 
would achieve 80% power to detect a difference of 180 MME at a significance level (alpha) of 
0.05 using a two sided Mann-Whitney Test. These results are based on 500 Monte Carlo samples 
from the null distributions: WeibullMS (450 500) and WeibullMS (450 500), and the alternative 
distributions: WeibullMS (450 500) and WeibullMS (270 250). Considering eventual losses to 
follow-up and contamination it will be required a sample size in each group of 150 patients. 

Therefore, considering a recruitment of 50 patients per month, it will require 6 months to obtain 
the sample size. 
 
Considering post-COVID-19 data, since 2022 our average number of patients on mechanical 
ventilation was: 
- 
MICU A had an average of 100 patients on mechanical ventilation per year 
- 
MICU B had an average of 250 patients on mechanical ventilation per year 
- 
MICU C had an average of 200 patients on mechanical ventilation per year 
- 
FICU had an average of 270 patients on mechanical ventilation per year 
 
There are no published estimates of intra-cluster coefficient (ICC) or within-/between-period 
correlations for opioid consumption (MME) in ICU settings and using retrospective data to obtain 
ICC is likely to be biased as treatment choice is influenced by clinical factors. To account for ICC, 
as previously recommended, we chose to: 
- 
Inflate the sample size by about 10% to account for potential clustering effects. 
- 
Additionally evaluate the sample size under alternative modeling assumptions (including 
mixed-effects modeling), which resulted in a similar magnitude of inflation (~10%). 
- 
Use our anticipated enrollment rate (50–70 patients/month) conservatively based on the 
lower bound, making it likely that the final sample size will exceed the minimum required, further 
mitigating potential loss of power. 
Importantly, the true ICC in this study is likely to be small, as the two clusters (ICUs) are highly 
comparable in terms of patient population, staffing structure, clinical protocols and care 
environment. Also, our crossover accounts for season (fall, winter and spring) variability to 
decrease between-periods variation. Thus, any clustering effect is expected to be decreased. 
 
16.1.2 Definitions 

Intention-to-treat analysis: patients will be included in the intention-to-treat analysis if 
- 
Meeting inclusion criteria for the study 
- 
Are in an ICU randomized and assigned to an intervention group 
 
Patients readmitted to the ICU within the study period will only have the index admission 
considered for outcomes perspective. 
 
16.2 Data Analysis Plan 
16.2.1 Descriptive Statistics 
As recommended by CONSORT guidelines, patient flow information will be presented. Patients 
screened, randomized, excluded, those who received the intervention, withdraws, loss to follow-
up, death and hospital discharge will be presented. Patients randomized will be described as 
overall baseline characteristics for both interventions. Continuous data will be described as 
median and interquartile range, while categorical variables will be present as frequency and 
percentage. We will not perform statistical testing for baseline differences.  
 
16.2.2 Methods of Analysis 
Categorical variables will be described as number and percentage. Continuous variables will be 
described as median and 95% confidence intervals.  
 
Primary Outcome 
We will use intention-to-treat analysis. Our primary outcome, the daily MME requirement during 
mechanical ventilation, will be analyzed within the framework of cluster analysis. Therefore, we 
will use Generalized Linear Mixed Models (GLMM) where the cluster will be treated as a random 
effect. The final link function will be determined based on the daily MME distribution (linear for 
normally distribute, negative binomial if deviates from the assumption of normality). For the MME 

calculation we will use all the MME received during the MV period, including alternate and 
crossover opioids. 
 
Secondary Outcomes 
For 28 day vasopressor free day, 28 day ICU free day, 28 day VFD, requirement of adjunctive 
sedation, requirement of adjunctive analgesia, percentage of time without coma and delirium, 28 
day restraints free days and daily average bowel movements we will use GLMM. 
 
For our 28-day mortality, we will use Kaplan-Meier curves and log-rank tests and censor patients 
at time of death. We will consider the time 0 as the time of enrollment.  
For categorical variables we will use GLMM. 
 
 
Multiple Comparisons 
No adjustment will be made for multiple comparisons when examining pre-defined secondary 
outcomes as recommended [31]. However, caution will be used to interpret results by noting the 
number of significant tests that would occur by chance alone.  
 
16.3 Missing Data 
We do not expect missing data to be present for our primary outcome. However, considering that 
it may occur for the primary outcome and also secondary outcomes, missing data will be imputed 
via multiple imputation methods. 
 
16.4 Prespecified Subgroup and Sensitivity Analysis 
We will include the following as prespecified subgroup/sensitivity analysis: 
- 
Different sedative medications (e.g., propofol, ketamine, midazolam, dexmedetomidine) 

- 
Patients with sepsis on ICU admission 
- 
Patients requiring vasopressors 
- 
Patients with ARDS 
- 
Patients with acute or chronic liver failure (liver dysfunction) 
- 
Per ICU site (MICU A, B and C versus FICU) 
- 
Per type of admission (medical or surgical) 
- 
Patients with acute kidney injury and/or chronic kidney injury 
- 
Patients requiring renal replacement therapy 
- 
Patients on previous opioid infusion prior to randomization 
- 
Patients on neuromuscular blockade agents 
- 
Excluding patients admitted from outside hospital ICU and/or within system ICU 
- 
Previous opioid exposure for more than 24 hours 
- 
Excluding patients with < 48 hours or > 14 days of mechanical ventilation 
- 
Patients on ECMO 
- 
Per protocol analysis and evaluating different cut-offs for definition of cross-over (25%, 
50%) 
- 
We will also perform sensitivity analyses using multivariable regression to adjust for 
imbalances in baseline factors. For 28 day ventilation free days, 28 day ICU free days and 
28 day vasopressor free days we will use linear regression and for time-to-event outcomes 
such as 28 day mortality we will use Cox regression. 
- 
We will perform a sensitivity analysis using different MME conversion for hydromorphone 
and fentanyl 
 
17. Benefits and Possible Risks 
17.1 Benefits 

To date, there are no well established benefits related to the selection of fentanyl or 
hydromorphone for mechanically ventilated patients. The differences in pharmacokinetics and 
pharmacodynamics and its clinical implications to critically ill population are unknown. One small 
phase II randomized clinical trial comparing remifentanil with morphine showed potential benefit 
with remifentanil regarding mean percentage on optimal sedation. There was also a small 
reduction in mechanical ventilation duration of 4 hours (18.1 ± 3.4 hours versus 14.1 ± 2.8 hours) 
[13]. A cluster randomized trial comparing fentanyl with morphine showed a 0.79 (95% CI, 0.31–
1.28) day reduction in days alive and free of mechanical ventilation at 28 days. There was also a 
statistically significant decrease in ICU-free days at day 28 and a non-statistically significant 
decrease in hospital-free day at day 28 and day-28 mortality [14]. However, it is unclear if these 
benefits would apply to a larger population and different interventions (fentanyl versus 
hydromorphone).  
 
17.2 Risks 
A potential risk to the study patients involves data collection of personal information. Multiple steps 
will be taken to avoid associated risks such as: 
- 
Data collected to database will be de-identified 
- 
Minimize data necessary to conduct the study 
- 
Data will be collected in a secure database 
Risks to the exposure to fentanyl and hydromorphone include bradypnea, apnea, delirium, 
oversedation, hypotension, altered mental status, nausea, vomiting, ileus, urinary retention, 
pruritus, constipation, withdrawal and opiate induced hyperalgesia. Since patients would receive 
an opioid infusion even if not participating in the trial, the additional risk of the study regarding 
opioid side effects are not different. To avoid unnecessary risk exposure to fentanyl or 
hydromorphone side effects based on pharmacodynamics and pharmacokinetics we will exclude 

patients with contra-indications to either of them. To mitigate risks adverse events will be 
monitored (13. Safety Monitoring).  
 
18. Study Withdrawal and Discontinuation 
The patients can be withdrawn from the study by the investigators for safety reasons, if the patient 
or family requests to be withdrawn. The reason for withdrawal will be recorded in the patient’s 
study chart.  
 
19. Privacy 
19.1 Data Security 
Patient identities will not be revealed. The patient identifier to their specific data will be destroyed 
as soon as possible. The data from the electronic medical record will be uploaded to an online 
secure (password-protected) database behind a firewall. On that database, patients will have a 
unique study number, which will be erased as soon as possible. 
 
19.2 Dissemination of Research Results 
Once the results of the study are available and published we will make it available at the Beth 
Israel Deaconess Medical Center portal and website.  

 
20. Study Chart Retention 
Patient data will be stored in MIMICs database and in our online secure (password-protected) 
REDcap database. The information will be stored for an indefinite period of time for future 
reference and possible subsequent post-hoc analysis. However, the patient identifier to their 
specific data will be destroyed as soon as possible. 
 
21. Roles and Responsibilities 
Trial Steering Committee: EMHP, AW, MH, DF, AS, AG, MAA, ENBK 
Trial Management Group: EMHP, AS, AG, MAA 
Data Monitoring Committee: Not Required by IRB 
Endpoint adjudication Committee: NA 
Data management team: EMHP, AW, AN, KN, SH, GC, KC, VN 
Other individuals or groups overseeing the trial: VMBG, KC, DT 
 
22. Funding 
None. This is an investigator initiated study with no trial sponsor and funder. 
 
23. Conflicts of Interest 
Dr. David M. Furfaro: One-time advisory board member for InflaRx Pharmaceuticals in 4/2024, 
no longer ongoing. 

Other authors have no conflict of interest to declare. 
 
 

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