Individualized Analgesia in the Intensive Care Unit With a New Pain Assessment Bundle and Protocolized Analgesia Adjustments (INVISIBLE)

Individualized Analgesia in the Intensive Care Unit With a New Pain Assessment Bundle and Protocolized Analgesia Adjustments (INVISIBLE) - an Observational Single-Centre Study in Critically Ill Patients

Both severe pain and opioid therapy are associated with negative effects. The experience of pain is common in the intensive care unit, but it is highly individual and difficult to assess, as patients are often unable to communicate. This especially applies to patients who are mechanically ventilated. Behavioral assessment tools can help to identify pain in this population, but do not register overdose of opioid therapy. The AlgiScan® delivers the Pupillary Pain Index (PPI), an objective assessment of nociception level, which has been shown to be useful in small studies with respect to reduction of opioid dose without leading to more pain.

New institutional protocols for the assessment of pain include the behavioral pain assessment tool Zurich Observational Pain Assessment (ZOPA) and the PPI. This project aims to evaluate the impact of the new institutional protocols on opioid administration and occurrence of pain compared to a historical cohort by analyzing routinely collected data during mechanical ventilation (Part A). In a second part (Part B), promising biomarkers for detection of pain, subjective ratings by nurses and physicians and an additional behavioral pain scale will be evaluated using an observational study design. After screening and enrolment (day 1/visit 1), characteristics of pain will be assessed on 4 occasions during 2 days (day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5). On visit 2 and 4, biomarkers (alpha-amylase, cortisol) will be sampled.

Study Overview

• Status: Not yet recruiting
• Conditions: Pain; Critical Illness; Pain Management

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Sascha I David, Professor; Phone Number: +41 43 253 19 02; Email: Sascha.David@usz.ch
• Study Contact Backup: Name: Rolf Erlebach, MD; Phone Number: +41 43 253 90 63; Email: Rolf.Erlebach@usz.ch

Study Locations

• Switzerland
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8091
      • University Hospital Zurich
      • Contact: Institute of Intensive Care Medicine; Phone Number: +41 44 255 23 76; Email: intensivmedizin@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Mechanically ventilated adult patients in the intensive care unit.

Description

Inclusion Criteria:

Part A

• Admission to the intensive care unit
• Adults (≥18 years) of all sex and gender
• Mechanical ventilation Part B
• Admission to the intensive care unit
• Adults (≥18 years) of all sex and gender
• mechanical ventilation
• Continuous opioid therapy
• Richmond Agitation Sedation Scale (RASS) ≤ -4
• Presumed duration of mechanical ventilation until the end of observations (until day 3)
• Established vascular access suitable for blood sampling independent of study inclusion (arterial line or central venous catheter)

Exclusion Criteria:

Part A

• None Part B
• Previous enrolment into the current investigation
• Tracheostomy
• Chronic opioid use
• Regional anaesthesia
• Implanted pacemaker device
• Allergy to silicone or ECG-electrodes
• Ophthalmologic disease (e.g. ocular trauma, glaucoma) or past eye surgery
• Fixed pupils
• Known or suspected neurologic disease (including hypoxic encephalopathy)
• Therapy with atropine or topical mydriatics in previous 24 hours or planned
• Therapy with systemic steroids in previous 24 hours or planned
• Therapy with neuromuscular blocking agents in previous 24 hours or planned
• Stomatitis
• Active oral or nasal bleeding

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Prospective Cohort; Critically ill and mechanical ventilated patients after implementation of a new institutional protocol for pain assessment and analgesia adjustments
Historic Cohort; Critically ill and mechanical ventilated patients before implementation of a new institutional protocol for pain assessment and analgesia adjustments

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral morphine equivalent (OME) per day of mechanical ventilation.	OME is a standardized method to quantify and compare the potency of different opioid drugs by converting their doses into the equivalent amount of oral morphine. Doses are weighted based on the potency of the opioid and then summarized into a final value. Days of mechanical ventilation are weighted based on the hours of mechanical ventilation divided by 24 hours (relevant for days of intubation and extubation).	Part A: during mechanical ventilation (up to 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sufentanil dose per day of mechanical ventilation	average dose [mcg/min]	Part A: during mechanical ventilation (up to 28 days)
Opioid dose adjustments - Number of adjustments	Number of dose adjustments [/hour] and direction	Part A: during mechanical ventilation (up to 28 days)
Opioid dose adjustments - Relative change during pain assessment	Relative change of dose 45min after vs. 15min before ZOPA/PPI	Part A: during mechanical ventilation (up to 28 days)
Number of rescue analgesics administered per day	Bolus administration of opioids	Part A: during mechanical ventilation (up to 28 days)
Occurrence of adverse effects of pain per day of mechanical ventilation	Intravenous antihypertensive treatment [y/n]; Atrial fibrillation [y/n]; anti-infective treatment [y/n]; Richmond Agitation Sedation Scale (RASS) > +1 [y/n]	Part A: during mechanical ventilation (up to 28 days)
Number of sedatives used per day of mechanical ventilation	Average number of sedatives used in the intensive care unit (e.g. Propofol, Clonidine, Dexmedetomidine, Ketamine, Sevoflurane and Midazolam)	Part A: during mechanical ventilation (up to 28 days)
Richmond Agitation Sedation Scale (RASS) < -3	Duration of Richmond Agitation Sedation Scale (RASS) < -3 per total ventilation days. The RASS is a validated 10-point scale with a range from -5 (unarousable) to +4 (combative), with 0 being "alert and calm".	Part A: during mechanical ventilation (up to 28 days)
Time to extubation	Time to extubation from stop of analgosedation [hours]	Part A: From time of stop of analgosedation (during mechanical ventilation, up to 28 days) until extubation (up to 7 days). Events such as death or referrals while being intubated will be censored.
Opioid prescription at ICU discharge	- Opioid prescription at ICU discharge [y/n] in patients discharged alive (as listed in the ICU discharge report)	Part A: at ICU discharge assessed up to 5 days
Opioid prescription at hospital discharge	- Opioid prescription at hospital discharge [y/n] in patients discharged alive (as listed in the hospital discharge report)	Part A: at hospital discharge assessed up to 10 days
Target nociception level	Target Pupillary Pain Index. The Pupillary Pain Index (PPI) is a scale with range from 1 to 9 indicating the pupillary response to a noxious stimulus. A lower value indicates a deeper nociception level (a more intense stimulus is necessary to trigger pupillary dilation). A higher value indicates a lighter nociception level (a less intense stimulus triggers pupillary dilation).	Part A: during mechanical ventilation (up to 28 days)
Opioid-free days in the ICU	Days free of opioid administration [%]	Part A: from ICU admission to ICU discharge (up to 100 days)
Pupillary Pain Index	Objective pain measurement of nociception level. The Pupillary Pain Index (PPI) is a scale with range from 1 to 9 indicating the pupillary response to a noxious stimulus. A lower value indicates a deeper nociception level (a more intense stimulus is necessary to trigger pupillary dilation). A higher value indicates a lighter nociception level (a less intense stimulus triggers pupillary dilation).	- Part A: During mechanical ventilation - Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5
Cortisol	blood and saliva levels [nmol/L]	Part B: day 2/visit 2, day 3/visit 4
Amylase	blood and saliva [U/L]	Part B: day 2/visit 2, day 3/visit 4
Critical Care Pain Observation Tool (CPOT)	Validated behavioural pain assessment tool used in other intensive care units. The CPOT evaluates 4 dimensions. A score of 2 or less is regarded as likely minimal to no pain. A score of more than 2 is regarded as unacceptable level of pain.	Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5
Subjective pain rating	Questionnaire based rating of pain [y/n] by physician and nurses	Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5
Subjective rating of nociception level	Questionnaire based rating of nociception level [light/moderate/deep] by physician and nurses: light: moderate stimulus triggers pain; moderate: strong stimulus triggers pain; deep: strong stimulus does not trigger pain; Rated by physicians and ICU nurses	Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5
Trust in the Zurich Observational Pain Assessment (ZOPA)	Trust rated by ICU physicians and ICU nurses on a numeric scale with a range from 0 to 10. 0 indicates no trust in the ZOPA and 10 indicates maximal trust in the ZOPA.	Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5
Trust in the Pupillary Pain Index (PPI)	Trust rated by ICU physicians and ICU nurses on a numeric scale with a range from 0 to 10. 0 indicates no trust in the PPI and 10 indicates maximal trust in the PPI.	Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5
Pupil size before stimulation	Pupil size before stimulation PPI measurement [mm]	Part A: during mechanical ventilation (up to 28 days)
Percentage pupil's variation	Pupil variation [%] during PPI measurement	Part A: during mechanical ventilation (up to 28 days)
Maximal size variation	Maximal variation in pupil size [mm] during PPI measurment.	Part A: during mechanical ventilation (up to 28 days)
Neuron-specific Enolase (NSE) [mcg/L]	NSE [mcg/L] in patients after cardiac arrest at 24, 48 and 72 hours	Part A: From cardiac arrest until 72 hours after cardiac arrest
Zurich Observational Pain Assessment (ZOPA)	The Zurich Observational Pain Assessment (ZOPA) is a validated behavioural pain assessment tool routinely used in the intensive care unit. The ZOPA includes 13 items in 4 categories. Each item is rated on a binary scale (yes or no), resulting in a minimum of zero and a maximum of 13 points. One or more positive item (meaning the item is rated with "yes") is interpreted as probable existing pain.	Part A: during mechanical ventilation Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delirium	Positive delirium assessment based on ICDSC and/or CAM-ICU The Intensive Care Delirium Screening Checklist (ICDSC) is an 8-item tool used to assess and detect delirium in critically ill patients. A score of 4 or more suggests the presence of delirium. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is a bedside tool used by clinicians to diagnose delirium in critically ill patients. It assesses 4 dimensions. The output is a qualitative result: "delirium absent" or "delirium present".	Part A: during mechanical ventilation (up to 28 days)
ICU mortality	[y/n]	Part A: from date of inclusion up to 100 days
ICU length of stay	in [days]	Part A: from date of inclusion up to 100 days
Duration of mechanical ventilation	in [days]	Part A: from date of inclusion up to 100 days
Hospital mortality	[y/n]	Part A: from date of inclusion up to 100 days

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Rolf Erlebach, MD, University of Zurich

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: December 22, 2025
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: intensive care unit; mechanical ventilation; Pain management; Critical illness; Pain assessment; Pupillary pain index
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Disease Attributes; Neurobehavioral Manifestations; Perceptual Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Critical Illness; Agnosia
• Other Study ID Numbers: INVISIBLE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Ethical restrictions

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No