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NCT Number: NCT07473115

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

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.

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Key information

Conditions

Pain Agnosia Critical Illness Disease Attributes Nervous System Diseases Neurobehavioral Manifestations Neurologic Manifestations Pain Management Pathologic Processes Pathological Conditions, Signs and Symptoms Perceptual Disorders Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

University Hospital Zurich

Zurich, Canton of Zurich, 8091, Switzerland

Location contact

Institute of Intensive Care Medicine

CONTACT

[email protected]

+41 44 255 23 76

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Primary outcomes

  1. Oral morphine equivalent (OME) per day of mechanical ventilation.

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    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).

Secondary outcomes

  1. Sufentanil dose per day of mechanical ventilation

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    average dose [mcg/min]

  2. Opioid dose adjustments - Number of adjustments

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Number of dose adjustments [/hour] and direction

  3. Opioid dose adjustments - Relative change during pain assessment

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Relative change of dose 45min after vs. 15min before ZOPA/PPI

  4. Zurich Observational Pain Assessment (ZOPA)

    Time frame: Part A: during mechanical ventilation Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    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.

  5. Number of rescue analgesics administered per day

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Bolus administration of opioids

  6. Occurrence of adverse effects of pain per day of mechanical ventilation

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    • Intravenous antihypertensive treatment [y/n]
    • Atrial fibrillation [y/n]
    • anti-infective treatment [y/n]
    • Richmond Agitation Sedation Scale (RASS) > +1 [y/n]

  7. Number of sedatives used per day of mechanical ventilation

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Average number of sedatives used in the intensive care unit (e.g. Propofol, Clonidine, Dexmedetomidine, Ketamine, Sevoflurane and Midazolam)

  8. Richmond Agitation Sedation Scale (RASS) < -3

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    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".

  9. Time to extubation

    Time frame: 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.

    Time to extubation from stop of analgosedation [hours]

  10. Opioid prescription at ICU discharge

    Time frame: Part A: at ICU discharge assessed up to 5 days

    • Opioid prescription at ICU discharge [y/n] in patients discharged alive (as listed in the ICU discharge report)

  11. Opioid prescription at hospital discharge

    Time frame: Part A: at hospital discharge assessed up to 10 days

    • Opioid prescription at hospital discharge [y/n] in patients discharged alive (as listed in the hospital discharge report)

  12. Target nociception level

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    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).

  13. Opioid-free days in the ICU

    Time frame: Part A: from ICU admission to ICU discharge (up to 100 days)

    Days free of opioid administration [%]

  14. Pupillary Pain Index

    Time frame: - Part A: During mechanical ventilation - Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    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).

  15. Cortisol

    Time frame: Part B: day 2/visit 2, day 3/visit 4

    blood and saliva levels [nmol/L]

  16. Amylase

    Time frame: Part B: day 2/visit 2, day 3/visit 4

    blood and saliva [U/L]

  17. Critical Care Pain Observation Tool (CPOT)

    Time frame: Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    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.

  18. Subjective pain rating

    Time frame: Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    Questionnaire based rating of pain [y/n] by physician and nurses

  19. Subjective rating of nociception level

    Time frame: Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    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

  20. Trust in the Zurich Observational Pain Assessment (ZOPA)

    Time frame: Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    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.

  21. Trust in the Pupillary Pain Index (PPI)

    Time frame: Part B: day 2/visit 2, day 2/visit 3, day 3/visit 4, day 3/visit 5

    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.

  22. Pupil size before stimulation

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Pupil size before stimulation PPI measurement [mm]

  23. Percentage pupil's variation

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Pupil variation [%] during PPI measurement

  24. Maximal size variation

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    Maximal variation in pupil size [mm] during PPI measurment.

  25. Neuron-specific Enolase (NSE) [mcg/L]

    Time frame: Part A: From cardiac arrest until 72 hours after cardiac arrest

    NSE [mcg/L] in patients after cardiac arrest at 24, 48 and 72 hours

Other outcomes

  1. Delirium

    Time frame: Part A: during mechanical ventilation (up to 28 days)

    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".

  2. ICU mortality

    Time frame: Part A: from date of inclusion up to 100 days

    [y/n]

  3. ICU length of stay

    Time frame: Part A: from date of inclusion up to 100 days

    in [days]

  4. Duration of mechanical ventilation

    Time frame: Part A: from date of inclusion up to 100 days

    in [days]

  5. Hospital mortality

    Time frame: Part A: from date of inclusion up to 100 days

    [y/n]

Study contacts

Contact information is provided by the study sponsor or research team.

Rolf Erlebach, MD

CONTACT

[email protected]

+41 43 253 90 63

Sascha I David, Professor

CONTACT

[email protected]

+41 43 253 19 02

Sponsors and collaborators

Lead sponsor

University of Zurich

Other

Registry information

Official study title

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

Acronym: INVISIBLE

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Mar 16, 2026
Registry last updated
Mar 17, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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