Department of Clinical Research

Background: Assessment of the pupils regarding symmetry and reactivity to light are important parts of the neurological evaluation of critically ill patients treated in intensive care units. Thereby, anisocoria can be found in up to 60% of patients with acute neurologic injuries(2). Furthermore, anisocoria or pupillary areflexia can be signs of increasing intracranial hypertension with brain herniation, ischemia in traumatic brain injury, cerebrovascular accidents, intoxication with psychotropic and neurotropic drugs including anticholinergic, opioids, and cannabinoids. While anisocoria or impaired pupillary reactivity may result from such devastating cerebral injuries, they can also be caused by more benign and potentially reversible scenarios, such as pharmacological effects (e.g. agents such as ipatroprium bromide) or as part of the Horner’s syndrome following jugular central venous cannulation. Despite these well-known underlying pathomechanisms of pupillary anomalias, data on the prevalence and associated clinical consequences of anisocoria in non-selected general ICU populations is scarce. Due to the lack of data on the prognostic implications of anisocoria or changes in pupillary reactivity for non-neurological ICU patients, the new onset of any pupillary abnormality necessitates a rapid and thorough evaluation usually including clinical neurological examination and the performance of neuroimaging, such as a cerebral computed tomography (CT) or magnetic resonance imaging (MRI). Considering the the variety of more benign and reversible causes of pupillary abnormalities, alongside the potential for missed underlying pathomechanisms with severe clinical implications, it is highly probable that a significant number of unremarkable CT or MRI scans are conducted to investigate acute pupillary abnormalities. This practice may expose patients to unnecessary risks and contribute to increased healthcare costs. While quantitative pupillometry with dynamic pupil assessments after light has shown some promise to distinguish between clinically relevant anisocoria and benign variations, further validation is still lacking. Unfortunately, studies elucidating to what extent a cerebral CT or MRI detects clinically relevant findings in specific patient groups with particular clinical contexts, and in which clinical scenarios CTs are likely to provide no clinical relevance beyond exposing the patient to radiation are still pending.

Objectives: This retrospective single-center cohort study has four primary objectives. 

-   First, it aims to determine the prevalence of acute "new onset" pupillary abnormalities (anisocoria and/or impaired light-reactive pupillary response) in adult ICU patients. 

-   Second, it seeks to assess the clinical impact of these abnormalities, particularly in terms of the frequency of diagnostic tests ordered, such as neuroimaging (i.e., head CT or MRI scans, and ophthalmologic and neurologic consultations. 

-   Third, the study aims to identify specific clinical contexts in which significant pathological findings lead to treatment modifications, as well as those scenarios where no clinically relevant findings are detected.

-   Finally, it evaluates the prognostic implications of these pupillary abnormalities on patient outcomes.

Background

Cancer-related pain is among the most prevalent and distressing symptoms experienced by patients, significantly contributing to their overall suffering. Due to limited supporting evidence for many pharmacological therapies, patients may not receive potentially effective pain management.

Rationale

The potential benefit of adding non-opioid analgesics to opioid therapy in cancer pain management—such as improved symptom control or reduced opioid dosage—remains unproven, though recommended by guidelines from WHO, ASCO, and ESMO. The efficacy evidence for widely used non-opioid analgesics, specifically dipyrone (metamizole) and ibuprofen, when combined with opioids, is extremely limited, leaving many patients untreated or receiving suboptimal therapy. Safety concerns further complicate the use of both dipyrone and ibuprofen. Paracetamol (acetaminophen), another widely used non-opioid, has been examined in multiple randomized controlled trials (RCTs) showing a lack of efficacy as an adjunct to opioids; thus, it is excluded from this trial.

Aims/Methodology

This multicenter, randomized, double-blind, placebo-controlled, three-armed superiority trial assess the efficacy of dipyrone and ibuprofen, when used alongside opioids, compared to a placebo, for managing cancer-related pain.

Relevance to patients and current treatment guidelines

This study holds critical relevance for patients and clinical practice. First, combining non-opioid analgesics with opioids in cancer pain management is practiced by some clinicians, though limited evidence on its efficacy results in many patients either not receiving adjunct non-opioids or receiving suboptimal choices. Second, our research directly aligns with priorities identified by the James Lind Alliance, focusing on reducing cancer pain while minimizing reliance on opioids, which often cause undesirable side effects. Using non-opioid analgesics in combination with opioids may lower the opioid dosage required for effective pain control. Third, many cancer studies exclude patients with low performance status, though they experience the highest symptom burden. Due to this evidence gap, thousands of cancer patients in Switzerland and internationally may not receive optimal pharmaceutical care despite potential benefits and clear need. Members of the Association for Palliative Medicine of Great Britain and Ireland, for instance, recently called for such a study. Our study’s results will directly impact and promptly inform current treatment guidelines, as the lead investigators are part of the national guideline development team.

Public Patient Involvment: https://dkf.unibas.ch/de/aktuell/ppi-in-der-nodoubt-studie/