Effects of PNB Timing on Postoperative Delirium for Hip Fracture

Delirium is a common complication among older adults hospitalized with hip fracture and is associated with adverse clinical outcomes. Acute pain is a potentially modifiable contributor to delirium, while opioid analgesics, although commonly used for hip fracture pain, may themselves contribute to adverse effects such as sedation and worsening cognitive dysfunction. Peripheral nerve blocks (PNBs), including fascia iliaca and femoral nerve blocks, provide effective regional analgesia and may reduce opioid requirements. However, the relationship between the timing of PNB administration after hospital presentation and the subsequent development and severity of delirium remains unclear.

This is a prospective, longitudinal, dual-centre pilot study designed to evaluate the association between the timing of PNB administration and delirium outcomes in adults aged 65 years or older admitted with a hip fracture requiring surgical repair and planned use of a PNB. The study will be conducted at the University Hospital and Victoria Hospital campuses of London Health Sciences Centre in London, Ontario, Canada.

The study is observational. Participation will not determine or alter the timing or type of PNB, surgical management, analgesic therapy, or other aspects of clinical care. Participants will receive standard hospital care, including multimodal analgesia, PNBs, surgery, and medical management as clinically indicated. PNBs may be performed in the Emergency Department or Block Room as part of routine clinical care. Delirium and cognitive assessments that are routinely obtained during hospitalization will be used for study purposes, together with additional study data collected from participants, caregivers, and the electronic medical record.

Approximately 60 patient participants will be recruited during the planned 2-month pilot recruitment period using consecutive convenience sampling. Approximately 60 caregiver participants will also be recruited to provide information regarding the patient's baseline and follow-up cognitive and functional status. The pilot sample size is based on feasibility rather than a formal statistical power calculation. The study is intended to provide preliminary estimates of recruitment feasibility, delirium incidence, and the magnitude and direction of associations between PNB timing and delirium outcomes to inform the design and sample-size calculation of a future adequately powered prospective study.

The primary exposure of interest is the elapsed time between hospital presentation with hip fracture and administration of the PNB. PNB timing will be evaluated using three prespecified categories:

Early PNB: less than 6 hours after hospital presentation; Intermediate PNB: 6 to 12 hours after hospital presentation; and Late PNB: more than 12 hours after hospital presentation.

Actual elapsed time from hospital presentation to PNB administration will also be evaluated as a continuous exposure to explore whether increasing delay to PNB is associated with delirium outcomes.

The primary outcome is the development of new-onset delirium during hospitalization. Delirium will be assessed using the 4 A's Test (4AT), a brief screening instrument evaluating alertness, orientation, attention, and acute change or fluctuation in mental status. A 4AT score of 4 or greater is considered consistent with possible delirium. New-onset delirium is defined as a 4AT score of 4 or greater occurring after admission in a participant with a baseline 4AT score below 4, or a new increase in 4AT score consistent with delirium in a patient who did not have delirium at admission. Participants with delirium at admission will not be included in the primary analysis of new-onset delirium.

The study will also evaluate the severity and overall burden of delirium during hospitalization. Serial 4AT scores will be obtained as part of routine clinical care and followed until discharge. Measures of delirium burden may include the maximum 4AT score, mean daily 4AT score, number and proportion of assessed hospital days with a 4AT score of 4 or greater, time from admission to the first delirium-positive assessment, time from PNB administration to the first delirium-positive assessment, and duration of delirium.

Baseline cognitive status will also be characterized using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), which obtains caregiver or informant information regarding changes in cognitive function over time. Baseline functional status will be assessed using the Older Americans Resources and Services Activities of Daily Living (OARS ADL) instrument. The Family Confusion Assessment Method (Fam-CAM), a caregiver-administered delirium screening tool, will be used to obtain caregiver-reported information regarding delirium.

In addition to delirium outcomes, data collected will include patient age, biological sex, relevant medical comorbidities, fracture type, type of surgical procedure, time from hospital admission to surgery, type of PNB, and opioid exposure. PNB characteristics will include the type of block and, where applicable, whether the technique involved a single injection or continuous catheter.

Perioperative opioid consumption will be examined as a secondary outcome. Opioid doses will be converted to standardized intravenous morphine-equivalent doses using a prespecified institutional conversion method. Opioid use may be summarized over clinically relevant periods, including admission to PNB administration, PNB administration to surgery, the intraoperative period, the postoperative period, and the total hospitalization where data are available. Opioid exposure will be compared among the early, intermediate, and late PNB groups.

Other secondary outcomes include hospital length of stay and 30-day mortality. Length of stay will be measured from hospital admission to discharge. Thirty-day mortality will be determined following hospital admission and is expected to be analyzed primarily descriptively because of the pilot sample size.

Participants will also undergo follow-up at approximately 3 months after hospital discharge. Functional status will be reassessed using the OARS ADL instrument, allowing evaluation of change from baseline functional status. Caregiver-reported delirium or cognitive symptoms will be assessed using the Fam-CAM. These follow-up measures will be compared across PNB timing groups on an exploratory basis.

The primary analysis will estimate the association between PNB timing and new-onset delirium. Delirium incidence will be summarized within each PNB timing group. Where supported by the number of outcome events, multivariable logistic regression will be used to estimate the association between PNB timing and delirium while accounting for clinically relevant potential confounders. Potential confounding variables may include age, biological sex, baseline cognitive status, baseline functional status, relevant comorbidity burden, opioid exposure, fracture type, time to surgery, and PNB type. Because this is a pilot study with a limited sample size, the number of variables included in adjusted models will be restricted to reduce the risk of model overfitting.

Longitudinal delirium severity will be evaluated using repeated 4AT measurements obtained during hospitalization. Where appropriate, mixed-effects modelling will be used to account for correlation among repeated assessments within the same participant and to examine differences in delirium trajectories among PNB timing groups. Exploratory analyses will also examine the relationship between actual time to PNB administration and measures of delirium severity and burden.

Because the timing of delirium onset may be clinically relevant, exploratory time-to-event analyses may be conducted using hospital admission as the starting point and the first occurrence of new-onset delirium as the event. Participants who do not develop delirium will be censored at hospital discharge. If the number of events and sample size permit, sensitivity analyses may account for PNB administration as a time-dependent exposure.

All statistical analyses are exploratory because this is a pilot study and no formal efficacy-based sample-size calculation has been performed. Interpretation will therefore emphasize the magnitude, direction, and precision of estimated associations, including confidence intervals, rather than statistical significance alone. Results will be used to assess study feasibility and to inform outcome selection, analytic methods, and sample-size requirements for a future adequately powered prospective study evaluating the relationship between the timing of PNB administration and delirium in older adults with hip fracture.

The study hypothesis is that earlier PNB administration, particularly within 6 hours of hospital presentation, will be associated with a lower incidence and severity of delirium compared with later PNB administration.