Real-world Opioid-Sparring Effects of Infiltration between the Popliteal Artery and the Capsule of the Knee (IPACK) in Patients Undergoing Anterior Cruciate Ligament Reconstruction

This single-center difference-in-differences cohort study investigates the real-world impact of implementing an ultrasound-guided IPACK nerve block on immediate postoperative opioid consumption and other recovery outcomes in patients undergoing anterior cruciate ligament reconstruction at Bispebjerg Hospital, Denmark, between February 2024 and June 2025.

The Gist

Imagine your knee is a busy construction site. When a surgeon repairs a torn ligament (the ACL), it's like fixing a major structural beam. Naturally, this causes a lot of "noise" and "pain" at the site. Usually, to quiet down the noise, doctors use strong painkillers called opioids. But opioids are like a heavy blanket: they stop the pain, but they also make you groggy, nauseous, and slow to recover. They can even get you hooked on them later.

Doctors have been looking for a way to turn down the volume on the pain without needing the heavy blanket. They found a technique called IPACK. Think of IPACK as a "smart sprinkler system." Instead of watering the whole garden (the whole body), the surgeon injects a local anesthetic (a numbing liquid) right behind the knee, specifically between the main artery and the joint capsule. This targets the specific "wires" (nerves) that carry pain signals from the back of the knee, silencing them right at the source.

The Big Question
This paper is a plan (a protocol) to test if this "smart sprinkler" works for ACL surgery patients. The researchers want to know: If we use this IPACK sprinkler, will patients need fewer opioid "heavy blankets," wake up faster, and feel less sick?

How They Are Testing It (The "Before and After" Game)
Since they can't test this on just one person, they are looking at a huge group of patients at a hospital in Denmark. They are using a clever statistical trick called a "Difference-in-Differences" study. Here is how to visualize it:

1. The Main Group (The ACL Crew): These are patients getting their torn ligament fixed.
   • Before Jan 1, 2025: They got the surgery without the IPACK sprinkler.
   • After Jan 1, 2025: They got the surgery with the IPACK sprinkler.
2. The Control Group (The Other Knee Crew): These are patients getting different, but similar, knee surgeries (like fixing the kneecap). They never get the IPACK sprinkler, even after Jan 1, 2025.

Why have two groups?
Imagine you are trying to see if a new fertilizer makes plants grow. If you just look at your garden before and after, you might think the fertilizer worked, but maybe it was just a sunny summer!
By having the "Other Knee Crew" who didn't get the fertilizer, the researchers can see if the weather (time) changed for everyone. If the ACL group suddenly grows faster than the Other Knee group only after the IPACK starts, they know it's the IPACK, not the weather.

What Are They Measuring?
They aren't just guessing; they are looking at hard numbers:

• The Main Score: How much opioid medicine did the patient need in the first 2 hours after surgery? (Less is better).
• The Pain Score: How much did it hurt? (On a scale of 0 to 10).
• The Nausea Score: Did they feel sick or vomit?
• The Speed: How long did they stay in the recovery room and the hospital?
• The Environment: They are even calculating the "carbon footprint" (the pollution) of the needles and drugs used, because green healthcare matters too!

The "Real-World" Twist
Most medical studies are like a science lab where everything is perfect and controlled. This study is different; it's a "real-world" test. They are looking at actual patients in a real hospital, with real doctors who might have bad days or different habits. This makes the results much more useful for regular people.

The Goal
If this study proves that the IPACK "smart sprinkler" works, it could change how knee surgeries are done everywhere. It could mean:

• Less pain medication needed.
• Patients going home sooner.
• Fewer people getting addicted to painkillers.
• A cleaner, greener hospital environment.

In short, this paper is the blueprint for a study that hopes to prove that a simple, targeted injection can make a major knee surgery much easier on the body, the mind, and the planet.

Technical Summary

Based on the provided manuscript, here is a detailed technical summary of the study protocol and its intended analysis.

1. Problem Statement

Patients undergoing Anterior Cruciate Ligament (ACL) reconstruction frequently experience severe postoperative pain, which hinders early mobilization, delays discharge, and necessitates the use of fast-acting opioids. The reliance on opioids carries risks of side effects (e.g., nausea, vomiting) and the potential for long-term opioid dependence. While the Infiltration between the Popliteal Artery and the Capsule of the Knee (IPACK) block has shown efficacy in reducing pain and opioid use in other knee procedures, its specific real-world effectiveness in ACL reconstruction patients has not yet been investigated. Furthermore, traditional "before-and-after" observational studies are prone to confounding by underlying temporal trends in clinical care.

2. Methodology

This study is designed as a single-centre, difference-in-differences (DiD) cohort study conducted at Bispebjerg Hospital, Denmark.

• Study Design & Population:
  • Intervention Cohort: All patients undergoing ACL reconstruction from February 1, 2024, to June 30, 2025.
    • Control Period: Patients treated before January 1, 2025.
    • Intervention Period: Patients treated after January 1, 2025 (when IPACK was implemented).
  • Reference Cohort: A control group of patients undergoing other knee surgeries (trochleaplasty, Elmslie-Trillat, or MPFL reconstruction) during the same period and at the same hospital. This group did not receive IPACK and serves to adjust for secular trends in perioperative care.
• Intervention:
  • Implementation of an ultrasound-guided IPACK block immediately prior to surgery.
  • Dosage: 20 mL of ropivacaine 0.5% injected between the popliteal artery and the posterior knee capsule.
  • Target: Anaesthetization of the popliteal branches of the tibial, common peroneal, and obturator nerves.
• Standardized Care:
  • All patients received a standardized multimodal analgesic regimen (paracetamol, NSAIDs, dexamethasone, ondansetron) and an ultrasound-guided Adductor Canal Block (ACB).
  • General anesthesia protocols remained unchanged throughout the study period.
• Outcomes:
  • Primary Outcome: Cumulative opioid consumption (converted to Intravenous Morphine Equivalents [IMEs]) from surgical incision to 2 hours postoperatively.
  • Secondary Outcomes: Opioid consumption (0–24h), worst pain score (0–10 NRS) within 24h, incidence of postoperative nausea/vomiting (PONV), length of PACU stay, length of hospital stay, and nerve injuries.
  • Exploratory Outcome: Carbon dioxide emissions per case related to the IPACK procedure.
• Statistical Analysis:
  • Main Analysis: A two-way fixed effects DiD regression model using R.
    • Model: outcome ~ surgery + surgery:after_IPACK + time2
    • Adjusts for the surgical cohort (ACL vs. Reference), the time period (pre/post IPACK), and a continuous time trend.
  • Sensitivity Analyses:
    • Clustering: Standard errors clustered by surgeon to account for surgeon-specific techniques or prescribing habits.
    • Parallel Trends: Testing for interaction between surgery group and time to ensure the control and intervention groups followed similar trends prior to the intervention.
    • Learning Effects: Testing for interaction between the intervention and time to see if the effect of IPACK improved over time.
    • Statistical Process Control: Use of Xbar and P control charts (Anhøj rules) to visualize shifts in outcomes relative to the implementation date.
  • Population: Primary analysis on a per-protocol basis; sensitivity analysis on an intention-to-treat (ITT) basis.

3. Key Contributions

• First Investigation in ACL: This study aims to be the first to evaluate the real-world efficacy of IPACK specifically in the context of ACL reconstruction.
• Robust Observational Design: By utilizing a Difference-in-Differences approach with a concurrent reference cohort, the study mitigates the limitations of simple pre-post comparisons, effectively controlling for unmeasured time-varying confounders (e.g., changes in nursing protocols or general opioid prescribing trends).
• Comprehensive Outcome Scope: The study evaluates not only clinical efficacy (pain and opioids) but also organizational outcomes (length of stay), safety (nerve injuries), and environmental impact (carbon emissions).
• Protocol Transparency: The authors have pre-registered the protocol and statistical analysis plan (SAP) on Zenodo to minimize bias and ensure reproducibility.

4. Results

• Status: No results are currently available.
• Reason: This document is a protocol paper (preprint) describing the study design, methods, and analysis plan. The "Results" section in the manuscript is provided as a template with placeholders (e.g., "XX mg," "XX patients") indicating where the data will be inserted once the study is completed and analyzed. The study period extends to June 30, 2025, and the preprint was posted in March 2026, suggesting the data collection is either ongoing or just concluding at the time of writing.

5. Significance

• Clinical Impact: If IPACK is proven effective in reducing opioid consumption and pain in ACL patients, it could become a standard component of Enhanced Recovery After Surgery (ERAS) protocols for knee reconstruction, potentially reducing hospital stays and long-term opioid dependence.
• Methodological Benchmark: The study demonstrates a rigorous approach to evaluating real-world interventions using observational data, offering a template for how to handle confounding in non-randomized surgical studies.
• Environmental Awareness: By including carbon emissions as an exploratory outcome, the study addresses the growing need to quantify the environmental footprint of anesthetic procedures.
• Policy Implication: Successful results could influence hospital guidelines and resource allocation for regional anesthesia in orthopedic surgery.

Note: As this is a preprint that has not yet undergone peer review, the findings (once generated) should be interpreted with caution until validated by the broader scientific community.