This double-blind, placebo-controlled proof-of-concept clinical trial is intended to demonstrate that preemptive oral administration of cocoa flavanol for five days before surgery will attenuate the surgery-evoked increase of HMGB1 in blood plasma and NFkB signaling in innate immune cells shortly after surgery. A secondary aim is to capture preliminary patient-centered outcomes data and relate these outcomes to the intake of oral cocoa flavanol and surgery-evoked activation of the HMGB1-NFkB signaling axis. Participants will be randomized to receive either an over the counter supplement containing cocoa flavanols, or placebo, for 5 days before surgery.

During the last two decades significant effort has been made to enhance recovery after surgery. Despite the implementation of pragmatic and standardized clinical protocols to enhance recovery and shorten hospital length of stay, the utility of these protocols for improving patient-centered recovery cost-effectively remains uncertain. Critical elements of recovery that greatly matter to patients and health care providers include the resolution of pain, daily functioning, and loss of postoperative fatigue. A patient-centered and cost-effective focus on postoperative recovery pays tribute to three goals of health care: Improving patients' experience, improving health, and constraining per capita cost. As such, novel and cost-effective strategies are greatly needed to accelerate patient-recovery after surgery.

Preliminary data by Dr. Angst and his collaborators indicate that administration of a cocoa flavanol extract that is equivalent in dose to the amount of cocoa flavanol contained in about 50 grams of dark chocolate decreases plasma levels of HMGB1. HMGB1 is an archetypical alarmin, i.e., an endogenous mediator that is released upon cellular stress and injury. HMGB1 triggers a pro-inflammatory cascade by binding to toll-like receptors (TLRs) on innate immune and other cells, which results in activation of pro-inflammatory transcription factors (e.g. NFkB) and the subsequent release of major pro-inflammatory cytokines (e.g. TNFα). The prominent role of the HMGB1-TLR axis in inflammatory disease states including surgery, trauma, stroke, and myocardial infarction has recently been highlighted.16-19 Importantly, dampening activity along this pathway in preclinical injury models has been shown to improve outcomes.

The potential of HMGB1 as a therapeutic target in acute inflammatory disease states has recently been emphasized. A major challenge is the identification of effective and non-toxic clinical strategies that can safely modulate HMGB1 in humans. This research study will evaluate a safe, highly scalable, and relatively cheap pre-surgical nutritional intervention that has significant potential to do just that, safely modulate HMGB1 and improve clinical recovery after surgery. As such, this proposed research could change clinical practice within years. While studied intervention targets a specific pro-inflammatory pathway implicated in aggravated tissue damage and delayed healing/recovery, the use of broader and less specific anti-inflammatory interventions in the perioperative period including non-steroidal anti-inflammatory drugs and corticosteroids is common clinical practice.

Inclusion Criteria:

1. 18 - 90 years of age
2. Male or female
3. Planning to undergo total hip or knee arthroplasty, either primary or revision
4. Fluent in English
5. Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures

Exclusion Criteria:

1. Infectious disease within the last month
2. Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
3. Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake > 30 mg)
4. Major surgery within the last 3 months or minor surgery within the last month.
5. History of substance abuse (e.g., alcoholism, drug dependency)
6. Pregnancy
7. Autoimmune disease interfering with data interpretation (e.g. lupus)
8. Renal, hepatic, cardiovascular, or respiratory diseases resulting in clinically relevant impaired function
9. Active malignancy
10. Participation in another clinical trial of an investigational drug or device within the last month that, in the investigator's opinion, would create an increased risk to the participant or compromise the integrity of the study
11. Other conditions compromising a participant's safety or the integrity of the study
12. Allergy to active ingredient of CocoaVia®, the study intervention.
13. Frequent consumption of dark chocolate and flavanol containing foods (e.g. black tea, red wine, apples)

8 weeks

Placebo and active treatments will be formulated in identical capsules, and bottled and labeled with coded study numbers that will allow for all parties to remain blinded throughout the data collection phase.