Caffeine for Postoperative Delirium

Overseen By Amy McKinney, MA

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan

Disqualifiers: Severe cognitive impairment, Seizure disorder, Caffeine intolerance, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 30

Duration: 3 days

250 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether caffeine, specifically caffeine citrate, can reduce confusion and memory issues some people face after major surgery. Researchers are testing two different caffeine doses to assess their impact on recovery. The trial seeks adults over 70 undergoing certain types of surgery who will remain in the hospital for at least two days afterward. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the study team for guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that caffeine citrate is generally safe for people. It is already approved for use in premature babies, indicating a strong safety record. Past studies found that caffeine helps adults by reducing post-surgery pain, potentially decreasing the need for painkillers.

This trial tests both low and high doses of caffeine citrate. Although specific side effects for these doses are not yet available, a safety board closely monitors the trial to ensure participant safety. Early results suggest that caffeine citrate is safe, particularly given its approval for infants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using caffeine citrate for postoperative delirium because it offers a novel approach to managing this condition. Unlike standard treatments that often involve antipsychotics or sedatives, caffeine citrate works by stimulating the central nervous system, potentially improving alertness and reducing delirium symptoms. Additionally, caffeine's well-known safety profile and rapid onset of action make it a promising option for quick relief. This trial explores both low-dose and high-dose caffeine, providing insights into optimal dosing strategies to maximize benefits while minimizing risks.

What evidence suggests that caffeine citrate could be an effective treatment for postoperative delirium?

Research has shown that caffeine might help reduce confusion after surgery, known as postoperative delirium. In this trial, participants will receive either low-dose or high-dose caffeine citrate through an IV after surgery to determine the most effective dose. Specifically, studies have shown that patients who received caffeine were less likely to become confused. Caffeine likely helps by blocking certain brain signals, keeping people more alert and thinking clearly. Early results are promising, suggesting that caffeine could aid recovery by maintaining mental clarity after surgery. ^{1 2 3 6 7}

Who Is on the Research Team?

Phillip Vlisides, MD

Principal Investigator

Assistant Professor of Anesthesiology

Are You a Good Fit for This Trial?

This trial is for adults aged 70 or older who are having major surgery (not involving the heart, brain, or major blood vessels) that requires general anesthesia and a hospital stay of at least two days. Participants must be able to follow study procedures and give informed consent. People with acute liver failure, weight over 130 kg, pheochromocytoma diagnosis, caffeine allergy/intolerance, severe kidney issues pre-surgery, significant hearing/vision loss, non-English speakers or those in emergency/outpatient surgeries cannot join.

Inclusion Criteria

I am 70 or older and will have surgery under general anesthesia with a planned hospital stay of at least 48 hours.

Provision of signed and dated informed consent form.

Stated willingness to comply with all study procedures and availability for the duration of the study.

Exclusion Criteria

I am unable to understand and give consent for medical procedures.

I have been diagnosed with pheochromocytoma.

My weight is over 130 kg.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either low-dose or high-dose caffeine citrate or placebo at multiple postoperative time points over a 30-minute infusion period

3 days

Multiple visits during hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of delirium, sedation, agitation, headache, and cognitive function

30 days

Follow-up assessments at 30 days post-discharge

What Are the Treatments Tested in This Trial?

Interventions

• Caffeine citrate
• Dextrose Water

Trial Overview The CAPACHINOS-2 Study is testing whether caffeine can help reduce problems with thinking and confusion (delirium) after surgery. Patients will receive either caffeine citrate or dextrose water to see if there's a difference in their recovery from cognitive impairments following their operations.

How Is the Trial Designed?

Group I: Low-dose Caffeine Experimental Treatment 1 Intervention

Prepared intravenous low-dose caffeine citrate (1.5 mg/kg) at multiple postoperative time points over a 30-minute infusion period.

Group II: High-dose Caffeine Experimental Treatment 1 Intervention

Prepared intravenous high-dose caffeine citrate (3 mg/kg) at multiple postoperative time points over a 30-minute infusion period.

Group III: Control Placebo Group 1 Intervention

Prepared intravenous piggyback solution of 5 percent dextrose water at multiple postoperative time points over a 30-minute infusion period.

Caffeine citrate is already approved in United States, European Union for the following indications:

Approved in United States as Cafcit for:

• Apnea of prematurity

Approved in European Union as Gencebok for:

• Apnea of prematurity

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Caffeine withdrawal in postoperative patients can lead to increased headaches, but administering caffeine prophylactically can effectively prevent this issue.

Caffeine administration in the ICU can help patients emerge from sedation and anesthesia more quickly, particularly for those at higher risk of complications, and is considered safe in moderate doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of therapeutic caffeine in acute care postoperative and critical care settings: a scoping review. Bright, M., Raman, V., Laupland, KB.[2021]

In a study of 40 patients undergoing minor surgery, those who received caffeine tablets equivalent to their usual daily intake experienced significantly fewer postoperative headaches compared to those who received a placebo, with 50% of placebo patients reporting headaches.

The results suggest that administering caffeine prophylactically could be beneficial for patients with high caffeine consumption to prevent withdrawal headaches after surgery, as none of the caffeine group reported headaches postoperatively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative administration of caffeine tablets for prevention of postoperative headaches. Hampl, KF., Schneider, MC., Rüttimann, U., et al.[2018]

In a study of 233 surgical outpatients, those who regularly consumed caffeine experienced significantly fewer postoperative headaches (17%) if they continued caffeine intake on the day of surgery compared to those who abstained (28%).

The research suggests that caffeine withdrawal may contribute to postoperative headaches, indicating that maintaining caffeine consumption perioperatively could improve patient outcomes for those who are habitual caffeine users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative ingestion of caffeine and postoperative headache. Weber, JG., Ereth, MH., Danielson, DR.[2019]

In a study of 140 elderly patients undergoing transcatheter aortic valve replacement (TAVR), postoperative delirium (POD) occurred in 12.7% of patients, with higher rates observed in males and those with lower cognitive function as indicated by MMSE scores.

Intraoperative music and positive suggestions did not significantly affect the incidence of POD, pain levels, or the need for analgesics, suggesting that these interventions may not be effective in reducing POD in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative suggestions to prevent postoperative delirium in patients undergoing transaortic valvular replacement: a randomized placebo-controlled trial. Kaufmann, C., Zech, N., Brandt, F., et al.[2023]

The review aims to evaluate the effectiveness and potential harms of medications used to treat delirium in adults recovering from cardiac surgery in intensive care units (ICUs).

Key outcomes being assessed include the duration and severity of delirium episodes, length of ICU and hospital stays, functional capacity, quality of life, and mortality rates among critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and harms of pharmacological interventions in the treatment of delirium in adults in intensive care units post cardiac surgery: a systematic review protocol. Leigh, V., Tufanaru, C., Elliott, R.[2023]

A study involving 120 preterm infants showed that high-dose caffeine citrate significantly reduced extubation failure and the frequency of apnea of prematurity compared to low-dose caffeine.

While high-dose caffeine increased episodes of tachycardia, it did not lead to significant adverse effects, suggesting that higher doses may be a safe and effective option for treating apnea in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial. Mohammed, S., Nour, I., Shabaan, AE., et al.[2022]

Caffeine citrate injection remains stable in various intravenous admixtures and parenteral nutrition solutions when stored at room temperature for up to 24 hours.

This stability suggests that caffeine citrate can be safely used in clinical settings without concerns of degradation during this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of caffeine citrate injection in intravenous admixtures and parenteral nutrition solutions. Nahata, MC., Zingarelli, J., Durrell, DE.[2019]

A study of 566 preterm infants showed that a high maintenance dose of caffeine citrate (10 mg/kg per day) significantly reduced the need for high-concentration oxygen and the duration of oxygen therapy compared to a low dose (5 mg/kg per day).

While the high-dose group experienced benefits in respiratory support and reduced incidence of apnea and bronchopulmonary dysplasia, it also had a higher rate of feeding intolerance, indicating a need for further research on this side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical effect of different maintenance doses of caffeine citrate in the treatment of preterm infants requiring assisted ventilation: a pilot multicenter study. Yang, Y., Lu, KY., Cheng, R., et al.[2022]

In a study of 122 elderly patients undergoing major lower limb surgeries, transcranial direct current stimulation (tDCS) significantly reduced the incidence of postoperative delirium (POD) from 19.7% in the sham group to only 4.9% in the active-tDCS group, indicating its potential efficacy in preventing this serious complication.

Patients receiving active-tDCS also reported lower anxiety, depression, and pain scores compared to those receiving sham treatment, suggesting that tDCS not only helps reduce POD but may also improve overall postoperative recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of transcranial direct current stimulation on postoperative delirium in elderly patients undergoing lower limb major arthroplasty: A randomized controlled trial. Tao, M., Zhang, S., Han, Y., et al.[2023]

In a study of 680 adult surgical patients, 18.8% developed postoperative delirium (POD), which was linked to higher mortality rates and longer hospital stays, indicating its serious impact on recovery.

Key independent risk factors for developing POD included older age, higher ASA physical status scores, undergoing emergency surgery, and the total amount of fresh frozen plasma given during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative delirium in intensive care patients: risk factors and outcome. Veiga, D., Luis, C., Parente, D., et al.[2015]

A population pharmacokinetic (PPK) model for caffeine citrate was developed using data from 46 preterm infants, providing a tailored approach for treating apnea of prematurity in this population.

The model identified weight and post-natal age as key factors influencing caffeine clearance and distribution, which can help optimize individualized treatment for Chinese premature infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic study of caffeine citrate in Chinese premature infants with apnea. Guo, A., Zhu, Z., Xue, J., et al.[2022]

In a study of 42 elderly patients undergoing major surgery, a delirium-free protocol (DFP) using medications significantly reduced the incidence of postoperative delirium (POD) from 35% in the non-DFP group to 5% in the DFP group.

The DFP treatment, which involved administering diazepam and flunitrazepam, was effective in preventing POD without severe complications, although 40% of patients experienced morning lethargy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Aizawa, K., Kanai, T., Saikawa, Y., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10186430/

Caffeine, Postoperative Delirium And Change In Outcomes ... This trial tests the hypothesis that intravenous caffeine, given postoperatively, will reduce the incidence of delirium in older adults after major non-cardiac ...

2. bmjopen.bmj.com bmjopen.bmj.com/content/13/5/e073945

Caffeine, Postoperative Delirium And Change In Outcomes ... This trial tests the hypothesis that intravenous caffeine, given postoperatively, will reduce the incidence of delirium in older adults after major non-cardiac ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37188468/

2: protocol for a randomised controlled trial - PubMed - NIH This trial tests the hypothesis that intravenous caffeine, given postoperatively, will reduce the incidence of delirium in older adults after major non-cardiac ...

4. bmjopen.bmj.com bmjopen.bmj.com/content/bmjopen/13/5/e073945.full.pdf

Caffeine, Postoperative Delirium And Change In Outcomes ... Based on preliminary data, this trial tests the hypothesis that intravenous caffeine, given postoperatively, will reduce the incidence of ...

5. withpower.com withpower.com/trial/phase-2-delirium-2023-53854

Caffeine for Postoperative Delirium The objective of this study is to test the effects of caffeine on neurocognitive and clinical recovery after major surgery. Specifically, this trial tests ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03577730

Caffeine and Neurologic Recovery Following Surgery and ... Preliminary laboratory and clinical findings demonstrate that caffeine may reduce pain after surgery, which may translate to lower opioid requirements.

7. clinicaltrials.eu clinicaltrials.eu/inn/caffeine-citrate/

Caffeine Citrate: A Medication for Premature Infants Additionally, it examines potential benefits for adult patients in areas such as postoperative delirium and liver disease. The trials investigate different ...