Safety and efficacy of ketorolac in improving the prognosis of acute type A aortic dissection patients: a protocol of a randomized, double-blinded, and placebo-controlled study.

BACKGROUND: Acute type A aortic dissection (aTAAD) is a critical and life-threatening condition. Previous research has demonstrated that the use of ketorolac not only reduces the progression, incidence, and severity of aortic aneurysms in animal models, but also decreases postoperative mortality and complications in patients undergoing open abdominal aortic aneurysm replacement. However, there is a lack of studies investigating the efficacy of ketorolac in treating aTAAD in humans. Therefore, we conducted a study to evaluate the safety and efficacy of ketorolac in patients with aTAAD. Our hypothesis was that ketorolac treatment for aTAAD patients would meet safety indicators and effectively improve patient prognosis. METHODS/DESIGN: This study is a single-center, randomized, double-blinded, and placebo-controlled study. A total of 120 patients with aTAAD will be recruited and will be randomized into the ketorolac group and placebo group with a ratio of 1:1. Ketorolac tromethamine 60 mg per 2 ml will be intramuscularly injected within 2 h before surgery, followed by intramuscular injections of 30 mg per 1 ml BID. on the first and second postoperative days in the Ketorolac group, while 0.9% saline will be administered at the same dose, dosage form, and time in the placebo group. This study aims to evaluate the safety and efficacy of ketorolac in improving the prognosis of aTAAD. The primary endpoint is the composite endpoint event concerning drug-related adverse events. Secondary endpoints include drug-related adverse events, laboratory examination of blood, diagnostic imaging tests, clinical biomarkers, etc. DISCUSSION: This study has been approved by the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College (approval number: 2023-197-02). This study is designed to evaluate the safety and efficacy of ketorolac in patients with aTAAD. All participating patients will sign an informed consent form, and the trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION: The Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) ChiCTR2300074394. Registered on 4 October 2023.

Ketorolac Injections for Musculoskeletal Conditions: A Narrative Review.

Musculoskeletal conditions of the upper and lower extremities are commonly treated with corticosteroid injections. Ketorolac, a parenteral nonsteroidal anti-inflammatory drug, represents an alternative injectant for common shoulder, hip, and knee conditions. A review of the current literature was conducted on the efficacy of ketorolac injection in musculoskeletal diseases. Several studies support the use and efficacy of ketorolac injection in subacromial bursitis, adhesive capsulitis, and hip and knee osteoarthritis. Given the systemic effects of glucocorticoid injections, ketorolac may be a safe and effective alternative in patients with musculoskeletal disease. However, more evidence is required to better understand the effects ketorolac has on the human body during inflammatory processes.

Effect of perioperative ketorolac on postoperative bleeding after pediatric tonsillectomy.

INTRODUCTION: Ketorolac is a frequently used anesthetic pain agent which is traditionally avoided during tonsillectomy due to concern for postoperative hemorrhage. Our goal was to assess the degree of risk associated with the use of Ketorolac following pediatric tonsillectomy. METHODS: The TriNetX electronic health records research database was queried in January 2024 for patients undergoing tonsillectomy with or without adenoidectomy under the age of 18 years and without a diagnosed bleeding disorder. Patients were separated into two cohorts either having received or not having received ketorolac the same day as surgery. Propensity score matching was performed for age at the time of surgery, sex, race, ethnicity, and preoperative diagnoses. The outcomes assessed were postoperative hemorrhage requiring operative control within the first day (primary hemorrhage) and within the first month after surgery (secondary hemorrhage). RESULTS: 17,434 patients were identified who had undergone pediatric tonsillectomy with or without adenoidectomy and had received ketorolac the same day as surgery. 290,373 patients were identified who had undergone pediatric tonsillectomy with or without adenoidectomy and had not received ketorolac the same day as surgery. 1:1 propensity score matching resulted in 17,434 patients within each cohort. Receipt of ketorolac the same day as surgery resulted in an increased risk of primary hemorrhage OR 2.158 (95 % CI 1.354, 3.437) and secondary hemorrhage OR 1.374 (95 % CI 1.057, 1.787) requiring operative control. CONCLUSION: Ketorolac use during pediatric tonsillectomy with or without adenoidectomy was associated with an increased risk of postoperative primary and secondary bleeding requiring surgery.

Resorbable nanofibrous membranes for local and sustained co-delivery of acyclovir and ketorolac in herpes therapy.

Herpes simplex and herpes zoster are both viral infections caused by members of the herpesvirus family. The former is characterized by painful, fluid-filled blisters or sores on the skin and mucous membranes, while the latter presents as a painful rash with blisters, typically occurring in a single band or patch along one side of the body. The treatment remains a challenge since current antiviral therapy via oral administration may lead to unfavorable side effects such as headaches, nausea, and diarrhea. This study used electrospinning to develop biodegradable nanofibrous poly(lactic-co-glycolic acid) (PLGA) membranes for delivery of both acyclovir and ketorolac. The structure of the spun nanofibers was assessed via scanning electron microscopy (SEM), and the appearance of loaded acyclovir and ketorolac in the nanofibers was confirmed with Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Release profiles of these drugs from the nanofibrous membranes were assessed using in vitro elution studies, high-performance liquid chromatography (HPLC) assays, and in vivo drug release patterns. The electrospun nanofibers had a size range of 283-725 nm in diameter, resembling the extracellular matrix of natural tissue and demonstrated excellent flexibility and extensibility. Notably, the drug-eluting nanofibers exhibited an extended release of high levels of acyclovir and ketorolac over a 21-day period. Thus, biodegradable drug-eluting membranes with a prolonged drug release could be a potential therapeutic approach for treating herpes infections.

Early versus late caffeine and/or non-steroidal anti-inflammatory drugs (NSAIDS) for prevention of intermittent hypoxia-induced neuroinflammation in the neonatal rat.

Preterm infants often experience frequent intermittent hypoxia (IH) episodes which are associated with neuroinflammation. We tested the hypotheses that early caffeine and/or non-steroidal inflammatory drugs (NSAIDs) confer superior therapeutic benefits for protection against IH-induced neuroinflammation than late treatment. Newborn rats were exposed to IH or hyperoxia (50% O2) from birth (P0) to P14. For early treatment, the pups were administered: 1) daily caffeine (Caff) citrate (Cafcit, 20 mg/kg IP loading on P0, followed by 5 mg/kg from P1-P14); 2) ketorolac (Keto) topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Ibu, Neoprofen, 10 mg/kg loading dose on P0 followed by 5 mg/kg/day on P1 and P2); 4) Caff+Keto co-treatment; 5) Caff+Ibu co-treatment; or 6) equivalent volume saline (Sal). On P14, animals were placed in room air (RA) with no further treatment until P21. For late treatment, pups were exposed from P0 to P14, then placed in RA during which they received similar treatments from P15-P21 (Sal, Caff, and/or Keto), or P15-P17 (Ibu). RA controls were similarly treated. At P21, whole brains were assessed for histopathology, apoptosis, myelination, and biomarkers of inflammation. IH caused significant brain injury and hemorrhage, inflammation, reduced myelination, and apoptosis. Early treatment with Caff alone or in combination with NSAIDs conferred better neuroprotection against IH-induced damage than late treatment. Early postnatal treatment during a critical time of brain development, may be preferable for the prevention of IH-induced brain injury in preterm infants.

R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. METHODS: Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2 mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. RESULTS: Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P = 0.0009). Chemotherapy resulted in a 10% survival rate 14 days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P = 0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61 ± 1.82 vs. -4.48 ± 2.0 g, P = 0.0004) and CHX207 (-0.49 ± 0.33 vs. -2.49 ± 0.93 g, P = 0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7 ± 7.1% vs. -27.8 ± 8.3%, P = 0.0007) and gonadal white adipose tissue (-18.8 ± 49% vs. -69 ± 15.6%, P = 0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334 ± 151 to 164 ± 123 pg/mL (P = 0.047) in C26 and from 93 ± 39 to 35 ± 6 pg/mL (P = 0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8 ± 42% vs. -49.2 ± 12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. CONCLUSIONS: RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

The Impact of Ketorolac Utilization on Outcomes for Lumbar Spine Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs commonly used in spine surgery. The purpose of this study is to examine the impact of ketorolac utilization with or without other medications on a patient's postoperative course after lumbar surgery. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed using PubMed, CINAHL, MEDLINE, and Web of Science in July 2023. Inclusion criteria were RCTs that used ketorolac for lumbar surgery. RESULTS: Thirteen RCTs were included (N = 997; mean age, 54.6 ± 7.8 years; n = 535 in the ketorolac group) in this systematic review. There was no significant difference in the 24-hour and total postoperative morphine utilization (P = 0.185 and P = 0.109, respectively), 24-hour and final postoperative pain scores (0-10 scale) (P = 0.065 and P = 0.582, respectively), and length of stay at the hospital (P = 0.990) between patients in the ketorolac group and patients in the non-ketorolac group who underwent lumbar surgery. Overall, patients had similar rates of major complications (3.7% vs. 5.4%) and minor complications (42.1% vs. 51.7%) between groups after lumbar surgery. However, patients in the ketorolac group had a significantly lower rate of nausea and/or vomiting compared with the non-ketorolac group after lumbar surgery (21.6% vs. 37.1%, respectively; P = 0.018). CONCLUSIONS: There is no significant difference in 24-hour and total postoperative morphine utilization, pain scores, or length of stay, with similar complication rates after lumbar surgery between patients receiving ketorolac and patients not receiving ketorolac via meta-analysis of RCTs.

Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways.

AIMS: Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model. MAIN METHODS: In anesthetized male Sprague-Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 µg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day. KEY FINDINGS: NPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin. SIGNIFICANCE: In conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.

Neurotrophic Keratopathy after wide retinal endolaser and postoperative Ketorolac eye drops: A case series.

PURPOSE: We report a series of 5 cases, happened in a period of 5 months, who developed neurotrophic keratopathy (NK) following pars plana vitrectomy (PPV) and retinal endolaser for rhegmatogenous retinal detachment (RRD). In our several decennary experience of surgical center predominantly based on vitreoretinal surgery, we had rare cases of postoperative NK. These recent cases of post-surgical NK happened contextually to our change of postoperative non-steroidal anti-inflammatory drugs (NSAIDs) drops, based on Ketorolac Tromethamine 0.5% eye drops. CASES PRESENTATION: Five patients with a mean age of 61 ± 7.3 years were treated with one or more PPV with intraoperative peripheral endolaser for RRD. Nobody had previous herpetic keratitis, systemic disease like diabetes mellitus or other predisposing factors for NK. In the postoperative period, all patients received Ketorolac Tromethamine 0.5% eye drops for a mean period of 54 ± 25 days. During follow-up visits they developed NK and they were successfully treated with suspension of Ketorolac eye drops, application of therapeutic contact lens or amniotic membrane patch and topical lubricant therapy. CONCLUSIONS: Postoperative Ketorolac eye drops, in patients who underwent PPV with endolaser, may reduce the corneal sensitivity, predispose to epithelial disruption and NK development. Studies are needed to explore the effect of NSAIDs on corneal sensitivity reduction in patient who will undergo PPV and extensive endolaser.

Superior analgesic efficacy of preemptive low-dose ketorolac compared with parecoxib after total knee arthroplasty: A retrospective propensity score matching study.

BACKGROUND: Total knee arthroplasty (TKA) is a routine orthopedic procedure often associated with significant postoperative pain. Efficient pain management is paramount for patient recovery, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a common choice. Nevertheless, the specific NSAID and its dosing regimen can have varying impacts on outcomes. METHODS: In this retrospective cohort study spanning from January 2016 to December 2020, we analyzed patients who underwent TKA. These patients were divided into two groups: one receiving preemptive low-dose ketorolac (15 mg) followed by 15 mg every 6 h for 48 h, and the other receiving parecoxib (40 mg) every 12 h for the same duration. We assessed pain scores, opioid consumption, and monitored adverse events. RESULTS: Our findings reveal that ketorolac yielded superior results compared to parecoxib. Specifically, patients receiving ketorolac reported significantly lower Visual Numeric Rating Scale (VNRS) scores at 8- and 20-h post-surgery. This trend was further confirmed by linear mixed models (p = .0084). Additionally, ketorolac was associated with reduced opioid consumption during the initial 24 h. Importantly, the rates of adverse events were comparable between the two groups. CONCLUSION: The utilization of preemptive low-dose ketorolac demonstrates promising potential in bolstering pain control within the initial 24 h post-TKA, potentially reducing the need for opioids. However, further exploration is required to thoroughly assess its prolonged analgesic effects and safety across various surgical contexts. These investigations could provide invaluable insights for optimizing pain management protocols.

Safety and efficacy of ketorolac continuous infusion for multimodal analgesia of vaso-occlusive crisis in patients with sickle cell disease.

Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72 h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients' hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain.

A meta-analysis of topical Ketorolac's effect on surgical site wound healing post-cataract surgery.

This meta-analysis evaluates the impact of topical ketorolac on surgical site wound healing and scar formation after cataract surgery. A thorough literature search, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, identified eight relevant studies from 2348 articles. The selected studies were analysed for wound healing efficacy, using the redness, edema, ecchymosis, discharge and approximation (REEDA) scale, and scar formation, assessed by the Manchester scar scale (MSS). Results indicated that ketorolac significantly improved wound healing, with lower REEDA scores 1 week post-surgery (I2 = 97%; Random: standardised mean difference (SMD): -10.93, 95% CI: -13.85 to -8.00, p < 0.01), and reduced scar formation, evidenced by lower MSS scores 3 months post-surgery (I2 = 74%; Random: SMD: -9.67, 95% CI: -11.03 to -8.30, p < 0.01). The findings suggest that topical ketorolac is beneficial in post-cataract surgery care, enhancing wound healing and reducing scarring.

Ibuprofen for acute postoperative pain in children.

BACKGROUND: Children often require pain management following surgery to avoid suffering. Effective pain management has consequences for healing time and quality of life. Ibuprofen, a frequently used non-steroidal anti-inflammatory drug (NSAID) administered to children, is used to treat pain and inflammation in the postoperative period. OBJECTIVES: 1) To assess the efficacy and safety of ibuprofen (any dose) for acute postoperative pain management in children compared with placebo or other active comparators. 2) To compare ibuprofen administered at different doses, routes (e.g. oral, intravenous, etc.), or strategies (e.g. as needed versus as scheduled). SEARCH METHODS: We used standard Cochrane search methods. We searched CENTRAL, MEDLINE, Embase, CINAHL and trials registries in August 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children aged 17 years and younger, treated for acute postoperative or postprocedural pain, that compared ibuprofen to placebo or any active comparator. We included RCTs that compared different administration routes, doses of ibuprofen and schedules. DATA COLLECTION AND ANALYSIS: We adhered to standard Cochrane methods for data collection and analysis. Our primary outcomes were pain relief reported by the child, pain intensity reported by the child, adverse events, and serious adverse events. We present results using risk ratios (RR) and standardised mean differences (SMD), with the associated confidence intervals (CI). We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 43 RCTs that enroled 4265 children (3935 children included in this review). We rated the overall risk of bias at the study level as high or unclear for 37 studies that had one or several unclear or high risk of bias judgements across the domains. We judged six studies as having a low risk of bias across all domains. Ibuprofen versus placebo (35 RCTs) No studies reported pain relief reported by the child or a third party, or serious adverse events. Ibuprofen probably reduces child-reported pain intensity less than two hours postintervention compared to placebo (SMD -1.12, 95% CI -1.39 to -0.86; 3 studies, 259 children; moderate-certainty evidence). Ibuprofen may reduce child-reported pain intensity, two hours to less than 24 hours postintervention (SMD -1.01, 95% CI -1.24 to -0.78; 5 studies, 345 children; low-certainty evidence). Ibuprofen may result in little to no difference in adverse events compared to placebo (RR 0.79, 95% CI 0.51 to 1.23; 5 studies, 384 children; low-certainty evidence). Ibuprofen versus paracetamol (21 RCTs) No studies reported pain relief reported by the child or a third party, or serious adverse events. Ibuprofen likely reduces child-reported pain intensity less than two hours postintervention compared to paracetamol (SMD -0.42, 95% CI -0.82 to -0.02; 2 studies, 100 children; moderate-certainty evidence). Ibuprofen may slightly reduce child-reported pain intensity two hours to 24 hours postintervention (SMD -0.21, 95% CI -0.40 to -0.02; 6 studies, 422 children; low-certainty evidence). Ibuprofen may result in little to no difference in adverse events (0 events in each group; 1 study, 44 children; low-certainty evidence). Ibuprofen versus morphine (1 RCT) No studies reported pain relief or pain intensity reported by the child or a third party, or serious adverse events. Ibuprofen likely results in a reduction in adverse events compared to morphine (RR 0.58, 95% CI 0.40 to 0.83; risk difference (RD) -0.25, 95% CI -0.40 to -0.09; number needed to treat for an additional beneficial outcome (NNTB) 4; 1 study, 154 children; moderate-certainty evidence). Ibuprofen versus ketorolac (1 RCT) No studies reported pain relief or pain intensity reported by the child, or serious adverse events. Ibuprofen may result in a reduction in adverse events compared to ketorolac (RR 0.51, 95% CI 0.27 to 0.96; RD -0.29, 95% CI -0.53 to -0.04; NNTB 4; 1 study, 59 children; low-certainty evidence). AUTHORS' CONCLUSIONS: Despite identifying 43 RCTs, we remain uncertain about the effect of ibuprofen compared to placebo or active comparators for some critical outcomes and in the comparisons between different doses, schedules and routes for ibuprofen administration. This is largely due to poor reporting on important outcomes such as serious adverse events, and poor study conduct or reporting that reduced our confidence in the results, along with small underpowered studies. Compared to placebo, ibuprofen likely results in pain reduction less than two hours postintervention, however, the efficacy might be lower at two hours to 24 hours. Compared to paracetamol, ibuprofen likely results in pain reduction up to 24 hours postintervention. We could not explore if there was a different effect in different kinds of surgeries or procedures. Ibuprofen likely results in a reduction in adverse events compared to morphine, and in little to no difference in bleeding when compared to paracetamol. We remain mostly uncertain about the safety of ibuprofen compared to other drugs.

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms.

BACKGROUND: While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. METHODS: Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of Staphylococcus aureus and Staphylococcus epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6 h) and established (24 h) biofilms were grown on 316L stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, minimum biofilm eradication concentration (MBEC) measurement for GS, visualization by live/dead imaging, scanning electron microscopy, gene expression of biofilm-associated genes, and bacterial membrane fluidity assessment. RESULTS: Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. CONCLUSION: The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

A Randomized Controlled Trial of a Novel Formulation of Ketorolac Tromethamine for Continuous Infusion (NTM-001) in Healthy Volunteers.

INTRODUCTION: There is an urgent unmet medical need for a safe, effective, nonopioid analgesic agent for postoperative pain control. METHODS: This first-in-man study was designed to explore a data-informed, model-based candidate dosage regimen and safety of a novel formulation of ketorolac tromethamine (NTM-001) delivered as a 12.5-mg intravenous (IV) bolus followed immediately by 3.5 mg/h continuous infusion over 24 h compared versus IV bolus dosing of 30 mg generic ketorolac every 6 h. The study evaluated pharmacokinetic parameters and safety profiles based on a targeted product profile. A graphical overlay method and model-based comparisons were used to assess the concentration-time curve. RESULTS: Healthy adults (n = 28, 50% men) received NTM-001 and bolus dosing in an open-label crossover design. Observed plasma concentrations were tightly aligned with predicted values with no outliers. Graphical overlay comparisons showed low between-subject variability and agreed with forecasted concentration-time targets. The pharmacokinetic (PK) base models fit with preliminary PK data from both the NTM-001 and bolus groups with model fit median profiles within 95% prediction limits and no updating of the models. Consistent with serum concentration-time profiles, pain relief scores fell within predicted limits, with initial pain relief scores of NTM-001 slightly above the target profile, likely because the initial serum ketorolac concentrations were somewhat higher than predicted. The 24-h pain relief predicted for NTM-001 based on the area under the median ketorolac pain relief versus time curve was about 6% below that of the pain relief target. Both treatments were well tolerated and no subject withdrew because of adverse events. CONCLUSIONS: The PK parameters for NTM-001 and comparator bolus were similar to the modeling targets with no updating of the base model. There were no outliers and little intersubject variability. NTM-001 delivered as a bolus of 12.5 mg IV followed immediately by continuous infusion of 3.5 mg/h using a standard hospital infusion pump may offer an alternative to opioids for acute postoperative pain control.

Opioids are effective analgesics but the risk for opioid use disorder (OUD) and opioid-associated side effects limit their use even for postoperative pain. Ketorolac is an established nonopioid pain reliever that may be as efficacious as morphine in this setting. This study evaluated a new ketorolac product (NTM-001) compared to generic ketorolac. Both were delivered using a standard hospital intravenous (IV) drug pump. The new ketorolac product was administered first with a loading dose of 12.5 mg followed immediately by a continuous IV infusion of 3.5 mg/h. This was compared to IV generic ketorolac administered as a bolus dose of 30 mg every 6 h. The study enrolled 28 healthy adult volunteers. As a crossover study, subjects underwent both treatments: once with the continuous infusion (NTM-001) and once with the IV injection every 6 h (bolus group) with a "washout" period in between. Blood was collected from the volunteers at several time-determined points during the 48-h study to chart ketorolac concentrations in the blood, which can be correlated to predicted levels of pain control. In this study, blood concentrations of ketorolac were reliably predictable and side effects were generally mild with no unexpected adverse events. The continuous infusion group achieved analgesic benefit at a lower total dose than did the every-6-h group over 24 h.

Understanding Hematoma Risk: Study of Patient and Perioperative Factors in a Large Cohort of Young Women Undergoing Reduction Mammaplasty.

BACKGROUND: Despite high satisfaction rates, reduction mammaplasty can have complications such as hematoma. Factors such as age, tobacco use, and comorbidities are known contributors, whereas the influence of race, BMI, certain medications, and blood pressure (BP) remain contentious. This study investigates hematoma risk factors in young women undergoing reduction mammaplasty. STUDY DESIGN: A retrospective review was conducted including all female patients who underwent bilateral reduction mammaplasty at a single institution between 2012 and 2022. Data on demographics, BMI, medical comorbidities, surgical techniques, medications, and perioperative BP were collected. Differences between patients who developed a hematoma and those who did not were assessed using chi-square, Fisher's exact, and t -tests. The relationship between perioperative BP and hematoma formation was assessed using logistic regression. RESULTS: Of 1,754 consecutive patients, 3% developed postoperative hematoma of any kind, with 1.8% returning to the operating room. Age (odds ratio [OR] 1.14, p = 0.01) and ketorolac use (OR 3.93, p = 0.01) were associated with hematoma development. Controlling for baseline BP, each 10 mmHg incremental increase in peak intraoperative BP (systolic BP [SBP]: OR 1.24, p = 0.03; mean arterial pressure: OR 1.24, p = 0.01) and postoperative BP (SBP: OR 1.41, p = 0.01; mean arterial pressure: OR 1.49, p = 0.01) escalated the odds of hematoma. Postoperative SBP variability also incrementally increased hematoma odds (OR 1.48, p < 0.01). Other factors, including race and surgical technique, were not significantly influential. CONCLUSIONS: Age, ketorolac use, and intra- and postoperative BP peaks and variability are risk factors for hematoma in reduction mammaplasty. This emphasizes the importance of perioperative BP management and optimizing pain management protocols.

Comparison of the Effect of Intracarpal Injection of Ketorolac With Triamcinolone in Carpal Tunnel Syndrome: A Randomized Controlled Trial.

BACKGROUND: The most prevalent entrapment neuropathy is carpal tunnel syndrome (CTS). Although nonsteroidal antiinflammatory drugs (NSAIDs) are frequently prescribed for musculoskeletal disorders, oral NSAIDs do not provide any additional benefits for CTS. Nevertheless, the use of NSAID phonophoresis has shown significant improvement, possibly due to increased concentration in the target tissue. The effects of intracarpal injection of NSAIDs on CTS have not been studied. OBJECTIVE: We conducted a controlled trial to compare the efficacy of ketorolac and triamcinolone in treating CTS. METHODS: Mild to moderate CTS patients were randomly assigned to receive either a local injection of 30 mg ketorolac or 40 mg triamcinolone. Patients were evaluated using visual analog scale (VAS) for pain, severity, function, electrodiagnostic findings, patient satisfaction, and any complications at the injection site, at baseline and 12 weeks after the procedures. RESULTS: Fifty patients participated, and 43 completed the study. Both groups showed significant improvement in the VAS, severity, function, and electrodiagnostic scores at 3 months compared with the baseline. A comparison of the groups showed significant differences in VAS, severity, and function, with the improvement being significantly higher in the triamcinolone group. CONCLUSION AND RELEVANCE: The present study showed that injection of triamcinolone or ketorolac into the carpal tunnel relieved pain, increased function, and improved electrodiagnostic findings in patients with mild to moderate CTS. It also showed that triamcinolone was superior to ketorolac in terms of analgesic effect and resulted in greater improvement in symptom severity and function.