Screening Computed Tomography Angiography to Identify Patients at Low Risk for Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage.

Introduction: Delayed cerebral ischemia (DCI) occurs during a risk period of 3-21 days following aneurysmal subarachnoid hemorrhage (aSAH) and is associated with worse outcomes. The identification of patients at low risk for DCI might permit triage to less intense monitoring and management. While large-vessel vasospasm (LVV) is a distinct clinical entity from DCI, the presence of moderate-to-severe LVV is associated with a higher risk of DCI. Our hypothesis was that the absence of moderate-to-severe LVV on screening computed tomographic angiography (CTA) performed within the first few days of the DCI risk period will accurately identify patients at low risk for subsequent DCI. Methods: This was a retrospective cohort study. Our institutional SAH outcomes registry was queried for all aSAH patients admitted in 2016-2019 who underwent screening CTA brain between days 4 and 8 following ictus. We excluded patients diagnosed with DCI prior to the first CTA performed during this time period. All variables are prospectively entered into the registry, and outcomes including DCI and LVV are prospectively adjudicated. We evaluated the predictive value and accuracy of moderate-to-severe LVV on CTA performed 4-8 days following ictus for the prediction of subsequent DCI. Results: A total of 243 aSAH patients were admitted during the study timeframe. Of the 54 patients meeting the eligibility criteria, 11 (20%) had moderate-to-severe LVV on the screening CTA study performed during the risk period. Seven of the 11 (64%) patients with moderate-to-severe LVV on the days 4-8 screening CTA vs. six of 43 (14%) patients without, subsequently developed DCI. On multivariate analysis, the presence of LVV on days 4-8 screening CTA was an independent predictor of DCI (odds ratio 10.26, 95% CI 1.69-62.24, p = 0.011). NPV for the subsequent development of DCI was 86% (95% CI 77-92%). Sensitivity was 54% (25-81%), specificity 90% (77-97%), and positive predictive value 64% (38-83%). Conclusions: The presence of moderate-to-severe LVV on screening CTA performed between days 4 and 8 following aSAH was an independent predictor of DCI, but achieved only moderate diagnostic accuracy, with NPV 86% and sensitivity 54%. Complementary risk-stratification strategies are likely necessary.

Volumetric quantification of aneurysmal subarachnoid hemorrhage independently predicts hydrocephalus and seizures.

OBJECTIVE: Hydrocephalus and seizures greatly impact outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH); however, reliable tools to predict these outcomes are lacking. The authors used a volumetric quantitative analysis tool to evaluate the association of total aSAH volume with the outcomes of shunt-dependent hydrocephalus and seizures. METHODS: Total hemorrhage volume following aneurysm rupture was retrospectively analyzed on presentation CT imaging using a custom semiautomated computer program developed in MATLAB that employs intensity-based k-means clustering to automatically separate blood voxels from other tissues. Volume data were added to a prospectively maintained aSAH database. The association of hemorrhage volume with shunted hydrocephalus and seizures was evaluated through logistic regression analysis and the diagnostic accuracy through analysis of the area under the receiver operating characteristic curve (AUC). RESULTS: The study population comprised 288 consecutive patients with aSAH. The mean total hemorrhage volume was 74.9 ml. Thirty-eight patients (13.2%) developed seizures. The mean hemorrhage volume in patients who developed seizures was significantly higher than that in patients with no seizures (mean difference 17.3 ml, p = 0.01). In multivariate analysis, larger hemorrhage volume on initial CT scan and hemorrhage volume > 50 ml (OR 2.81, p = 0.047, 95% CI 1.03-7.80) were predictive of seizures. Forty-eight patients (17%) developed shunt-dependent hydrocephalus. The mean hemorrhage volume in patients who developed shunt-dependent hydrocephalus was significantly higher than that in patients who did not (mean difference 17.2 ml, p = 0.006). Larger hemorrhage volume and hemorrhage volume > 50 ml (OR 2.45, p = 0.03, 95% CI 1.08-5.54) were predictive of shunt-dependent hydrocephalus. Hemorrhage volume had adequate discrimination for the development of seizures (AUC 0.635) and shunted hydrocephalus (AUC 0.629). CONCLUSIONS: Hemorrhage volume is an independent predictor of seizures and shunt-dependent hydrocephalus in patients with aSAH. Further evaluation of aSAH quantitative volumetric analysis may complement existing scales used in clinical practice and assist in patient prognostication and management.

Length of Stay Beyond Medical Readiness in a Neurosurgical Patient Population and Associated Healthcare Costs.

BACKGROUND: Length of stay beyond medical readiness (LOS-BMR) leads to increased expenses and higher morbidity related to hospital-acquired conditions. OBJECTIVE: To determine the proportion of admitted neurosurgical patients who have LOS-BMR and associated risk factors and costs. METHODS: We performed a prospective, cohort analysis of all neurosurgical patients admitted to our institution over 5 mo. LOS-BMR was assessed daily by the attending neurosurgeon and neuro-intensivist with a standardized criterion. Univariate and multivariate logistic regressions were performed. RESULTS: Of the 884 patients admitted, 229 (25.9%) had a LOS-BMR. The average LOS-BMR was 2.7 ± 3.1 d at an average daily cost of $9 148.28 ± $12 983.10, which resulted in a total cost of $2 076 659.32 over the 5-mo period. Patients with LOS-BMR were significantly more likely to be older and to have hemiplegia, dementia, liver disease, renal disease, and diabetes mellitus. Patients with a LOS-BMR were significantly more likely to be discharged to a subacute rehabilitation/skilled nursing facility (40.2% vs 4.1%) or an acute/inpatient rehabilitation facility (22.7% vs 1.7%, P < .0001). Patients with Medicare insurance were more likely to have a LOS-BMR, whereas patients with private insurance were less likely (P = .048). CONCLUSION: The most common reason for LOS-BMR was inefficient discharge of patients to rehabilitation and nursing facilities secondary to unavailability of beds at discharge locations, insurance clearance delays, and family-related issues.

Neurosurgical patients admitted via the emergency department initiating comfort care measures: a prospective cohort analysis.

BACKGROUND: Given the serious nature of many neurosurgical pathologies, it is common for hospitalized patients to elect comfort care (CC) over aggressive treatment. Few studies have evaluated the incidence and risk factors of CC trends in patients admitted for neurosurgical emergencies. OBJECTIVES: To analyze all neurosurgical patients admitted to a tertiary care academic referral center via the emergency department (ED) to determine incidence and characteristics of those who initiated CC measures during their initial hospital admission. METHODS: We performed a prospective, cohort analysis of all consecutive adult patients admitted to the neurosurgical service via the ED between October 2018 and May 2019. The primary outcome was the initiation of CC measures during the patient's hospital admission. CC was defined as cessation of life-sustaining measures and a shift in focus to maintaining the comfort and dignity of the patient. RESULTS: Of the 428 patients admitted during the 7-month period, 29 (6.8%) initiated CC measures within 4.0 ± 4.0 days of admission. Patients who entered CC were significantly more likely to have a medical history of cerebrovascular disease (58.6% vs. 33.3%, p = 0.006), dementia (17.2% vs. 1.5%, p = 0.0004), or cancer with metastatic disease (24.1% vs. 7.0%, p = 0.001). Patients with a presenting pathology associated with cerebrovascular disease were significantly more likely to initiate CC (62.1% vs. 35.3, p = 0.04). Patients who underwent emergent surgery were significantly more likely to enter CC compared with those who had elective surgery (80.0% vs. 42.7%, p = 0.02). Only 10 of the 29 (34.5%) patients who initiated CC underwent a neurosurgical operation (p = 0.002). Twenty of the 29 (69.0%) patients died within 0.8 ± 0.8 days after the initiation of CC measures. CONCLUSION: CC measures were initiated in 6.8% of patients admitted to the neurosurgical service via the ED, with the majority of patients entering CC before an operation and presenting with a cerebrovascular pathology.

The Predictive Value of the HOSPITAL Score and LACE Index for an Adult Neurosurgical Population: A Prospective Analysis.

OBJECTIVE: The HOSPITAL score (HS) and LACE index (LI) are 2 validated methods for quantifying the risk of 30-day unplanned readmission after discharge. However, neither score has been validated in the neurosurgical population. This study evaluated the HS and LI in the neurosurgical population as effective predictors for 30-day unplanned readmission. METHODS: We performed a prospective, cohort analysis of all consecutive adult patients admitted to the neurosurgical service between October 1, 2018 and May 1, 2019. Patient medical records were used to calculate HS and LI. HS defined groups as low risk (0-4), intermediate (5-6), and high (7-12); LI defined risk as low (1-4), moderate (5-9), and high (10-19). Data analysis used univariate and multivariate logistic regressions. RESULTS: The 1242 patients included 626 women (50.4%). The average age was 57.9 years, and most patients (86.5%) underwent surgery during their admission. In multivariate logistic regression, intermediate-risk HS was not predictive of 30-day readmission (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.57-1.88; P = 0.53), whereas high-risk HS did predict readmission (OR, 2.87; 95% CI, 1.49-5.54; P = 0.002). Likewise, moderate-risk LI was not predictive of 30-day unplanned readmission or mortality (OR, 1.59; 95% CI, 0.88-2.85; P = 0.12); however, high-risk LI did predict unplanned readmission or mortality (OR, 2.58; 95% CI, 1.16-5.73; P = 0.02). Both HS and LI showed poor to moderate discrimination (C = 0.62 and 0.60, respectively). CONCLUSIONS: A high-risk HS and high-risk LI were predictive of 30-day unplanned readmission. Although neither score is ideal for predicting moderate risk for 30-day unplanned readmission in neurosurgical patients, both have some predictiveness that may be clinically valuable.

Clinical Factors Associated With ICU-Specific Care Following Supratentoral Brain Tumor Resection and Validation of a Risk Prediction Score.

OBJECTIVES: The postoperative management of patients who undergo brain tumor resection frequently occurs in an ICU. However, the routine admission of all patients to an ICU following surgery is controversial. This study seeks to identify the frequency with which patients undergoing elective supratentorial tumor resection require care, aside from frequent neurologic checks, that is specific to an ICU and to determine the frequency of new complications during ICU admission. Additionally, clinical predictors of ICU-specific care are identified, and a scoring system to discriminate patients most likely to require ICU-specific treatment is validated. DESIGN: Retrospective observational cohort study. SETTING: Academic neurosurgical center. PATIENTS: Two-hundred consecutive adult patients who underwent supratentorial brain tumor surgery. An additional 100 consecutive patients were used to validate the prediction score. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Univariate statistics and multivariable logistic regression were used to identify clinical characteristics associated with ICU-specific treatment. Eighteen patients (9%) received ICU-specific care, and 19 (9.5%) experienced new complications or underwent emergent imaging while in the ICU. Factors significantly associated with ICU-specific care included nonelective admission, preoperative Glasgow Coma Scale, and volume of IV fluids. A simple clinical scoring system that included Karnofsky Performance Status less than 70 (1 point), general endotracheal anesthesia (1 point), and any early postoperative complications (2 points) demonstrated excellent ability to discriminate patients who required ICU-specific care in both the derivation and validation cohorts. CONCLUSIONS: Less than 10% of patients required ICU-specific care following supratentorial tumor resection. A simple clinical scoring system may aid clinicians in stratifying the risk of requiring ICU care and could inform triage decisions when ICU bed availability is limited.

A propensity score analysis of the impact of surgical intervention on unexpected 30-day readmission following admission for subdural hematoma.

OBJECTIVE: Subdural hematoma (SDH) is a common disease that is increasingly being managed nonoperatively. The all-cause readmission rate for SDH has not previously been described. This study seeks to describe the incidence of unexpected 30-day readmission in a cohort of patients admitted to an academic neurosurgical center. Additionally, the relationship between operative management, clinical outcome, and unexpected readmission is explored. METHODS: This is an observational study of 200 consecutive adult patients with SDH admitted to the neurosurgical ICU of an academic medical center. Demographic information, clinical characteristics, and treatment strategies were compared between readmitted and nonreadmitted patients. Multivariable logistic regression, weighted by the inverse probability of receiving surgery using propensity scores, was used to evaluate the association between operative management and unexpected readmission. RESULTS: Of 200 total patients, 18 (9%) died during hospitalization and were not included in the analysis. Overall, 48 patients (26%) were unexpectedly readmitted within 30 days. Sixteen patients (33.3%) underwent SDH evacuation during their readmission. Factors significantly associated with unexpected readmission were nonoperative management (72.9% vs 54.5%, p = 0.03) and female sex (50.0% vs 32.1%, p = 0.03). In logistic regression analysis weighted by the inverse probability of treatment and including likely confounders, surgical management was not associated with likelihood of a good outcome at hospital discharge, but was associated with significantly reduced odds of unexpected readmission (OR 0.19, 95% CI 0.08-0.49). CONCLUSIONS: Over 25% of SDH patients admitted to an academic neurosurgical ICU were unexpectedly readmitted within 30 days. Nonoperative management does not affect outcome at hospital discharge but is significantly associated with readmission, even when accounting for the probability of treatment by propensity score weighted logistic regression. Additional research is needed to validate these results and to further characterize the impact of nonoperative management on long-term costs and clinical outcomes.

A Propensity Score Analysis of the Impact of Dexamethasone Use on Delayed Cerebral Ischemia and Poor Functional Outcomes After Subarachnoid Hemorrhage.

OBJECTIVE: An inflammatory response occurs after aneurysmal subarachnoid hemorrhage (aSAH) and predicts poor outcomes. Glucocorticoids suppress inflammation and promote fluid retention. Dexamethasone is often administered after aSAH for postoperative cerebral edema and refractory headache. Our objective was to examine the impact of dexamethasone use on functional outcomes and delayed cerebral ischemia (DCI) after aSAH. METHODS: Patients with aSAH admitted between 2010 and 2015 were included; the data source was a single-center subarachnoid hemorrhage registry. The intervention of interest was a dexamethasone taper used <7 days from ictus. The primary outcome was poor discharge functional outcome, with a modified Rankin Scale score >3. Other outcomes included DCI and infection. A propensity score for use of dexamethasone was calculated using a logistic regression model that included potential predictors of dexamethasone use and outcome. The impact of dexamethasone on outcomes of interest was calculated and the propensity score was controlled for. RESULTS: A total of 440 patients with subarachnoid hemorrhage were admitted during the study period and 309 met eligibility criteria. Dexamethasone was administered in 101 patients (33%). A total of 127 patients (41%) had a discharge modified Rankin Scale score >3, 105 (34%) developed DCI, and 94 (30%) developed an infection. After propensity score analysis, dexamethasone use was associated with a significant reduction in poor functional outcomes (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.19-0.66) but showed no significant association with DCI (OR, 0.93; 95% CI, 0.53-1.64) or infection (OR, 0.60; 95% CI, 0.34-1.06). CONCLUSIONS: Dexamethasone use after aSAH was associated with a reduction in poor functional outcomes at discharge but not DCI, controlling for predictors of dexamethasone use.

Twenty-four-hour emergency intervention versus early intervention in aneurysmal subarachnoid hemorrhage.

OBJECTIVE Recent observational data suggest that ultra-early treatment of ruptured aneurysms prevents rebleeding, thus improving clinical outcomes. However, advances in critical care management of patients with ruptured aneurysms may reduce the rate of rebleeding in comparison with earlier trials, such as the International Cooperative Study on the Timing of Aneurysm Surgery. The objective of the present study was to determine if an ultra-early aneurysm repair protocol will or will not significantly reduce the number of incidents of rebleeding following aneurysmal subarachnoid hemorrhage (SAH). METHODS A retrospective analysis of data from a prospectively collected cohort of patients with SAH was performed. Rebleeding was diagnosed as new or expanded hemorrhage on CT, which was determined by independent review conducted by multiple physicians. Preventability of rebleeding by ultra-early aneurysm clipping or coiling was also independently reviewed. Standard statistics were used to determine statistically significant differences between the demographic characteristics of those with rebleeding compared with those without. RESULTS Of 317 patients with aneurysmal SAH, 24 (7.6%, 95% CI 4.7-10.5) experienced rebleeding at any time point following initial aneurysm rupture. Only 1/24 (4.2%, 95% CI -3.8 to 12.2) incidents of rebleeding could have been prevented by a 24-hour ultra-early aneurysm repair protocol. The other 23 incidents could not have been prevented for the following reasons: rebleeding prior to admission to the authors' institution (14/23, 60.9%); initial diagnostic angiography negative for aneurysm (4/23, 17.4%); postoperative rebleeding (2/23, 8.7%); patient unable to undergo operation due to medical instability (2/23, 8.7%); intraoperative rebleeding (1/23, 4.3%). CONCLUSIONS At a single tertiary academic center, the overall rebleeding rate was 7.6% (95% CI 4.7-10.5) for those presenting with ruptured aneurysms. Implementation of a 24-hour ultra-early aneurysm repair protocol would only result in, at most, a 0.3% (95% CI -0.3 to 0.9) reduction in the incidence of rebleeding.

A Randomized Trial of Central Venous Catheter Type and Thrombosis in Critically Ill Neurologic Patients.

BACKGROUND: Observational studies suggest peripherally inserted central venous catheters (PICCs) are associated with a high risk of catheter-related large vein thrombosis (CRLVT) in critically ill neurologic patients. We evaluated the difference in thrombosis risk between PICCs and centrally inserted central venous catheters (CICVCs). METHODS: We conducted a pragmatic, randomized controlled trial of critically ill adult neurologic patients admitted to neurological and trauma critical care units at two level I trauma centers. Patients were randomized to receive either a PICC or CICVC and undergo active surveillance for CRLVT or death within 15 days of catheter placement. RESULTS: In total, 39 subjects received a PICC and 41 received a CICVC between February 2012 and July 2015. The trial was stopped after enrollment of 80 subjects due to feasibility affected by slow enrollment and funding. In the primary intention-to-treat analysis, 17 (43.6 %) subjects that received a PICC compared to 9 (22.0 %) that received a CICVC experienced the composite of CRLVT or death, with a risk difference of 21.6 % (95 % CI 1.57-41.71 %). Adjusted common odds ratio of CRLVT/death was significantly higher among subjects randomized to receive a PICC (adjusted OR 3.08; 95 % CI 1.1-8.65). The higher adjusted odds ratio was driven by risk of CRLVT, which was higher in those randomized to PICC compared to CICVC (adjusted OR 4.66; 95 % CI 1.3-16.76) due to increased large vein thrombosis without a reduction in proximal deep venous thrombosis. CONCLUSIONS: Our trial demonstrates that critically ill neurologic patients who require a central venous catheter have significantly lower odds of ultrasound-diagnosed CRLVT with placement of a CICVC as compared to a PICC.

The Association Between Spontaneous Hyperventilation, Delayed Cerebral Ischemia, and Poor Neurological Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: The frequency and associations of spontaneous hyperventilation in subarachnoid hemorrhage (SAH) are unknown. Because hyperventilation decreases cerebral blood flow, it may exacerbate delayed cerebral ischemia (DCI) and worsen neurological outcome. METHODS: This is a retrospective analysis of data from a prospectively collected cohort of SAH patients at an academic medical center. Spontaneous hyperventilation was defined by PaCO2 <35 mmHg and pH >7.45 and subdivided into moderate and severe groups. Clinical and demographic characteristics of patients with and without spontaneous hyperventilation were compared using χ (2) or t tests. Bivariate and multivariable logistic regression analyses were conducted to examine the association of moderate and severe hyperventilation with DCI and discharge neurological outcome. RESULTS: Of 207 patients, 113 (55 %) had spontaneous hyperventilation. Spontaneously hyperventilating patients had greater illness severity as measured by the Hunt-Hess, World Federation of Neurosurgical Societies (WFNS), and SAH sum scores. They were also more likely to develop the following complications: pneumonia, neurogenic myocardial injury, systemic inflammatory response syndrome (SIRS), radiographic vasospasm, DCI, and poor neurological outcome. In a multivariable logistic regression model including age, gender, WFNS, SAH sum score, pneumonia, neurogenic myocardial injury, etiology, and SIRS, only moderate [odds ratio (OR) 2.49, 95 % confidence interval (CI) 1.10-5.62] and severe (OR 3.12, 95 % CI 1.30-7.49) spontaneous hyperventilation were associated with DCI. Severe spontaneous hyperventilation (OR 4.52, 95 % CI 1.37-14.89) was also significantly associated with poor discharge outcome in multivariable logistic regression analysis. CONCLUSION: Spontaneous hyperventilation is common in SAH and is associated with DCI and poor neurological outcome.

A case-cohort study with propensity score matching to evaluate the effects of mannitol on venous thromboembolism.

Mannitol has been shown to damage endothelial cells and activate coagulation pathways leading to intravascular thrombosis. Dehydration and hemagglutination have also been associated with mannitol use, although the risk of clinically evident venous thromboembolism (VTE) disease is not well-defined. The aim of this study was to compare the risk of VTE in critically ill neurological patients who received mannitol compared to only hypertonic saline. A case-cohort study design with propensity score matching was used to evaluate the risk of VTE among patients who received mannitol compared to those who received hypertonic saline alone. The odds of thrombosis were evaluated by the Cochran-Mantel-Haenszel method and conditional logistic regression was used to adjust for year of treatment. Ninety-one of 330 patients (27.6%; 95% confidence interval [CI] 23-33%) developed a VTE; however, the yearly proportion remained unchanged over the 8 year study period. Cumulative use of mannitol declined and use of hypertonic saline increased significantly. The odds of thrombosis for those exposed to mannitol compared to hypertonic saline alone was 1.11 (95% CI 0.65-1.73; p=0.75). This remained insignificant after adjusting for year of injury. In conclusion, despite a significant change in the pattern of osmotic therapy used at our institution, the proportion of patients with VTE remained unchanged. We found no evidence that mannitol use was associated with VTE compared to hypertonic saline alone.

Inter-observer agreement on the diagnosis of neurocardiogenic injury following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Neurocardiogenic injury results from increased sympathetic nervous system activation following acute brain injury. No diagnostic criteria for neurocardiogenic injury exist, and agreement has not been tested. We investigated the agreement by neurointensivists for the presence of neurocardiogenic injury on routine cardiac studies. METHODS: Six neurointensivists rated 100 consecutive cases of aneurysmal subarachnoid hemorrhage (aSAH) for the presence of neurocardiogenic injury. A fixed-panel design was employed for the agreement among the whole cohort, as well as stratified by modified Fisher Scale (mFs), Hunt and Hess grade, gender, and the presence of elevated cardiac enzymes. Overall percent agreement, paired agreement, and agreement above change (Fleiss' Kappa) were calculated. Overall percent agreement between groups was compared using Chi square tests. RESULTS: Six raters completed the survey for a total 600 responses. Overall percent agreement was 79.3 %, and agreement among cases at least one rater thought had neurocardiogenic injury was 66.5 % (paired agreement). Fleiss' Kappa was 0.66 (95 % CI, 0.1-0.71; p < 0.0001), indicating substantial agreement above chance. Similarly, on subgroup analysis, significant agreement beyond chance was seen in all groups (p < 0.001). Overall percent agreement was significantly better among mFs 3-4 compared to mFs ≤ 2 (81.3 vs. 63.6 %; p = 0.018) and among cases with positive cTI (96.9 vs. 70.1 %; p ≤ 0.001). CONCLUSIONS: Overall, we demonstrated substantial agreement for the presence of neurocardiogenic injury on early cardiac studies following aSAH. However, inter-observer variability increased when evaluating patients without the objective finding of elevated cTI and among those with lower clinical and radiographic grades.

Hyaluronic acid of high molecular weight inhibits proliferation and induces cell death in U937 macrophage cells.

Hyaluronic acid (HA), a major glycosaminoglycan component of the extracellular matrix, has regulatory influences on cells and cellular activities. To explore the effects of a high concentration (1 mg/mL) of high molecular weight HA (500-730 kD) on U937 macrophage growth dynamics, three factors that influence overall cellular growth, namely proliferation, apoptosis, and cell death, were examined. Cells were cultured with HA and were analyzed by flow cytometry every 24 hours during a 168-hour period for proliferation and the presence of apoptotic and dead cells. These analyses demonstrated that HA inhibits U937 macrophage proliferation in a time-dependent manner. Through the first 72 hours, cells exhibited slowed proliferation. However, no evidence of cell division arrest or reduced cell viability was observed. Thereafter, HA continued to diminish proliferation, but induced apoptosis. This data is consistent with regulatory influences secondary to HA binding to CD44 and/or RHAMM cell surface receptors, both of which were shown to be expressed on U937 macrophages. This study demonstrates that a high concentration of high molecular weight HA greatly inhibits macrophage population growth by the dual actions of impeding cell proliferation and inducing apoptosis.

Hyalgan has a dose-dependent differential effect on macrophage proliferation and cell death.

The intra-articular injection of high molecular weight hyaluronic acid (HA) has been reported to be an effective treatment for pain of osteoarthritis of the knee. However, the mechanism by which HA exerts its effect is unknown. To explore HA's influence on the growth of U937 human macrophages, cells were incubated for 168 h with three concentrations, 1, 0.1 and 0.01 mg/mL, of Hyalgan, a high molecular weight HA preparation. At 24-h increments, the cells were examined for proliferation, cell cycle distribution as well as the number of apoptotic and dead cells. Exposing macrophages to 1 mg/mL Hyalgan significantly reduced the rate of cellular proliferation and altered the cell cycle distribution to yield decreased proportions of G0/G1 cells but increased S and G2/M cells. Concomitantly, a 10-fold increase in apoptotic cells and a 12-fold increase in dead cells were observed. The population doubling time (PDT) for cells treated with 1.0 mg/mL Hyalgan increased from 23.6 to 52.9 h. By contrast, the two lower Hyalgan concentrations significantly promoted macrophage proliferation in a dose-dependent manner. They also increased the proportion of G2/M cells, but had no effect on the number of apoptotic or dead cells. The PDTs of 21.5 and 22.2 h were less than the control time of 23.6 h. These results demonstrate that Hyalgan concentrations have a differential effect on macrophage growth dynamics and suggest an anti-inflammatory effect at high HA concentrations.