The Effects of Pulmonary Risk Factors and Combination Thoracic Osseous Fractures on Mortality and Outcomes of Surgical Stabilization of Rib Fractures.

BACKGROUND: Rib fixation for traumatic rib fractures is advocated to decrease morbidity and mortality in select patient populations. We intended to investigate the effect of combination osseous thoracic injuries on mortality with the hypothesis that combination injuries will worsen overall mortality and that SSRF will improve outcomes in combination injuries and in high-risk patients. METHODS: Patients with rib fractures were identified from the Trauma Quality Improvement Project registry from 2019. Patients were then divided into rib fracture(s) alone or in combination with sternal, thoracic vertebra, or scapula fracture. Patients were also categorized into those with COPD and smokers. Patients with AIS >3 outside of thorax were excluded. Patients were subcategorized into those who had rib fixation verse nonoperative management for all subgroups. Analysis was performed to evaluate the efficacy of rib fixation. RESULTS: A total of 111,066 patients were included for analysis. The overall mortality was 1.4%. Patients with COPD had over double the mortality risk, with an overall mortality of 3.4%. Combination injuries did not appear to increase mortality. SSRF did not decrease mortality; however, the number of patients in this group was too small to complete statistical analysis. The overall complication rate was 0.43%. There was a trend towards an increase in extrapulmonary complications in the group that underwent surgical fixation. DISCUSSION: Mortality from rib fractures with concomitant osseous thoracic fracture appears to be low. However, mortality is increased in patients with COPD regardless of rib fracture pattern. The number of patients who underwent SSRF was too small to make a statistical comparison.

Diagnostic Adjunct Techniques in the Assessment of Hypovolemia: A Prospective Pilot Project.

INTRODUCTION: Measuring the hypovolemic resuscitation end point remains a critical care challenge. Our project compared clinical hypovolemia (CH) with three diagnostic adjuncts: 1) noninvasive cardiac output monitoring (NICOM), 2) ultrasound (US) static IVC collapsibility (US-IVC), and 3) US dynamic carotid upstroke velocity (US-C). We hypothesized US measures would correlate more closely to CH than NICOM. METHODS: Adult trauma/surgical intensive care unit patients were prospectively screened for suspected hypovolemia after acute resuscitation, excluding patients with burns, known heart failure, or severe liver/kidney disease. Adjunct measurements were assessed up to twice a day until clinical improvement. Hypovolemia was defined as: 1) NICOM: ≥10% stroke volume variation with passive leg raise, 2) US-IVC: <2.1 cm and >50% collapsibility (nonventilated) or >18% collapsibility (ventilated), 3) US-C: peak systolic velocity increase 15 cm/s with passive leg raise. Previously unknown cardiac dysfunction seen on US was noted. Observation-level data were analyzed with a Cohen's kappa (κ). RESULTS: 44 patients (62% male, median age 60) yielded 65 measures. Positive agreement with CH was 47% for NICOM, 37% for US-IVC and 10% for US-C. None of the three adjuncts correlated with CH (κ -0.045 to 0.029). After adjusting for previously unknown cardiac dysfunction present in 10 patients, no adjuncts correlated with CH (κ -0.036 to 0.031). No technique correlated with any other (κ -0.118 to 0.083). CONCLUSIONS: None of the adjunct measurements correlated with CH or each other, highlighting that fluid status assessment remains challenging in critical care. US should assess for right ventricular dysfunction prior to resuscitation.

Gender-Based Frailty in Multiple Orthopedic Fractures.

The 5-factor modified frailty index (mFI-5) has been used as a prognostic tool to identify patients at higher risk for complications and mortality but has not been used to assess the relationship between frailty and extent of injury following ground-level falls. The aim of this study was to determine if mFI-5 is associated with increased risk for combined femur-humerus fractures compared to isolated femur fractures in geriatric patients. A retrospective analysis of 2017-2018 American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) data identified 190 836 patients with femur fractures and 5054 patients with combined femur-humerus fractures. In multivariate analysis, gender was the only statistically significant predictor for risk of combined vs isolated fractures (OR 1.69, 95% CI [1.65, 1.74], P < .001). While outcome data for the mFI-5 repeatedly shows increased risk for adverse events, this tool may over-estimate the disease specific risk factors rather than the overall frailty state of the patient and diminish its predictive power.

Combined Upper-Lower Extremities Fractures in the Elderly.

Age-related bone loss is believed to increase the risk of traumatic fragility fractures in both men and women. We aimed to determine the risk factors associated with simultaneous fractures in the upper-lower extremities. This retrospective study utilized the ACS-TQIP database from 2017 to 2019 to identify patients with respective fractures caused by ground-level falls. A total of 403,263 patients with femur fractures and 7,575 patients with combined upper-lower extremities (humerus-femur) fractures were identified. Patients had higher odds of combined upper-lower extremities fractures with increasing age: 18-64 (OR 1.05, P < .001); 65-74 (OR 1.72, P < .001); and 75-89 (OR 1.90, P < .001) while adjusting for other statistically significant risk factors. Advanced age increases the risk of traumatic combined upper-lower extremities fractures. Prevention strategies should be emphasized to reduce the burden of simultaneous injury in the upper-lower extremities.

Age-Related Outcomes in Le Fort Fractures.

This study aims to provide patient characteristics and short-term clinical outcomes of Le Fort fractures. Using the National Surgical Quality Improvement Program database from 2016 to 2019, cases involving Le Fort fractures on initial encounters were reviewed. 130 cases from 3293 facial fractures were identified. 70 cases were diagnosed with type I, 41 with type II, and 19 with type III. The male-to-female ratio was 4.9:1. Compared to geriatric patients (>65 years old), Le Fort fractures were more common among patients between the ages of 18 and 65 (P < .003). 5.4% of patients had in-hospital complications, including sepsis, superficial-deep incisional surgical site infection, and wound disruption. Two patients (1.5%) were readmitted, while three (2.3%) underwent reoperation. Type I fractures in adult males are the most common presentation. Overall complication rates for surgical repairs are low.

Development of Imaging Criteria for Geriatric Blunt Trauma Patients.

INTRODUCTION: Current decision tools to guide trauma computed tomography (CT) imaging were not validated for use in older patients. We hypothesized that specific clinical variables would be predictive of injury and could be used to guide imaging in this population to minimize risk of missed injury. METHODS: Blunt trauma patients aged 65 y and more admitted to a Level 1 trauma center intensive care unit from January 2018 to November 2020 were reviewed for histories, physical examination findings, and demographic information known at the time of presentation. Injuries were defined using the patient's final abbreviated injury score codes, obtained from the trauma registry. Abbreviated injury score codes were categorized by corresponding CT body region: Head, Face, Chest, C-Spine, Abdomen/Pelvis, or T/L-Spine. Variable groupings strongly predictive of injury were tested to identify models with high sensitivity and a negative predictive value. RESULTS: We included 608 patients. Median age was 77 y (interquartile range, 70-84.5) and 55% were male. Ground-level fall was the most common injury mechanism. The most commonly injured CT body regions were Head (52%) and Chest (42%). Variable groupings predictive of injury were identified in all body regions. We identified models with 97.8% sensitivity for Head and 98.8% for Face injuries. Sensitivities more than 90% were reached for all except C-Spine and Abdomen/Pelvis. CONCLUSIONS: Decision aids to guide imaging for older trauma patients are needed to improve consistency and quality of care. We have identified groupings of clinical variables that are predictive of injury to guide CT imaging after geriatric blunt trauma. Further study is needed to refine and validate these models.

Home Medication Regimens Increase in Complexity After Admission for Fall in the Older Trauma Patient.

BACKGROUND: Hospitalization for the older trauma patient is an opportunity to assess polypharmacy. We hypothesized that medication regimen complexity (RxCS) and pain medication prescriptions (PRxs) would increase in older home-going patients admitted for a fall. METHODS: We retrospectively chart reviewed patients ≥45 years old admitted for a fall at a level 1 trauma center who were discharged home with full medication documentation. RxCS was compared pre-admission and post-discharge with Wilcoxon signed-rank tests; opioid and non-opioid PRxs were compared with Fisher's exact test, α = .05. RESULTS: 103 patients met inclusion criteria; 58% were ≥65 years old. RxCS (9 [.5-13] to 11 [4.5-15], P < .01) increased on discharge. Opioid PRx rates increased significantly in all age groups. Non-opioid PRx rates increased significantly for patients <65 but not for patients ≥65. CONCLUSIONS: Admission for a fall was associated with increases in RxCS, while PRx changes were age-dependent. Providers should recognize that admissions for older patients who fall after trauma are underutilized opportunities to address polypharmacy in high-risk patients.

What If We Do Not Operate? Outcomes of Nonoperatively Managed Emergency General Surgery Patients.

INTRODUCTION: Although two-thirds of patients with emergency general surgery (EGS) conditions are managed nonoperatively, their long-term outcomes are not well described. We describe outcomes of nonoperative management in a cohort of older EGS patients and estimate the projected risk of operative management using the NSQIP Surgical Risk Calculator (SRC). MATERIALS AND METHODS: We studied single-center inpatients aged 65 y and more with an EGS consult who did not undergo an operation (January 2019-December 2020). For each patient, we recorded the surgeon's recommendation as either an operation was "Not Needed" (medical management preferred) or "Not Recommended" (risk outweighed benefits). Our main outcome of interest was mortality at 30 d and 1 y. Our secondary outcome of interest was SRC-projected 30-day postoperative mortality risk (median % [interquartile range]), calculated using hypothetical low-risk and high-risk operations. RESULTS: We included 204 patients (60% female, median age 75 y), for whom an operation was "Not Needed" in 81% and "Not Recommended" in 19%. In this cohort, 11% died at 30 d and 23% died at 1 y. Mortality was higher for the "Not Recommended" cohort (37% versus 5% at 30 d and 53% versus 16% at 1 y, P < 0.05). The SRC-projected 30-day postoperative mortality risk was 3.7% (1.3-8.7) for low-risk and 5.8% (2-11.8) for high-risk operations. CONCLUSIONS: Nonoperative management in older EGS patients is associated with very high risk of short-term and long-term mortality, particularly if a surgeon advised that risks of surgery outweighed benefits. The SRC may underestimate risk in the highest-risk patients.

In-person radiologist to review the trauma panscan: a high-fidelity simulation training program for radiology trainees at an academic level 1 trauma center.

BACKGROUND: Radiology trainees were uncomfortable going to the CT scanner to review trauma panscans and interacting with trauma surgeons. OBJECTIVE: This study aims to determine if radiology residents can be trained to accurately identify injuries requiring immediate surgical attention at the CT scanner. METHODS: A high-fidelity simulation model was created to provide an immersive training experience. Between February 2015 and April 2017, 62 class 1 trauma panscans were read at the CT scanner by 11 PGY-3 radiology residents. Findings made at the scanner were compared to resident preliminary and attending radiology reports and correlated with clinical outcomes. Timestamps were recorded and analyzed. Surveys were administered to assess the impact of training on radiology residents' self-confidence and to assess trauma surgeons' preference for radiology at the scanner. Significance level was set at p < 0.05. RESULTS: The mean time to provide results at the CT scanner was 11.1 min. Mean time for the preliminary report for CT head and cervical spine was 24.4 ± 9.8 min, and for the CT chest, abdomen, and pelvis was 16.3 ± 6.9 min. 53 traumatic findings on 62 panscans were identified at the scanner and confirmed at preliminary and final reports, for a concordance rate of 85%, compared to 72% for the control group. Radiology residents agreed or strongly agreed the training prepared them for trauma panscan reporting. Trauma surgeons shifted in favor of radiology presence at the scanner. CONCLUSION: Radiology residents can be trained to accurately and rapidly identify injuries requiring immediate surgical attention at the CT scanner. CLINICAL IMPACT: These findings support the value-added of an in-person radiologist at the CT scanner for whole-body trauma panscans to facilitate timely detection of life-threatening injuries and improve professional relations between radiologists and trauma surgeons.

Re-Admission in Patients with Necrotizing Soft Tissue Infections: Continuity of Care Matters.

Background: Necrotizing soft tissue infections (NSTIs) are rapidly progressive infections with high mortality and complication rates. The incidence of NSTIs has been increasing steadily whereas mortality has decreased; survivors have a high risk of re-hospitalization. We hypothesized that re-admission to the index hospital where the first admission occurred would be associated with better clinical outcomes compared with re-admission to a non-index hospital. Patients and Methods: We identified patients from the 2017 Nationwide Readmissions Database with an index admission for NSTIs and examined all-cause re-admissions within 90 days of discharge. We noted whether re-admission occurred at the index or a non-index hospital. Survey-weighted logistic regression identified factors associated with death at the first re-admission and re-admission to index hospital. We also compared patient outcomes between patients admitted to index versus non-index hospitals. Results: We identified 27,051 NSTI survivors, of whom 6,954 (25.7%) had an unplanned re-admission within 90 days. A large proportion of re-admission occurred at non-index hospitals (28.3%; n = 1,966). Factors associated with non-index re-admission included prolonged index length of stay, discharge to short-term hospital, and leaving against medical advice. Patients re-admitted to index hospitals had a lower mortality rate (4.7% vs. 6.7%; p = 0.003), lower admission costs (in $1000; 45 [23-88] vs. 50 [24-104]; p = 0.004) and higher discharge rate to home (55.7% vs. 48.6%; p < 0.001). Conclusions: More than one-quarter of re-admissions among NSTI survivors were to non-index hospitals. Continuity of care is important because re-admission to the index hospital was associated with better patient outcomes.

Do new trauma centers provide needed or redundant access? A nationwide analysis.

BACKGROUND: Our prior research has demonstrated that increasing the number of trauma centers (TCs) in a state does not reliably improve state-level injury-related mortality. We hypothesized that many new TCs would serve populations already served by existing TCs, rather than in areas without ready TC access. We also hypothesized that new TCs would also be less likely to serve economically disadvantaged populations. METHODS: All state-designated adult TCs registered with the American Trauma Society in 2014 and 2019 were mapped using ArcGIS Pro (ESRI Inc., Redlands, CA). Trauma centers were grouped as Level 1 or 2 (Lev12) or Level 3, 4 or 5 (Lev345). We also obtained census tract-level data (73,666 tracts), including population counts and percentage of population below the federal poverty threshold. Thirty-minute drive-time areas were created around each TC. Census tracts were considered "served" if their geographic centers were located within a 30-minute drive-time area to any TC. Data were analyzed at the census tract level. RESULTS: A total of 2,140 TCs were identified in 2019, with 256 new TCs and 151 TC closures. Eighty-two percent of new TCs were Levels 3 to 5. Nationwide, coverage increased from 75.3% of tracts served in 2014 to 78.1% in 2019, representing an increased coverage from 76.0% to 79.4% of the population. New TC served 17,532 tracts, of which 87.3% were already served. New Lev12 TCs served 9,100 tracts, of which 91.2% were already served; new Lev345 TCs served 15,728 tracts, of which 85.9% were already served. Of 2,204 newly served tracts, those served by Lev345 TCs had higher mean percentage poverty compared with those served by Lev12 TCs (15.7% vs. 13.2% poverty, p < 0.05). DISCUSSION: Overall, access to trauma care has been improving in the United States. However, the majority of new TCs opened in locations with preexisting access to trauma care. Nationwide, Levels 3, 4, and 5 TCs have been responsible for expanding access to underserved populations. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level IV.

Predictors for Withdrawal of Life-Sustaining Therapies in Patients With Traumatic Brain Injury: A Retrospective Trauma Quality Improvement Program Database Study.

Many patients with severe traumatic brain injuries (TBIs) undergo withdrawal of life-sustaining therapies (WLSTs) or transition to comfort measures, but noninjury factors that influence this decision have not been well characterized. We hypothesized that WLST would be associated with institutional and geographic noninjury factors. All patients with a head Abbreviated Injury Scale score ≥3 were identified from 2016 Trauma Quality Improvement Program data. We analyzed factors that might be associated with WLST, including procedure type, age, sex, race, insurance, Glasgow Coma Scale score, mechanism of injury, geographic region, and institutional size and teaching status. Adjusted logistic regression was performed to examine factors associated with WLST. Sixty-nine thousand fifty-three patients were identified: 66% male, 77% with isolated TBI, and 7.8% had WLST. The median age was 56 years (34-73). A positive correlation was found between increasing age and WLST. Women were less likely to undergo WLST than men (odds ratio 0.91 [0.84-0.98]) and took more time to for WLST (3 vs 2 days, P < .001). African Americans underwent WLST at a significantly lower rate (odds ratio 0.66 [0.58-0.75]). Variations were also discovered based on US region, hospital characteristics, and neurosurgical procedures. WLST in severe TBI is independently associated with noninjury factors such as sex, age, race, hospital characteristics, and geographic region. The effect of noninjury factors on these decisions is poorly understood; further study of WLST patterns can aid health care providers in decision making for patients with severe TBI.

The combined effects of alcohol and marijuana use prior to traumatic brain injury on mortality.

BACKGROUND: Alcohol (ETOH) intoxication is a common comorbidity in traumatic brain injury (TBI), and marijuana (THC) has been implicated as a major risk factor for trauma. The objective this study was to investigate the combined effects of ETOH and THC on mortality after TBI. MATERIALS AND METHODS: A retrospective review of patient data was performed to assess adult (>18 years) patients with brain injuries between January 2012 and December 2018. Included patients sustained TBI (Abbreviated Injury Scale (AIS 1-6)) and were divided into two groups: No Substances and THC + ETOH. RESULTS: 1085 (median age 52 years [range: 18-97 years]; 33.5% female (364/1085)) patients met the inclusion criteria. Significant differences for mortality at discharge were found between groups (p = 0.0025) with higher mortality in the No Substances group. On multiple logistic regression, a positive test for both ETOH + THC was found not to independently predict mortality at discharge, while age, Glasgow Coma Scale, intensive care unit stay, Injury Severity Score, length of hospital stay, and days on ventilator were independent predictors. CONCLUSIONS: After controlling for confounding variables, positive ETOH + THC screens were not found to be independent predictors of mortality at discharge. Therefore, our results indicated no survival benefit for TBI patients with concomitant ETOH and THC use prior to injury.

The effects of alcohol and marijuana on survival after severe traumatic brain injury: A retrospective cohort study.

BACKGROUND: Alcohol (ETOH) and marijuana (THC) use have previously shown to improve outcomes after Traumatic Brain Injury (TBI). However, whether TBI severity impacts outcomes among patients tested positive for both ETOH and THC remains unclear. MATERIALS AND METHODS: A retrospective review from the Northern Ohio Regional Trauma Registry, which includes deidentified data from six regional hospitals, including three Level 1 and three Level 3 trauma centers, was performed to assess adult (>18 years) patients with severe TBI (head Abbreviated Injury Score ≥ 3) between January 2012 and December 2018 having an alcohol and drug toxicology screen and data regarding outcome at discharge. Patients were divided into two groups: 1) patients with a negative ETOH and drug test, and 2) patients positive for ETOH + THC. Mortality at discharge was the primary outcome measure and multiple logistic regression was used to assess predictors of mortality at discharge. RESULTS: A total of 854 (median age: 51 years [range: 18-72]; 34.4% female [294/854]) patients were included. On multiple logistic regression, age (p = 0.003), days in intensive care unit (ICU) (p < 0.001), Glasgow Coma Scale (GCS) (p < 0.001), Injury Severity Score (ISS) (p < 0.001), length of stay (LOS) (p < 0.001), and days on ventilator support (p = 0.032) were significant predictors of mortality at discharge. Blood alcohol content (BAC), cause of TBI, drug class, and sex were not significant predictors of mortality at discharge. CONCLUSIONS: After severe TBI, positive THC and BAC screening did not predict mortality at discharge after controlling for confounding variables, indicating no survival benefit for patients with severe TBI.

Grade of injury, not initial management, is associated with unplanned interventions in liver injury.

INTRODUCTION: Risk factors for complications after liver injury do not distinguish between patients undergoing selective non-operative management (sNOM) vs operative management (OM) as the initial treatment strategy. Our objective was to identify risk factors for complications requiring an unplanned intervention following sNOM or OM. We hypothesized that patient undergoing sNOM will have fewer unplanned interventions. METHODS: Adults presenting to a level I trauma center with grade III or higher liver injury over a period of 6 years were reviewed. Patient and injury factors, initial management strategy, subsequent complications and interventions were obtained. Bivariate analysis was performed between patients undergoing sNOM vs OM to determine factors associated with unplanned interventions, defined as intervention >48 h after injury. Logistic regression was performed to identify independent risk factors for unplanned interventions. RESULTS: 191 patients were identified: 105 (55%) grade III, 64 (34%) grade IV, and 22 (12%) grade V injury; 136 (71%) underwent sNOM and 55 (29%) underwent OM. 21 (15%) patients required an unplanned intervention: 26 percutaneous drainage, 10 ERCP, and 3 angiography; 12 had multiple procedures. Male gender, younger age, higher ISS, higher grade of injury, firearm mechanism, and initial OM (all p < 0.05) were associated with unplanned interventions. Firearm mechanism and injury grade IV and V, but not initial OM, were independent risk factors for an unplanned intervention. CONCLUSIONS: Grade of liver injury, not the initial mode of treatment, was significantly associated with requiring an unplanned intervention for liver-related complications. Surveillance at 7-10 days, or prior to discharge, in the high-risk group may be able to capture those requiring unplanned intervention and readmission.

Opioid prescribing in minimally injured trauma patients: Effect of a state prescribing limit.

BACKGROUND: Opioid-prescribing practices for minimally injured trauma patients are unknown. We hypothesized that opioid-prescribing frequency and morphine-equivalent doses prescribed have decreased in recent years, specifically surrounding an acute prescribing limit implemented in August 2017 mandating opioid prescriptions not exceed 210 morphine-equivalent doses. METHODS: A single-center retrospective study was performed in the month of May during the years 2015 to 2018 on minimally injured trauma patients in a level I trauma center. Minimally injured trauma patients included patients discharged within 2 midnights of trauma evaluation without surgical intervention. Primary outcomes were discharge opioid-prescribing frequency and dosing in morphine-equivalent doses. Secondary outcomes were occurrence and timing of postdischarge follow-up. RESULTS: For 673 minimally injured trauma patients, opioid-prescribing frequency and morphine-equivalent doses prescribed decreased between 2015 and 2017 (49.3% to 31.5%, P = .006, mean 229 to 146 morphine-equivalent doses, P = .007). Decreases between 2017 and 2018 were not statistically significant. Acute prescribing limit compliance was 97% in 2018. After the acute prescribing limit was implemented, outpatient opioid prescribing did not increase and time to earliest follow-up did not decrease. CONCLUSION: Opioid-prescribing frequency and morphine-equivalent doses prescribed to minimally injured trauma patients decreased dramatically between 2015 and 2018. These changes occurred primarily before the implementation of an acute prescribing limit; however, incremental improvement and high compliance since implementation are demonstrated. Patients did not have significantly earlier follow-up encounters for pain or additional opioid prescriptions. Prospective research on pain control for minimally injured trauma patients is needed.

Sociodemographic Patterns of Outpatient Falls: Do Minority Patients Fall Less Frequently?

INTRODUCTION: Falls are the most common cause of injury in the elderly, resulting in $50 billion of annual spending. Social and demographic factors associated with falling are not well understood. We hypothesized minority groups (minority race, lower income, and lower education levels) would experience similar rates of falling to majority groups after adjustment for medical factors. MATERIAL AND METHODS: We used the 2013 Medicare Current Beneficiary Survey Public Use File, a representatively sampled cross-sectional survey of Medicare outpatients. Fall was defined as at least one self-reported fall in the previous year. Logistic regression was performed to determine sociodemographic factors (age, sex, race, ethnicity, income, education level, and marital status) associated with fall. Health factors, physical limitations, and cognitive limitations were included as possible confounders. Data are presented as extrapolated weighted population proportions (±SE). RESULTS: 13,924 Medicare beneficiaries, representing 47 million people, were included. 26.6% (±0.4) reported falling. In adjusted logistic regression, black and Hispanic patients had significantly fewer self-reported falls than white patients, after adjustment for medical conditions, physical limitations, and cognitive limitations. DISCUSSION: Black and Hispanic Medicare patients are significantly less likely to have reported a fall than non-Hispanic whites. This finding differs from other health-related disparities in which minorities most commonly experience higher risk or more severe diseases. These data may also represent differences in self-reporting, indicating disparities in self-reported data in these cohorts. Further studies on social factors related to falling are needed in this population.

Direct binding and activation of protein kinase C isoforms by aldosterone and 17beta-estradiol.

Protein kinase C (PKC) is a signal transduction protein that has been proposed to mediate rapid responses to steroid hormones. Previously, we have shown aldosterone directly activates PKCalpha whereas 17beta-estradiol activates PKCalpha and PKCdelta; however, neither the binding to PKCs nor the mechanism of action has been established. To determine the domains of PKCalpha and PKCdelta involved in binding of aldosterone and 17beta-estradiol, glutathione S-transferase fusion recombinant PKCalpha and PKCdelta mutants were used to perform in vitro binding assays with [(3)H]aldosterone and [(3)H]17beta-estradiol. 17beta-Estradiol bound both PKCalpha and PKCdelta but failed to bind PKC mutants lacking a C2 domain. Similarly, aldosterone bound only PKCalpha and mutants containing C2 domains. Thus, the C2 domain is critical for binding of these hormones. Binding affinities for aldosterone and 17beta-estradiol were between 0.5-1.0 nM. Aldosterone and 17beta-estradiol competed for binding to PKCalpha, suggesting they share the same binding site. Phorbol 12,13-dybutyrate did not compete with hormone binding; furthermore, they have an additive effect on PKC activity. EC(50) for activation of PKCalpha and PKCdelta by aldosterone and 17beta-estradiol was approximately 0.5 nM. Immunoblot analysis using a phospho-PKC antibody revealed that upon binding, PKCalpha and PKCdelta undergo autophosphorylation with an EC(50) in the 0.5-1.0 nm range. 17beta-Estradiol activated PKCalpha and PKCdelta in estrogen receptor-positive and -negative breast cancer cells (MCF-7 and HCC-38, respectively), suggesting estrogen receptor expression is not required for 17beta-estradiol-induced PKC activation. The present results provide first evidence for direct binding and activation of PKCalpha and PKCdelta by steroid hormones and the molecular mechanisms involved.