Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high risk locus in patients with diabetic macular edema.

Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a multi-ancestry GWAS to assess DME risk in a total of 1,502 DME patients and 5,603 non-DME controls in discovery and replication datasets. Two loci reached GWAS significance (p<5x10-8). The strongest association was rs2239785, (K150E) in APOL1. The second finding was rs10402468, which co-localized to PLVAP and ANKLE1 in vascular / endothelium tissues. We conducted multiple sensitivity analyses to establish that the associations were specific to DME status and did not reflect diabetes status or other diabetic complications. Here we report two novel loci for risk of DME which replicated in multiple clinical trial and biobank derived datasets. One of these loci, containing the gene APOL1, is a risk factor in African American DME and DKD patients, indicating that this locus plays a broader role in diabetic complications for multiple ancestries. Trial Registration: NCT00473330, NCT00473382, NCT03622580, NCT03622593, NCT04108156.

Alternative Complement Pathway Inhibition by Lampalizumab: Analysis of Data From Chroma and Spectri Phase III Clinical Trials.

Purpose: Lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in the phase III Chroma/Spectri trials, we investigated the impact of lampalizumab on the complement system in vivo. We developed 6 novel assays to measure changes in complement pathway activities in aqueous humor samples collected from patients enrolled in these trials. Design: Chroma/Spectri were double-masked, sham-controlled, 96-week trials. Participants: Aqueous humor samples from 97 patients with bilateral GA across all groups (i.e., intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested. Methods: Novel antibody capture assays were developed on the Simoa platform for complement factor B (CFB), the Bb fragment of CFB, intact complement component 3 (C3), processed C3, intact complement component 4 (C4), and processed C4. Main Outcome Measures: The ratio of processed vs. intact complement factors (i.e., complement activity) in aqueous humor were assessed. Results: Patients treated with either of the lampalizumab regimens demonstrated an increase in CFD level at week 24 compared with baseline, along with a corresponding median reduction in the Bb:CFB ratio of 41% to 43%. There were no strong correlations between lampalizumab concentrations in aqueous humor and change in CFD levels or Bb:CFB ratio over time. No change in downstream C3 processing was observed with lampalizumab treatment. Additionally, there was no change in C4 processing. Conclusions: The collection of aqueous humor samples from patients in Chroma and Spectri trials provided key insights on the effects of lampalizumab, a novel complement inhibitor, on local ocular complement activation. Lampalizumab inhibited the alternative complement pathway in the eyes of patients with GA; however, this did not translate into a measurable reduction in either classical or total complement activity, based on absence of changes in C4 and C3 processing, respectively. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

The Role of the Complement Pathway in Clinical Progression of Geographic Atrophy: Analysis of the Phase III Chroma and Spectri Trials.

Purpose: To investigate the relationship between complement pathway activities and progression of geographic atrophy (GA) secondary to age-related macular degeneration in samples collected from patients enrolled in the Chroma and Spectri trials. Design: Chroma and Spectri were phase III, double-masked, and sham-controlled, 96-week trials. Participants: Aqueous humor (AH) samples collected at baseline and week 24 visits from 81 patients with bilateral GA across all 3 treatment groups (intravitreal lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested, along with patient-matched plasma samples collected at baseline. Methods: Antibody capture assays using the Simoa platform were used to measure the levels of complement factor B, the Bb fragment of complement factor B, intact complement component 3 (C3), processed C3, intact complement C4, and processed C4. Complement factor D levels were measured using enzyme-linked immunosorbent assay. Main Outcome Measures: Correlations of complement levels and activities (i.e., processed:intact ratio of complement component) in AH and plasma with baseline GA lesion size and growth rate. Results: In baseline AH, there were strong correlations (Spearman's rho ≥ 0.80) between intact complement proteins, between processed complement proteins, and between linked processed and intact complement proteins; weak correlations (rho ≤ 0.24) were found between complement pathway activities. There were no strong correlations between complement protein levels and activities measured in AH and plasma at baseline (rho ≤ 0.37). Baseline complement levels and activities in AH and plasma did not correlate with baseline GA lesion size or change from baseline in GA lesion area at week 48 (i.e., annualized growth rate). There were no strong correlations between changes in complement levels/activities in the AH from baseline to week 24 and annualized GA lesion growth rate. Genotype analysis did not reveal a meaningful correlation between complement-related, age-related macular degeneration risk single-nucleotide polymorphisms and complement levels and activities. Conclusions: Complement levels or activities in AH and plasma did not correlate with GA lesion size or growth rate. This suggests that local complement activation as measured in AH does not appear to be related to GA lesion progression. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models.

Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines ß-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

Emergency department length of stay is an independent predictor of hospital mortality in trauma activation patients.

BACKGROUND: The early resuscitation occurs in the emergency department (ED) where intensive care unit protocols do not always extend and monitoring capabilities vary. Our hypothesis is that increased ED length of stay (LOS) leads to increased hospital mortality in patients not undergoing immediate surgical intervention. METHODS: We examined all trauma activation admissions from January 2002 to July 2009 admitted to the Trauma Service (n = 3,973). Exclusion criteria were as follows: patients taken to the operating room within the first 2 hours of ED arrival, nonsurvivable brain injury, and ED deaths. Patients spending >5 hours in the ED were not included in the analysis because of significantly lower acuity and mortality. RESULTS: Patients spent a mean of 3.2 hours ± 1 hour in the ED during their initial evaluation. Hospital mortality increases for each additional hour a patient spends in the ED, with 8.3% of the patients staying in the ED between 4 hours and 5 hours ultimately dying (p = 0.028). ED LOS measured in minutes is an independent predictor of mortality (odds ratio, 1.003; 95% confidence interval, 1.010-1.006; p = 0.014) when accounting for Injury Severity Score, Revised Trauma Score, and age. Linear regression showed that a longer ED LOS was associated with anatomic injury pattern rather than physiologic derangement. CONCLUSION: In this patient population, a longer ED LOS is associated with an increased hospital mortality even when controlling for physiologic, demographic, and anatomic factors. This highlights the importance of rapid progression of patients through the initial evaluation process to facilitate placement in a location that allows implementation of early goal directed trauma resuscitation.

Undertriage Despite Use of Geriatric-Specific Trauma Team Activation Guidelines : Who Are We Missing?

BACKGROUND: Elderly trauma patients are at risk for undertriage, resulting in substantial morbidity and mortality. The objective of this study was to determine whether implementation of geriatric-specific trauma team activation (TTA) protocols appropriately identified severely-injured elderly patients. METHODS: This single-center retrospective study evaluated all severely injured (injury severity score [ISS] >15), geriatric (≥65 years) patients admitted to our Level 1 tertiary-care hospital between January 2014 and September 2017. Undertriage was defined as the lack of TTA despite presence of severe injuries. The primary outcome was all-cause in-hospital mortality; secondary outcomes were mortality within 48 hours of admission and urgent hemorrhage control. A multivariable logistic regression analysis was performed to identify predictors of appropriate triage in this study. RESULTS: Out of 1039 severely injured geriatric patients, 628 (61%) did not undergo TTA. Undertriaged patients were significantly older and had more comorbidities. In-hospital mortality was 5% and 31% in the undertriaged and appropriately triaged groups, respectively (P < .0001). One percent of undertriaged patients needed urgent hemorrhage control, compared to 6% of the appropriately triaged group (P < .0001). One percent of undertriaged patients died within 48 hours compared to 19% in the appropriately triaged group (P < .0001). Predictors of appropriate triage include GCS, heart rate, systolic blood pressure, lactic acid, ISS, shock, and absence of dementia, stroke, or alcoholism. DISCUSSION: Geriatric-specific TTA guidelines continue to undertriage elderly trauma patients when using ISS as a metric to measure undertriage. However, undertriaged patients have much lower morbidity and mortality, suggesting the geriatric-specific TTA guidelines identify those patients at highest risk for poor outcomes.

Screening for Bacteremia in Trauma Patients: Traditional Markers Fall Short.

BACKGROUND: Deranged physiology in trauma complicates the clinical identification of sepsis, resulting in overscreening for bacteremia. No clinical signs or biomarkers accurately diagnose sepsis in this population. Our objective was to evaluate the accuracy of the current criteria used to prompt screening for bacteremia in trauma patients and determine independent predictors of bacteremia. MATERIALS AND METHODS: Adult trauma patients admitted to our level I academic trauma center who had blood cultures (BCs) drawn were identified. Those with positive BCs were compared to those with negative or false positive BCs. False positive was defined as a BC deemed contaminated and not treated at the discretion of the attending physician. RESULTS: Over a 2-year period, 366 trauma patients had BCs drawn. After excluding surveillance cultures (those drawn to demonstrate bacteremia clearance), 492 unique BC sets were evaluated; 104 (21.1%) BC sets were positive; 30 (28.8%) of these were falsely positive, resulting in a true-positive rate of 15% in the screened population. Univariate analysis suggested temperature and heart rate were associated with positive BC, while multivariable analysis found only the presence of a central line and lactic acid to be predictive. Procalcitonin (PCT) was poorly predictive, with a positive predictive value of 18% and a negative predictive value of 91%. CONCLUSION: Current tools for identifying bacteremia in trauma patients result in overscreening. PCT may have a limited role as a negative predictor for bacteremia. Given that false-positive BCs have negative patient and economic consequences, future study should focus on development of alternative screening modalities.

Surgical intensive care unit mobility is increased after institution of a computerized mobility order set and intensive care unit mobility protocol: a prospective cohort analysis.

In some populations, intensive care unit (ICU) mobility has been shown to be safe and beneficial. We gathered data on 50 nonintubated surgical patients in a 10-bed surgical ICU (SICU) who met physiologic inclusion criteria beginning in May 2008 (A group). In January 2009, we began mandatory entry of computerized mobility orders as part of a standardized ICU order set. We also created a mobility protocol for nurses in this ICU. We then collected data on 50 patients in this postintervention cohort (B group). Both groups had similar baseline characteristics. A group patients had some form of mobility orders entered in 29 patients (58%) versus 47 patients (82%) in the B group, P < 0.05. In the A group, 11 patients (22%) were mobilized; in the B group, 40 patients (80%) were mobilized, P < 0.05. In our SICU patient population, mandatory entry of computerized mobility orders as part of a standard SICU order set and establishment of an ICU mobility nursing protocol was associated with an increase in number of mobility orders entered as well as an increase in SICU patient activity. Further studies should focus on measurement of the effect of mobility interventions on patient outcomes.

Uncovering multiple axonal targeting pathways in hippocampal neurons.

Neuronal polarity is, at least in part, mediated by the differential sorting of membrane proteins to distinct domains, such as axons and somata/dendrites. We investigated the pathways underlying the subcellular targeting of NgCAM, a cell adhesion molecule residing on the axonal plasma membrane. Following transport of NgCAM kinetically, surprisingly we observed a transient appearance of NgCAM on the somatodendritic plasma membrane. Down-regulation of endocytosis resulted in loss of axonal accumulation of NgCAM, indicating that the axonal localization of NgCAM was dependent on endocytosis. Our data suggest the existence of a dendrite-to-axon transcytotic pathway to achieve axonal accumulation. NgCAM mutants with a point mutation in a crucial cytoplasmic tail motif (YRSL) are unable to access the transcytotic route. Instead, they were found to travel to the axon on a direct route. Therefore, our results suggest that multiple distinct pathways operate in hippocampal neurons to achieve axonal accumulation of membrane proteins.

The Golden Opportunity: Multidisciplinary Simulation Training Improves Trauma Team Efficiency.

OBJECTIVE: Every trauma patient has a golden hour, and resuscitation efficiency within that hour has large implications for patients. We instituted simulation based trauma resuscitation training with the hypothesis that it would improve trauma team efficiency. METHODS: Five simulation training sessions were conducted with immediate debriefing. Metrics collected in actual trauma resuscitations before and after simulation training included time of primary and secondary surveys and time to computed tomography (CT) scan. Study participants were from multidisciplinary specialties involved in trauma resuscitations as well as former trauma patients from the Trauma Survivors Network. RESULTS: Seventy-three patients undergoing trauma resuscitations were screened and 67 patients were included. Time to CT scan and secondary survey completion were significantly reduced in actual trauma patient activations following implementation of the curriculum (reduction of 23 to 16 minutes for CT scan p < 0.05, and reduction from 14 to 6 minutes for secondary survey, p < 0.05). Time to primary survey completion did not change (5 minutes). CONCLUSIONS: Multidisciplinary simulation training was associated with improved trauma team efficiency in the form of reduced assessment time. As emergency department length of stay is an independent predictor of hospital mortality following trauma activation, team-based simulation training has the potential to improve patient outcomes. Multidisciplinary involvement was a key factor, and Trauma Survivors Network involvement brought credibility from the patient perspective.

Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy.

Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by ß-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.

Colonic resection in the setting of damage control laparotomy: is delayed anastomosis safe?

Based on a large body of literature concerning the subject, trauma surgeons are becoming more comfortable with anastomosis rather than stoma creation in patients with destructive colon injuries requiring resection. This literature was largely generated before the widespread acceptance of the importance of damage control laparotomy (DCL). Thus, when such injuries occur in patients initially left in colonic discontinuity after DCL, the question of anastomosis versus stoma becomes more difficult, and there are no data to guide management decisions. The goal of this report is to describe the results of our early experience with delayed anastomosis (DA) after destructive colon injury in the setting of DCL. We reviewed the records of patients with destructive colon injuries at our Level I trauma center over a 5.5-year period for demographics, injury characteristics, and outcome. Studied outcomes included anastomotic leak, intra-abdominal abscess, and colon injury-related death. The decision to proceed with DA was based on individual surgeon opinion at the time of re-exploration. From January 1, 2000 to July 31, 2006, 92 patients sustained colon injury, 55 of which required resection (31 blunt mechanism and 24 penetrating). Twenty-two resections occurred in the setting of DCL. Six of these patients underwent stoma creation and 11 underwent DA. Three died before reoperation, and two had an anastomosis created during the initial DCL. The remaining 33 resections occurred during initial definitive operation, and 21 underwent anastomosis, whereas 12 had a stoma created. Comparing the 11 patients undergoing DA with the 21 undergoing immediate anastomosis, the anastomotic leak rate (0% vs 5%), abscess rate (36% vs 24%), and colon related-death rate (9% vs 0%; all P > 0.05) were similar. Six patients undergoing DA had a right hemicolectomy with ileocolonic anastomosis, four had a segmental left colon resection, and one had a near total abdominal colectomy with ileosigmoid anastomosis. Delayed anastomosis of colon injuries after DCL is safe in selected patients and has a similar complication rate as resection and anastomosis performed during initial definitive operation. DA avoids stoma creation in some patients who are not candidates for anastomosis during initial DCL. To our knowledge, this represents the first reported series of DA after DCL, an area in which further work is needed to carefully define indications for the safe application of this concept.

Increased insulin requirements are associated with pneumonia after severe injury.

BACKGROUND: Hyperglycemia after severe injury has been associated with an increased risk of infection and death. Strict glycemic control has been found to be valuable in select surgical populations. Varying amounts of insulin by infusion are required to maintain blood glucose levels within normal limits. Little is known about how insulin requirements are affected by the presence of infection, and therefore, the purpose of this study was to characterize this relationship. METHODS: Medical records of all intubated, injured patients admitted to the intensive care unit during a 16-month period were reviewed. Patients were included if they were managed with an insulin infusion, and they had a single bronchoalveolar lavage (BAL) culture performed for presumed pneumonia between 48 hours and 8 days. Mean hourly and 24-hour insulin requirements were analyzed before BAL was performed and then compared with values after cultures were obtained. This difference was then compared between patients with and without pneumonia. RESULTS: Eighty-two patients met inclusion criteria during the 16-month study period. The hourly and 24-hour insulin requirements significantly increased from before to after BAL was performed in patients with pneumonia (n = 54) and not in those without (n = 28) (p = 0.008). The 24-hour insulin requirement increased by 26.2 units from before to after BAL in the pneumonia group versus 7.6 units in the nonpneumonia group (p = 0.029). A mean hourly insulin requirement increase of 1.2 units more than the pre-BAL level demonstrated an 86% positive predictive value and 89% specificity for pneumonia. CONCLUSIONS: An increase in insulin requirements at the time of obtaining pulmonary cultures is associated with the presence of pneumonia and may represent a valuable tool for earlier recognition.

Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.

Loss-of-function mutations in GRN cause frontotemporal dementia (FTD) with transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying therapies for either FTD or NCL, in part because of a poor understanding of how mutations in genes such as GRN contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by GRN, we discovered multiple lines of evidence that PGRN deficiency results in impairment of autophagy, a key cellular degradation pathway. PGRN-deficient mice are sensitive to Listeria monocytogenes because of deficits in xenophagy, a specialized form of autophagy that mediates clearance of intracellular pathogens. Cells lacking PGRN display reduced autophagic flux, and pathological forms of TDP-43 typically cleared by autophagy accumulate more rapidly in PGRN-deficient neurons. Our findings implicate autophagy as a novel therapeutic target for GRN-associated NCL and FTD and highlight the emerging theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis spectrum of neurodegenerative disease.

Predicting Mortality and Independence at Discharge in the Aging Traumatic Brain Injury Population Using Data Available at Admission.

BACKGROUND: Aging worsens outcome in traumatic brain injury (TBI), but available studies may not provide accurate outcomes predictions due to confounding associated injuries. Our goal was to develop a predictive tool using variables available at admission to predict outcomes related to severity of brain injury in aging patients. STUDY DESIGN: Characteristics and outcomes of blunt trauma patients, aged 50 or older, with isolated TBI, in the National Trauma Data Bank (NTDB), were evaluated. Equations predicting survival and independence at discharge (IDC) were developed and validated using patients from our trauma registry, comparing predicted with actual outcomes. RESULTS: Logistic regression for survival and IDC was performed in 57,588 patients using age, sex, Glasgow Coma Scale score (GCS), and Revised Trauma Score (RTS). All variables were independent predictors of outcome. Two models were developed using these data. The first included age, sex, and GCS. The second substituted RTS for GCS. C statistics from the models for survival and IDC were 0.90 and 0.82 in the GCS model. In the RTS model, C statistics were 0.80 and 0.67. The use of GCS provided better discrimination and was chosen for further examination. Using a predictive equation derived from the logistic regression model, outcome probabilities were calculated for 894 similar patients from our trauma registry (January 2012 to March 2016). The survival and IDC models both showed excellent discrimination (p < 0.0001). Survival and IDC generally decreased by decade: age 50 to 59 (80% IDC, 6.5% mortality), 60 to 69 (82% IDC, 7.0% mortality), 70 to 79 (76% IDC, 8.9% mortality), and 80 to 89 (67% IDC, 13.4% mortality). CONCLUSIONS: These models can assist in predicting the probability of survival and IDC for aging patients with TBI. This provides important data for loved ones of these patients when addressing goals of care.

Damage control operations in non-trauma patients: defining criteria for the staged rapid source control laparotomy in emergency general surgery.

BACKGROUND: The staged laparotomy in the operative management of emergency general surgery (EGS) patients is an extension of trauma surgeons operating on this population. Indications for its application, however, are not well defined, and are currently based on the lethal triad used in physiologically-decompensated trauma patients. This study sought to determine the acute indications for the staged, rapid source control laparotomy (RSCL) in EGS patients. METHODS: All EGS patients undergoing emergent staged RSCL and non-RSCL over 3 years were studied. Demographics, physiologic parameters, perioperative variables, outcomes, and survival were compared. Logistic regression models determined the influence of physiologic parameters on mortality and postoperative complications. EGS-RSCL indications were defined. RESULTS: 215 EGS patients underwent emergent laparotomy; 53 (25 %) were staged RSCL. In the 53 patients who underwent a staged RSCL based on the lethal triad, adjusted multivariable regression analysis shows that when used alone, no component of the lethal triad independently improved survival. Staged RSCL may decrease mortality in patients with preoperative severe sepsis / septic shock, and an elevated lactate (≥3); acidosis (pH ≤ 7.25); elderly (≥70); male gender; and multiple comorbidities (≥3). Of the 162 non-RSCL emergent laparotomies, 27 (17 %) required unplanned re-explorations; of these, 17 (63 %) had sepsis preoperatively and 9 (33 %) died. CONCLUSIONS: The acute physiologic indicators that help guide operative decisions in trauma may not confer a similar survival advantage in EGS. To replace the lethal triad, criteria for application of the staged RSCL in EGS need to be defined. Based on these results, the indications should include severe sepsis / septic shock, lactate, acidosis, gender, age, and pre-existing comorbidities. When correctly applied, the staged RSCL may help to improve survival in decompensated EGS patients.

Selective management of cardiovascular dysfunction in posttraumatic SIRS and sepsis.

Cardiovascular dysfunction associated with the systemic inflammatory response syndrome (SIRS) is caused by a combination of decreased myocardial contractility and low vascular resistance. The contribution of each of these components can be determined at the bedside, and directed therapy can be appropriately initiated. Over an 8-month period of time, 23 consecutive patients who experienced posttraumatic SIRS while still being monitored with a volumetric pulmonary artery catheter (PAC) were prospectively evaluated. Ventricular pressure-volume diagrams were constructed to quantify myocardial contractility and afterload. In a resuscitation protocol, dobutamine was administered to patients with an isolated decrease in contractility, and dopamine or epinephrine was instituted for the combination of reduced contractility and afterload. Variables describing cardiovascular function were measured at the time of resolution of initial shock resuscitation (BASE), at the onset of SIRS (ONSET), and after administration of inotropic or vasoactive agents (TREAT). ONSET was associated with a significant decrease in left ventricular power (LVP) (362 +/- 96 to 235 +/- 55 mmHg.L/min/m(2), P < 0.00001) and stroke work index (SWI) (4670 +/- 1213 to 3060 +/- 848 mmHg.mL/m, P < 0.00001) from BASE. Sixteen patients (70%) demonstrated predominantly decreased contractility, which returned to near BASE values after the administration of dobutamine. The remaining seven patients (30%) had both decreased contractility and afterload, which was treated with dopamine or epinephrine. LVP and SWI significantly increased (235 +/- 55 to 328 +/- 77 mmHg.L/min/m(2), P < 0.00001, and 3060 +/- 848 to 4554 +/- 1423 mmHg.mL/m(2), P < 0.00001, respectively) on the initiation of directed therapy. Specific cardiovascular abnormalities can be identified at the bedside, and this information can guide pharmacologic management. Directed therapy improves cardiovascular function.