Lean Six Sigma to Reduce Intensive Care Unit Length of Stay and Costs in Prolonged Mechanical Ventilation.

OBJECTIVE: Patients with prolonged mechanical ventilation (PMV) represent important "outliers" of hospital length of stay (LOS) and costs (∼$26 billion annually in the United States). We tested the hypothesis that a Lean Six Sigma (LSS) approach for process improvement could reduce hospital LOS and the associated costs of care for patients with PMV. DESIGN: Before-and-after cohort study. SETTING: Multidisciplinary intensive care unit (ICU) in an academic medical center. PATIENTS: Adult patients admitted to the ICU and treated with PMV, as defined by diagnosis-related group (DRG). METHODS: We implemented a clinical redesign intervention based on LSS principles. We identified eight distinct processes in preparing patients with PMV for post-acute care. Our clinical redesign included reengineering daily patient care rounds ("Lean ICU rounds") to reduce variation and waste in these processes. We compared hospital LOS and direct cost per case in patients with PMV before (2013) and after (2014) our LSS intervention. RESULTS: Among 259 patients with PMV (131 preintervention; 128 postintervention), median hospital LOS decreased by 24% during the intervention period (29 vs. 22 days, p < .001). Accordingly, median hospital direct cost per case decreased by 27% ($66,335 vs. $48,370, p < .001). CONCLUSION: We found that a LSS-based clinical redesign reduced hospital LOS and the costs of care for patients with PMV.

Incidence and mortality of sepsis, severe sepsis, and septic shock in intensive care unit patients with candidemia.

In this incidence study, of 16 074 patients admitted to the intensive care unit (ICU) from 1/1/2003 to 7/31/2011, 161 cases of candidemia were identified. The incidence of sepsis (27%), severe sepsis (31%), and septic shock (40%) was remarkably high in these cases of candidemia, as was the all-cause in-hospital mortality for sepsis (30%), severe sepsis (44%), and septic shock (65%).

Risk of Clostridium difficile infection in intensive care unit patients with sepsis exposed to metronidazole.

BACKGROUND: Antimicrobial agents used to treat Clostridium difficile infection (CDI), such as metronidazole and vancomycin, have been used during antibiotic treatment of other infections to try to prevent the development of CDI. We evaluated the hypothesis that intensive care unit (ICU) patients who receive metronidazole as part of an antibiotic treatment regimen for sepsis have a lower risk of subsequently developing CDI. METHODS: This was a nested case-control study in a cohort of ICU patients who received antibiotic therapy for sepsis. RESULTS: A total of 10 012 patients aged ≥ 18 years were admitted to the Cooper University Hospital medical/surgical ICU from 1/1/2003 to 12/31/2008. After applying inclusion criteria including having received antibiotic therapy for sepsis and subsequently having developed CDI, 67 cases were identified. The cases were matched for age, gender, date of ICU admission, and hospital length of stay to 67 controls that also received antibiotic therapy for sepsis but did not subsequently develop CDI. In the multivariate analysis, there was no association between metronidazole exposure and the risk of CDI (odds ratio (OR) = 0.57; p = 0.23). The only significant associations on multivariate analysis were antifungal therapy (OR = 0.30; p = 0.02) and aminoglycoside and/or colistin therapy (OR = 0.17; p = 0.02). CONCLUSIONS: No association was found between metronidazole use and subsequent CDI in ICU patients who received antibiotic therapy for sepsis.

Timing of vasopressor initiation and mortality in septic shock: a cohort study.

INTRODUCTION: Despite recent advances in the management of septic shock, mortality remains unacceptably high. Earlier initiation of key therapies including appropriate antimicrobials and fluid resuscitation appears to reduce the mortality in this condition. This study examined whether early initiation of vasopressor therapy is associated with improved survival in fluid therapy-refractory septic shock. METHODS: Utilizing a well-established database, relevant information including duration of time to vasopressor administration following the initial documentation of recurrent/persistent hypotension associated with septic shock was assessed in 8,670 adult patients from 28 ICUs in Canada, the United States of America, and Saudi Arabia. The primary endpoint was survival to hospital discharge. Secondary endpoints were length of ICU and hospital stay as well as duration of ventilator support and vasopressor dependence. Analysis involved multivariate linear and logistic regression analysis. RESULTS: In total, 8,640 patients met the definition of septic shock with time of vasopressor/inotropic initiation documented. Of these, 6,514 were suitable for analysis. The overall unadjusted hospital mortality rate was 53%. Independent mortality correlates included liver failure (odds ratio (OR) 3.46, 95% confidence interval (CI), 2.67 to 4.48), metastatic cancer (OR 1.63, CI, 1.32 to 2.01), AIDS (OR 1.91, CI, 1.29 to 2.49), hematologic malignancy (OR 1.88, CI, 1.46 to 2.41), neutropenia (OR 1.78, CI, 1.27 to 2.49) and chronic hypertension (OR 0.62 CI, 0.52 to 0.73). Delay of initiation of appropriate antimicrobial therapy (OR 1.07/hr, CI, 1.06 to 1.08), age (OR 1.03/yr, CI, 1.02 to 1.03), and Acute Physiology and Chronic Health Evaluation (APACHE) II Score (OR 1.11/point, CI, 1.10 to 1.12) were also found to be significant independent correlates of mortality. After adjustment, only a weak correlation between vasopressor delay and hospital mortality was found (adjusted OR 1.02/hr, 95% CI 1.01 to 1.03, P <0.001). This weak effect was entirely driven by the group of patients with the longest delays (>14.1 hours). There was no significant relationship of vasopressor initiation delay to duration of vasopressor therapy (P = 0.313) and only a trend to longer duration of ventilator support (P = 0.055) among survivors. CONCLUSION: Marked delays in initiation of vasopressor/inotropic therapy are associated with a small increase in mortality risk in patients with septic shock.

Severe sepsis and septic shock: management and performance improvement.

Morbidity and mortality from sepsis remains unacceptably high. Large variability in clinical practice, plus the increasing awareness that certain processes of care associated with improved critical care outcomes, has led to the development of clinical practice guidelines in a variety of areas related to infection and sepsis. The Surviving Sepsis Guidelines for Management of Severe Sepsis and Septic Shock were first published in 2004, revised in 2008, and recently revised again and published in 2013. The first part of this manuscript is a summary of the 2013 guidelines with some editorial comment. The second part of the manuscript characterizes hospital based sepsis performance improvement programs and highlights the sepsis bundles from the Surviving Sepsis Campaign as a key component of such a program.

Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study.

INTRODUCTION: Data are sparse as to whether obesity influences the risk of death in critically ill patients with septic shock. We sought to examine the possible impact of obesity, as assessed by body mass index (BMI), on hospital mortality in septic shock patients. METHODS: We performed a nested cohort study within a retrospective database of patients with septic shock conducted in 28 medical centers in Canada, United States and Saudi Arabia between 1996 and 2008. Patients were classified according to the World Health Organization criteria for BMI. Multivariate logistic regression analysis was performed to evaluate the association between obesity and hospital mortality. RESULTS: Of the 8,670 patients with septic shock, 2,882 (33.2%) had height and weight data recorded at ICU admission and constituted the study group. Obese patients were more likely to have skin and soft tissue infections and less likely to have pneumonia with predominantly Gram-positive microorganisms. Crystalloid and colloid resuscitation fluids in the first six hours were given at significantly lower volumes per kg in the obese and very obese patients compared to underweight and normal weight patients (for crystalloids: 55.0 ± 40.1 ml/kg for underweight, 43.2 ± 33.4 for normal BMI, 37.1 ± 30.8 for obese and 27.7 ± 22.0 for very obese). Antimicrobial doses per kg were also different among BMI groups. Crude analysis showed that obese and very obese patients had lower hospital mortality compared to normal weight patients (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.66 to 0.97 for obese and OR 0.61, 95% CI 0.44 to 0.85 for very obese patients). After adjusting for baseline characteristics and sepsis interventions, the association became non-significant (OR 0.80, 95% CI 0.62 to 1.02 for obese and OR 0.69, 95% CI 0.45 to 1.04 for very obese). CONCLUSIONS: The obesity paradox (lower mortality in the obese) documented in other populations is also observed in septic shock. This may be related in part to differences in patient characteristics. However, the true paradox may lie in the variations in the sepsis interventions, such as the administration of resuscitation fluids and antimicrobial therapy. Considering the obesity epidemic and its impact on critical care, further studies are warranted to examine whether a weight-based approach to common therapeutic interventions in septic shock influences outcome.

Emergency department inter-hospital transfer for post-cardiac arrest care: initial experience with implementation of a regional cardiac resuscitation center in the United States.

OBJECTIVE: The American Heart Association recently recommended regional cardiac resuscitation centers (CRCs) for post-resuscitation care following out-of-hospital cardiac arrest (OHCA). Our objective was to describe initial experience with CRC implementation. METHODS: Prospective observational study of consecutive post-resuscitation patients transferred from community Emergency Departments (EDs) to a CRC over 9 months. Transfer criteria were: OHCA, return of spontaneous circulation (ROSC), and comatose after ROSC. Incoming patients were received and stabilized in the ED of the CRC where advanced therapeutic hypothermia (TH) modalities were applied. Standardized post-resuscitation care included: ED evaluation for cardiac catheterization, TH (33-34 °C) for 24h, 24h/day critical care physician support, and evidence-based neurological prognostication. Prospective data collection utilized the Utstein template. The primary outcome was survival to hospital discharge with good neurological function [Cerebral Performance Category 1 or 2]. RESULTS: Twenty-seven patients transferred from 11 different hospitals were included. The majority (21/27 [78%]) had arrest characteristics suggesting poor prognosis for survival (i.e. asystole/pulseless electrical activity initial rhythm, absence of bystander cardiopulmonary resuscitation, or an unwitnessed cardiac arrest). The median (IQR) time from transfer initiation to reaching TH target temperature was 7(5-13)h. Ten (37%) patients survived to hospital discharge, and of these 9/10 (90% of survivors, 33% of all patients) had good neurological function. CONCLUSIONS: Despite a high proportion of patients with cardiac arrest characteristics suggesting poor prognosis for survival, we found that one-third of CRC transfers survived with good neurological function. Further research to determine if regional CRCs improve outcomes after cardiac arrest is warranted.

Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis.

UNLABELLED: It is unclear whether practice-related aspects of antimicrobial therapy contribute to the high mortality from septic shock among patients with cirrhosis. We examined the relationship between aspects of initial empiric antimicrobial therapy and mortality in patients with cirrhosis and septic shock. This was a nested cohort study within a large retrospective database of septic shock from 28 medical centers in Canada, the United States, and Saudi Arabia by the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group between 1996 and 2008. We examined the impact of initial empiric antimicrobial therapeutic variables on the hospital mortality of patients with cirrhosis and septic shock. Among 635 patients with cirrhosis and septic shock, the hospital mortality was 75.6%. Inappropriate initial empiric antimicrobial therapy was administered in 155 (24.4%) patients. The median time to appropriate antimicrobial administration was 7.3 hours (interquartile range, 3.2-18.3 hours). The use of inappropriate initial antimicrobials was associated with increased mortality (adjusted odds ratio [aOR], 9.5; 95% confidence interval [CI], 4.3-20.7], as was the delay in appropriate antimicrobials (aOR for each 1 hour increase, 1.1; 95% CI, 1.1-1.2). Among patients with eligible bacterial septic shock, a single rather than two or more appropriate antimicrobials was used in 226 (72.9%) patients and was also associated with higher mortality (aOR, 1.8; 95% CI, 1.0-3.3). These findings were consistent across various clinically relevant subgroups. CONCLUSION: In patients with cirrhosis and septic shock, inappropriate and delayed appropriate initial empiric antimicrobial therapy is associated with increased mortality. Monotherapy of bacterial septic shock is also associated with increased mortality. The process of selection and implementation of empiric antimicrobial therapy in this high-risk group should be restructured.

Transfusion of packed red blood cells is not associated with improved central venous oxygen saturation or organ function in patients with septic shock.

BACKGROUND: The exact role of packed red blood cell (PRBC) transfusion in the setting of early resuscitation in septic shock is unknown. STUDY OBJECTIVE: To evaluate whether PRBC transfusion is associated with improved central venous oxygen saturation (ScvO(2)) or organ function in patients with severe sepsis and septic shock receiving early goal-directed therapy (EGDT). METHODS: Retrospective cohort study (n=93) of patients presenting with severe sepsis or septic shock treated with EGDT. RESULTS: Thirty-four of 93 patients received at least one PRBC transfusion. The ScvO(2) goal>70% was achieved in 71.9% of the PRBC group and 66.1% of the no-PRBC group (p=0.30). There was no difference in the change in Sequential Organ Failure Assessment (SOFA) score within the first 24 h in the PRBC group vs. the no-PRBC group (8.6-8.3 vs. 5.8-5.6, p=0.85), time to achievement of central venous pressure>8 mm Hg (732 min vs. 465 min, p=0.14), or the use of norepinephrine to maintain mean arterial pressure>65 mm Hg (81.3% vs. 83.8%, p=0.77). CONCLUSIONS: In this study, the transfusion of PRBC was not associated with improved cellular oxygenation, as demonstrated by a lack of improved achievement of ScvO(2)>70%. Also, the transfusion of PRBC was not associated with improved organ function or improved achievement of the other goals of EGDT. Further studies are needed to determine the impact of transfusion of PRBC within the context of early resuscitation of patients with septic shock.

The association of prior statin use in septic shock treated with early goal directed therapy.

BACKGROUND: Previous literature suggests statins may have a therapeutic role in sepsis. No data have examined if statin use may have a positive impact beyond that afforded by early goal directed therapy (EGDT). OBJECTIVE: To test the hypothesis that previous statin use is associated with improved clinically relevant outcomes in patients with severe sepsis and septic shock receiving EGDT. METHODS: Retrospective cohort study of 91 patients who presented in an academic center in severe sepsis or septic shock and received EGDT. Primary outcome was mortality and secondary outcomes included mechanical ventilation days, ICU length of stay, and hospital length of stay. RESULTS: Patients (87 of 91) presented to the Emergency Department before ICU admission. Patients (18 of 91) were receiving statin therapy before presentation. The statin group had a mortality rate of 22.2 vs. 39.7% in the nonstatin group (P=0.273). The statin group had fewer mechanical ventilation days (8.49 vs. 7.29 days, P=0.026), and a trend in improved hospital length of stay (17.9 vs. 14.4 days, P=0.065), and ICU length of stay (7.15 vs. 4.89 days, P=0.077). CONCLUSION: Prior statin use is associated with fewer mechanical ventilation days and a trend toward improvement in other clinically relevant outcomes. This trial is limited by its retrospective nature and small sample size. These results should serve as hypothesis generating for future prospective trials, as the lack of novel drug therapy and the mortality rate of septic shock both remain unacceptable.

The impact of packed red blood cell transfusion on clinical outcomes in patients with septic shock treated with early goal directed therapy.

BACKGROUND: The optimal hemoglobin level and transfusion threshold in patients with septic shock treated with an early, goal oriented approach to resuscitation remains unknown. AIMS: To assess the impact of packed red blood cell (PRBC) transfusion on clinically relevant outcomes in patients with septic shock treated with early goal directed therapy (EGDT). SETTINGS AND DESIGN: Retrospective cohort study of 93 patients who presented with septic shock, to a single center academic intensive care unit and received EGDT. MATERIALS AND METHODS: Data were collected on patients identified via the Surviving Sepsis Campaign Chart Review database and linked to Project IMPACT database. The PRBC group and no PRBC group were compared by the Pearson chi-square and Fisher's exact test to analyze statistical significance. RESULTS: The PRBC group had a mortality of 41.2% vs. 33.9% in the no PRBC transfusion group (P = NS). The PRBC group also had more mechanical ventilation days (11.2 days vs. 5.0 days, (P ≤ 0.05), longer hospital length of stay (25.9 days vs. 12.5 days, (P ≤ 0.05), and longer intensive care unit length of stay (11.4 days vs. 3.8 days, (P ≤ 0.05). CONCLUSIONS: In this retrospective cohort study, transfusion of PRBCs was associated with worsened clinical outcomes in patients with septic shock treated with EGDT. Further studies are needed to determine the impact of transfusion of PRBC within the context of early resuscitation of patients with septic shock, as the beneficial effects gained by an early and goal oriented approach to resuscitation may be lost by the negative effects associated with PRBC transfusion.

Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival.

STUDY OBJECTIVE: To study early microcirculatory perfusion indices in patients with severe sepsis/septic shock, compare early microcirculatory indices in sepsis survivors versus nonsurvivors, and identify systemic hemodynamic/oxygen transport variables that correlate with early microcirculatory perfusion indices. METHODS: This prospective observational study used orthogonal polarization spectral imaging to directly visualize the sublingual microcirculation in patients with severe sepsis/septic shock treated with early goal-directed therapy. We performed initial imaging within 6 hours of early goal-directed therapy initiation and late follow-up studies at 24-hour intervals until death or resolution of organ dysfunction. We imaged 5 sublingual sites and analyzed the data offline in a blinded fashion. We calculated 3 microcirculatory perfusion indices: flow velocity score, flow heterogeneity index, and capillary density. We analyzed early data to compare survivors versus nonsurvivors and examine correlations with systemic hemodynamic measurements. We used a linear mixed-effects model for longitudinal analyses. RESULTS: We performed 66 orthogonal polarization spectral studies in 26 sepsis patients. Early microcirculatory indices were more markedly impaired (lower flow velocity and more heterogeneous perfusion) in nonsurvivors compared with survivors. These same early indices, flow velocity and heterogeneity, were also more markedly impaired with increasing severity of systemic cardiovascular dysfunction (lower arterial pressure or increasing vasopressor requirement). CONCLUSION: Early microcirculatory perfusion indices in severe sepsis and septic shock are more markedly impaired in nonsurvivors compared with survivors and with increasing severity of global cardiovascular dysfunction.

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.

OBJECTIVE: To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock. DESIGN: A retrospective cohort study performed between July 1989 and June 2004. SETTING: Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States. PATIENTS: Medical records of 2,731 adult patients with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main outcome measure was survival to hospital discharge. Among the 2,154 septic shock patients (78.9% total) who received effective antimicrobial therapy only after the onset of recurrent or persistent hypotension, a strong relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted (adjusted odds ratio 1.119 [per hour delay], 95% confidence interval 1.103-1.136, p<.0001). Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital mortality rate was significantly increased relative to receiving therapy within the first hour (odds ratio 1.67; 95% confidence interval, 1.12-2.48). In multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest predictor of outcome. Median time to effective antimicrobial therapy was 6 hrs (25-75th percentile, 2.0-15.0 hrs). CONCLUSIONS: Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.

Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department.

OBJECTIVE: Early goal-directed therapy (EGDT) has been shown to decrease mortality in patients with severe sepsis and septic shock. Consensus guidelines now advocate EGDT for the first 6 h of sepsis resuscitation. However, EGDT has not yet been widely adopted in practice. A need for effective collaboration between emergency medicine and critical care medicine services has been identified as an obstacle for implementation. We aimed to determine if EGDT end points could reliably be achieved in real-world clinical practice. METHODS: EGDT was implemented as a collaborative emergency medicine/critical care quality improvement initiative. EGDT included the following: i.v. fluids (IVF) targeting central venous pressure > or = 8 mm Hg, vasopressors targeting mean arterial pressure > or = 65 mm Hg, and (if necessary) packed RBCs (PRBCs) and/or dobutamine targeting central venous oxygen saturation > or = 70%. A retrospective analysis was performed of emergency department (ED) patients with persistent sepsis-induced hypotension (systolic BP < 90 mm Hg despite 1.5 L of IVF) treated with EGDT during the first year of the initiative. Primary outcome measures included successful achievement of EGDT end points and time to achievement. A secondary analysis was performed comparing EGDT cases to historical control cases (nonprotocolized control subjects without invasive monitoring). RESULTS: All end points were achieved in 20 of 22 cases (91%). The median time to reach each end point was < or = 6 h. In the secondary analysis, patients (n = 38; EGDT, n = 22; pre-EGDT, n = 16) had similar age, do-not-resuscitate status, severity scores, hypotension duration, and vasopressor requirement (p = not significant). In the ED, EGDT used more IVF and included PRBC/dobutamine utilization, without any impact on the overall use of these therapies through the first 24 h in the ICU. EGDT was associated with decreased ICU pulmonary artery catheter (PAC) utilization (9.1% vs 43.7%, p = 0.01). CONCLUSIONS: With effective emergency medicine/critical care collaboration, we demonstrate that EGDT end points can reliably be achieved in real-world sepsis resuscitation. ED-based EGDT appears to decrease ICU PAC utilization.

Interleukin-10 blunts the human inflammatory response to lipopolysaccharide without affecting the cardiovascular response.

OBJECTIVE: The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant human IL-10 (rhIL-10) on inflammatory and cardiovascular responses in a human endotoxemia model of sepsis. DESIGN: The authors conducted a randomized, placebo-controlled, double-blind trial. SETTING: The study was conducted in a procedure room of an intensive-care unit. PARTICIPANTS: The study comprised 24 healthy male volunteers. INTERVENTIONS: Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 microg/kg either 2 mins or 2 hrs before Escherichia coli lipopolysaccharide (4 ng/kg) or placebo. MEASUREMENTS AND RESULTS: The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-beta and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography. CONCLUSION: Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.

Preload-independent mechanisms contribute to increased stroke volume following large volume saline infusion in normal volunteers: a prospective interventional study.

INTRODUCTION: Resuscitation with saline is a standard initial response to hypotension or shock of almost any cause. Saline resuscitation is thought to generate an increase in cardiac output through a preload-dependent (increased end-diastolic volume) augmentation of stroke volume. We sought to confirm this to be the mechanism by which high-volume saline administration (comparable to that used in resuscitation of shock) results in improved cardiac output in normal healthy volunteers. METHODS: Using a standardized protocol, 24 healthy male (group 1) and 12 healthy mixed sex (group 2) volunteers were infused with 3 l normal (0.9%) saline over 3 hours in a prospective interventional study. Individuals were studied at baseline and following volume infusion using volumetric echocardiography (group 1) or a combination of pulmonary artery catheterization and radionuclide cineangiography (group 2). RESULTS: Saline infusion resulted in minor effects on heart rate and arterial pressures. Stroke volume index increased significantly (by approximately 15-25%; P < 0.0001). Biventricular end-diastolic volumes were only inconsistently increased, whereas end-systolic volumes decreased almost uniformly. Decreased end-systolic volume contributed as much as 40-90% to the stroke volume index response. Indices of ventricular contractility including ejection fraction, ventricular stroke work and peak systolic pressure/end-systolic volume index ratio all increased significantly (minimum P < 0.01). CONCLUSION: The increase in stroke volume associated with high-volume saline infusion into normal individuals is not only mediated by an increase in end-diastolic volume, as standard teaching suggests, but also involves a consistent and substantial decrease in end-systolic volumes and increases in basic indices of cardiac contractility. This phenomenon may be consistent with either an increase in biventricular contractility or a decrease in afterload.

Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects.

OBJECTIVE: Pulmonary artery occlusion pressure and central venous pressure have been considered to be reliable measures of left and right ventricular preload in patients requiring invasive hemodynamic monitoring. Studies in recent years have questioned the correlation between these estimates of ventricular filling pressures and ventricular end-diastolic volumes/cardiac performance variables in specific patient groups, but clinicians have continued to consider the relationship valid in the broader context. The objective of this study was to assess the relationship between pressure estimates of ventricular preload (pulmonary artery occlusion pressure, central venous pressure) and end-diastolic ventricular volumes/cardiac performance in healthy volunteers. DESIGN: Prospective, nonrandomized, nonblinded interventional study. SETTING: Cardiac catheterization and echocardiography laboratories. SUBJECTS: Normal healthy volunteers (n = 12 group 1, n = 32 group 2). INTERVENTIONS: Pulmonary catheterization and radionuclide cineangiography (group 1) and volumetric echocardiography (group 2) during 3 L of normal saline infusion over 3 hrs. MEASUREMENTS AND MAIN RESULTS: In group 1, the initial pulmonary artery occlusion pressure and central venous pressure did not correlate significantly with initial end-diastolic ventricular volume indexes or cardiac performance (cardiac index and stroke volume index). Changes in pulmonary artery occlusion pressure and central venous pressure following saline infusion also did not correlate with changes in end-diastolic ventricular volume indexes or cardiac performance. In contrast, initial end-diastolic ventricular volume indexes and changes in these ventricular volume indexes in response to 3 L of normal saline loading correlated well with initial stroke volume index and changes in stroke volume index, respectively. The relationship between left ventricular end-diastolic volume index and stroke volume index was confirmed in group 2 subjects using mathematically independent techniques to measure these variables. In addition, initial central venous pressure, right ventricular end-diastolic volume index, pulmonary artery occlusion pressure, and left ventricular end-diastolic volume index failed to correlate significantly with changes in cardiac performance in response to saline infusion in group 1 subjects. CONCLUSIONS: Normal healthy volunteers demonstrate a lack of correlation between initial central venous pressure/pulmonary artery occlusion pressure and both end-diastolic ventricular volume indexes and stroke volume index. Similar results are found with respect to changes in these variables following volume infusion. In contrast, initial end-diastolic ventricular volume indexes and changes in end-diastolic ventricular volume indexes in response to saline loading correlate strongly with initial and postsaline loading changes in cardiac performance as measured by stroke volume index. These data suggest that the lack of correlation of these variables in specific patient groups described in other studies represents a more universal phenomenon that includes normal subjects. Neither central venous pressure nor pulmonary artery occlusion pressure appears to be a useful predictor of ventricular preload with respect to optimizing cardiac performance.

Cytokine modulation in sepsis and septic shock.

Sepsis and septic shock are a major cause of morbidity and mortality in patients admitted to the intensive care unit. Since the introduction of antibiotic therapy, the mortality associated with sepsis has remained within the 30- 50% range. Sepsis constitutes the systemic response to infection. This response encompasses both pro-inflammatory and anti-inflammatory phases that are marked by the sequential generation of pro- and anti-inflammatory cytokines. Among the most important pro-inflammatory cytokines are TNF-alpha and IL-1beta. The pro-inflammatory effects of such cytokines are inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines including IL-10 and transforming growth factor-beta. Modulation of the activity of both pro- and anti-inflammatory cytokines to improve outcome in patients with sepsis has been subject of multiple clinical studies. This review will examine clinical trials evaluating several strategies for blocking or attenuating TNF-alpha and IL-1beta activity. This review will also survey the current state of experimental therapies involving IL-10, transforming growth factor-beta, granulocyte colony-stimulating factor and IFN-phi. Finally, newer developments related to less known cytokines such as macrophage migration inhibitory factor and high mobility group 1 protein will be evaluated.