Francis Pike

A Randomized Trial of Protocol-Based Care for Early Septic Shock

BACKGROUND In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary. METHODS In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. RESULTS We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. CONCLUSIONS In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

Bidirectional Relationship between Cognitive Function and Pneumonia

RATIONALE Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems. OBJECTIVES To determine bidirectional relationships between cognition and pneumonia. METHODS We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate. MEASUREMENTS AND MAIN RESULTS Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = -0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62-3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections. CONCLUSIONS A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.

Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.

BACKGROUND After a single‐center trial and observational studies suggesting that early, goal‐directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta‐analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS We harmonized entry criteria, intervention protocols, outcomes, resource‐use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol‐based standard‐therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90‐day mortality. Secondary outcomes included 1‐year survival, organ support, and hospitalization costs. We tested for treatment‐by‐subgroup interactions for 16 patient characteristics and 6 care‐delivery characteristics. RESULTS We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS In this meta‐analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158.)

The Effects of Alternative Resuscitation Strategies on Acute Kidney Injury in Patients with Septic Shock

RATIONALE Septic shock is a common cause of acute kidney injury (AKI), and fluid resuscitation is a major part of therapy. OBJECTIVES To determine if structured resuscitation designed to alter fluid, blood, and vasopressor use affects the development or severity of AKI or outcomes. METHODS Ancillary study to the ProCESS (Protocolized Care for Early Septic Shock) trial of alternative resuscitation strategies (two protocols vs. usual care) for septic shock. MEASUREMENTS AND MAIN RESULTS We studied 1,243 patients and classified AKI using serum creatinine and urine output. We determined recovery status at hospital discharge, examined rates of renal replacement therapy and fluid overload, and measured biomarkers of kidney damage. Among patients without evidence of AKI at enrollment, 37.6% of protocolized care and 38.1% of usual care patients developed kidney injury (P = 0.90). AKI duration (P = 0.59) and rates of renal replacement therapy did not differ between study arms (6.9% for protocolized care and 4.3% for usual care; P = 0.08). Fluid overload occurred in 8.3% of protocolized care and 6.3% of usual care patients (P = 0.26). Among patients with severe AKI, complete and partial recovery was 50.7 and 13.2% for protocolized patients and 49.1 and 13.4% for usual care patients (P = 0.93). Sixty-day hospital mortality was 6.2% for patients without AKI, 16.8% for those with stage 1, and 27.7% for stages 2 to 3. CONCLUSIONS In patients with septic shock, AKI is common and associated with adverse outcomes, but it is not influenced by protocolized resuscitation compared with usual care.

Impact of Fatigue on Outcomes in the Hemodialysis (HEMO) Study

Background: Fatigue is a common debilitating symptom in chronic kidney disease patients on maintenance hemodialysis. However, little is known about its pathogenesis and association with survival. Methods: This study examines the correlates and outcomes of fatigue among 1,798 hemodialysis patients enrolled in the HEMO study. Fatigue was assessed using the SF-36 vitality scale. Multivariable analysis was used to assess independent associations of demographic and clinical characteristics with baseline fatigue and longitudinal changes in fatigue. The association of fatigue with all-cause and cause-specific mortality and cardiac hospitalizations was also assessed. Results: Higher index of coexistent diseases (ICED) score, diabetes, non-African-American race, lower serum albumin, use of medications for sleep and poor sleep quality were found to be significantly associated with more fatigue at baseline. In longitudinal analyses, patients who were older, had been on dialysis longer, had higher ICED score, and reported using medications for sleep were more likely to experience worsening fatigue, whereas higher serum albumin was strongly associated with an improvement in level of fatigue. A 10-point increase in vitality score was associated with 10% increase in mean survival (p < 0.0001). Conclusions: Demographic and clinical factors have significant associations with fatigue, which itself predicts mortality. Improving fatigue in the end-stage renal disease population may positively impact patient well-being and survival.

Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy

BACKGROUND Survivors of critical illness complicated by acute kidney injury requiring renal replacement therapy (RRT) are at an increased risk of dialysis dependence and death but the mechanisms are unknown. METHODS In a multicenter, prospective, cohort study of 817 critically ill patients receiving RRT, we examined association between Day 1 plasma inflammatory [interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-18; macrophage migration inhibitory factor (MIF) and tumor necrosis factor]; apoptosis [tumor necrosis factor receptor (TNFR)-I and TNFR-II and death receptor (DR)-5]; and growth factor (granulocyte macrophage colony stimulating factor) biomarkers and renal recovery and mortality at Day 60. Renal recovery was defined as alive and RRT independent. RESULTS Of 817 participants, 36.5% were RRT independent and 50.8% died. After adjusting for differences in demographics, comorbid conditions; premorbid creatinine; nephrotoxins; sepsis; oliguria; mechanical ventilation; RRT dosing; and severity of illness, increased concentrations of plasma IL-8 and IL-18 and TNFR-I were independently associated with slower renal recovery [adjusted hazard ratio (AHR) range for all markers, 0.70-0.87]. Higher concentrations of IL-6, IL-8, IL-10 and IL-18; MIF; TNFR-I and DR-5 were associated with mortality (AHR range, 1.16-1.47). In an analysis of multiple markers simultaneously, increased IL-8 [AHR, 0.80, 95% confidence interval (95% CI) 0.70-0.91, P < 0.001] and TNFR-I (AHR, 0.63, 95% CI 0.50-0.79, P < 0.001) were associated with slower recovery, and increased IL-8 (AHR, 1.26, 95% CI 1.14-1.39, P < 0.001); MIF (AHR, 1.18, 95% CI 1.08-1.28, P < 0.001) and TNFR-I (AHR, 1.26, 95% CI 1.02-1.56, P < 0.03) were associated with mortality. CONCLUSIONS Elevated plasma concentrations of inflammatory and apoptosis biomarkers are associated with RRT dependence and death. Our data suggest that future interventions should investigate broad-spectrum immune-modulation to improve outcomes.

Hospital factors associated with discharge bias in ICU performance measurement.

Objective:Performance assessments based on in-hospital mortality for ICU patients can be affected by discharge practices such that differences in mortality may reflect variation in discharge patterns rather than quality of care. Time-specific mortality rates, such as 30-day mortality, are preferred but are harder to measure. The degree to which the difference between 30-day and in-hospital ICU mortality rates—or “discharge bias”—varies by hospital type is unknown. The aim of this study was to quantify variation in discharge bias across hospitals and determine the hospital characteristics associated with greater discharge bias. Design:Retrospective cohort study. Setting:Nonfederal Pennsylvania hospital discharges in 2008. Patients:Eligible patients were 18 years old or older and admitted to an ICU. Interventions:None. Measurements and Main Results:We used logistic regression with hospital-level random effects to calculate hospital-specific risk-adjusted 30-day and in-hospital mortality rates. We then calculated discharge bias, defined as the difference between 30-day and in-hospital mortality rates, and used multivariable linear regression to compare discharge bias across hospital types. A total of 43,830 patients and 134 hospitals were included in the analysis. Mean (SD) risk-adjusted hospital-specific in-hospital and 30-day ICU mortality rates were 9.6% (1.3) and 12.7% (1.5), respectively. Hospital-specific discharge biases ranged from –1.3% to 6.6%. Discharge bias was smaller in large hospitals compared with small hospitals, making large hospitals appear comparatively worse from a benchmarking standpoint when using in-hospital mortality instead of 30-day mortality. Conclusions:Discharge practices bias in-hospital ICU mortality measures in a way that disadvantages large hospitals. Accounting for discharge bias will prevent these hospitals from being unfairly disadvantaged in public reporting and pay-for-performance.

Modality of RRT and Recovery of Kidney Function after AKI in Patients Surviving to Hospital Discharge

BACKGROUND AND OBJECTIVES Observational evidence has suggested that RRT modality may affect recovery after AKI. It is unclear whether initial choice of intermittent hemodialysis or continuous RRT affects renal recovery, survival, or development of ESRD in critically ill patients when modality choice is made primarily on hemodynamics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a retrospective cohort study examining adults (≥18 years old) admitted to intensive care units from 2000 to 2008 who received RRT for AKI and survived to hospital discharge or 90 days. We analyzed renal recovery (alive and not requiring RRT) and reasons for nonrecovery (death or ESRD) at 90 and 365 days. Conditional multivariable logistic regression was used to assess differences in renal recovery at 90 and 365 days between continuous RRT and intermittent hemodialysis. Models were stratified by propensity for continuous RRT and adjusted for age and reference creatinine. RESULTS Of 4738 patients with Kidney Disease Improving Global Outcomes stage 3 AKI, 1338 (28.2%) received RRT, and 638 (47.7%) survived to hospital discharge (353 intermittent hemodialysis and 285 continuous RRT). Recovery from AKI was lower for intermittent hemodialysis versus continuous RRT at 90 days (66.6% intermittent hemodialysis versus 75.4% continuous RRT; P=0.02) but similar at 365 days (54.1% intermittent hemodialysis versus 59.6% continuous RRT; P=0.17). In multivariable analysis, there was no difference in odds of recovery at 90 or 365 days for patients initially treated with continuous RRT versus intermittent hemodialysis (90 days: odds ratio, 1.19; 95% confidence interval, 0.91 to 1.55; P=0.20; 365 days: odds ratio, 0.93; 95% confidence interval, 0.72 to 1.2; P=0.55). CONCLUSIONS We found no significant difference in hazards for nonrecovery or reasons for nonrecovery (mortality or ESRD) with intermittent hemodialysis versus continuous RRT. These results suggest that, when initial RRT modality is chosen primarily on hemodynamics, renal recovery and clinical outcomes in survivors are similar between intermittent hemodialysis and continuous RRT.

Changes in Anthropometry and Mortality in Maintenance Hemodialysis Patients in the HEMO Study

BACKGROUND Poor nutritional status has been associated with worse patient survival in maintenance hemodialysis patients. Anthropometric values are important nutritional measures, incorporating muscle and fat mass. However, the association of changes in anthropometry, including midarm circumference (MAC) and skinfold measurements, with mortality in hemodialysis patients remains unknown. Accordingly, we explored this association in the Hemodialysis (HEMO) Study. STUDY DESIGN Post hoc analysis of cohort data from a clinical trial. SETTING & PARTICIPANTS 1,846 hemodialysis patients enrolled in the HEMO Study. PREDICTORS MAC and skinfold measurements. OUTCOMES Longitudinal changes in MAC and skinfolds were jointly modeled using repeated measures and survival modeling. Time-to-event outcomes were all-cause mortality, cardiac death and hospitalization, and infection-related death. RESULTS Mean MAC was 30.1 cm, and mean baseline sum of subscapular, biceps, and triceps skinfolds was 42.4 mm. During a median follow-up of 2.5 years, there were 845 deaths. During follow-up, MAC and the skinfold measurement declined 0.26 cm and 1.1 mm per year, respectively. Declines in MAC (per cm) and skinfold (per mm) measurements were associated with higher all-cause mortality (HRs of 1.58 [95% CI, 1.29-1.94; P < 0.001] and 1.06 [95% CI, 0.99-1.13; P = 0.09], respectively), poorer cardiac outcomes (HRs of 1.49 [95% CI, 1.23-1.81; P < 0.001] and 1.05 [95% CI, 0.99-1.10; P = 0.09], respectively), and higher infection-related hospitalization (HRs of 2.45 [95% CI, 1.55-3.88; P < 0.001] and 1.16 [95% CI, 0.98-1.37; P = 0.08], respectively). The association between declining MAC and skinfold with patient survival was most notable for those with body mass index (BMI) ≤25 kg/m2 (HRs of 2.41 [95% CI, 1.81-3.19; P < 0.001] and 1.22 [95% CI, 1.10-1.35; P < 0.001], respectively). LIMITATIONS Prevalent dialysis patients only, excluding individuals weighing >85 kg. CONCLUSIONS Declines in skinfold thickness were not associated significantly with outcomes except for participants with BMI ≤25 kg/m2. Declines in MAC are associated significantly with all-cause mortality and cardiac outcomes in hemodialysis patients, most notably in those with BMI ≤25 kg/m2.

Post-tonsillectomy bleeding in children with von Willebrand disease: A single-institution experience

Objectives: 1) Compare rates of post-tonsillectomy bleeding in pediatric patients with and without von Willebrand disease (vWD). 2) Identify factors that may increase the risk for post-tonsillectomy bleeding in children with and without vWD. Study Design: Historical cohort study. Setting: Tertiary care, university-based pediatric hospital. Subjects and Methods: Medical records were examined for 99 patients with vWD and 99 patients without vWD younger than 18 years who underwent tonsillectomy with or without adenoidectomy from August 1997 to October 2005. Subjects were matched for age, year of surgery, type of surgery, and indication for surgery. Results: Post-tonsillectomy hemorrhage occurred in eight of 99 (8%) vWD patients and in six of 99 (6%) non-vWD patients (P = 0.58, odds ratio 1.36, 95% CI 0.45-4.08). A two-sample test of proportions demonstrated lower and upper limits of −0.051 and 0.092. Four of eight children with vWD and two of six non-vWD patients required surgical intervention for control of bleeding. Ninety-three of 99 vWD patients received desmopressin acetate (DDAVP) preoperatively. In patients with vWD who responded to DDAVP challenge, there was no increased likelihood of post-tonsillectomy bleeding compared with non-vWD patients. No significant difference in the number of bleeding events was noted on the basis of demographics, preoperative laboratories, or use of aminocaproic acid. Conclusion: Children with vWD undergoing tonsillectomy have a postoperative bleeding rate similar to that of a matched group. However, the sample size was not sufficient to eliminate the possibility of a clinically important difference between the two groups.